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British HIV Association Guidelines on the Use of Vaccines in
HIV-Positive Adults 2015
Writing Group Members:
Prof Anna Maria Geretti,
Chair and Editor, Institute of Infection and Global Health, University of Liverpool, Liverpool, UK
Dr Gary Brook,
Central Middlesex Hospital, London, UK
Ms Claire Cameron,
Public Health England, London, UK
Dr David Chadwick,
James Cook University Hospital, Middlesbrough, UK
Prof Neil French,
University of Liverpool, Liverpool, UK
Prof Robert Heyderman,
University College London, London, UK
Dr Antonia Ho,
University of Liverpool, Liverpool, UK
Dr Michael Hunter,
Belfast Health and Social Care Trust, Belfast, UK
Dr Shamez Ladhani,
Public Health England, London, UK
Dr Mark Lawton,
Royal Liverpool University Hospital, Liverpool, UK
Dr Eithne MacMahon,
Guy’s & St Thomas’ NHS Foundation Trust, London, UK and King’s College London, London, UK
Dr John McSorley,
Central Middlesex Hospital, London, UK
Dr Anton Pozniak,
Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
Dr Alison Rodger,
University College London, London, UK
s2
DOI: 10.1111/hiv.12424
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
Table of contents
1. Introduction ................................................................................................................................................................................. s7
1.1 The need for updated guidance ........................................................................................................................................... s7
1.2 How to use the guidelines .................................................................................................................................................... s7
1.3 General principles .................................................................................................................................................................. s8
1.4 Sources of evidence............................................................................................................................................................... s8
1.5 Summary of the modified GRADE system......................................................................................................................... s9
1.6 References ............................................................................................................................................................................... s10
2. Summary of recommendations table................................................................................................ ........................................ s11
3. Anthrax ......................................................................................................................................................................................... s12
3.1 Infection and disease............................................................................................................................................................. s12
3.2 Epidemiology .......................................................................................................................................................................... s12
3.3 Anthrax in HIV-positive people .......................................................................................................................................... s12
3.4 Anthrax vaccine..................................................................................................................................................................... s12
3.5 Anthrax vaccine in HIV-positive adults............................................................................................................................. s12
3.6 Post-exposure prophylaxis ................................................................................................................................................... s12
3.7 Recommendations for HIV-positive adults ........................................................................................................................ s12
3.8 References ............................................................................................................................................................................... s13
4. Cholera........................................................................................................................................................................................... s14
4.1 Infection and disease............................................................................................................................................................. s14
4.2 Epidemiology .......................................................................................................................................................................... s14
4.3 Cholera in HIV-positive people ........................................................................................................................................... s14
4.4 Cholera vaccine ...................................................................................................................................................................... s14
4.5 Cholera vaccine in HIV-positive adults: ............................................................................................................................ s14
4.6 Recommendations for HIV-positive adults ........................................................................................................................ s15
4.7 References ............................................................................................................................................................................... s15
5. Diphtheria...................................................................................................................................................................................... s16
5.1 Infection and disease............................................................................................................................................................. s16
5.2 Epidemiology .......................................................................................................................................................................... s16
5.3 Diphtheria in HIV-positive people ...................................................................................................................................... s16
5.4 Diphtheria vaccine ................................................................................................................................................................. s16
5.5 Diphtheria vaccine in HIV-positive adults................................................................................................ ......................... s16
5.6 Post-exposure prophylaxis ................................................................................................................................................... s16
5.7 Recommendations for HIV-positive adults ........................................................................................................................ s17
5.8 References ............................................................................................................................................................................... s17
6. Haemophilus influenzae serotype B................................................................................................ .......................................... s18
6.1 Infection and disease............................................................................................................................................................. s18
6.2 Epidemiology .......................................................................................................................................................................... s18
6.3 Haemophilus influenzae in HIV-positive adults ............................................................................................................... s18
6.4 Hib vaccine ............................................................................................................................................................................. s18
6.5 Hib vaccine in HIV-positive adults ..................................................................................................................................... s18
6.6 Post-exposure prophylaxis ................................................................................................................................................... s18
6.7 Recommendations for HIV-positive adults ........................................................................................................................ s19
6.8 References ............................................................................................................................................................................... s19
7. Hepatitis A .................................................................................................................................................................................... s20
7.1 Infection and disease............................................................................................................................................................. s20
7.2 Epidemiology .......................................................................................................................................................................... s20
7.3 Hepatitis A in HIV-positive adults ...................................................................................................................................... s20
7.4 Hepatitis A vaccine................................................................................................................................................................ s20
7.5 HAV vaccine in HIV-positive adults................................................................................................................................... s20
7.6 Post-exposure prophylaxis ................................................................................................................................................... s21
7.7 Recommendations for HIV-positive adults ........................................................................................................................ s21
7.8 References ............................................................................................................................................................................... s21
8. Hepatitis B..................................................................................................................................................................................... s23
8.1 Infection and disease............................................................................................................................................................. s23
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s3
8.2 Epidemiology .......................................................................................................................................................................... s23
8.3 HBV in HIV-positive adults................................................................................................ .................................................. s23
8.4 Hepatitis B vaccine ................................................................................................................................................................ s23
8.5 HBV vaccine in HIV-positive adults ................................................................................................................................... s24
8.6 Post-exposure prophylaxis ................................................................................................................................................... s25
8.7 Recommendations for HIV-positive adults ........................................................................................................................ s25
8.8 References ............................................................................................................................................................................... s27
9. Human papilloma virus .............................................................................................................................................................. s29
9.1 Infection and disease............................................................................................................................................................. s29
9.2 Epidemiology .......................................................................................................................................................................... s29
9.3 HPV in HIV-positive adults .................................................................................................................................................. s29
9.4 HPV vaccine............................................................................................................................................................................ s29
9.5 HPV vaccine in HIV-positive adults ................................................................................................................................... s31
9.6 Recommendations for HIV-positive adults ........................................................................................................................ s31
9.7 References ............................................................................................................................................................................... s32
10. Influenza ..................................................................................................................................................................................... s35
10.1 Infection and disease........................................................................................................................................................... s35
10.2 Epidemiology........................................................................................................................................................................ s35
10.3 Influenza in HIV-positive people ...................................................................................................................................... s35
10.4 Influenza vaccine................................................................................................................................................................. s35
10.5 Influenza vaccine in HIV-positive adults ........................................................................................................................ s36
10.6 Antiviral therapy for pre- and post-exposure prophylaxis........................................................................................... s36
10.7 Recommendations for HIV-positive adults ...................................................................................................................... s36
10.8 References ............................................................................................................................................................................. s37
11. Japanese encephalitis ................................................................................................................................................................ s40
11.1 Infection and disease........................................................................................................................................................... s40
11.2 Epidemiology........................................................................................................................................................................ s40
11.3 JEV in HIV-positive adults................................................................................................ ................................................. s40
11.4 JEV vaccine .......................................................................................................................................................................... s40
11.5 JEV vaccine and HIV-positive adults ............................................................................................................................... s40
11.6 Recommendations for HIV-positive adults ...................................................................................................................... s40
11.7 References ............................................................................................................................................................................. s40
12. Measles, mumps and rubella.................................................................................................................................................... s42
12.1 Infection and disease........................................................................................................................................................... s42
12.2 Epidemiology........................................................................................................................................................................ s42
12.3 Measles, mumps and rubella in HIV-positive adults ..................................................................................................... s42
12.4 MMR vaccine........................................................................................................................................................................ s42
12.5 MMR vaccine in HIV-positive adults ............................................................................................................................... s42
12.6 Post-exposure prophylaxis ................................................................................................................................................. s43
12.7 Recommendations for HIV-positive adults ...................................................................................................................... s43
12.8 References ............................................................................................................................................................................. s43
13. Meningococcus........................................................................................................................................................................... s45
13.1 Infection and disease........................................................................................................................................................... s45
13.2 Epidemiology........................................................................................................................................................................ s45
13.3 Meningococcus in HIV-positive adults ............................................................................................................................ s45
13.4 Meningococcus vaccine ...................................................................................................................................................... s45
13.5 Meningococcus vaccine in HIV-positive adults.............................................................................................................. s46
13.6 Post-exposure prophylaxis ................................................................................................................................................. s46
13.7 Recommendations for HIV-positive adults ...................................................................................................................... s46
13.8 References ............................................................................................................................................................................. s46
14. Pertussis (whooping cough) ..................................................................................................................................................... s48
14.1 Infection and disease........................................................................................................................................................... s48
14.2 Epidemiology........................................................................................................................................................................ s48
14.3 Pertussis in HIV-positive adults ........................................................................................................................................ s48
14.4 Pertussis vaccine .................................................................................................................................................................. s48
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s4 BHIVA Writing Group
14.5 Pertussis vaccine in HIV-positive adults................................................................................................ .......................... s49
14.6 Post-exposure prophylaxis ................................................................................................................................................. s49
14.7 Recommendations for HIV-positive adults ...................................................................................................................... s49
14.8 References ............................................................................................................................................................................. s49
15. Pneumococcus............................................................................................................................................................................ s50
15.1 Infection and disease........................................................................................................................................................... s50
15.2 Epidemiology........................................................................................................................................................................ s50
15.3 Pneumococcus in HIV-positive adults................................................................................................ .............................. s50
15.4 Pneumococcal vaccine ........................................................................................................................................................ s51
15.5 Vaccine efficacy................................................................................................................................................................... s51
15.6 Pneumococcal vaccine in HIV-positive adults................................................................................................ ................ s52
15.7 Recommendations for HIV-positive adults ...................................................................................................................... s53
15.8 References ............................................................................................................................................................................. s53
16. Poliomyelitis............................................................................................................................................................................... s56
16.1 Infection and disease........................................................................................................................................................... s56
16.2 Epidemiology........................................................................................................................................................................ s56
16.3 Poliomyelitis in HIV-positive people................................................................................................................................ s56
16.4 Polio vaccine ........................................................................................................................................................................ s56
16.5 Polio vaccine in HIV-positive adults ................................................................................................................................ s56
16.6 Post-exposure prophylaxis ................................................................................................................................................. s56
16.7 Recommendations for HIV-positive adults ...................................................................................................................... s57
16.8 References ............................................................................................................................................................................. s57
17. Rabies .......................................................................................................................................................................................... s58
17.1 Infection and disease........................................................................................................................................................... s58
17.2 Epidemiology........................................................................................................................................................................ s58
17.3 Rabies in HIV-positive adults ............................................................................................................................................ s58
17.4 Rabies vaccine ...................................................................................................................................................................... s58
17.5 Post-exposure prophylaxis ................................................................................................................................................. s59
17.6 Rabies vaccine in HIV-positive adults.............................................................................................................................. s60
17.7 Recommendations for HIV-positive adults ...................................................................................................................... s60
17.8 References ............................................................................................................................................................................. s61
18. Smallpox ..................................................................................................................................................................................... s62
18.1 Infection and disease........................................................................................................................................................... s62
18.2 Smallpox vaccine................................................................................................................................................................. s62
18.3 Vaccine safety ...................................................................................................................................................................... s62
18.4 Smallpox vaccine in HIV-positive adults ................................................................................................ ........................ s63
18.5 Post-exposure prophylaxis ................................................................................................................................................. s63
18.6 Recommendations for HIV-positive adults ...................................................................................................................... s63
18.7 References ............................................................................................................................................................................. s64
19. Tetanus ........................................................................................................................................................................................ s65
19.1 Infection and disease........................................................................................................................................................... s65
19.2 Epidemiology........................................................................................................................................................................ s65
19.3 Tetanus in HIV-positive adults .......................................................................................................................................... s65
19.4 Tetanus vaccine................................................................................................ .................................................................... s65
19.5 Tetanus vaccine in HIV-positive adults ........................................................................................................................... s66
19.6 Post-exposure prophylaxis ................................................................................................................................................. s66
19.7 Recommendations for HIV-positive adults ...................................................................................................................... s66
19.8 References ............................................................................................................................................................................. s66
20. Tick-borne encephalitis............................................................................................................................................................. s68
20.1 Infection and disease........................................................................................................................................................... s68
20.2 Epidemiology........................................................................................................................................................................ s68
20.3 TBE in HIV-positive adults................................................................................................................................................. s68
20.4 TBE vaccine .......................................................................................................................................................................... s68
20.5 TBE vaccine in HIV-positive adults .................................................................................................................................. s68
20.6 Recommendations for HIV-positive adults ...................................................................................................................... s69
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s5
20.7 References ............................................................................................................................................................................. s69
21. Typhoid fever ............................................................................................................................................................................. s70
21.1 Infection and disease........................................................................................................................................................... s70
21.2 Epidemiology........................................................................................................................................................................ s70
21.3 Typhoid fever in HIV-positive adults ............................................................................................................................... s70
21.4 Typhoid vaccine................................................................................................................................................................... s70
21.5 Typhoid vaccine in HIV-positive adults........................................................................................................................... s70
21.6 Recommendations for HIV-positive adults ...................................................................................................................... s71
21.7 References ............................................................................................................................................................................. s71
22. Tuberculosis................................................................................................................................................................................ s72
22.1 Infection and disease........................................................................................................................................................... s72
22.2 Epidemiology........................................................................................................................................................................ s72
22.3 TB in HIV-positive adults ................................................................................................................................................... s72
22.4 Bacille Calmette-Guerin vaccine ....................................................................................................................................... s72
22.5 Vaccine safety ...................................................................................................................................................................... s73
22.6 Recommendations for HIV-positive adults ...................................................................................................................... s73
22.7 References ............................................................................................................................................................................. s73
23. Varicella zoster virus ................................................................................................................................................................ s74
23.1 Infection and disease........................................................................................................................................................... s74
23.2 Epidemiology........................................................................................................................................................................ s74
23.3 VZV in HIV-positive adults................................................................................................................................................ s74
23.4 Chickenpox vaccine............................................................................................................................................................. s74
23.5 Chickenpox vaccine in HIV-positive adults .................................................................................................................... s75
23.6 Shingles vaccine .................................................................................................................................................................. s75
23.7 Shingles vaccine in HIV-positive adults .......................................................................................................................... s75
23.8 Post-exposure prophylaxis ................................................................................................................................................. s75
23.9 Recommendations for HIV-positive adults ...................................................................................................................... s76
23.10 References ........................................................................................................................................................................... s76
24. Yellow fever virus...................................................................................................................................................................... s79
24.1 Infection and disease........................................................................................................................................................... s79
24.2 Epidemiology........................................................................................................................................................................ s79
24.3 Yellow fever in HIV-positive adults ................................................................................................................................. s79
24.4 YFV vaccine.......................................................................................................................................................................... s79
24.5 Vaccine safety ...................................................................................................................................................................... s79
24.6 YFV vaccine in HIV-positive adults ................................................................................................................................. s80
24.7 Recommendations for HIV positive adults ...................................................................................................................... s80
24.8 References ............................................................................................................................................................................. s80
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s6 BHIVA Writing Group
1. Introduction
1.1 The need for updated guidance
These guidelines provide updated, GRADE-based recom-
mendations on the use of vaccines in HIV-positive adults.
Several factors have made the updating of HIV-specific
vaccination guidelines important: effective antiretroviral
therapy (ART) has substantially modified the natural his-
tory of HIV infection, vaccination practices are evolving,
and a large number of novel vaccines are becoming
available in clinical care. The update contains important
new guidance regarding the use of new vaccines against
human papillomavirus (HPV), shingles (herpes zoster) and
pneumococcus. Further key updates are related to the use
of hepatitis B, meningococcus and pertussis vaccines.
Compared with HIV-negative individuals, HIV-positive
adults often have an increased risk of infection or experi-
ence more severe morbidity following exposure to vac-
cine-preventable infections, and therefore a lower
threshold for extending indications and offering vaccina-
tion may be appropriate relative to the general popula-
tion. Improved health and prognosis mean that HIV-
positive adults are also increasingly likely to engage in
travel or occupations that carry a risk of exposure to
infectious agents, and these otherwise healthy individuals
should not be denied protection or engagement with such
activities if evidence indicates vaccination is safe and
immunogenic. Immune responses to vaccination are often
sub-optimal in HIV-positive patients, and while these
improve with ART, they often remain lower and decline
more rapidly than in HIV-negative individuals. However,
many of these vaccines still afford protection and for
some vaccines it is possible to improve immunogenicity
by offering modified vaccine schedules, with higher or
more frequent doses, without compromising safety.
Non-replicating vaccines (e.g. whole inactivated,
polysaccharide, conjugated and subunit vaccines, or virus-
like particles) can be used safely in HIV-positive persons,
whereas replicating (live) vaccines have traditionally been
contraindicated. However, ART-induced immunorestora-
tion reduces the risk of adverse events, in many cases shift-
ing the risk–benefit ratio in favour of vaccination,
whereby the risk of disease with natural infection becomes
greater than the risk of live vaccine-related adverse events.
Important examples of replicating vaccines that can be
used in HIV-positive persons with good immunity include
those for measles, mumps and rubella (MMR), varicella-
zoster virus (VZV) and yellow fever. For vaccinated indi-
viduals, the importance of infection avoidance and infec-
tion control should continue to be emphasised.
It is envisaged that the HIV specialist should provide
overall guidance on vaccine use and enlist the help of
primary care physicians for vaccine administration. Edu-
cation of healthcare providers and good communication
are key requirements to ensure successful implementation
of this guidance. Despite evidence that HIV-positive per-
sons benefit from vaccination, there are persisting per-
ceptions about disease incidence and burden, and vaccine
effectiveness and safety, which affect vaccination prac-
tices among health professionals caring for HIV-
positive patients. It is hoped that this guidance will help
overcoming such barriers.
Key points: vaccination of HIV-positive adults
●High risk of
infection
Lowers threshold for vaccination
●High risk of
severe disease
Lowers threshold for vaccination
Extends indications for vaccination
●Improved prognosis Allows engagement with exposure-prone occupations
and travel
Increases the life-long impact of vaccine-preventable
infections
●Immunorestoration Improves vaccine immunogenicity
Overcomes traditional contraindications to
replicating vaccines
●Reduced
immunogenicity
May be overcome with higher and more frequent
vaccine doses
●Perceptions Create barriers to effective vaccination
●Evolving
knowledge
Requires education of healthcare professionals and
effective communication between primary and
specialist care providers
1.2 How to use the guidelines
•The guidelines are meant to highlight specific aspects of
vaccine use that are relevant to HIV-positive adults. They
are intended to be complementary to national guidance
available through The Green Book (www.gov.
uk/government/collections/immunisation-against-infec-
tious-disease-the-green-book), to which readers should
refer for the latest information on available vaccines and
vaccination procedures in the United Kingdom (UK).
•For epidemiological information relevant to the use of
travel-related vaccines, the reader is invited to consult
guidance for health professionals available through the
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s7
National Travel Health Network and Centre (nathnac.-
net). Country-specific information for travellers is also
available from Public Health England (www.
gov.uk/government/organisations/public-health-eng
land); Health Protection Scotland (www.hps.scot.
nhs.uk); Travax (www.travax.nhs.uk); and FitFor
Travel (www.fitfortravel.nhs.uk).
•A summary of the recommendations contained in the
guidelines can be found on page s11. The reader
should refer to the individual chapters for details.
1.3 General principles
1.3.1 Replicating (live) vaccines.
•HIV-positive adults with CD4 cell counts <200 cells/lL
must not be given replicating vaccines due to a poten-
tial risk of vaccine-associated disease; when indicated,
vaccination should be postponed until the CD4 cell
count has improved on ART (refer to individual chap-
ters for details).
•HIV-positive adults with a CD4 cell count of 200–
350 cells/lL have moderate immunodeficiency. Clinical
judgment should be used to guide the use of replicating
vaccines in these patients. Where exposure is likely, nat-
ural infection often carries a greater risk of adverse out-
comes than vaccination; a suppressed plasma HIV-1
RNA (“viral”) load on ART increases the safety and
immunogenicity of vaccination in this group.
•The co-administration of multiple replicating vaccines
is not recommended in HIV-positive adults due to
uncertainties over safety, immunogenicity and efficacy.
An interval of at least 4 weeks between vaccinations is
recommended [1D].
•Regardless of the CD4 cell count, contraindications to
the use of replicating vaccines that apply to the
general population (e.g. in relation to the use of
immunosuppressive therapy) also apply to HIV-positive
patients. The reader should refer to The Green Book for
details (www.gov.uk/government/collections/immunisa
tion-against-infectious-disease-the-green-book).
•Replicating vaccines (except yellow fever) should be
administered at least 14 days before or 3 months after
the administration of antibody-containing blood prod-
ucts, because passively acquired antibodies may inter-
fere with the response to the vaccine.
1.3.2 Patients with CD4 cell counts <200 cells/lL.
•Replicating (live) vaccines are contraindicated.
•Responses to non-replicating vaccines are reduced.
Depending on the level of risk, consideration may be
given to delaying vaccination until the CD4 cell count
has recovered with ART. Because responses to vaccina-
tion are observed in a substantial proportion of
patients with low CD4 cell counts however, the poten-
tial benefit of vaccination should not be denied to per-
sons at risk of exposure. If indicated, the vaccine
course can be repeated following immunorestoration
on ART, rather than postponed [1C].
1.3.3 Travel vaccines.
•Destination, itinerary, length of stay and planned
activities must be considered equally in HIV-positive
and HIV-negative travellers when recommending
vaccination. However, the consequences of not admin-
istering an indicated vaccine may be more severe in
people with HIV.
•HIV-positive vaccine recipients should be advised that
the levels and duration of vaccine-induced protection
might be reduced relative to HIV-negative individuals.
The importance of additional measures of protection
(e.g. hand washing, against insect bites, food hygiene)
should be emphasised.
1.3.4 Effects of vaccination on viral load.
•Transient, clinically non-significant increases in viral
load have been reported in HIV-positive persons after
the administration of several vaccines. Concerns related
to the induction of HIV replication are counterbalanced
by the benefit of vaccination, and do not preclude
vaccination.
1.3.5 General contraindications.
•As a general rule, vaccines are contraindicated in per-
sons with a history of previous severe adverse reaction
or allergy to the vaccine or its components. In addi-
tion, persons with acute moderate or severe febrile ill-
ness should not usually be vaccinated until their
symptoms have abated.
•Non-replicating vaccines may be used in pregnancy
and during breastfeeding if there is a significant risk of
infection or other clinical indication. Replicating vacci-
nes are contraindicated in pregnancy, although in most
cases the theoretical risk to the developing fetus is
expected to be low.
1.4 Sources of evidence
Available evidence was obtained from published peer-
reviewed studies and from studies presented at interna-
tional conferences in the last two years. In addition, the
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s8 BHIVA Writing Group
following websites were consulted: The Green
Book (www.gov.uk/government/collections/immunisation-
against-infectious-disease-the-green-book); the Centers
for Disease Control and Prevention (www.cdc.gov/vacci
nes/hcp/acip-recs/index.html); and the World Health
Organization (WHO; www.who.int/en). The following US
guidelines were also reviewed: Recommendations from
the Centers for Disease Control and Prevention, the
National Institutes of Health, and the HIV Medicine Asso-
ciation of the Infectious Diseases Society of America:
Guidelines for the Prevention and Treatment of Oppor-
tunistic Infections in HIV-Infected Adults and Adolescent
(updated April 2015; www.aidsinfo.nih.gov/contentfiles/
lvguidelines/adult_oi.pdf); and Hibberd PL. Immuniza-
tions in HIV-infected patients. UpToDate May 2015
(www.uptodate.com/).
1.5 Summary of the modified GRADE system
BHIVA revised and updated the association’s guideline
development manual in 2011. Further updates have been
carried out subsequently [1]. Full details of the guideline
development process, including the conflict of interest
policy, are outlined in the manual. BHIVA has adopted
the modified Grading of Recommendations Assessment,
Development and Evaluation (GRADE) system for the
assessment, evaluation and grading of evidence and the
development of recommendations [2,3]. Strong recom-
mendations are graded 1 A–D. Weak recommendations
are suggestions graded 2 A–D. Clinicians should follow a
strong recommendation unless there is a clear rationale
for an alternative approach. Consensus opinion on good
practice is indicated as GPP (Good Practice Point).
Summary of the modified GRADE system
Grade Quality of evidence Benefits, source of evidence, impact of further research, recommendation
1A High •Benefits clearly outweigh risks and burdens, or vice versa
•Consistent evidence from well performed randomised, controlled trials or overwhelming evidence of some other form
•Further research is unlikely to change confidence in estimate of benefits and risks
•Strong recommendations, can apply to most patients in most circumstances without reservation
1B Moderate •Benefits clearly outweigh risks and burdens, or vice versa
•Evidence from randomised, controlled trials with important limitations (inconsistent results, methods flaws, indirect or
imprecise), or very strong evidence of some other research design
•Further research may impact on confidence in the estimate of benefits and risks
•Strong recommendation and applies to most patients
1C Low •Benefits appear to outweigh risks and burdens, or vice versa
•Evidence from observational studies, unsystematic clinical experience, or from randomised, controlled trials with serious flaws
•Any estimate of effect is uncertain
•Strong recommendation, and applies to most patients. Some of the evidence base supporting the recommendation is,
however, of low quality
1D Very low •Benefits appear to outweigh risks and burdens, or vice versa
•Evidence limited to case studies
•Strong recommendation based mainly on case studies and expert judgment
2A High •Benefits closely balanced with risks and burdens
•Consistent evidence from well performed randomised, controlled trials or overwhelming evidence of some other form
•Further research is unlikely to change confidence in estimate of benefits and risks
•Weak recommendation, best action may differ depending on circumstances, patients, or societal values
2B Moderate •Benefits closely balanced with risks and burdens, some uncertainly in the estimates of benefits, risks and burdens
•Evidence from randomised, controlled trials with important limitations (inconsistent results, methods flaws, indirect or
imprecise)
•Further research may change the estimate of benefits and risks
•Weak recommendation, alternative approaches likely to be better for some patients under some circumstances
2C Low •Uncertainty in the estimates of benefits, risks, and burdens; benefits may be closely balanced with risks and burdens
•Evidence from observational studies, unsystematic clinical experience, or from randomised, controlled trials with serious flaws
•Any estimate of effect is uncertain
•Weak recommendation; other alternatives may be reasonable
2D Very low •Uncertainty in the estimates of benefits, risks, and burdens; benefits may be closely balanced with risks and burdens
•Evidence limited to case studies and expert judgment
•Very weak recommendation; other alternatives may be equally reasonable
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s9
1.6 References
1 BHIVA. Guideline Development Manual, 28 January 2014.
Available at: www.bhiva.org (accessed November 2015).
2 Guyatt GH, Oxman AD, Kunz R et al. Going from evidence
to recommendations. Br Med J 2008; 336: 1049–1051.
3 GRADE Working Group. Grading the quality of evidence
and the strength of recommendations. Available at:
www.gradeworkinggroup.org/intro.htm (accessed November
2015).
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s10 BHIVA Writing Group
2. Summary of recommendations table
Infection/disease Vaccine Replicating Primary course Indication Notes
Vaccines with broad indications
Hepatitis A Inactivated No 2 or 3 doses Non immune, at risk 3 doses if CD4 count <350 cells/lL
Hepatitis B Subunit No 4 doses All non-immune Dose: Engerix B 2 920 lg; HBvaxPRO
40 lg; Fendrix 20 lg
Human papilloma virus VLP No 3 doses Age and gender related 4vHPV or 9vHPV preferred; see BHIVA
guidance
Influenza Inactivated No 1 dose All, yearly Quadrivalent vaccine preferred
Meningococcus Conjugated No 2 doses Age related, at risk MenACWY; combined as Hib/MenC;
follow national guidance
Meningococcus Recombinant
protein +OMV
No 2 doses Age related, at risk MenB; follow national guidance
Pneumococcus Conjugated No 1 dose All, once PCV-13
Pneumococcus Polysaccharide No 1 dose At risk, once PPV-23; follow national guidance
Pertussis Acellular
multicomponent
No 1 dose Pregnant women Combined as dTaP/IPV; follow national
guidance
Measles, mumps, rubella Live attenuated Yes 2 doses All non-immune Combined as MMR; CD4 count >200
cells/lL
Varicella (chickenpox) Live attenuated Yes 2 doses All non-immune CD4 count >200 cells/lL
Herpes zoster (shingles) Live attenuated Yes 1 dose Age related CD4 count >200 cells/lL; VZV IgG+;
follow national guidance
Vaccines with predominantly travel-related indications
Cholera Inactivated +subunit No 2 doses Selective use WC/rBs; oral administration
Japanese encephalitis Vero cell-derived
inactivated
No 2 doses
Tick-borne encephalitis Inactivated No 3–4 doses
Tetanus Toxoid No 1 dose Combined as Td/IPV vaccine
Diphtheria Toxoid No 1 dose Combined as Td/IPV vaccine
Poliovirus Inactivated No 1 dose Combined as Td/IPV vaccine
Rabies Cell-culture derived No 3 doses 5 doses for post-exposure prophylaxis
Typhoid Polysaccharide No 1 dose ViCPS; parenteral
Yellow Fever Live attenuated Yes 1 dose <60 years only; CD4 >200 cells/lL
Vaccines with selected indications
Anthrax Filtrate of bacterial
proteins
No 4 doses Occupational AVP
Haemophilus influenzae
B Conjugated No 1 dose At risk Combined as Hib/MenC
Smallpox MVA No 2 doses Occupational
Not preferred and contraindicated vaccines
Hepatitis A/B combined No Not preferred Reduced immunogenicity
Hepatitis A/typhoid combined No Not preferred Reduced HAV immunogenicity
Influenza Live attenuated Yes Not preferred Intranasal
Smallpox vaccinia virus Live Yes Contraindicated
Tuberculosis BCG Yes Contraindicated
Typhoid Live attenuated Yes Contraindicated Oral administration
AVP, anthrax vaccine precipitated; dTaP/IPV, diphtheria/tetanus/acellular pertussis/inactivated poliovirus; Hib,
Haemophilus influenzae
B; MVA, modified
vaccinia Ankara; OMV, outer membrane vesicles; Td/IPV, tetanus/diphtheria/inactivated poliovirus; ViCPS, Vi capsular polysaccharide vaccine; VLP, virus-
like particle; VZV, varicella zoster virus.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s11
3. Anthrax
3.1 Infection and disease
Bacillus anthracis is a toxin-producing Gram-positive bac-
terium transmitted through spores that can be found in ani-
mal products and can remain viable in the environment for
years. The infection occurs primarily in herbivorous mam-
mals. Human infection is rare and occurs almost exclusively
after contact with infected animals or animal products. Per-
son-to-person transmission may occur through contact with
skin lesions but is unusual [1]. The disease may present as
one of three syndromes: cutaneous (50% of cases, rare mor-
tality); respiratory (50% mortality); and gastrointestinal
(very rare, 25–60% mortality). Meningitis may occur and is
usually fatal. Provided it is recognised early, anthrax can be
treated effectively with antibiotics.
3.2 Epidemiology
Anthrax occurs in Asia, Africa, and parts of Europe and the
Americas. In the UK, human anthrax is rare and is seen
almost entirely as an occupational disease in persons han-
dling imported animal products or working with infected
animals. Cases have been reported in abattoir workers, tan-
nery/leather workers, farm workers, butchers, engineers,
textile workers, and bone meal workers. In recent years, spo-
radic anthrax outbreaks have been reported among heroin
users in northern Europe (“injectional anthrax”), with non-
specific early symptoms, severe pathology, and a high case
fatality rate, indicating the need for clinical vigilance [2].
3.3 Anthrax in HIV-positive people
It is not known whether the natural history of anthrax is
modified by HIV infection.
3.4 Anthrax vaccine
The British vaccine –Anthrax Vaccine Precipitated (AVP) –
is non-replicating and contains a cell-free filtrate of B. an-
thracis proteins. The product licence (PL 1511/0058) is held
by the UK Department of Health. The anthrax vaccine
adsorbed (AVA) is licensed for use in humans in the US.
AVP is given by parenteral administration. There have
been no formal efficacy trials with AVP. Data from the UK
and US suggest that anthrax vaccination prevents disease
[3,4]. Anthrax vaccination is considered safe [5–14].
Injection site reactions occur in 47% of AVP recipients [5].
Follow-up data ranging from 3 to 6 years show no overall
adverse health effects following receipt of AVP [11].
3.4.1 General indications
Anthrax vaccination is indicated in those with a signifi-
cant risk of exposure. In the UK, it is available to the
Department of Health for occupational health purposes
and to the Ministry of Defence to protect service person-
nel from the use of anthrax as a biological weapon.
3.5 Anthrax vaccine in HIV-positive adults
No data are available on the immunogenicity, safety, and
efficacy of anthrax vaccination in HIV-positive persons.
3.6 Post-exposure prophylaxis
Following a credible or confirmed exposure to anthrax,
post-exposure prophylaxis consists of antibiotic therapy
(e.g. oral ciprofloxacin) and may also include the vaccine.
Vaccination is recommended because of the uncertainty
of when or if the inhaled spores may germinate. Advice
must be obtained from Public Health England or other
appropriate agencies.
3.7 Recommendations for HIV-positive adults
•We recommend that HIV-positive adults at significant
risk of anthrax exposure (typically through occupation)
be offered vaccination in accordance with general indi-
cations, and regardless of CD4 cell count, ART use, and
viral load [1D].
oWe recommend a primary vaccine course consisting of
four parental doses of the non-replicating AVP vaccine
given at 0, 3, 6 weeks, and 6 months, with a booster
dose given annually to those at continued risk [1D].
oWe recommend that patients with CD4 cell count
<200 cells/lL be counselled about potential non-
response to vaccination and managed accordingly.
Deferred or repeat vaccination may be indicated fol-
lowing immunorestoration on ART [1D].
•We recommend that following a credible or confirmed
exposure to anthrax, HIV-positive contacts receive
post-exposure prophylaxis with antibiotic therapy and
vaccination in accordance with standard recommenda-
tions [1D].
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s12 BHIVA Writing Group
3.8 References
1 Holty JE, Bravata DM, Liu H et al. A century of inhalational
anthrax cases from 1900 to 2005. Ann Intern Med 2006;
144: 270–280.
2 Ascough S, Altmann DM. Anthrax in injecting drug users:
the need for increased vigilance in the clinic. Expert Rev
Anti Infect Ther 2015; 13: 681–684.
3 Brachman PS, Gold H, Plotkin SA et al. Field evaluation of
a human anthrax vaccine. Am J Public Health 1962; 52:
632–645.
4 Hambleton P, Carman JA, Melling J. Anthrax: the disease in
relation to vaccines. Vaccine 1984; 2: 125–132.
5 Hayes SC, World MJ. Adverse reactions to anthrax
immunisation in a military field hospital. J R Army Med
Corps 2000; 146: 191–195.
6 Sato PA, Reed RJ, Smith TC, Wang L. Monitoring anthrax
vaccine safety in US military service members on active duty:
surveillance of 1998 hospitalizations in temporal association
with anthrax immunization. Vaccine 2002; 20: 2369–2374.
7 Enstone JE, Wale MC, Nguyen-Van-Tam JS, Pearson JC.
Adverse medical events in British service personnel following
anthrax vaccination. Vaccine 2003; 21: 1348–1354.
8 Lange JL, Lesikar SE, Rubertone MV, Brundage JF.
Comprehensive systematic surveillance for adverse effects of
anthrax vaccine adsorbed, US Armed Forces, 1998–2000.
Vaccine 2003; 21: 1620–1628.
9 Hunter D, Zoutman D, Whitehead J et al. Health effects of
anthrax vaccination in the Canadian forces. Mil Med 2004;
169: 833–838.
10 Niu MT, Ball R, Woo EJ et al. Adverse events after anthrax
vaccination reported to the Vaccine Adverse Event
Reporting System (VAERS), 1990–2007. Vaccine 2009; 27:
290–297.
11 Murphy D, Marteau TM, Wessely S. A longitudinal study
of UK military personnel offered anthrax vaccination:
informed choice, symptom reporting, uptake and
pre-vaccination health. Vaccine 2012; 30:
1094–1100.
12 Sulsky SI, Luippold R, Garman P et al. Disability among US
Army Veterans vaccinated against anthrax. Vaccine 2012;
30: 6150–6156.
13 Stewart B, Rose CE, Tokars JI et al. Health-related quality of
life in the CDC Anthrax Vaccine Adsorbed Human Clinical
Trial. Vaccine 2012; 30: 5875–5879.
14 Ryan MA, Smith TC, Sevick CJ et al. Birth defects among
infants born to women who received anthrax vaccine in
pregnancy. Am J Epidemiol 2008; 168: 434–442.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s13
4. Cholera
4.1 Infection and disease
Vibrio cholerae is a non-invasive, toxin-secreting
Gram-negative bacterium that colonises the small
bowel. Classification into over 200 serogroups is based
on the O antigen of the lipopolysaccharide. Cholera
epidemics are caused by the O1 serogroup and more
recently by the O139 serogroup in South and South-
east Asia [1]. Infection is acquired primarily by con-
suming contaminated water or food; person-to-person
transmission is rare. Humans are the only known host.
The disease is characterised by sudden onset of profuse
watery diarrhoea and responds to fluid- and elec-
trolyte-replacement therapy [1,2]. In extreme cases,
hypotension and death can occur within 6–8 h of the
onset of symptoms. Approximately 80% of infected
people have mild diarrhoea or may be asymptomatic.
Persons with underlying gastrointestinal disease may be
at increased risk of disease.
4.2. Epidemiology
Seven cholera pandemics have been recorded through-
out history. The latest started in 1961 and is still
ongoing in over 50 countries in regions of Asia, the
Middle East, Africa, and Central and Latin America,
with an estimated 3 million cases each year [3]. Large
outbreaks are usually caused by a contaminated water
supply. In developed countries cases are reported spo-
radically in travellers, with an overall risk of five cases
per 100 000 travellers to all destinations [4]. Cholera
is rare among UK travellers, and seen predominantly
among those who visit the Indian subcontinent. Trav-
ellers who follow usual tourist itineraries, use standard
tourist accommodation, and observe food safety rec-
ommendations while in countries reporting cholera are
at little risk. The risk increases for long-term travellers
and for those who drink untreated water, eat poorly
cooked or raw seafood, or live in unsanitary condi-
tions in disease-endemic areas (e.g. aid workers assist-
ing in disaster relief or refugee camps and adventurous
backpackers travelling to remote areas) [4]. Currently,
no country requires proof of vaccination against cho-
lera as a condition for entry. Local authorities, how-
ever, may require documentation of vaccination.
4.3 Cholera in HIV-positive people
In cholera-endemic areas, HIV infection is associated with
an increased risk for cholera [5]. The risk of severe dis-
ease may be increased by immunodeficiency.
4.4 Cholera vaccine
Several non-replicating oral cholera vaccines are avail-
able internationally [6]. The WC/rBs vaccine available in
the UK contains inactivated Inaba and Ogawa strains of
V. cholerae serotype O1, together with recombinant B-
subunit of the cholera toxin produced in Inaba strains
of V. cholerae serotype O1. The replicating, live attenu-
ated CVD 103-HgR vaccine, which has been tested in
HIV-positive adults in Mali [7], is currently unavailable.
In healthy persons, oral cholera vaccines given as two
oral doses 1–6 weeks apart confer 65–86% protection,
starting 10 days after the second dose, and lasting for
up to 2 years [8–14]. Interestingly, there is evidence of
herd protection from some vaccine campaigns [12,15].
The WC/rBS vaccine does not confer protection against
V. cholerae O139. WC/rBS appears to provide modest
protection against travellers’ diarrhoea caused by heat-
labile toxin-producing Escherichia coli during the first
3 months following vaccination [4]. However, use for
the specific prevention of travellers’ diarrhoea is not rec-
ommended. There are no major safety concerns with the
WC/rBS vaccine in immunocompetent individuals from
endemic or non-endemic countries [9–11,13,16]. The
vaccine may cause occasional gastrointestinal symptoms.
Systemic symptoms have been reported rarely [4].
4.4.1 General indications
Cholera vaccine is not indicated for most travellers, but is
considered for those who are unable to take adequate pre-
cautions in highly endemic or epidemic V. cholerae 01 set-
tings. These include those assisting in disaster relief or
refugee camps; and visitors to remote areas with limited
access to healthcare where there are outbreaks. The vaccine
should not be co-administered with other oral vaccines.
4.5 Cholera vaccine in HIV-positive adults
There have been no published reports of the efficacy of
the WC/rBS vaccine in HIV-positive travellers. A study
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s14 BHIVA Writing Group
conducted in Beira, Mozambique showed 72% protection
in a population including approximately 25% HIV-posi-
tive persons [14]. HIV-positive adults with CD4 cell
counts <100 cells/lL may be expected to respond poorly
to oral cholera vaccines, whereas those with CD4 cell
counts >100 cells/lL show improved responses after two
doses [17,18]. Intestinal immunogenicity may be pre-
served [19]. Duration of immunity is unknown. The vac-
cine is well tolerated in HIV-positive people [14,17–20].
4.6 Recommendations for HIV-positive adults
•We recommend that HIV-positive adults at significant
risk of cholera exposure (typically through specific tra-
vel) be offered vaccination in accordance with general
indications, and regardless of CD4 cell count, ART use,
and viral load [1B].
oWe recommend a primary vaccine course consist-
ing of two oral doses of the non-replicating WC/
rBS vaccine given 1–6 weeks apart and at least
1 week prior to exposure. If >6 weeks elapse
between doses, the primary course should be
restarted [1B].
oWe recommend a single booster dose after 2 years if
continued protection is required. If >2 years elapse
after completion of the primary vaccine course, the
full course should be repeated [1B].
4.7 References
1 Harris JB, LaRocque RC, Qadri F et al. Cholera. Lancet 2012;
379: 2466–2476.
2 Leibovici-Weissman Y, Neuberger A, Bitterman R et al.
Antimicrobial drugs for treating cholera. Cochrane Database
Syst Rev 2014; 6: CD008625.
3 Ali M, Lopez AL, You YA et al. The global burden of
cholera. Bull World Health Organ 2012; 90: 209–218.
4 Hill DR, Ford L, Lalloo DG. Oral cholera vaccines: use in
clinical practice. Lancet Infect Dis 2006; 6: 361–373.
5 von Seidlein L, Wang XY, Macuamule A et al. Is HIV
infection associated with an increased risk for cholera?
Findings from a case-control study in Mozambique. Trop
Med Int Health 2008; 13: 683–688.
6 Shin S, Desai SN, Sah BK, Clemens JD. Oral vaccines
against cholera. Clin Infect Dis 2011; 52: 1343–1349.
7 Perry RT, Plowe CV, Koumare B et al. A single dose of live
oral cholera vaccine CVD 103-HgR is safe and immunogenic
in HIV-infected and HIV-noninfected adults in Mali. Bull
World Health Organ 1998; 76:63–71.
8 Sanchez JL, Vasquez B, Begue RE et al. Protective efficacy
of oral whole-cell/recombinant-B-subunit cholera vaccine in
Peruvian military recruits. Lancet 1994; 344: 1273–1276.
9 Jertborn M, Svennerholm AM, Holmgren J. Evaluation of
different immunization schedules for oral cholera B
subunit-whole cell vaccine in Swedish volunteers. Vaccine
1993; 11: 1007–1012.
10 Sur D, Lopez AL, Kanungo S et al. Efficacy and safety of a
modified killed-whole-cell oral cholera vaccine in India: an
interim analysis of a cluster-randomised, double-blind,
placebo-controlled trial. Lancet 2009; 374: 1694–1702.
11 Bhattacharya SK, Sur D, Ali M et al. 5 year efficacy of a
bivalent killed whole-cell oral cholera vaccine in Kolkata,
India: a cluster-randomised, double-blind, placebo-
controlled trial. Lancet Infect Dis 2013; 13: 1050–1056.
12 Khatib AM, Ali M, von Seidlein L et al. Effectiveness of an
oral cholera vaccine in Zanzibar: findings from a mass
vaccination campaign and observational cohort study.
Lancet Infect Dis 2012; 12: 837–844.
13 Saha A, Chowdhury MI, Khanam F et al. Safety and
immunogenicity study of a killed bivalent (O1 and O139)
whole-cell oral cholera vaccine Shanchol, in Bangladeshi
adults and children as young as 1 year of age. Vaccine
2011; 29: 8285–8292.
14 Lucas ME, Deen JL, von Seidlein L et al. Effectiveness of
mass oral cholera vaccination in Beira, Mozambique. N Engl
J Med 2005; 352: 757–767.
15 Ali M, Emch M, Yunus M et al. Vaccine Protection of
Bangladeshi infants and young children against cholera:
implications for vaccine deployment and person-to-
person transmission. Pediatr Infect Dis J 2008; 27:
33–37.
16 Legros D, Paquet C, Perea W et al. Mass vaccination with a
two-dose oral cholera vaccine in a refugee camp. Bull
World Health Organ 1999; 77: 837–842.
17 Lewis DJ, Gilks CF, Ojoo S et al. Immune response
following oral administration of cholera toxin B subunit to
HIV-1-infected UK and Kenyan subjects. AIDS 1994; 8:
779–785.
18 Westrop SJ, Moyle G, Jackson A et al. CCR5 antagonism
impacts vaccination response and immune profile in HIV-1
infection. Mol Med 2012; 18: 1240–1248.
19 Eriksson K, Kilander A, Hagberg L et al. Intestinal antibody
responses to oral vaccination in HIV-infected individuals.
AIDS 1993; 7: 1087–1091.
20 Ortigao-de-Sampaio MB, Shattock RJ, Hayes P et al.
Increase in plasma viral load after oral cholera
immunization of HIV-infected subjects. AIDS 1998; 12:
F145–F150.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s15
5. Diphtheria
5.1 Infection and disease
Diphtheria is caused by toxigenic strains of the Gram-
positive bacteria Corynebacterium diphtheriae and
Corynebacterium ulcerans, and affects the upper respira-
tory tract and occasionally the skin. The infection is
transmitted via airborne droplets, generally requiring
close contact with symptomatic patients or asymptomatic
carriers. Alternative modes of transmission are direct
contact with skin lesions or infected cattle and other farm
animals (C. ulcerans). Rare human cases have been asso-
ciated with the consumption of raw unpasteurised dairy
products. Life-threatening complications include cardiac
failure and paralysis.
5.2 Epidemiology
Both C. diphtheriae and C. ulcerans cause diphtheria in
the UK. Since the 1990s, C. ulcerans has been the pre-
dominant cause of infection resulting in sporadic deaths
[1]. As a result of successful vaccination programmes, the
circulation of C. diphtheria has virtually ceased in the
UK. The majority of cases are now mild infections in par-
tially immunised individuals, or in adults who have been
fully immunised but have waning immunity. Susceptibil-
ity to diphtheria increases with age. In the UK, approxi-
mately 50% of adults >30 years of age are estimated to
be susceptible to diphtheria [2]. Diphtheria cases continue
to be reported from India, South-east Asia, South Amer-
ica, Africa, former Soviet States, and Eastern Europe; thus
there is potential for exposure through travel, and re-
introduction of C. diphtheriae into the UK may also occur
through immigration from these regions.
5.3 Diphtheria in HIV-positive people
It is not known whether the natural history of diphtheria
is modified by HIV infection.
5.4 Diphtheria vaccine
The diphtheria vaccine is non-replicating and is made
from cell-free purified toxin extracted from C. diphthe-
riae and converted into diphtheria toxoid. The vaccine is
given to adults in combination with tetanus toxoid and
inactivated polio vaccine (Td/IPV) in a preparation
containing a lower dosage of diphtheria toxoid than
preparations designed for use in childhood. The vaccine
is given by parenteral administration. The diphtheria vac-
cine induces protective antitoxin levels in 95% of recipi-
ents after three doses, and shows a clinical efficacy of
over 97% [3,4]. The vaccine is well tolerated. Injection
site reactions are common but usually self-limited and
may occur more frequently following subsequent doses.
Fever and other systemic reactions are uncommon. Severe
systemic reactions are rare.
5.4.1 General indications
The aim of the UK national vaccination programme is
to ensure that all individuals receive at least five vac-
cine doses. Td/IPV is recommended for vaccination of
those aged ≥10 years. Adults who are either unvacci-
nated or have an uncertain vaccination history are
advised to receive primary immunisation with three
vaccine doses at monthly intervals. Two further doses
are scheduled 5 and 10 years after the last dose. Adults
who have received partial vaccination are advised to
receive the remaining doses, regardless of the interval
since the last dose and type of vaccine previously
received. It is also recommended that travellers to epi-
demic and endemic areas should ensure they are fully
vaccinated.
5.5 Diphtheria vaccine in HIV-positive adults
Limited data exist on the immunogenicity and clinical
efficacy of the diphtheria vaccine in HIV-positive adults.
Vaccine responses may be reduced compared to
HIV-negative persons, especially in those with advanced
disease and low CD4 cell counts, but improve with ART
[5–8]. No increased risk of side effects or adverse reac-
tions to vaccination has been reported in individuals with
HIV infection.
5.6 Post-exposure prophylaxis
Contacts of a case or a carrier of C. diphtheriae or C. ul-
cerans require antibiotic prophylaxis (e.g. erythromycin).
Fully immunised individuals also receive a single rein-
forcing dose of the vaccine; others are offered to com-
plete the vaccine course.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s16 BHIVA Writing Group
5.7 Recommendations for HIV-positive adults
•We recommend that HIV-positive adults who require
vaccination against diphtheria, tetanus, or polio be
given the parenteral Td/IPV vaccine in accordance with
general indications, and regardless of CD4 cell count,
ART use, and viral load [1B].
oWe recommend that individuals who are either
unvaccinated or have an uncertain vaccination his-
tory receive three vaccine doses at 1 month interval,
followed by two booster doses after 5 and 10 years;
partially vaccinated individuals should complete the
five-dose vaccine course [1B].
oWe recommend that fully vaccinated individuals
(five doses) receive a booster dose every 10 years if
at risk of exposure, typically through travel [1C].
•We recommend that individuals who may be occupa-
tionally exposed to diphtheria (e.g. laboratory workers)
be tested for diphtheria antibodies 3 months after vac-
cination to confirm protective immunity, and be revac-
cinated if required [1C].
•We recommend that following a credible or confirmed
exposure to diphtheria, HIV-positive contacts receive
post-exposure prophylaxis with antibiotic therapy and
vaccination in accordance with standard recommenda-
tions [1C].
5.8 References
1 Wagner KS, White JM, Crowcroft NS et al. Diphtheria in the
United Kingdom, 1986–2008: the increasing role of
Corynebacterium ulcerans.Epidemiol Infect 2010; 138:
1519–1530.
2 Edmunds WJ, Pebody RG, Aggerback H et al. The sero-
epidemiology of diphtheria in Western Europe. Epidemiol
Infect 2000; 125: 113–125.
3 Myers MG, Beckman CW, Vosingh RA, Hankins WA.
Primary immunisation with tetanus and diphtheria toxoids:
reaction rates and immunogenicity in older children and
adults. JAMA 1982; 248: 2478–2480.
4 Galazka AM, Robertson SE. Immunisation against diphtheria
with special emphasis on immunization of adults. Vaccine
1996; 14: 845–857.
5 Poland GA, Love KR, Hughes CE. Routine immunizations in
the HIV-positive asymptomatic patient. J Gen Inter Med
1990; 5: 147–152.
6 Kroon FP, Van Dissel JT, Labadie J et al. Antibody response to
diphtheria, tetanus, and poliomyelitis vaccines in relation to the
number of CD4+T lymphocytes in adults infected with human
immunodeficiency virus. Clin Infect Dis 1995; 21: 1197–1203.
7 Valdez H, Smith KY, Landay A et al. Response to
immunization with recall and neoantigens after prolonged
administration of an HIV-1 protease inhibitor-containing
regimen. AIDS 2000; 14:11–21.
8 Bonetti TC, Succi RC, Weckx LY et al. Tetanus and diphtheria
antibodies and response to a booster dose in Brazilian HIV-1-
infected women. Vaccine 2004; 22: 3707–3712.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s17
6.
Haemophilus influenzae
serotype B
6.1 Infection and disease
Haemophilus influenzae is a Gram-negative coccobacillus
that can cause invasive disease in young children and in
people with predisposing conditions [1–3]. Hib can colo-
nise the nasopharynx in the absence of symptoms. Trans-
mission occurs through respiratory droplets and close
contact with a case or a carrier. Invasive disease is usu-
ally caused by one of six encapsulated serotypes (a–f),
and less commonly by encapsulated non-typeable strains.
Serotype b (Hib) is the most virulent strain and, prior to
the introduction of routine vaccination, was responsible
for >80% of invasive infections, primarily meningitis,
among children <5 years of age. Non-encapsulated
strains (ncHi) mainly cause respiratory disease; invasive
ncHi disease is uncommon and usually occurs in preg-
nant women, newborns, and individuals with underlying
conditions (immunosuppression, chronic respiratory dis-
ease, head trauma, or neurological disease) [4]. Risk fac-
tors for invasive Hib disease are similar to those
associated with other encapsulated bacteria. Patients with
anatomical or functional asplenia and those with comple-
ment deficiencies are at an increased risk of disease.
6.2 Epidemiology
Hib remains one of the major vaccine-preventable causes
of morbidity and mortality worldwide [5]. In industri-
alised countries, the introduction of Hib conjugate vacci-
nes into national childhood vaccination programmes over
the past two decades has resulted in a sustained decline
in the incidence of invasive Hib infections across all age-
groups, through a combination of direct and indirect
(herd) protection [6,7]. In England and Wales, invasive
Hib disease is now infrequent [8]. Most cases occur in
adults who typically present with pneumonia and often
have pre-existing medical conditions, with an overall
case-fatality rate of 9% [8]. Average vaccine coverage
remains suboptimal in many developing countries [9].
6.3 Haemophilus influenzae in HIV-positive adults
In HIV-positive adults, the risk of invasive H. influenzae
disease is increased compared to the general population
[10,11]. In one study, cumulative incidence reached 79.6/
100 000 among men with AIDS aged 20–49 years; how-
ever, only one-third of cases was due to the Hib serotype
indicating that the Hib vaccine would not be protective
[10]. In countries with established Hib vaccination pro-
grammes such as the UK, invasive Hib disease is now
uncommon among people with HIV [8].
6.4 Hib vaccine
The Hib vaccine is non-replicating and contains capsular
polysaccharide conjugated to a protein (e.g. tetanus tox-
oid). It is typically part of multivalent vaccines for use in
infants, including the diphtheria/tetanus/acellular pertus-
sis/inactivated polio/Hib vaccine (DTaP/IPV/Hib) and the
Hib/meningococcal group C vaccine (Hib/MenC). The vac-
cine is given by parenteral administration. The Hib vac-
cine is highly immunogenic and efficacious in children
[3,5,6,12]; it only protects against invasive Hib disease
and offers no protection against other serotypes or
against ncHi. Although the duration of protection is
unknown, no booster doses are routinely recommended
after 12 months of age. The vaccine is well tolerated.
Injection site reactions occur in 5–30% of recipients.
Systemic reactions are infrequent.
6.4.1 General indications
The objective of the UK Hib vaccination programme is to
protect all individuals <10 years of age and older indi-
viduals at elevated risk from invasive Hib disease, includ-
ing individuals who develop asplenia or splenic
dysfunction or when complement deficiency is diagnosed.
6.5. Hib vaccine in HIV-positive adults
The vaccine has been shown to induce protective anti-
bodies in HIV-positive children [13–16] and adults [17–
19]. The magnitude and longevity of responses are related
to the CD4 cell count and can be reduced relative to HIV-
negative individuals. Clinical effectiveness may also be
reduced by HIV infection. In South Africa, 47% of chil-
dren who developed invasive Hib disease during 2003–
2009 despite being fully immunised with the conjugate
Hib vaccine were HIV-positive [20]. No safety concerns
have emerged in HIV-positive vaccine recipients.
6.6 Post-exposure prophylaxis
Household contacts of a Hib case are given antibiotic
prophylaxis (e.g. rifampicin), regardless of their
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s18 BHIVA Writing Group
immunisation status, starting as soon as the index case is
diagnosed.
6.7 Recommendations for HIV-positive adults
•Hib vaccination is not recommended routinely in HIV-
positive adults, including patients who develop Hib
disease. We recommend however that HIV-positive
adults with asplenia, splenic dysfunction or comple-
ment deficiency (including those receiving complement
inhibitor therapy) receive one parental dose of a Hib-
containing vaccine (e.g. Hib/MenC in the UK) whether
or not they were immunised previously, and regardless
of CD4 cell count, ART use, and viral load [1B].
•We recommend that HIV-positive adults who are
household contacts of a Hib case are offered antibiotic
prophylaxis in accordance with standard recommenda-
tions [1C].
6.8 References
1 Ladhani S, Neely F, Heath PT et al. Recommendations for
the prevention of secondary Haemophilus influenzae type b
(Hib) disease. J Infect 2009; 58:3–14.
2 Ladhani S, Slack MP, Heath PT et al. Invasive Haemophilus
influenzae disease, Europe, 1996–2006. Emerg Infect Dis
2010; 16: 455–463.
3 Ladhani SN. Two decades of experience with the
Haemophilus influenzae serotype b conjugate vaccine in the
United Kingdom. Clin Ther 2012; 34: 385–399.
4 Gkentzi D, Slack MP, Ladhani SN. The burden of
nonencapsulated Haemophilus influenzae in children and
potential for prevention. Curr Opin Infect Dis 2012; 25:
266–272.
5 Watt JP, Wolfson LJ, O’Brien KL et al. Burden of disease
caused by Haemophilus influenzae type b in children younger
than 5 years: global estimates. Lancet 2009; 374: 903–911.
6 Peltola H. Worldwide Haemophilus influenzae type b disease
at the beginning of the 21st century: global analysis of the
disease burden 25 years after the use of the polysaccharide
vaccine and a decade after the advent of conjugates. Clin
Microbiol Rev 2000; 13: 302–317.
7 Morris SK, Moss WJ, Halsey N. Haemophilus influenzae type
b conjugate vaccine use and effectiveness. Lancet Infect Dis
2008; 8: 435–443.
8 Collins S, Ramsay M, Campbell H et al. Invasive
Haemophilus influenzae type b disease in England and
Wales: who is at risk after two decades of routine childhood
vaccination? Clin Infect Dis 2013; 57: 1715–1721.
9 World Health Organisation (WHO). Haemophilus influenzae
type b (Hib) Vaccination WHO position paper: July 2013-
Recommendations. Vaccine 2013; 31: 6168–6169.
10 Steinhart R, Reingold AL, Taylor F et al. Invasive
Haemophilus influenzae infections in men with HIV
infection. JAMA 1992; 268: 3350–3352.
11 Selwyn PA, Feingold AR, Hartel D et al. Increased risk of
bacterial pneumonia in HIV-infected intravenous drug users
without AIDS.AIDS 1988; 2: 267–272.
12 Mangtani P, Mulholland K, Madhi SA et al. Haemophilus
influenzae type b disease in HIV-infected children: a review
of the disease epidemiology and effectiveness of Hib
conjugate vaccines. Vaccine 2010; 28: 1677–1683.
13 Wenger JD, Pierce R, Deaver KA et al. Efficacy of
Haemophilus influenzae type b polysaccharide-diphtheria
toxoid conjugate vaccine in US children aged 18–
59 months. Lancet 1991; 338: 395–398.
14 Gibb D, Spoulou V, Giacomelli A et al. Antibody responses
to Haemophilus influenzae type b and Streptococcus
pneumoniae vaccines in children with human
immunodeficiency virus infection. Pediatr Infect Dis J 1995;
14: 129–135.
15 Rutstein RM, Rudy BJ, Cnaan A. Response of human
immunodeficiency virus-exposed and -infected infants to
Haemophilus influenzae type b conjugate vaccine. Arch
Pediatr Adolesc Med 1996; 150: 838–841.
16 Kale KL, King JC Jr, Farley JJ et al. The immunogenicity of
Haemophilus influenzae type b conjugate (HbOC) vaccine in
human immunodeficiency virus-infected and uninfected
infants. Pediatr Infect Dis J 1995; 14: 350–354.
17 Steinhoff MC, Auerbach BS, Nelson KE et al. Antibody
responses to Haemophilus influenzae type B vaccines in
men with human immunodeficiency virus infection. N Engl
J Med 1991; 325: 1837–1842.
18 Dockrell DH, Poland GA, Steckelberg JM et al.
Immunogenicity of three Haemophilus influenzae type b
protein conjugate vaccines in HIV seropositive adults and
analysis of predictors of vaccine response. Vaccine 1999;
17: 2779–2785.
19 De Sousa dos Santos S, Lopes MH, Simonsen V et al.
Haemophilus influenzae type b immunization in adults
infected with the human immunodeficiency virus. AIDS Res
Hum Retroviruses 2004; 20: 493–496.
20 von Gottberg GA, Cohen C, Whitelaw A et al. Invasive
disease due to Haemophilus influenzae serotype b ten years
after routine vaccination, South Africa, 2003–2009. Vaccine
2012; 30: 565–571.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s19
7. Hepatitis A
7.1 Infection and disease
Hepatitis A virus (HAV) is transmitted faeco-orally through
close personal contact, contaminated food and water, and
rarely through blood exposure. Person-to-person spread is
the most common method of transmission in developed
countries. There is evidence that the infection may be
spread during sexual contact in men who have sex with
men (MSM) [1]. Infection may be asymptomatic, but sever-
ity tends to increase with age. Jaundice occurs in 10% of
children below the age of 6 years, 40–50% of older chil-
dren and 70–80% of adults. Fulminant hepatitis is rare
(<1% overall) and predominantly occurs in older age
groups, but carries a 45% risk of mortality. Patients with
chronic liver disease are at risk of severe complications [2].
Although approximately 15% of cases show prolonged or
relapsing symptoms, chronic HAV infection is not known
to occur. Infection is followed by lifelong immunity.
7.2 Epidemiology
HAV prevalence is low in Northern and Western Europe,
North America, Australia, New Zealand and Japan, and
intermediate to high in Mexico, Central and South Amer-
ica, the Caribbean, Africa, Asia and Eastern Europe. In
the UK, those at risk for infection include:
•Household and sexual contacts of infected persons.
•Travellers to countries where HAV is common.
•Men who have sex with men.
•Injecting and non-injecting drug users.
•Individuals at risk of infection during outbreaks.
•Those with occupational exposure to HAV (e.g. labora-
tory workers, sewage workers).
•Persons with haemophilia.
•Persons with special needs living in residential institu-
tions, and their carers.
7.3 Hepatitis A in HIV-positive adults
Hepatitis A does not appear to be worse in HIV-positive
patients when compared to HIV-negative persons,
although HAV viraemia may be prolonged [3,4].
7.4 Hepatitis A vaccine
The HAV vaccine is non-replicating and contains whole
inactivated virus. Combined hepatitis A/hepatitis B and
hepatitis A/typhoid vaccines are also available. The vac-
cine is given by parenteral administration. The standard
vaccine course comprises two doses given 6–12 months
apart. In healthy persons, the HAV vaccine is highly
immunogenic and efficacious, without safety concerns.
Protective levels of antibodies develop in 97–100% of
individuals within 1 month of the first dose and in virtu-
ally 100% after the second dose. The level of protection
against clinical hepatitis is 79–100% after a single dose.
The combined hepatitis A/hepatitis B vaccine is also
highly efficacious in health individuals. Successful immu-
nisation is thought to confer protection for at least
10 years and possibly for life [5,6].
7.4.1 General indications
The HAV vaccine is indicated for persons at risk of expo-
sure (listed above).
7.5 HAV vaccine in HIV-positive adults
The rate, magnitude, and longevity of immune responses
to HAV vaccination are generally reduced in HIV-positive
persons, although they improve with increasing CD4 cell
counts and viral load suppression on ART [7–13]. Less
than half of vaccine recipients experience seroconversion
after a single vaccine dose; responses increase to over
70% after two doses, while remaining lower than those
measured in HIV-negative adults. Further increasing the
number of vaccine doses improves antibody levels and
the longevity of response but does not significantly
improve overall seroconversion rates. In a randomised
study, HIV-positive adults were assigned to receive either
two (0 and 6 months) or three (0, 1, and 6 months) HAV
vaccine doses. At week 28 after the first vaccine dose,
seroconversion rates were 72% vs. 88%, respectively in
the observed analysis (P=0.06); the three-dose group
had significantly higher antibody titres at week 28 and
week 72 [7]. Multivariate analysis indicated that absence
of tobacco smoking was an independent predictor of
response to HAV vaccine [odds ratio (OR) 2.92; 95% con-
fidence interval (CI) 1.07–7.97; P=0.04]. A prospective
cohort study compared responses between HIV-positive
MSM receiving two (0 and 6 months) or three (0, 1, and
6 months) doses of HAV vaccine and HIV-negative MSM
receiving two vaccine doses [12]. At week 48, HAV sero-
conversion rates were 76%, 78%, and 89%, respectively.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s20 BHIVA Writing Group
In HIV-positive MSM, antibody titres were significantly
higher with three doses than two doses. Responses to
HAV vaccination also appear to be higher with the
monovalent HAV vaccine than for the combined HAV/
HBV vaccine, particularly with low CD4 cells counts and
detectable viral load, and among patients not completing
the vaccine course [13]. Most patients with high CD4 cell
counts show a durable response during up to 5 years of
follow-up after HAV vaccination [14]. The HAV vaccine
is safe and well tolerated in HIV-positive individuals,
including those receiving three vaccine doses over
6 months [7,13]. Injection site reactions are the most fre-
quent side effect.
7.6. Post-exposure prophylaxis
Following a high-risk contact (e.g. in the household set-
ting or other intimate contact) HAV vaccine plus human
normal immunoglobulin (HNIG) given intramuscularly (at
different sites) within 14 days of exposure can prevent or
attenuate disease in susceptible persons. Efficacy beyond
14 days of exposure is unknown; disease may be attenu-
ated rather than prevented. In HIV-negative people the
clinical efficacy of prophylaxis is in the range 47–87%
[15,16]. Early vaccination alone (without HNIG) seems
equally effective in HIV-negative people. There are no
data on the efficacy of post-exposure prophylaxis in
HIV-positive persons.
7.7 Recommendations for HIV-positive adults
•We recommend that HIV-positive adults at risk of hep-
atitis A exposure (see risk groups) be offered vaccina-
tion with the monovalent HAV vaccine [1A].
oPatients with CD4 cell counts >350 cells/lL should be
offered two vaccine doses at 0 and 6 months [1A].
oPatients with CD4 cell counts <350 cells/lL should
receive three vaccine doses at 0, 1, and 6 months in
order to increase antibody levels and longevity,
especially if they are likely to be at continued risk
of exposure [1C].
oPre-vaccination testing for evidence of HAV immu-
nity may be cost-effective in some clinical settings:
screening may target those who were born in or
lived for extensive periods in geographical areas
that have a high to intermediate HAV endemicity,
MSM, injecting drug users, and those aged
>50 years [GPP].
•We recommend that patients at continued risk of expo-
sure receive a boosting vaccine dose every 10 years
[1C].
•We recommend that in circumstances where a pro-
foundly immunocompromised patient (CD4 cell count
<200 cell/lL) must be protected from likely exposure to
HAV, HNIG may be considered alongside the vaccine for
temporary (~3 weeks) pre-exposure prophylaxis [1D].
•We recommend that following a significant exposure,
HIV-positive contacts who are HAV seronegative
receive post-exposure prophylaxis with the HAV vac-
cine, with the first dose given as soon as possible and
within 14 days of exposure; if the CD4 cell count is
<200 cells/lL they should also receive HNIG [1C].
oWhile HAV serostatus should be determined if
unknown, prophylaxis should not be delayed while
waiting for the results [GPP].
oWe suggest that in some circumstances post-expo-
sure prophylaxis may be considered up to 28 days
after the contact [2D].
7.8 References
1 Urbanus AT, van Houdt R, van de Laar TJ, Coutinho RA.
Viral hepatitis among men who have sex with men,
epidemiology and public health consequences. Euro Surveill
2009; 14: 1025.
2 Mackinney-Novelo I, Barahona-Garrido J, Castillo-Albarran
Fet al. Clinical course and management of acute hepatitis
A infection in adults. Ann Hepatol 2012; 11: 652–657.
3 Ida S, Tachikawa N, Nakajima A et al. Influence of human
immunodeficiency virus type 1 infection on acute hepatitis
A virus infection. Clin Infect Dis 2002; 34: 379–385.
4 Costa-Mattioli M, Allavena C, Poirier AS et al. Prolonged
hepatitis A infection in an HIV-1- seropositive patient.
J Med Virol 2002; 68:7–11.
5 Van Damme P, Van HK. A review of the long-term
protection after hepatitis A and B vaccination. Travel Med
Infect Dis 2007; 5:79–84.
6 Rendi-Wagner P, Korinek M, Winkler B et al. Persistence of
seroprotection 10 years after primary hepatitis A
vaccination in an unselected study population. Vaccine
2007; 25: 927–931.
7 Launay O, Grabar S, Gordien E et al. Immunological
efficacy of a three-dose schedule of hepatitis A vaccine in
HIV-infected adults: HEPAVAC study. J Acquir Immune
Defic Syndr 2008; 49: 272–275.
8 Crum-Cianflone NF, Wilkins K, Lee AW et al. Long-term
durability of immune responses after hepatitis A vaccination
among HIV-infected adults. J Infect Dis 2011; 203: 1815–
1823.
9 Kourkounti S, Mavrianou N, Paparizos VA et al. Immune
response to hepatitis A vaccination in HIV-infected men in
Greece. Int J STD AIDS 2012; 23: 464–467.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s21
10 Kourkounti S, Papaizos V, Leuow K et al. Hepatitis A
vaccination and immunological parameters in HIV-infected
patients. Viral Immunol 2013; 26: 357–363.
11 Mena G, Garcia-Basteiro AL, Llupia A et al. Factors
associated with the immune response to hepatitis A
vaccination in HIV-infected patients in the era of highly
active antiretroviral therapy. Vaccine 2013; 31: 3668–
3674.
12 Tseng YT, Chang SY, Liu WC et al. Comparative
effectiveness of two doses versus three doses of hepatitis A
vaccine in human immunodeficiency virus-infected and -
uninfected men who have sex with men. Hepatology 2013;
57: 1734–1741.
13 Jimenez HR, Hallit RR, Debari VA, Slim J. Hepatitis A
vaccine response in HIV-infected patients: are TWINRIX
and HAVRIX interchangeable? Vaccine 2013; 31: 1328–
1333.
14 Jabłonowska E, Kuydowicz J. Durability of response to
vaccination against viral hepatitis A in HIV-infected
patients: a 5-year observation. Int J STD AIDS 2014; 25:
745–750.
15 Victor JC, Monto AS, Surdina TY et al. Hepatitis A vaccine
versus immune globulin for postexposure prophylaxis. N
Engl J Med 2007; 357: 1685–1694.
16 Kohl I, Nemecek V, Summerov
aMet al. Long-term
protective effect of post-exposure Havrix administration
during viral hepatitis Type A outbreaks. Eur J Epidemiol
2006; 21: 893–899.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s22 BHIVA Writing Group
8. Hepatitis B
8.1 Infection and disease
The hepatitis B virus (HBV) is transmitted through sexual
intercourse, percutaneous and parenteral exposure to blood
and infected body fluids, and vertically from mother to
child. The severity of acute infection varies from asymp-
tomatic to fulminant hepatitis. After primary infection,
HBV persists in 90% of infants infected perinatally, 25–
50% of children aged 1–5 years and 1–5% of immunocom-
petent adults and older children. Chronic infection can lead
to liver cirrhosis and hepatocellular carcinoma.
8.2 Epidemiology
Based on the prevalence of the infection, three geograph-
ical categories can be identified: low prevalence (<2%),
intermediate prevalence (2–8%), and high prevalence
(>8%). Regions of low prevalence include Western, North-
ern and Central Europe, North America, and Australia.
Worldwide, the risk of infection is increased in injecting
drug users (IDUs), men who have sex with men (MSM),
those with multiple sexual partners, household and other
close contacts of HBV-infected persons, those receiving
blood or blood products, patients and staff of haemodial-
ysis centres, people sharing unsterile medical and dental
equipment, people providing and receiving acupuncture
and tattooing with unsterile devices, healthcare workers,
staff and residents of residential accommodation for those
with mental disabilities, and travellers to areas of high or
intermediate HBV prevalence if engaging in exposure-
prone activities (including undertaking relief aid work
and/or participating in contact sports).
8.3 HBV in HIV-positive adults
Both the risk of HBV infection and that of chronicity are
increased in HIV-seropositive persons [1]. Chronic HBV
infection is found in 5–10% of HIV-positive persons
worldwide and co-infected persons show increased rates
of progression to cirrhosis and liver cancer and a higher
mortality than persons with either infection alone [2].
8.4 Hepatitis B vaccine
The yeast-derived HBV vaccine is prepared with biosyn-
thetic surface antigen made using recombinant
technology. There is also a combined hepatitis A/hepatitis
B vaccine. Newly developed pre-S/S HBV vaccines are
under evaluation and may in the future play a role in
improving vaccine response rates in special risk groups
including HIV-positive patients [3,4]. The vaccine is given
by parenteral administration. In HIV-negative adults, the
schedule of administration can be: typical (three doses at
0, 1, and 6 months); accelerated (four doses at 0, 1, 2,
and 12 months); or ultra-rapid (four doses at 0, 7–
10 days, 21 days, and 12 months). Approximately 80–
90% of healthy young adults achieve HBV surface anti-
body (HBsAb) levels >10 IU/L after a complete vaccine
course. Antibody levels >100 IU/L are regarded as ideal
whereas a level <10 IU/L is classified as non-response [5].
Factors that reduce responses to HBV vaccination include
age >40 years, obesity, male gender, haemodialysis,
smoking, and immunocompromise, including HIV infec-
tion.
HBsAb levels decline over time after successful vacci-
nation. After 20 years, 18–37% of adults have HBsAb
levels >10 IU/L [6,7]. There is some evidence that protec-
tive immunity is still present even though HBsAb levels
have fallen <10 IU/L. Infection may occur, but it is
mostly transient [7–10]. In a study from the Gambia, ado-
lescents and young adults vaccinated in infancy showed
a risk of HBV infection, but this did not usually result in
a chronic infection [7]. Time since vaccination and a low
peak HBsAb response were the strongest risk factors for
HBV infection. There is limited evidence regarding the
need for booster vaccine doses in healthy individuals. UK
guidelines recommend that persons at ongoing risk
receive a single booster 5 years after completion of the
primary vaccine course.
8.4.1 General indications
In the UK HBV vaccination is offered to individuals who
are at increased risk of infection or severe disease. The
groups include IDUs, individuals who change sexual part-
ners frequently (e.g. sex workers), MSM, close contacts of
people with HBV infection, families adopting children
from countries with a high or intermediate HBV preva-
lence, foster carers, individuals receiving regular blood or
blood products and their carers, patients with chronic
renal failure, patients with chronic liver disease, inmates
of custodial institutions, individuals in residential accom-
modation for those with learning difficulties, people
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s23
travelling to or going to reside in areas of high or inter-
mediate prevalence, and individuals at occupational risk.
8.5 HBV vaccine in HIV-positive adults
HBV vaccination significantly reduces the risk of incident
HBV infection in HIV-positive persons, and also reduces
the risk of a newly acquired infection becoming chronic
[11]. HIV infection however affects responses to HBV
vaccination, reducing HBsAb seroconversion rates, and
HBsAb levels and longevity [12–16]. After standard vac-
cination, rates of HBsAb seroconversion (>10 IU/L) range
between 7% and 88%, and correlate strongly with CD4
cell counts and viral load [12–21]. Strategies to improve
responses have included revaccination of non-responders
once the viral load is suppressed on ART and the CD4 cell
count is >350–500 cells/lL, and the use of larger and
more frequent vaccine doses [19–23]. When using yeast-
based HBV vaccines, high-dose vaccination improves
HBsAb responses in HIV-positive people. A systematic
review and meta-analysis of five studies including a total
of 883 patients compared HBsAb response with high-dose
(40 lg) vs. standard-dose (20 or 10 lg depending on vac-
cine type) vaccination [22]. High-dose vaccination
increased response rates with a pooled OR of 1.96 (95%
CI 1.47–2.61). With four studies that included only vac-
cine-naive patients the OR was 1.82 (95% CI 1.35–2.47).
No study heterogeneity was found. An open-label, multi-
centre, randomised trial of patients with CD4 cell counts
>200 cell/lL evaluated three HBV vaccination strategies:
(i) three standard-dose (20 lg) intramuscular administra-
tions at 0, 1, and 6 months (n=145); (ii) four high-dose
(40 lg) intramuscular administrations at 0, 1, 2, and
6 months (n=148); and (iii) four low-dose (4 lg) intra-
dermal administrations at 0, 1, 2, and 6 months (n=144)
[20]. Response rates (HBsAb ≥10 IU/L) 4 weeks after the
last vaccine dose in patients who received at least one
vaccine dose (missing HBsAb titre =non-responder) was
65% (95% CI 56–72%) in group (i) vs. 82% (77–88%) in
group (ii) (P<0.001) and 77% (69–84%) in group (iii)
(P=0.02). A cohort study also found that HBAbs
response rates were 83% and 91% after three and four
double-doses, respectively and HBsAb levels were higher
with the four-dose schedule [24].
The ultra-rapid vaccination course (three vaccine doses
given over 3 weeks) is immunogenic and can improve
completion rates in healthy adults. However, a ran-
domised study comparing the ultra rapid-vaccine course
(0, 7, and 21 days) with the typical course (0, 1, and
6 months) in HIV-positive adults found that the former
had reduced immunogenicity in patients with CD4 cell
counts <500 cells/lL [25]. The study used standard-dose
vaccine; there are no data for using high-dose vaccine in
an ultra-rapid schedule.
The relationship between HBsAb levels and protection
has been investigated by comparing rates of HBV infec-
tion among vaccine recipients with initial HBsAb levels
<10 or ≥10 IU/L [26]. Overall, 46/409 (11%) vaccine
recipients with HBsAb <10 IU/L acquired HBV infection
compared with 11/217 (5%) vaccine recipients with
HBsAb ≥10 IU/L [hazard ratio (HR) 0.51; 95% CI 0.3–1.0].
Furthermore, in participants with initial HBsAb levels
<10 IU/L, 16/46 (35%) incident infections became
chronic, whereas no chronic infections were detected in
those with initial HBsAb levels ≥10 IU/L (P=0.02). Based
upon these data, it seems desirable to attempt to induce
an HBsAb response in patients who fail to respond to the
primary vaccine course, as determined by measuring
HBsAb levels 4–8 weeks after the last vaccine dose. As
longer time to revaccination predicts non-response to
revaccination, the management of non-responders should
be timely [27]. Both standard-dose [27] and high-dose
[23,28] revaccination has been evaluated in HIV-positive
non-responders. One study found that high-dose revacci-
nation significantly increased HBsAb response rates (OR
4.2; CI 1.3–13.6; P=0.018) [28]. In two other studies,
high-dose revaccination was effective in inducing HBsAb
in 51% of 144 [23] and 67% of 30 [29] non-responders
respectively. The data have not been consistent however.
In a small randomised trial, revaccination of non-respon-
ders induced HBsAb in 60 patients (67%) receiving stan-
dard-dose revaccination, compared with 64 patients
(74%) receiving double-dose vaccination, while showing
no increased toxicity in the higher dose group [30].
Emerging data suggest that using one [31] or four [32]
standard doses of the adjuvanted vaccine Fendrix may
improve response rates among people who do not make a
HBsAb response to the primary vaccine course. In one
cohort study, 18/22 (82%) HIV-positive non-responders
showed HBsAb levels >100 IU/L following a four-dose
schedule, with an additional three (14%) subjects achiev-
ing titres of 10–100 IU/L [32].
Duration of vaccine-induced protection is unknown in
HIV-positive persons, but in general terms post-vaccina-
tion HBsAb levels are lower and disappear more quickly
than in HIV-negative persons. Among HIV-positive
responders to HBV vaccination, the HBsAb level mea-
sured 4 weeks after the completion of the vaccination
course is strongly predictive of the longevity of response
[33,34]. In a cohort study of 155 HIV-positive vaccine
recipients, the mean time to loss of detectable HBsAb was
2.0, 3.7 and 4.4 years for patients with HBsAb levels 10–
100, >100–1000, and >1000 IU/L, respectively [34]. In
addition, viral load suppression on ART during
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s24 BHIVA Writing Group
vaccination and at follow-up predicts longer persistence
of HBsAb levels >10 IU/L [34]. These data indicate that it
is desirable to boost the HBsAb response of vaccine recip-
ients that show HBsAb levels >10 but <100 IU/L after the
primary vaccine course, with the aim improving the long-
evity of the response. Further boosting requirements for
patients who make a response to vaccination are not well
defined in immunocompromised patients. The available
evidence indicates that while it may be practical to screen
all immunised patients for HBsAb yearly, the frequency
of HBsAb monitoring among successfully vaccinated
patients could be reduced based upon the strength of the
initial HBsAb response, and CD4 cell count, ART status,
and viral load at vaccination and during follow-up. Con-
sensus opinion is that booster doses are indicated in sub-
jects whose HBsAb levels decline <10 IU/L if at ongoing
risk of exposure. Importantly, vaccinated patients should
continue to undergo HBV surveillance as they remain at
risk of infection [26]. People receiving ART with teno-
fovir may be protected through antiviral prophylaxis.
The HBV vaccine is safe and well tolerated in HIV-
positive individuals. Injection site reactions are the most
frequent side effects. HBV vaccination completion rates
are closely dependent on the clinical setting providing
HIV care [16], indicating that compliance should be
audited regularly.
8.5.1 “Occult” HBV infection and vaccination
Patients who test HBsAg negative, HBcAb positive and
HBsAb negative (isolated HBcAb positivity) have tradi-
tionally posed a management challenge. These patients
may belong to one of the following groups: (i) recent
resolving HBV infection (HBV core IgM positive); (ii)
occult HBV infection (low-level HBV DNA persistently
or intermittently detectable in blood and detectable in
the liver); (iii) HBsAg diagnostic escape mutants (HBV
DNA levels usually high in blood in untreated patients);
(iv) resolved HBV infection (strong HBcAb reactivity,
possible HBeAb positivity, anamnestic HBsAb response
>10 IU/L observed 1–2 weeks after a single HBV vac-
cine dose); and (v) false-positive HBcAb result and sus-
ceptibility to infection. While some experts recommend
HBV DNA testing, HBV DNA detection in blood may
be intermittent in those with occult HBV infection [35].
HBV vaccination can elicit an anamnestic HBsAb
response as evidence of past infection and immunity.
One study in HIV-negative patients showed anamnestic
responses (HBsAb ≥10 IU/L) in 20/21 subjects with iso-
lated HBcAb after one vaccine dose [36]. In contrast,
studies in HIV-positive patients found an anamnestic
response in 24–33% [37,38].
8.6 Post-exposure prophylaxis
After a recognised exposure to an HBsAg-positive con-
tact, post-exposure prophylaxis is guided by the vaccina-
tion history of the patient. Hepatitis-B-specific
immunoglobulin (HBIg) can protect from infection or
attenuate disease if given within 7 days of exposure.
HBIg is given by intramuscular injection. A rapid (three
injections given over 3 months) vaccination course
started within 7 days of exposure appears to be as effec-
tive as vaccination plus HBIg in healthy persons. There
are no data on the efficacy of post-exposure prophylaxis
by either strategy in HIV-positive persons.
8.7 Recommendations for HIV-positive adults
•We recommend that HIV-positive adults be screened
for evidence of HBV infection or immunity, and that
non-immune individuals (HBsAg negative, HBcAb neg-
ative, HBsAb negative) be offered HBV vaccination
[1A].
oWe recommend that when using yeast-based vacci-
nes, high-dose (40 lg) vaccination be offered [1A].
In the UK, Engerix B should be given as a double-
dose (total 40 lg) [1A]; with HBvaxPRO the 40 lg
formulation should be used [1B].
oWe recommend that when using the adjuvanted
vaccine Fendrix the standard 20 lg formulation be
given [1B].
oWe recommend that, regardless of vaccine type, four
vaccine doses are given at 0, 1, 2, and 6 months
[1B].
oWe recommend that an ultra-rapid vaccination
course (three standard-dose administrations given
over 3 weeks) be considered only in selected
patients with CD4 cell counts >500 cells/lL where
there is an imperative need to ensure rapid comple-
tion of vaccination and/or where compliance with a
full course is doubtful [1B]. We recommend against
using high-dose vaccination in an ultra-rapid sched-
ule due to the lack of safety data [1D].
•We recommend that following completion of the pri-
mary vaccine course, HBsAb levels be measured
4–8 weeks after the last vaccine dose [1A].
•We recommend that individuals who after the primary
vaccine course have HBsAb levels <10 IU/L receive
three further vaccine doses at monthly intervals [1B].
oThese should be given at high dose (40 lg) with
Engerix B or HBvaxPRO [1C], and standard dose
(20 lg) with Fendrix [1B].
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s25
oWe suggest that revaccination with Fendrix may be
preferred in non-responders [2C].
oRetesting for HBsAb is indicated 4–8 weeks after the
final vaccine dose [GPP].
oWe suggest that depending on the level of risk,
revaccination of non-responders may be delayed
until the viral load is suppressed on ART and the
CD4 cell count has increased >350 cells/lL [2B].
•We recommend that individuals who after the pri-
mary vaccine course have HBsAb levels ≥10 but
<100 IU/L receive one booster dose (see above for
dosing) [1B].
oRetesting for HBsAb is indicated 4–8 weeks after the
final vaccine dose [GPP].
•We recommend that responders to HBV vaccination
(HBsAb >10 IU/L after completion of a full vaccine
course) undergo regular HBsAb testing in order to
guide subsequent boosting requirement [1B].
oWe recommend that HBsAb screening intervals be
guided by the initial HBsAb level (measured after
completion of the primary vaccine course), risk of
exposure, and CD4 cell count, ART use, and viral
load at the time of vaccination and during follow-
up [1B]. Longer intervals (i.e. 2–4 years) are indi-
cated for subjects with initial HBsAb levels >100 IU/
L, CD4 cell counts >350 cells/lL, and viral load sup-
pression on ART [1C]. Other subjects should undergo
yearly HBsAb screening [1C].
oWe recommend that subjects with an initial HBsAb
response who show a decline of HBsAb levels
<10 IU/L are offered a booster dose (see above for
dosing) [1C].
•We recommend individuals who have no evidence of
protective vaccine-induced immunity have an annual
HBsAg test or more frequent testing if there are known
and ongoing risk factors for HBV acquisition [1B].
HBsAg, HBcAb, HBsAb negave: non-immune Isolated HBcAb posivity
(see text)
4–8 weeks aer last vaccine dose
HBsAb
HBsAb <10 IU/L HBsAb: 10–100 IU/L HBsAb >100 IU/L
Inial non-responder: Re-vaccinate
3 vaccine doses (0, 1, 2 months)**
NB: consider waing unl established
on effecve ART (see text)
Boost
1 vaccine dose*
1 vaccine dose*
CD4 >350 cells/μL
Viral load suppression on ART at
vaccinaon and follow-up
HBsAb
every 2–4 years
HBsAb
annually
YesNo
2 weeks aer vaccine dose
HBsAb
HBsAb <10 IU/L
Complete vaccine course:
3 further doses (1, 2, 6 months)*
HBsAb <10 IU/L
Boost, 1 dose*
Manage follow-up as indicated in
vaccine recipients
4–8 weeks aer last vaccine dose
HBsAb
HBsAg negave
HBcAb posive
HBsAb posive
Non-responder
Annual HBsAg
NB: if significant
HBV exposure,
eligible for HBIG
Past infecon
Immune
New paent: HBsAg, HBcAb, HBsAb
Primary vaccinaon
4 vaccine doses (0, 1, 2, 6 months)*
Past infecon
Immune
HBsAg posive
Current HBV
infecon
*Vaccine dosage:
Engerix B® 40 µg
HBVaxPRO® 40 µg
Fendrix® 20 µg
** Fendrix® 20 µg preferred
HBsAb >10 IU/L
HBsAb <10 IU/L HBsAb: 10–100 IU/L HBsAb >100 IU/L
HBV vaccination decision flow-chart
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s26 BHIVA Writing Group
•We recommend patients with isolated HBcAb positivity
be offered one HBV vaccine dose (see above for dos-
ing), be tested for HBsAb 2 weeks later, and be offered
completion of the vaccine course if the HBsAb level is
<10 IU/L [1C].
•We recommend that compliance with HBV vaccination
policy is audited regularly [1B].
•We recommend that following a high-risk exposure to
an HBsAg-positive source, the HBV status of the HIV-
positive contact be determined urgently if not known
[1C].
oNo prophylaxis is required in those with evidence of
a current or past HBV infection.
oVaccinated patients with initial HBsAb >10 IU/L
should be offered one booster dose and if the CD4
cell count is <200 cells/lL also receive HBIg [1C].
oNon-responders to previous HBV vaccination (initial
HBsAb <10 IU/L) should be offered a booster vac-
cine dose and also receive HBIg regardless of CD4
cell count [1C].
oPatients who have not been vaccinated or have an
uncertain vaccination history should be offered a
rapid vaccine course (0, 1, 2 months; see above for
dosing) and also receive HBIg regardless of CD4 cell
count [1C].
oWhen indicated, two doses of HBIg should be given
1 month apart.
oPost-exposure prophylaxis should be given within
7 days of exposure [1D]. We suggest that prophy-
laxis beyond 7 days (up to 6 weeks after exposure)
may be considered in selected cases; specialist
advice should be sought [2D].
8.8 References
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human immunodeficiency virus infection on chronic hepatitis
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2 Mart
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3 Shouval D. Hepatitis B vaccines. J Hepatol 2003; 39 (Suppl
1): S70–S76.
4 Shouval D, Roggendorf H, Roggendorf M. Enhanced
immune response to hepatitis B vaccination through
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5 Jack AD, Hall AJ, Maine N et al. What level of hepatitis B
antibody is protective? J Infect Dis 1999; 179: 489–492.
6 Bagheri-Jamebozorgi M, Keshavarz J, Nemati M et al. The
persistence of anti-HBs antibody and anamnestic response
20 years after primary vaccination with recombinant
hepatitis B vaccine at infancy. Hum Vaccin Immunother
2014; 10: 3731–3736.
7 Mendy M, Peterson I, Hossin S et al. Observational study of
vaccine efficacy 24 years after the start of hepatitis B
vaccination in two Gambian villages: no need for a booster
dose. PLoS One 2013; 8: e58029.
8 Wainwright RB, Bulkow LR, Parkinson AJ et al. Immune
response to hepatitis A vaccination in HIV-infected men in
Greece. Protection provided by hepatitis B vaccine in a
Yupik Eskimo population: results of a 10-year study.
J Infect Dis 1997; 175: 674–677.
9 Yuen MF, Lim WL, Cheng CC et al. Twelve year follow-up
of a prospective randomized trial of recombinant DNA yeast
vaccine vs. plasma-derived vaccine without booster doses in
children. Hepatology 1999; 29: 924–927.
10 European Consensus Group on Hepatitis B Immunity. Are
booster immunisations needed for lifelong hepatitis B
immunity? Lancet 2000; 355: 561–565.
11 Kellerman SE, Hanson DL, McNaghten AD, Fleming PL.
Prevalence of chronic hepatitis B and incidence of acute
hepatitis B infection in human immunodeficiency virus-
infected subjects. J Infect Dis 2003; 188: 571–577.
12 Biggar RJ, Goedert JJ, Hoofnagle J. Accelerated loss of
antibody to hepatitis B surface antigen among
immunodeficient homosexual men infected with HIV. N
Engl J Med 1987; 316: 630–631.
13 Collier AC, Corey L, Murphy VL, Handsfield HH. Antibody
to human immunodeficiency virus (HIV) and suboptimal
response to hepatitis B vaccination. Ann Intern Med 1988;
109: 101–105.
14 Tayal SC, Sankar KN. Impaired response to recombinant
hepatitis B vaccine in asymptomatic HIV-infected
individuals. AIDS 1994; 8: 558–559.
15 Veiga APR, Casseb J, Duarte AJS. Humoral response to
hepatitis B vaccination and its relationship with T CD45RA
(naive) and CD45RO (memory) subsets in HIV-1-infected
subjects. Vaccine 2006; 24: 7124–7128.
16 Tedaldi EM, Baker RK, Moorman AC et al. Hepatitis A and
B vaccination practices for ambulatory patients infected
with HIV. Clin Infect Dis 2004; 38: 1478–1484.
17 Rey D, Krantz V, Partisani M et al. Increasing the number
of hepatitis B injections augments anti-HBs response rate in
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18 Fonseca MO, Pang LW, de Paula Cavalheiro N et al.
Randomized trial of recombinant hepatitis B vaccine in
HIV-infected adult patients comparing a standard dose to a
double dose. Vaccine 2005; 23: 2902–2908.
19 Flynn PM, Cunningham CK, Rudy B et al. Hepatitis B
vaccination in HIV-infected youth: a randomized trial of
three regimens. J Acquir Immune Defic Syndr 2011; 56:
325–332.
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20 Launay O, van der Vliet D, Rosenberg AR et al. Safety and
immunogenicity of 4 intramuscular double doses and 4
intradermal low doses vs standard hepatitis B vaccine
regimen in adults with HIV-1: a randomized controlled trial.
JAMA 2011; 305: 1432–1440.
21 Whitaker JA, Rouphael NG, Edupuganti S et al. Strategies
to increase responsiveness to hepatitis B vaccination in
adults with HIV-1. Lancet Infect Dis 2012; 12: 966–976.
22 Ni JD, Xiong YZ, Wang XJ, Xiu LC. Does increased
hepatitis B vaccination dose lead to a better immune
response in HIV-infected patients than standard dose
vaccination: a meta-analysis. Int J STD AIDS 2013; 24:
117–122.
23 de Vries-Sluijs TE, Hansen BE, van Doornum GJ et al. A
prospective open study of the efficacy of high-dose
recombinant hepatitis B rechallenge vaccination in HIV-
infected patients. J Infect Dis 2008; 197: 292–294.
24 Potsch DV, Oliveira ML, Ginu
ıno C et al. High rates of
serological response to a modified hepatitis B vaccination
schedule in HIV-infected adults subjects. Vaccine 2010; 28:
1447–1450.
25 de Vries-Sluijs TE, Hansen BE, van Doornum GJ et al. A
randomized controlled study of accelerated versus standard
hepatitis B vaccination in HIV-positive patients. J Infect Dis
2011; 203: 984–991.
26 Landrum ML, Hullsiek KH, Ganesan A et al. Hepatitis B
vaccination and risk of hepatitis B infection in HIV-infected
individuals. AIDS 2010; 24: 545–555.
27 Irungu E, Mugo N, Ngure K et al. Immune response to
hepatitis B virus vaccination among HIV-1 infected and
uninfected adults in Kenya. J Infect Dis 2013; 207: 402–410.
28 Psevdos G, Kim JH, Groce V, Sharp V. Efficacy of double-
dose hepatitis B rescue vaccination in HIV-infected patients.
AIDS Patient Care STDs 2010; 24: 403–407.
29 Pettit NN, DePestel DD, Malani PN et al. Factors associated
with seroconversion after standard dose hepatitis B
vaccination and high-dose revaccination among HIV-
infected patients. HIV Clin Trials 2010; 11: 332–339.
30 Rey D, Piroth L, Wendling MJ et al. Safety and
immunogenicity of double-dose versus standard-dose hepatitis
B revaccination in non-responding adults with HIV-1 (ANRS
HB04 B-BOOST): a multicentre, open-label, randomised
controlled trial. Lancet Infect Dis 2015; 15:1283–1291.
31 Hoebe CJ, Vermeiren AP, Dukers-Muijrers NH.
Revaccination with Fendrix
â
or HBVaxPro
â
results in better
response rates than does revaccination with three doses of
Engerix-B
â
in previous non-responders. Vaccine 2012; 30:
6734–6737.
32 de Silva TI, Green ST, Cole J et al. Successful use
of Fendrix in HIV-infected non-responders to standard
hepatitis B vaccines. J Infect 2014; 68: 397–399.
33 Powis JE, Raboud J, Ostrowski M et al. The recombinant
hepatitis B surface antigen vaccine in persons with HIV: is
seroconversion sufficient for long-term protection? J Infect
Dis 2012; 205: 1534–1538.
34 Lopes VB, Hassing RJ, de Vries-Sluijs TE et al. Long-term
response rates of successful hepatitis B vaccination in HIV-
infected patients. Vaccine 2013; 31: 1040–1044.
35 Nebbia G, Garcia-Diaz A, Ayliffe U et al. Predictors and
kinetics of occult hepatitis B virus (HBV) infection in HIV-
infected persons. J Med Virol 2007; 79: 1464–1471.
36 Su FH, Bai CH, Chu FY et al. Significance and
anamnestic response in isolated hepatitis B core antibody-
positive individuals 18 years after neonatal hepatitis B
virus vaccination in Taiwan. Vaccine 2012; 30: 4034–
4039.
37 Gandhi RT, Wurcel A, Lee H et al. Response to hepatitis B
vaccine in HIV-1-positive subjects who test positive for
isolated antibody to hepatitis B core antigen: implications
for hepatitis B vaccine strategies. J Infect Dis 2005; 191:
1435–1441.
38 Chakvetadze C, Bani-Sadr F, Le Pendeven C et al. Serologic
response to hepatitis B vaccination in HIV-Infected patients
with isolated positivity for antibodies to hepatitis B core
antigen. Clin Infect Dis 2010; 50: 1184–1186.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s28 BHIVA Writing Group
9. Human papilloma virus
9.1 Infection and disease
HPV establishes infection in the skin and mucous mem-
branes. Transmission occurs through direct contact, when
microtears allow the virus to invade basal epithelial cells.
Most HPV infections are subclinical and resolve sponta-
neously. Persistence can lead to disease, including pre-
malignant and malignant lesions [1]. Over 150 HPV types
have been identified and are classified according to the
oncogenic potential. HPV-6 and HPV-11 are non-onco-
genic and responsible for about 90% of genital warts and
most cases of recurrent respiratory papillomatosis. Onco-
genic types cause cancers of the cervix, vulva, and
vagina in women, penis in men, and anus and orophar-
ynx in women and men [1]. Just over 60% of HPV-asso-
ciated cancers are caused by HPV-16 or HPV-18; HPV
types 31, 33, 45, 52, and 58 account for ~10% of cases
[1–4]. Co-infection with multiple HPV types is common
[5].
9.2 Epidemiology
HPV is the most prevalent sexually transmitted infection
in industrialised countries. Transmission between sexual
partners is common, and appears to be more frequent
from females to males than from males to females. Con-
doms reduce the risk of infection [6], although they are
not fully protective (~70% efficacy with consistent use).
In women, HPV acquisition increases with age through
the early 20s and then decreases, although acquisition
continues in older women [7]. Men show a relatively con-
stant incidence over a wide age range. HPV is a dominant
cause of cancer worldwide. Cervical cancer remains a
major health burden, particularly in less developed
regions where screening and vaccination programmes are
less well established. Other HPV-related cancers are
increasing in incidence among both men and women [1].
There is evidence indicating that HIV acquisition is sig-
nificantly associated with HPV infection [8].
9.3 HPV in HIV-positive adults
Men and women with HIV infection show an increased
risk and rate of HPV acquisition and persistence, frequent
carriage of multiple HPV types, and an increased
risk of HPV-related disease including rapidly progressive
malignancies [9–38]. HPV carriage rates and overall
disease risk increase at low CD4 cell counts. However,
despite effective ART HIV-positive men and women
remain disproportionately affected by HPV-related
anogenital disease compared with HIV-negative people.
Overall prevalence of HPV-16 and HPV-18 in HIV-posi-
tive women aged 13–45 years in the United States, Brazil,
and South Africa is 32% and 20%, respectively [39]. Anal
HPV infection is highly prevalent in HIV-positive men
who have sex with men (MSM). An Australian study of
MSM aged 18–75 years showed a HPV-16 seroprevalence
of 44%, with a seroincidence of 1.3 per 100 person/years
continuing in the mid-40s [19]. A meta-analysis of
34 189 HIV-positive and 114 260 HIV-negative individu-
als in North America reported that between 1996 and
2007 the incidence of anal cancer per 100 000 person/
years was 131 in HIV-positive MSM, 46 in other HIV-
positive men, 30 in HIV-positive women, 2 in HIV-nega-
tive men, and zero in the HIV-negative women surveyed
in this study [21]. The analysis reported that incidence of
anal cancer was higher in ART era, which is likely to be
reflecting improved survival and increased awareness and
diagnosis.
9.4 HPV vaccine
Three virus-like particle (VLP) sub-unit vaccines based on
the L1 capsid protein are currently in use for the preven-
tion of HPV disease around the world [2,3]. They com-
prise a bivalent product (2vHPV; Cervarix,
GlaxoSmithKline; HPV types 16 and 18) and a quadriva-
lent product (4vHPV; Gardasil 4, Merck; HPV types 6, 11,
16, 18), which were introduced in 2006 and 2007, respec-
tively, and a nonavalent product (9vHPV; Gardasil 9,
Merck; HPV types 6, 11, 16, 18, 31, 33, 45, 52, 58), which
was licensed by the FDA in 2014. Both vaccine types are
adjuvanted. VLPs are similar in shape and size to the
HPV virion, but do not contain viral DNA, and are there-
fore non-infectious and non-oncogenic. The vaccines are
given by parenteral administration. HPV vaccines are
more immunogenic than natural infection, and highly
efficacious in protecting susceptible women against cervi-
cal infection and pre-cancer related to HPV-16 and HPV-
18. Protection is maintained for at least 10 years. Ongo-
ing studies will determine whether effectiveness declines
with time, and the requirement for boosters. The vaccines
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s29
are also efficacious in preventing HPV-16 and HPV-18
infections at other anatomical sites in both sexes, includ-
ing the precursors of vulvar, vaginal and anal cancer
related to the vaccine types [2–4,40–42]. The 4vHPV and
9vHPV vaccines also reduce the incidence of genital
warts associated with the vaccine types. Partial cross-pro-
tection against non-vaccine HPV types has been reported,
but its effectiveness and duration is unknown. HPV vac-
cines are well tolerated and no safety concerns have
emerged from clinical trials and post-license evaluations
[43]. Non-inferiority of immune response and an accept-
able safety profile have been demonstrated when the HPV
vaccine is co-administered with other vaccines (assessed
with meningococcal conjugate, hepatitis A, hepatitis B,
combined hepatitis A/B, tetanus, diphtheria, acellular per-
tussis, and inactivated poliovirus vaccines) [44].
9.4.1 General indications
In the UK, since 2008, HPV vaccination is routinely rec-
ommended for all girls aged 12–13, along with a catch
up programme for girls 13 to under 18 years of age. Two
vaccine doses are given to those aged 9–14 years, and
three doses to those aged 15–18 years. In November
2014, the Joint Committee on Vaccination and Immuni-
sation (JCVI) issued an interim position statement recom-
mending HPV vaccination with a threedose series (0, 1–2,
and 6 months) for MSM aged up to 40 years attending
sexual health services after considering evidence on the
impact and cost-effectiveness of a targeted vaccination
programme in this group [45]. The price of the vaccine
and HIV status of MSM impacted on the cost effective-
ness of this recommendation. Other males of any age and
women >18 years of age are not currently covered by the
UK national programme, although this is under review.
Gardasil (4vHPV currently) is the preferred vaccine in the
UK due to the additional protection against genital warts.
In February 2015, the US Advisory Committee on Immu-
nization Practices (ACIP) recommended 9vHPV as one of
three HPV vaccines that can be used for routine vaccina-
tion of females, whereas 4vHPV or 9vHPV are recom-
mended for males. ACIP recommends vaccination for
women up to 26 years, males up to 21 years, MSM up to
26 years, and immunocompromised persons (including
those with HIV infection) up to 26 years [2].
9.4.2 Cost-effectiveness considerations
HPV vaccination has been shown to be cost-effective in
pre-adolescent females. As HPV vaccines protect against
HPV types not already acquired, cost-effectiveness decli-
nes with increasing likelihood of previous exposure. For
women, studies differ in their conclusions about the age
cut-off at which the cost-effectiveness ratio becomes
unfavourable, ranging from 15 to 26 years within avail-
able data. The cost-effectiveness of vaccinating young
males is generally lower than with young females, firstly
because the burden of disease is lower in men than in
women, and secondly because men derive benefits from
female-only vaccination programmes via herd immunity,
particularly if vaccine coverage is high [2–4,41,42,46].
Population-based studies in countries with high female
vaccine coverage confirm a beneficial impact of herd
immunity in heterosexual males; the benefit however is
not extended to MSM. One US-based study addressed the
cost-effectiveness of vaccinating MSM through 26 years
of age, and concluded that vaccination is likely to be a
cost-effective intervention for the prevention of genital
warts and anal cancer in this group [46]. Outcomes were
most sensitive to variations in anal cancer incidence,
duration of vaccine protection, and HIV prevalence in
MSM. A more recent unpublished analysis reviewed by
the JCVI analysed the cost-effectiveness of vaccinating
MSM up to age of 40 years [45]. In this model, cost-
effectiveness was higher for 4vHPV due to the added pro-
tection against genital warts. Under the criteria used by
JCVI, vaccinating HIV-positive MSM aged 16–25 years
was cost-effective at the list price of the vaccine. Vacci-
nating HIV-positive MSM aged 16–40 years was also
incrementally cost-effective under the base case assump-
tions. Extending vaccination to all MSM aged 16–
40 years was not incrementally cost-effective when using
the list price of the vaccines. However, vaccination of all
MSM aged 16–40 years was cost-effective under the cri-
teria used by JCVI at a threshold vaccine price below the
list price. The JCVI highlighted that key operational and
delivery issues remain to be addressed for the programme
to be considered. In US-based models assuming that
9vHPV would cost $13 more per dose than 4vHPV, intro-
duction of 9vHPV was cost-effective when compared with
4vHPV for both sexes [2]. Because the additional five
types in 9vHPV account for a higher proportion of HPV-
associated cancers in females compared with males and
cause cervical pre-cancers, the additional protection from
9vHPV is expected to benefit mostly females.
9.4.3 Vaccine safety
For eligible individuals, HPV vaccination is indicated
regardless of a previous history of abnormal smear test
results, pre-cancer lesions likely to be HPV-associated, or
anogenital warts, although the benefit of vaccination
decreases with increasing likelihood of a previous expo-
sure to the vaccine types. There are no data to support
laboratory testing to exclude a prior HPV exposure before
vaccination. Whilst the vaccines are not expected to have
therapeutic effects, vaccination of individuals pre-
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s30 BHIVA Writing Group
exposed to the vaccine types is safe, may boost immu-
nity, and may prevent re-infection or reduce recurrences
in people with established disease [47,48]. For those with
incomplete vaccination, completion of the course is indi-
cated with the appropriate vaccine type, although there
are no strict contraindications to changing the vaccine
mid-course [2]. HPV vaccines are contraindicated for per-
sons with a history of immediate hypersensitivity to any
vaccine component. 4vHPV and 9vHPV are contraindi-
cated for persons with a history of immediate hypersensi-
tivity to yeast [2]. HPV vaccines are not recommended
for use in pregnant women, as pregnant women were not
included in the vaccine clinical trials. Whilst pregnancy
testing is not indicated before vaccination, if a woman is
found to be pregnant after initiating the vaccination ser-
ies, the remainder of the three-dose series should be
delayed until after pregnancy. If a vaccine dose has been
administered during pregnancy, no intervention is
needed. A new pregnancy registry has been established
for 9vHPV and no safety signal has been identified to
date. Pregnancy registries for 2vHPV and 4vHPV have
been closed [2].
9.5 HPV vaccine in HIV-positive adults
In studies that have most commonly employed 4vHPV,
vaccination has been shown to be safe and immunogenic
in HIV-positive children [49,50]; females aged 16–
23 years [51], 18–25 years [52], or 13–45 years [39];
males aged 22–61 years [53]; and males and females
aged 13–27 years [54,55]. Cervarix and Gardasil have
also been compared in older HIV-positive people [56].
Overall seroconversion rates are high in all groups, and
both seroconversion rates and antibody titres are higher
than with natural infection, and highest in those receiv-
ing ART and showing high CD4 cell counts and a sup-
pressed viral load. A study of men and women aged 13–
27 years compared responses to 4vHPV in 46 HIV-nega-
tive individuals and 46 HIV-positive patients with CD4
cell counts >200 cells/lL (mean 715 cells/lL) and a sta-
bly suppressed viral load [54]. Seroconversion rates
1 month after the administration of the third vaccine
dose were 91% (HIV-negative) and 85% (HIV-positive)
respectively (P=0.52), and there was no significant dif-
ference in antibody titres. In a study of males aged 22–
61 years, the proportion exhibiting seroconversion was
95% or greater for each of the four HPV types included
in 4vHPV [53]. Anti-HPV 16 antibody concentrations
were lower than those historically reported in HIV-nega-
tive women but similar to those reported in HIV-negative
MSM, and were higher in subjects receiving ART. The
median CD4 cell count at the time of vaccination was
517 cells/lL (IQR 423–680) in the study population, and
92% of subjects had a viral load <10 000 copies/mL;
there was no impact of nadir CD4 cell count on immune
responses. In a study of HIV-positive women aged 13–
45 years, seroconversion proportions 1 month after the
administration of the third dose of 4vHPV for HPV types
6, 11, 16, and 18 were 96%, 98%, 99%, and 91%, respec-
tively, at CD4 cell count >350 cells/lL; 100%, 98%, 98%,
and 85%, respectively, at CD4 cell count 201–350 cells/
lL, and 84%, 92%, 93%, and 75%, respectively, at CD4
cell count ≤200 cells/lL [53]. Women with viral load
>10 000 copies/mL had lower rates of seroconversion. In
one study of HIV-positive adults, 4vHPV was reported to
induce similar antibody responses in males and females
[39]. Following vaccination, local reactions like pain,
swelling and redness occur in 9% of HIV-negative and
33% of HIV-positive subjects [43], but are usually of
short duration. Systemic adverse reactions may include
headache (2% of HIV-negative and 14% of HIV-positive
subjects [43]), and occasionally fever, nausea, dizziness,
fatigue, and myalgia, but these are also short-lived. No
adverse impact on CD4 cell counts and viral load have
been observed in HIV-positive patients.
Studies are ongoing to demonstrate the clinical efficacy
of HPV vaccines in HIV-positive individuals. Meanwhile,
factors that inform the cost–benefit evaluation include (i) a
high rate of HPV carriage, limiting vaccine efficacy; (ii)
uncertainties about the duration of vaccine-induced pro-
tection; (iii) the consideration that seropositivity for all
vaccine types is uncommon, indicating that at least partial
protection can be achieved; (iv) evidence that HPV acquisi-
tion continues in adults; (v) the high burden of disease in
spite of effective ART; (vi) the safety of HPV vaccines,
including safety in those with established HPV infection
and disease; (vii) the demonstrated ability of HPV vaccines
to boost natural immunity, which may reduce the risk of
re-infection; and (viii) a high level of willingness to be
vaccinated among surveyed groups [45]. While younger
HIV-positive people are likely to benefit the most from
vaccination, older men and women may continue to derive
at least partial benefit from vaccination.
9.6 Recommendations for HIV-positive adults
•We recommend that previously unvaccinated HIV-
positive men and women aged up to 26 years be
offered HPV vaccination, regardless of CD4 cell count,
ART use, and viral load [1B].
•We recommend that previously unvaccinated HIV-
positive MSM aged up to 40 years be offered HPV
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s31
vaccination, regardless of CD4 cell count, ART use, and
viral load [1B].
•We suggest that previously unvaccinated HIV-positive
women aged up to 40 years be offered HPV vaccina-
tion, regardless of CD4 cell count, ART use, and viral
load [2D].
•We suggest that in ART-na€
ıve patients with CD4 cell
counts <200 cells/lL vaccination may be deferred until
the patient is established on ART [2B].
•We recommend that three doses of the quadrivalent
4vHPV vaccine be administered at 0, 1–2, and
6 months [1B]. We recommend maintaining the three-
dose regimen in HIV-positive patients [1A]. If the vac-
cine schedule is interrupted, the vaccination series
should be completed rather than restarted.
•We recommend that all eligible HIV-positive adults
who have received fewer than three vaccine doses
before the age of 18 years complete a three-dose vac-
cination course with 4vHPV [1C].
•We recommend that 9vHPV be used in both men and
women once it becomes available in place of 4vHPV
[1C].
•We suggest that HPV vaccination be considered for
HIV-positive patients who develop high-grade HPV
disease with the aim of potentially reducing the risk of
recurrences [2C].
9.7 References
1 Wakeham K, Kavanagh K. The burden of HPV-associated
anogenital cancers. Curr Oncol Rep 2014; 16: 402.
2 Petrosky E, Bocchini JA Jr, Hariri S et al. Use of 9-valent
human papillomavirus (HPV) vaccine: updated HPV
vaccination recommendations of the advisory committee on
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2015; 64: 300–304.
3 Pils S, Joura EA. From the monovalent to the nine-valent
HPV vaccine. Clin Microbiol Infect 2015; 21: 827–833.
4 Bosch FX, Broker TR, Forman D et al. Comprehensive
control of human papillomavirus infections and related
diseases. Vaccine 2013; 31 (Suppl 6): G1–G31.
5 King EM, Gilson R, Beddows S et al. Human papillomavirus
DNA in men who have sex with men: type-specific
prevalence, risk factors and implications for vaccination
strategies. Br J Cancer 2015; 112: 1585–1593.
6 Lam JU, Rebolj M, Dugu
e PA, Bonde J, von Euler-Chelpin M,
Lynge E. Condom use in prevention of Human Papillomavirus
infections and cervical neoplasia: systematic review of
longitudinal studies. J Med Screen 2014; 21:38–50.
7 Grainge MJ, Seth R, Guo L et al. Cervical human
papillomavirus screening among older women. Emerg Infect
Dis 2005; 11: 1680–1685.
8 Lissouba P, Van de Perre P, Auvert B. Association of genital
human papillomavirus infection with HIV acquisition: a
systematic review and meta-analysis. Sex Transm Infect
2013; 89: 350–356.
9 Conley LJ, Ellerbrock TV, Bush TJ, Chiasson MA, Sawo D,
Wright TC. HIV-1 infection and risk of vulvovaginal and
perianal condylomata acuminata and intraepithelial neoplasia:
a prospective cohort study. Lancet 2002; 359:108–113.
10 Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM.
Incidence of cancers in people with HIV/AIDS compared
with immunosuppressed transplant recipients: a meta-
analysis. Lancet 2007; 370:59–67.
11 D’Souza G, Wiley DJ, Li X et al. Incidence and
epidemiology of anal cancer in the Multicenter AIDS Cohort
Study. J Acquir Immune Defic Syndr 2008; 48: 491–499.
12 Patel P, Hanson DL, Sullivan PS et al. Incidence of types of
cancer among HIV-infected persons compared with the
general population in the United States, 1992–2003. Ann
Intern Med 2008; 148: 728–736.
13 de Pokomandy A, Rouleau D, Ghattas G et al. Prevalence,
clearance, and incidence of anal human papillomavirus
infection in HIV-infected men. J Infect Dis 2009; 199: 965–
973.
14 Hessol NA, Holly EA, Efird JT et al. Anal intraepithelial
neoplasia in a multisite study of HIV-infected and high-risk
HIV-uninfected women. AIDS 2009; 23:59–70.
15 Palefsky J. Human papillomavirus-related disease in people
with HIV. Curr Opin HIV AIDS 2009; 4:52–56.
16 Kreuter A, Wieland U. Human papillomavirus diseases in
HIV-infected men who have sex with men. Curr Opin Infect
Dis 2009; 22: 109–114.
17 Kojic EM, Cu-Uvin S, Conley L et al. Human papillomavirus
infection and cytologic abnormalities of the anus and
cervix among HIV-infected women in the study to
understand the natural history of HIV/AIDS in the era of
effective therapy (the SUN study). Sex Transm Dis 2011; 38:
253–259.
18 Low AJ, Clayton T, Konate I et al. Genital warts and
infection with human immunodeficiency virus in high-risk
women in Burkina Faso: a longitudinal study. BMC Infect
Dis 2011; 11: 20.
19 Poynten IM, Jin F, Templeton DJ et al. Prevalence,
incidence, and risk factors for human papillomavirus 16
seropositivity in Australian homosexual men. Sex Transm
Dis 2012; 39: 726–732.
20 Kahn JA, Burk RD, Squires KE et al. Prevalence and risk
factors for HPV in HIV-positive young women receiving
their first HPV vaccination. J Acquir Immune Defic Syndr
2012; 61: 390–399.
21 Silverberg MJ, Lau B, Justice AC et al. Risk of anal cancer
in HIV-infected and HIV-uninfected individuals in North
America. Clin Infect Dis 2012; 54: 1026–1034.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s32 BHIVA Writing Group
22 Machalek DA, Poynten M, Jin F et al. Anal human
papillomavirus infection and associated neoplastic
lesions in men who have sex with men: a systematic
review and meta-analysis. Lancet Oncol 2012; 13: 487–
500.
23 Abraham AG, Strickler HD, Jing Y et al. Invasive cervical
cancer risk among HIV-infected women: a North American
multi-cohort collaboration prospective study. J Acquir
Immune Defic Syndr 2013; 62: 405–413.
24 Nicol AF, Grinsztejn B, Friedman RK et al. Seroprevalence
of HPV vaccine types 6, 11, 16 and 18 in HIV-infected and
uninfected women from Brazil. J Clin Virol 2013; 57: 147–
151.
25 Dartell M, Rasch V, Munk C et al. Risk factors for high-risk
human papillomavirus detection among HIV-negative and
HIV-positive women from Tanzania. Sex Transm Dis 2013;
40: 737–743.
26 Wiley DJ, Li X, Hsu H et al. Factors affecting the
prevalence of strongly and weakly carcinogenic and lower-
risk human papillomaviruses in anal specimens in a cohort
of men who have sex with men (MSM). PLoS One 2013; 8:
e79492.
27 Mooij SH, Boot HJ, Speksnijder AG et al. Oral human
papillomavirus infection in HIV-negative and HIV-infected
MSM. AIDS 2013; 27: 2117–2128.
28 Videla S, Darwich L, Ca~
nadas MP et al. Natural history of
human papillomavirus infections involving anal, penile, and
oral sites among HIV-positive men. Sex Transm Dis 2013;
40:3–10.
29 Konopnicki D, Manigart Y, Gilles C et al. High-risk human
papillomavirus infection in HIV-positive African women
living in Europe. J Int AIDS Soc 2013; 16: 18023.
30 Heard I, Cubie HA, Mesher D. Sasieni P; MACH-1 Study
Group. Characteristics of HPV infection over time in
European women who are HIV-1 positive. Br J Obstet
Gynaecol 2013; 120:41–49.
31 Hernandez AL, Efird JT, Holly EA et al. Incidence of and
risk factors for type-specific anal human papillomavirus
infection among HIV-positive MSM. AIDS 2014; 28: 1341–
1349.
32 Tong WW, Hillman RJ, Kelleher AD et al. Anal
intraepithelial neoplasia and squamous cell carcinoma in
HIV-infected adults. HIV Med 2014; 15:65–76.
33 Olesen TB, Munk C, Christensen J et al. Human
papillomavirus prevalence among men in sub-Saharan
Africa: a systematic review and meta-analysis. Sex Transm
Infect 2014; 90: 455–462.
34 Schim van der Loeff MF, Mooij SH, Richel O et al. HPV and
anal cancer in HIV-infected individuals: a review. Curr HIV/
AIDS Rep 2014; 11: 250–262.
35 Stier EA, Sebring MC, Mendez AE et al. Prevalence of anal
human papillomavirus infection and anal HPV-related
disorders in women: a systematic review. Am J Obstet
Gynecol 2015; 213: 278–309.
36 Ananworanich J, Prasitsuebsai W, Kerr SJ et al. Cervical
cytological abnormalities and HPV infection in perinatally
HIV-infected adolescents. J Virus Erad 2015; 1:30–37.
37 Supindham T, Chariyalertsak S, Utaipat U et al. High
prevalence and genotype diversity of anal HPV infection
among MSM in Northern Thailand. PLoS One 2015; 10:
e0124499.
38 Welling CA, Mooij SH, van der Sande MA et al. Association
of HIV infection with anal and penile low-risk human
papillomavirus infections among men who have sex with
men in Amsterdam. Sex Transm Dis 2015; 42: 297–304.
39 Kojic EM, Kang M, Cespedes MS et al. Immunogenicity
and safety of a quadrivalent human papillomavirus
vaccine in HIV-1-infected women. Clin Infect Dis 2014;
59: 127–135.
40 Palefsky JM, Giuliano AR, Goldstone S et al. HPV vaccine
against anal HPV infection and anal intraepithelial
neoplasia. N Engl J Med 2011; 365: 1576–1585.
41 Dochez C, Bogers JJ, Verhelst R, Rees H. HPV vaccines to
prevent cervical cancer and genital warts: an update.
Vaccine 2014; 32: 1595–1601.
42 Herrero R, Gonz
alez P, Markowitz LE. Present status of
human papillomavirus vaccine development and
implementation. Lancet Oncol 2015; 16: e206–e216.
43 Macartney K, Chiu C, Georgousakis M, Brotherton JML.
Safety of human papillomavirus vaccines: a review. Drug
Saf 2013; 36: 393–412.
44 Noronha AS, Markowitz LE, Dunne EF. Systematic review of
human papillomavirus vaccine coadministration. Vaccine
2014; 32: 2670–2674.
45 Joint Committee on Vaccination and Immunisation (JCVI).
Interim position statement on HPV vaccination of men who
have sex with men (MSM). Available at: https://
www.gov.uk/government/uploads/system/uploads/
attachment_data/file/373531/
JCVI_interim_statement_HPV_vacc.pdf (accessed November
2015).
46 Kim J. Targeted human papillomavirus vaccination of men
who have sex with men in the USA –a cost-effectiveness
modelling analysis. Lancet Infect Dis 2010; 10: 845–852.
47 Swedish KA, Factor SH, Goldstone SE. Prevention of
recurrent high-grade anal neoplasia with quadrivalent
human papillomavirus vaccination of men who have sex
with men: a nonconcurrent cohort study. Clin Infect Dis
2012; 54: 891–898.
48 Miltz A, Price H, Shahmanesh M et al. Systematic review
and meta-analysis of L1-VLP-based human papillomavirus
vaccine efficacy against anogenital pre-cancer in women
with evidence of prior HPV exposure. PLoS One 2014; 9:
e90348.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
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49 Levin MJ, Moscicki AB, Song LY et al. Safety and
immunogenicity of a quadrivalent human papillomavirus
(types 6, 11, 16, and 18) vaccine in HIV-infected children 7
to 12 years old. J Acquir Immune Defic Syndr 2010; 55:
197–204.
50 Weinberg A, Song LY, Saah A et al. Humoral, mucosal, and
cell-mediated immunity against vaccine and nonvaccine
genotypes after administration of quadrivalent human
papillomavirus vaccine to HIV-infected children. J Infect
Dis 2012; 206: 1309–1318.
51 Kahn JA, Xu J, Kapogiannis BG, Rudy B et al.
Immunogenicity and safety of the human papillomavirus 6,
11, 16, 18 vaccine in HIV-infected young women. Clin
Infect Dis 2013; 57: 735–744.
52 Denny L, Hendricks B, Gordon C et al. Safety and
immunogenicity of the HPV-16/18 AS04-adjuvanted
vaccine in HIV-positive women in South Africa: a partially-
blind randomised placebo-controlled study. Vaccine 2013;
31: 745–753.
53 Wilkin T, Lee JY, Lensing SY et al. Safety and
immunogenicity of the quadrivalent human papillomavirus
vaccine in HIV-1-infected men. J Infect Dis 2010; 202:
1246–1253.
54 Giacomet V, Penagini F, Trabattoni D et al. Safety and
immunogenicity of a quadrivalent human papillomavirus
vaccine in HIV-infected and HIV-negative adolescents and
young adults. Vaccine 2014; 32: 5657–5661.
55 Rainone V, Giacomet V, Penagini F et al. Human
papilloma virus vaccination induces strong human
papilloma virus specific cell-mediated immune responses
in HIV-infected adolescents and young adults. AIDS 2015;
29: 739–743.
56 Toft L, Storgaard M, M€
uller M et al. Comparison of the
immunogenicity and reactogenicity of Cervarix and Gardasil
human papillomavirus vaccines in HIV-infected adults: a
randomized, double-blind clinical trial. J Infect Dis 2014;
209: 1165–1173.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s34 BHIVA Writing Group
10. Influenza
10.1 Infection and disease
There are three types of influenza viruses –A, B and C.
Influenza A and influenza B account for most cases of
the disease. Influenza is highly infectious. Transmission
occurs through respiratory droplets and aerosols. Severity
varies from asymptomatic to fatal infections. Influenza
can exacerbate underlying medical conditions and lead to
serious complications. The greatest morbidity and risk for
complications, hospitalisation, and death are seen in very
young children, those aged ≥65 years, pregnant women,
and patients with underlying conditions including the
immunocompromised [1,2]. In 2012, the World Health
Organization identified pregnant women as the highest
priority group for influenza vaccination [3].
10.2 Epidemiology
Influenza A viruses undergo changes in the principal sur-
face antigens, haemagglutinin (H) and neuraminidase (N).
Minor changes (“antigenic drift”) occur progressively
from season to season. Major changes (“antigenic shift”)
result periodically in the emergence of new subtypes that
can cause epidemics or pandemics. Influenza B viruses
are also subject to antigenic drift but with less frequent
changes. Three influenza A pandemics occurred in the
last century (1918, 1957, 1968). The most recent pan-
demic occurred in 2009 with a novel strain of influenza
A/H1N1; a disproportionately high mortality was
observed among children, young adults, and pregnant
women [4]. Outbreaks of influenza A occur most years.
Influenza B causes less extensive outbreaks, usually
between outbreaks of influenza A. The influenza season
is October–May in the northern hemisphere and April–
September in the southern hemisphere. In the tropics,
influenza may occur all year round.
10.3 Influenza in HIV-positive adults
HIV infection is associated with increased severity of
influenza and greater risk of complications, resulting in
excess hospitalisation and mortality during influenza sea-
sons [5–14]. Effective ART reduces the rates of hospitali-
sations and mortality, although the risk of severe
outcomes remains comparable to that of other high-risk
groups for which annual influenza vaccination is
recommended [15,16]. In the recent 2009 A/H1N1 pan-
demic, HIV-positive adults with advanced immunosup-
pression or co-morbid conditions were found to be at an
increased risk of influenza-related complications [17].
10.4 Influenza vaccine
Influenza vaccines are prepared twice yearly using virus
strains considered most likely to be circulating in the
forthcoming winter (for northern and southern hemi-
spheres), as recommended by WHO according to global
epidemiological surveillance. There are two types of
influenza vaccines available in the UK –inactivated and
live-attenuated vaccines. Inactivated vaccines are usually
multivalent. Trivalent inactivated vaccines (TIVs) typi-
cally contain two influenza A strains and one influenza B
strain. Quadrivalent preparations contain one additional
influenza B virus. Monovalent vaccines are prepared in
response to specific epidemiological circumstances such
as emergence of a shifted strain. Inactivated vaccines are
most commonly made from virus grown in hen eggs. In
adults, they are usually given as a single dose by intra-
muscular injection (or deep subcutaneous injection in
those with bleeding disorders), or less commonly by
intradermal injection. A live attenuated influenza vaccine
for administration by nasal spray is approved for use in
the UK in healthy children aged 2–18 years. Data on
safety and efficacy in adults with HIV infection are lack-
ing at present, although it seems likely that the vaccine
may be given safely to adults with good immune status
on ART. Studies are currently assessing numerous vaccine
candidates including inactivated egg-grown and cell-cul-
ture derived subunit or whole virus vaccines, adjuvanted
vaccines, and live attenuated vaccines. A high-dose
(four-times higher antigen content) TIV is licensed in the
US for those aged ≥65 years (Fluzone high-dose) [18].
In healthy adults, TIVs provide around 60% protection
against virologically proven influenza infection [19].
Development of protective antibodies occurs about
2 weeks after vaccination and protection lasts for about
1 year. Although responses to vaccination are often
reduced in the elderly and those with underlying condi-
tions, vaccination can still protect against severe disease,
complications such as bronchopneumonia, hospital
admission, and mortality [20–23]. Inactivated influenza
vaccines are safe and well tolerated and are
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s35
recommended for use in pregnant and breastfeeding
women [24].
10.4.1 General indications
In the UK, annual influenza vaccination is recommended
for all children aged 2–4 years, those aged ≥65 years,
adults and children aged over 6 months in clinical risk
groups, pregnant women, and healthcare workers in
direct contact with patients. Clinical risk groups include
patients with:
•Chronic respiratory, heart, renal, liver, or neurological
disease.
•Diabetes.
•Immunocompromise (including HIV infection).
•Asplenia or splenic dysfunction.
•Morbid obesity.
10.5 Influenza vaccine in HIV-positive adult
With inactivated influenza vaccines, antibody responses
have been found to be lower in HIV-positive patients
compared with HIV-negative controls, and to be corre-
lated with CD4 cell counts and viral load [25–37]. Whilst
ART improves responses, the degree of immune restora-
tion remains unclear, with some studies indicating a per-
sistent defect relative to HIV-negative subjects [37–44].
In one recent study, HIV infection worsened age-asso-
ciated defects in antibody responses to influenza vaccine
among women aged above 55 years [44]. One other study
comparing HIV-positive and HIV-negative individuals
suggested merely quantitative differences in the vaccine
responses, thus offering a rationale for boosting strategies
in the HIV-positive population [43]. In HIV-positive
adults however, administering higher/more frequent doses
of standard non-adjuvanted vaccine preparations has not
been consistently associated with improved immuno-
genicity, whilst enhanced responses have been observed
with novel adjuvanted preparations [40,45–55]. Data on
the clinical efficacy of influenza vaccination in HIV-posi-
tive adults are limited. A previous systematic review and
meta-analysis concluded that a reasonable estimate could
not be derived from available data [56]. A more recent
systematic review and meta-analysis set out to assess the
efficacy and effectiveness of influenza vaccination in
respect to the prevention of all clinical outcomes, includ-
ing influenza, all-cause hospitalisation, pneumonia, and
mortality [37]. Three randomised-controlled trials and
three cohort studies were identified, including a total of
1562 HIV-positive individuals. In adults (but not in chil-
dren), TIV prevented laboratory-confirmed influenza with
a pooled efficacy of 85% (95% CI 22–97%; evidence
quality: moderate); no significant effects on other clinical
outcomes were demonstrable (evidence quality: moderate
to low; high risk of bias detected in the cohort studies),
indicating the need for further studies. A recent ran-
domised-controlled trial of TIV in HIV-positive pregnant
women demonstrated a vaccine efficacy of 58% (95% CI
0.2–82%) [42].
Inactivated influenza vaccines are safe and well tol-
erated in HIV-positive individuals [26–55]. Injection site
reactions are the most frequent side effects. Systemic
side effects are uncommon, and include allergic reac-
tions most likely to be due to hypersensitivity to resid-
ual egg protein. The vaccines also appear to be safe
when administered to HIV-positive pregnant women
[42,57].
10.6 Antiviral therapy for pre- and post-exposure
prophylaxis
Antiviral therapy with either oral oseltamivir or inhaled
zanamivir can be used for the pre- and post-exposure
prophylaxis of influenza [58]. The efficacy in HIV-posi-
tive persons is unknown.
10.7 Recommendations for HIV-positive adults
•We recommend that HIV-positive adults be offered
annual influenza vaccination with a parenteral non-
replicating vaccine, and this includes HIV-positive
pregnant women [1A].
oWe recommend the vaccine be given between
September and early November [1B]. We suggest
that depending on the epidemiological circum-
stances, there is still a potential benefit of vaccina-
tion until March [2D].
oWe suggest that a quadrivalent vaccine may be pre-
ferred where available [1D].
oWe recommend a single vaccine dose be given [1B].
There is insufficient evidence to recommend high-
er/more frequent doses in order to increase
immunogenicity when using the inactivated influ-
enza vaccines currently available in the UK. This
area will be kept under review.
•We recommend that HIV services, in partnership with
primary care, devise strategies to ensure prioritised
patients receive annual vaccination, such as patient
recall and notification [1C].
•Pending further analyses of safety and efficacy, we
recommend against the use of replicating live attenu-
ated influenza vaccines in HIV-positive adults [1D].
This recommendation will be kept under review.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s36 BHIVA Writing Group
•We recommend that close contacts of HIV-positive per-
sons be offered annual influenza vaccination, which
should be preferably with inactivated rather than live
attenuated vaccines where the HIV-positive person is
profoundly immunocompromised [1D].
•We recommend that in identified circumstances of
exposure, antiviral prophylaxis be considered for
patients who are either unvaccinated or unlikely to
benefit from vaccination (CD4 cell ounts <200 cells/lL
or poor match between vaccine and circulating influ-
enza strain) if at risk of complications, particularly if
profoundly immunocompromised [1D]. Expert advice
should be sought.
10.8 References
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20 Mangtani P, Cumberland P, Hodgson CR et al. A cohort
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22 Puig-Barbera J, Diez-Domingo J, Arnedo-Pena A et al.
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23 Kwong JC, Campitelli MA, Gubbay JB et al. Vaccine
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24 Naleway AL, Irving SA, Henninger ML et al. Safety of
influenza vaccination during pregnancy: a review of
subsequent maternal obstetric events and findings from two
recent cohort studies. Vaccine 2014; 32: 3122–3127.
25 Nelson KE, Clements ML, Miotti P et al. The influence of
human immunodeficiency virus (HIV) infection on antibody
responses to influenza vaccines. Ann Intern Med 1988; 109:
383–388.
26 Kroon FP, van Dissel JT, de Jong JC, van Furth R. Antibody
response to influenza, tetanus and pneumococcal vaccines
in HIV-seropositive individuals in relation to the number of
CD4+lymphocytes. AIDS 1994; 8: 469–476.
27 Iorio AM, Alatri A, Francisci D et al. Immunogenicity of
influenza vaccine (1993–94 winter season) in HIV-
seropositive and -seronegative ex-intravenous drug users.
Vaccine 1997; 15:97–102.
28 Fowke KR, D’Amico R, Chernoff DN et al. Immunologic and
virologic evaluation after influenza vaccination of HIV-1-
infected patients. AIDS 1997; 11: 1013–1021.
29 Fuller JD, Craven DE, Steger KA et al. Influenza vaccination
of human immunodeficiency virus (HIV)-infected adults:
impact on plasma levels of HIV type 1 RNA and
determinants of antibody response. Clin Infect Dis 1999; 28:
541–547.
30 Amendola A, Boschini A, Colzani D et al. Influenza
vaccination of HIV-1-positive and HIV-1-negative former
intravenous drug users. J Med Virol 2001; 65: 644–648.
31 Yamanaka H, Teruya K, Tanaka M et al. Efficacy and
immunologic responses to influenza vaccine in HIV-1-
infected patients. J Acquir Immune Defic Syndr 2005; 39:
167–173.
32 Tebas P, Frank I, Lewis M et al. Poor immunogenicity of the
H1N1 2009 vaccine in well controlled HIV-infected
individuals. AIDS 2010; 24: 2187–2192.
33 Crum-Cianflone NF, Eberly LE, Duplessis C et al.
Immunogenicity of a monovalent 2009 influenza A (H1N1)
vaccine in an immunocompromised population: a
prospective study comparing HIV-infected adults with HIV-
uninfected adults. Clin Infect Dis 2011; 52: 138–146.
34 Yanagisawa N, Maeda K, Ajisawa A et al. Reduced immune
response to influenza A (H1N1) 2009 monovalent vaccine in
HIV-infected Japanese subjects. Vaccine 2011; 29: 5694–
5698.
35 Tiu CT, Lin YS, Pagala M et al. Antibody response to
inactivated influenza A (H1N1) 2009 monovalent vaccine in
patients with and without HIV. J Acquir Immune Defic
Syndr 2011; 58: e99–e102.
36 Parmigiani A, Alcaide ML, Freguja R et al. Impaired
antibody response to influenza vaccine in HIV-infected and
uninfected aging women is associated with immune
activation and inflammation. PLoS One 2013; 8: e79816.
37 Remschmidt C, Wichmann O, Harder T. Influenza
vaccination in HIV-infected individuals: systematic review
and assessment of quality of evidence related to vaccine
efficacy, effectiveness and safety. Vaccine 2014; 32: 5585–
5592.
38 Kroon FP, Rimmelzwaan GF, Roos MT et al. Restored
humoral immune response to influenza vaccination in HIV-
infected adults treated with highly active antiretroviral
therapy. AIDS 1998; 12: F217–F223.
39 Launay O, Desaint C, Durier C et al. Safety and
immunogenicity of a monovalent 2009 influenza A/H1N1v
vaccine adjuvanted with AS03A or unadjuvanted in HIV-
infected adults: a randomized, controlled trial. J Infect Dis
2011; 204: 124–134.
40 Durier C, Desaint C, Lucht F et al. Long-term
immunogenicity of two doses of 2009 A/H1N1v vaccine
with and without AS03(A) adjuvant in HIV-1-infected
adults. AIDS 2013; 27:87–93.
41 Nunes MC, Cutland CL, Dighero B et al. Kinetics of
hemagglutination-inhibiting antibodies following maternal
influenza vaccination among mothers with and those
without HIV infection and their infants. J Infect Dis 2015;
212: 1976–1987.
42 Madhi SA, Cutland CL, Kuwanda L et al. Influenza
vaccination of pregnant women and protection of their
infants. N Engl J Med 2014; 71: 918–931.
43 Weinberg A, Muresan P, Richardson KM et al. Determinants
of vaccine immunogenicity in HIV-infected pregnant
women: analysis of B and T cell responses to pandemic
H1N1 monovalent vaccine. PLoS One 2015; 10: e0122431.
44 George VK, Pallikkuth S, Parmigiani A et al. HIV
infection worsens age-associated defects in antibody
responses to influenza vaccine. J Infect Dis 2015; 211:
1959–1968.
45 Iorio AM, Francisci D, Camilloni B et al. Antibody
responses and HIV-1 viral load in HIV-1-seropositive
subjects immunised with either the MF59-adjuvanted
influenza vaccine or a conventional non-adjuvanted subunit
vaccine during highly active antiretroviral therapy. Vaccine
2003; 21: 3629–3637.
46 Bickel M, von Hentig N, Wieters I et al. Immune response
after two doses of the novel split virion, adjuvanted
pandemic H1N1 influenza A vaccine in HIV-1-infected
patients. Clin Infect Dis 2011; 52: 122–127.
47 Cooper C, Thorne A, Klein M et al. Immunogenicity is not
improved by increased antigen dose or booster dosing of
seasonal influenza vaccine in a randomized trial of HIV
infected adults. PLoS One 2011; 6: e17758.
48 Hatakeyama S, Iwatsuki-Horimoto K, Okamoto K et al.
Unadjuvanted pandemic H1N1 influenza vaccine in HIV-1-
infected adults. Vaccine 2011; 29: 9224–9228.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s38 BHIVA Writing Group
49 Ho J, Moir S, Wang W et al. Enhancing effects of
adjuvanted 2009 pandemic H1N1 influenza A vaccine on
memory B-cell responses in HIV-infected individuals. AIDS
2011; 25: 295–302.
50 Nielsen AB, Nielsen HS, Nielsen L et al. Immune response
after one or two doses of pandemic influenza A (H1N1)
monovalent, AS03-adjuvanted vaccine in HIV infected
adults. Vaccine 2012; 30: 7067–7071.
51 Santini-Oliveira M, Camacho LA, Souza TM et al.
H1N1pdm09 adjuvanted vaccination in HIV-infected adults:
a randomized trial of two single versus two double doses.
PLoS One 2012; 7: e39310.
52 El Sahly HM, Davis C, Kotloff K et al. Higher antigen
content improves the immune response to 2009 H1N1
influenza vaccine in HIV-infected adults: a randomized
clinical trial. J Infect Dis 2012; 205: 703–712.
53 Cooper C, Klein M, Walmsley S et al. High-level
immunogenicity is achieved vaccine with adjuvanted
pandemic H1N1(2009) and improved with booster dosing in
a randomized trial of HIV-infected adults. HIV Clin Trials
2012; 13:23–32.
54 Lagler H, Grabmeier-Pfistershammer K, Touzeau-Romer V
et al. Immunogenicity and tolerability after two doses of
non-adjuvanted, whole-virion pandemic influenza A (H1N1)
vaccine in HIV-infected individuals. PLoS One 2012; 7:
e36773.
55 McKittrick N, Frank I, Jacobson JM et al. Improved
immunogenicity with high-dose seasonal influenza
vaccine in HIV-infected persons: a single-center, parallel,
randomized trial. Ann Intern Med 2013; 158:19–26.
56 Anema A, Mills E, Montaner J et al. Efficacy of influenza
vaccination in HIV-positive patients: a systematic review
and meta-analysis. HIV Med 2008; 9:57–61.
57 Abzug MJ, Nachman SA, Muresan P et al. Safety and
immunogenicity of 2009 pH1N1 vaccination in HIV-infected
pregnant women. Clin Infect Dis 2013; 56: 1488–1497.
58 Jefferson T, Jones MA, Doshi P et al. Neuraminidase
inhibitors for preventing and treating influenza in healthy
adults and children. Cochrane Database Syst Rev 2014; 4:
CD008965.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s39
11. Japanese encephalitis
11.1 Infection and disease
Japanese encephalitis virus (JEV) is a mosquito-borne fla-
vivirus [1]. Approximately 1:250 infections become clini-
cally apparent. Severity ranges from a flu-like illness to
life-threatening encephalitis. The case-fatality ratio of
patients with encephalitis is 20–30%, and survivors have
a 30% risk of permanent sequelae. Infection during the
first or second trimesters of pregnancy can cause miscar-
riage. No antiviral therapy is available.
11.2 Epidemiology
JEV is a leading cause of encephalitis in Asia, mainly
affecting the South-east and Western Pacific regions [1].
Infections occur predominantly in rice growing and pig
farming rural areas, and occasionally in urban areas. The
highest transmission rates are during and just after wet
seasons, but seasonal patterns vary both within individual
countries and from year to year.
11.3 JEV in HIV-positive adults
It is not known whether the natural history of Japanese
encephalitis is modified by HIV infection.
11.4 JEV vaccine
Several JEV vaccines are available globally, including
inactivated mouse brain-derived vaccines (no longer rec-
ommended), inactivated Vero cell-derived vaccines, live
attenuated vaccines, and live recombinant (chimeric)
vaccines [1,2]. The internationally licensed IXIARO vac-
cine is Vero cell-derived and available in the UK. The
IXIARO vaccine is safe and immunogenic in healthy
subjects [1,2]. The vaccine is given by parenteral admin-
istration. The IXIARO vaccine is given to adults in two
doses 24–28 days apart. Following completion of the
primary course, a booster is recommended after 12–
24 months for those at continued risk. Responses are
long-lived, and emerging data suggest that further boos-
ter doses may be scheduled 10 years following the first
booster [3]. A randomised clinical trial evaluated short-
term antibody responses to an accelerated course of 2
vaccine doses 1 week apart (and co-administered with
rabies vaccine) in healthy persons aged 18–65 years [4].
Short-term immunogenicity with the accelerated course
was non-inferior to that measured with the standard
schedule.
11.4.1 General indications
In the UK, the IXIARO vaccine is offered to travellers to
South and South-east Asia and the Far East if staying for
a month or longer in endemic areas during the transmis-
sion season, especially if travel will include rural areas.
Other travellers with shorter exposure periods are immu-
nised if the risk is considered sufficient. The vaccine is
also recommended for those who are going to reside in
an area where JEV is endemic or epidemic, and for those
at risk of occupational exposure (e.g. laboratory workers).
11.5 JEV vaccine and HIV-positive adults
No studies have been published on the safety, immuno-
genicity, and clinical efficacy of JEV vaccination in HIV-
positive adults. Studies in children show that inactivated
vaccines are safe and immunogenic [1]. Immune
responses are reduced relative to HIV-negative children,
although improved by ART [5–8]. There is insufficient
evidence for modifying dosing or boosting requirements
relative to standard recommendations.
11.6 Recommendations for HIV-positive adults
•We recommend that HIV-positive adults who are at
risk of JEV exposure (e.g. through travel or occupation)
be offered an inactivated Vero cell-derived JEV vac-
cine (typically IXIARIO), with two doses given 24–
28 days apart [1C].
oWe recommend against the use of an abbreviated
vaccination schedule (typically two doses 1 week
apart), unless there is an urgent need to complete
primary vaccination prior to a risk of exposure [1C].
•We recommend that following completion of the pri-
mary course, a booster vaccine dose is offered 12–
24 months later for those at continued risk, with a fur-
ther booster planned after 10 years [1C].
11.7 References
1 World Health Organization. Japanese encephalitis vaccines:
WHO position paper –February 2015. Wkly Epidemiol Rec
2015; 90:69–87.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s40 BHIVA Writing Group
2 Wang SY, Cheng XH, Li JX, Li XY, Zhu FC, Liu P.
Comparing the immunogenicity and safety of three
Japanese encephalitis vaccines in Asia-Pacific area: a
systematic review and meta-analysis. Hum Vaccin
Immunother 2015; 11: 1418–1425.
3 Paulke-Korinek M, Kollaritsch H, Kundi M et al. Persistence
of antibodies six years after booster vaccination with
inactivated vaccine against Japanese encephalitis. Vaccine
2015; 33: 3600–3604.
4 Jelinek T, Burchard GD, Dieckmann S et al. Short-term
immunogenicity and safety of an accelerated pre-exposure
prophylaxis regimen with Japanese encephalitis vaccine in
combination with a rabies vaccine: a phase III, multicenter,
observer-blind study. J Travel Med 2015; 22: 225–231.
5 Rojanasuphot S, Shaffer N, Chotpitayasunondh T et al.
Response to JE vaccine among HIV-infected children,
Bangkok, Thailand. Southeast Asian J Trop Med Public
Health 1998; 29: 443–450.
6 Puthanakit T, Aurpibul L, Yoksan S, Sirisanthana T,
Sirisanthana V. Japanese encephalitis vaccination in HIV-
infected children with immune recovery after highly active
antiretroviral therapy. Vaccine 2007; 25: 8257–8261.
7 Puthanakit T, Aurpibul L, Yoksan S, Sirisanthana T,
Sirisanthana V. A 3-year follow-up of antibody response in
HIV-infected children with immune recovery vaccinated
with inactivated Japanese encephalitis vaccine. Vaccine
2010; 28: 5900–5902.
8 Chokephaibulkit K, Plipat N, Yoksan S et al. A comparative
study of the serological response to Japanese
encephalitis vaccine in HIV-infected and uninfected Thai
children. Vaccine 2010; 28: 3563–3566.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s41
12. Measles, mumps and rubella
12.1 Infection and disease
Measles and mumps are paramyxoviruses, whereas
rubella is a togavirus. Measles, mumps and rubella are
transmitted by the respiratory route. Measles is highly
communicable and carries a high risk of complications
including hepatitis (60%), diarrhoea (8%), otitis media
(7%), pneumonia (1–6%) and encephalitis (0.1%), leading
to death in 2:1000 cases in developed countries. Up to
30% of mumps infections are asymptomatic and symp-
tomatic infections are typically in the form of parotitis;
neurological complications, usually mild aseptic meningi-
tis, occur in up to 15% of symptomatic cases but perma-
nent neurological sequelae are rare, including deafness
(1:20 000 cases). Other complications of mumps are
orchitis (20–50% of post-pubertal males) and pancreatitis
(2–5%); the mortality rate is 1–3:10 000 cases. Rubella is
usually a mild illness; in up to 70% of adult women it is
complicated by arthralgia or arthritis. Pregnant women
are at increased risk of fatal pneumonitis and miscarriage
after measles and of fetal damage after rubella infection.
12.2 Epidemiology
Measles, mumps and rubella remain common diseases in
many countries of the world. Patients are at risk of expo-
sure while travelling abroad, or within the UK [1–3].
There has been a substantial increase in measles cases
reported in the UK in recent years due to a reduction in
vaccine coverage in children, with ongoing risk of com-
munity-wide transmission. This reflects poor herd immu-
nity and the high secondary attack rate of measles in a
susceptible population.
12.3 Measles, mumps and rubella in HIV-positive
adults
There is no evidence to suggest that mumps and rubella
are more severe in the HIV setting. However, measles can
be life-threatening in people with advanced HIV infection
[4–6]. There may be no rash, and complications such as
pneumonitis and encephalitis may present several months
after the initial infection. A history of measles immunisa-
tion is not a reliable predictor of measles IgG seropositive
status and seropositivity does not guarantee protection
[7,8].
12.4 MMR vaccine
The MMR vaccine contains replicating live attenuated
viruses. The vaccine is given by parenteral administra-
tion. In adults, two doses are required to confer protec-
tion against measles, with the second dose given at any
time but at least 1 month after the first. MMR is highly
immunogenic and clinically efficacious in preventing
measles, mumps and rubella in children [9]. Measles IgG
develop in 90% of healthy subjects after one dose of
MMR, and 99% after two doses. Side effects include:
•Fever and rash (5–15% of vaccine recipients), usually
starting 7–12 days after vaccination and lasting
1–2 days.
•Arthralgia and/or arthritis (up to 25% of women), usu-
ally mild and transient.
•Transient lymphadenopathy.
•Parotitis and deafness (rare).
•Clinically apparent thrombocytopenia (<1 per 30 000
doses).
•Neurological complications, including aseptic meningi-
tis, encephalitis and encephalopathy (<1:1 000 000
doses).
•Allergic reaction; severe anaphylaxis is rare
(<1:1 000 000 doses).
With the exception of allergic reactions, side effects
are less frequent following the first dose and occur pri-
marily among the small proportion of persons who did
not respond to the first dose. The MMR vaccine is con-
traindicated in immunocompromised patients and in
pregnancy, and pregnancy should be avoided for
1 month after vaccination. The vaccine is not contraindi-
cated in breast-feeding women. MMR vaccine recipients
do not act as a potential source of infection to their con-
tacts.
12.5 MMR vaccine in HIV-positive adults
Vaccine responses are reduced in HIV-positive patients
[7,10–12], although improved by effective ART [13–18].
Revaccination of previously immunised individuals
following immune reconstitution on ART provides a
strategy for improving seroconversion rates and magni-
tude and longevity of vaccine-induced responses. While
the MMR vaccine is also contraindicated in persons who
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s42 BHIVA Writing Group
are severely immunocompromised, including HIV-positive
patients with CD4 cell counts <200 cells/lL, it is in gen-
eral safe in HIV-positive patients with less profound
immunocompromise [13–18]. Prior to 1993, it was advo-
cated for both asymptomatic and symptomatic patients. A
change in policy was prompted by a case of fatal
measles-vaccine-associated pneumonitis in a severely
immunocompromised man, presenting almost 1 year after
vaccination [19]. Vaccine-associated pneumonitis and
encephalitis have also been described in severely
immunocompromised patients. Serious illnesses have not
been reported in HIV-positive individuals in association
with mumps or rubella vaccine administration.
12.6 Post-exposure prophylaxis
Following contact with a case of measles, passive
immune prophylaxis with intramuscular human normal
immunoglobulin (HNIG) is indicated in selected groups,
including immunocompromised patients. In most cases,
an urgent (within 3 days of contact) measles IgG test is
requested to decide upon the need for prophylaxis. A
prophylactic dose of HNIG is not likely to benefit measles
IgG-positive contacts, although patients with profound
deficits of cellular immunity (typically those with pri-
mary immunodeficiency) may still benefit. HNIG is given
as soon as possible after the contact, ideally within
3 days, and no later than 6 days [20,21]. In selected
cases, intravenous immunoglobulin (IVIG) may be con-
sidered up to 18 days after exposure, in which case it
may attenuate rather than prevent the infection. There is
no evidence to support the use of HNIG following expo-
sure to mumps or rubella. Because of the rapid induction
of the measles antibody, contacts of measles may be pro-
tected by MMR vaccination administered within 3 days
of exposure. This is not the case for the mumps and
rubella components. There are no data regarding the use
of post-exposure MMR vaccination following measles
exposure in individuals with HIV or other immunocom-
promised patients.
12.7 Recommendations for HIV-positive adults
•We recommend that HIV-positive adults be screened
for measles IgG regardless of a history of childhood
vaccination [1B].
oWe recommend that measles seronegative patients
with CD4 cell counts >200 cells/lL who are clini-
cally stable are offered two doses of the MMR vac-
cine at an interval of at least 1 month [1B].
oWe suggest that based on the likelihood of expo-
sure, vaccination may be postponed in patients with
CD4 cell counts >200 cells/lL who are not yet
established on ART [2C].
oWe recommend that in selected circumstances
when measles seronegative patients are at a sig-
nificant risk of exposure but cannot receive the
MMR vaccine due to a low CD4 cell count,
patients be offered pre-exposure prophylaxis with
HNIG [1C]. Any protection afforded will be short-
lived (~3 weeks).
•We recommend that after a recognised exposure to
measles, HIV-positive adults be screened for measles
IgG within 3 days of exposure and regardless of a his-
tory of previous vaccination (although prophylaxis
should not be delayed while waiting for the results)
[1C]. We recommend that a risk assessment be under-
taken about the need for and mode of post-exposure
prophylaxis, along the following guidelines:
oMeasles seronegative, CD4 cell count >200 cells/lL,
preferably with stable viral load suppression on
ART: MMR vaccine within 3 days of contact [1D] or
HNIG within 6 days of contact [1C].
oOther measles seronegative: HNIG within 6 days of
contact [1C] or IVIG up to 18 days after contact
[1D].
oCD4 cell count <200 cells/lL (regardless of measles
IgG serostatus): HNIG within 6 days of contact [1C]
or in selected high-risk cases IVIG up to 18 days
after contact [1D].
•We recommend that HIV-positive women of child-
bearing age are screened for rubella IgG if their rubella
IgG status is unknown, and that rubella seronegative
women be offered MMR vaccination provided their
CD4 cell count is >200 cells/lL and they are not preg-
nant [1C].
oWe suggest that either one MMR vaccine dose fol-
lowed 4 weeks later by repeat rubella serology and
revaccination if required, or two vaccine doses
1 month apart may be considered acceptable options
for rubella seronegative women who are measles
seropositive [2C]. Women who are also measles
seronegative should receive two vaccine doses
1 month apart [1B].
12.8 References
1 Jansen VA, Stollenwerk N, Jensen HJ et al. Measles
outbreaks in a population with declining vaccine uptake.
Science 2003; 301: 804.
2 Vivancos R, Keenan A, Farmer S et al. An ongoing large
outbreak of measles in Merseyside, England, January to
June 2012. Euro Surveill 2012; 17: pii: 20226.
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British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s43
3 European Centre for Disease Prevention and Control.
Surveillance report. Measles and rubella monitoring,
February 2014. Reporting on January–December 2013
surveillance data and epidemic intelligence data to the end
of February 2014. Stockholm: ECDC, 2014. Available at:
www.ecdc.europa.eu/en/publications/Publications/measles-
rubella-monitoring-February-2014.pdf (accessed November
2015).
4 Kaplan LJ, Daum RS, Smaron M, McCarthy CA. Severe
measles in immunocompromised patients. JAMA 1992; 267:
1237–1241.
5 Mustafa MM, Weitman SD, Winick NJ et al. Subacute
measles encephalitis in the young immunocompromised
host: report of 2 cases diagnosed by polymerase chain
reaction and treated with ribavirin and review of the
literature. Clin Infect Dis 1993; 16: 654–660.
6 Moss WJ, Fisher C, Scott S et al. HIV type 1 Infection Is a
risk factor for mortality in hospitalized Zambian children
with measles. Clin Infect Dis 2008; 46: 523–527.
7 Belaunzar
an-Zamudio PF, Garc
ıa-Le
on ML, Wong-Chew RM
et al. Early loss of measles antibodies after MMR vaccine
among HIV-infected adults receiving HAART. Vaccine 2009;
27: 7059–7064.
8 Palumbo P, Hoyt L, Demasio K et al. Population-based
study of measles and measles immunization in human
immunodeficiency virus-infected children. Pediatr Infect Dis
J1992; 11: 1008–1014.
9 Demicheli V, Rivetti A, Debalini MG, Di Pietrantonj C.
Vaccines for measles, mumps and rubella in children.
Cochrane Database Syst Rev 2012; 2: D004407.
10 Sprauer MA, Markowitz LE, Nicholson JK et al. Response of
human immunodeficiency virus-infected adults to measles-
rubella vaccination. J Acquir Immune Defic Syndr 1993; 6:
1013–1016.
11 Wallace MR, Hooper DG, Graves SJ, Malone JL. Measles
seroprevalence and vaccine response in HIV-infected adults.
Vaccine 1994; 12: 1222–1224.
12 Stermole BM, Grandits GA, Roediger MP et al. Long-term
safety and serologic response to measles, mumps, and
rubella vaccination in HIV-1 infected adults. Vaccine 2011;
29: 2874–2880.
13 Berkelhamer S, Borock E, Elsen C et al. Effect of highly
active antiretroviral therapy on the serological response to
additional measles vaccinations in human-
immunodeficiency virus-infected children. Clin Infect Dis
2001; 32: 1090–1094.
14 Farquhar C, Wamalwa D, Selig S et al. Immune responses to
measles and tetanus vaccines among Kenyan human
immunodeficiency virus type 1 (HIV-1)-infected children
pre- and post-highly active antiretroviral therapy and
revaccination. Pediatr Infect Dis J 2009; 28: 295–299.
15 Aurpibul L, Puthanakit T, Sirisanthana T, Sirisanthana V.
Persistence of measles, mumps, and rubella protective
antibodies 3 years after revaccination in HIV-infected
children receiving antiretroviral therapy. Clin Infect Dis
2010; 50: 1415–1418.
16 Scott P, Moss WJ, Gilani Z, Low N. Measles vaccination in
HIV-infected children: systematic review and meta-analysis
of safety and immunogenicity. J Infect Dis 2011; 204
(Suppl 1): S164–S178.
17 Abzug MJ, Qin M, Levin MJ et al. Immunogenicity,
immunologic memory, and safety following measles re-
vaccination in HIV-infected children receiving highly active
antiretroviral therapy. J Infect Dis 2012; 206: 512–522.
18 McLean HQ, Fiebelkorn AP, Temte JL, Wallace GS.
Prevention of measles, rubella, congenital rubella
syndrome, and mumps, 2013: summary recommendations
of the Advisory Committee on Immunization Practices
(ACIP). MMWR Morb Mortal Wkly Rep 2013; 62 (RR-04):
1–34.
19 Centers for Disease Control and Prevention. Measles
pneumonitis following Measles-Mumps-Rubella vaccination
of a patient with HIV infection, 1993. MMWR Morb Mortal
Wkly Rep 1996; 45: 603–606.
20 Ramsay M, Manikkavasagan G, Brown K, Craig L. Post
exposure prophylaxis for measles: Health Protection
Agency. Revised guidance, 2009. Available at:
www.gov.uk/government/uploads/system/uploads/
attachment_data/file/322634/
Post_exposure_prophylaxis_for_measles.pdf (accessed
November 2015).
21 Young MK, Nimmo GR, Cripps AW, Jones MA. Post-
exposure passive immunisation for preventing measles.
Cochrane Database Syst Rev 2014; 4: CD010056.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s44 BHIVA Writing Group
13. Meningococcus
13.1 Infection and disease
Neisseria meningitidis is a Gram-negative bacterium. There
are at least 12 capsular groups including the clinically
important A, B, C, Y, and W135. Around 5–11% of adults
carry the bacterium in the nasopharynx in the absence of
symptoms. Transmission occurs via the respiratory route
during close contact and is often associated with over-
crowded conditions. Neisseria meningitidis is a common
cause of meningitis and septicaemia in children and young
adults, with a high risk of mortality or permanent sequelae.
The case fatality rate is <10% overall. Less common mani-
festations include myocarditis, endocarditis, pericarditis,
arthritis, conjunctivitis, urethritis, pharyngitis, and cervici-
tis. It is not fully understood why the disease develops in
some individuals but not in others. Patients with anatomi-
cal or functional asplenia and those with complement defi-
ciencies are at an increased risk of disease.
13.2 Epidemiology
Following the widespread use of group C conjugate vac-
cines, group B is now the major cause of bacterial menin-
gitis and septicaemia in young children in Europe, and
accounts for most cases of invasive meningococcal dis-
ease (IMD) in the UK. In June 2015 Public Health Eng-
land declared a national incident related to the rapid and
accelerating increase in cases of IMD caused by group W
[1]. In the US, groups C, B, and Y account for 35%, 32%,
and 26% of isolates, respectively. Groups A and W135
are common epidemic strains in sub-Saharan Africa and
the Middle East, respectively. Proof of vaccination within
the past 3 years is required for visitors arriving in Saudi
Arabia for the Hajj and Umrah pilgrimages. Outbreaks of
meningococcal infection have been observed in univer-
sity campuses, and have also been reported among men
who have sex with men (MSM) in Europe and North
America. In 2012, the incidence rate of IMD among MSM
aged 18–64 years in New York City was 12.6 per 100 000
persons, compared with 0.16 per 100 000 persons among
other males of the same age [2].
13.3 Meningococcus in HIV-positive adults
Recent data indicate that HIV-positive patients remain at
increased risk of IMD in the ART era [3–5]. In an
observational study from New York City, Miller et al. [4]
identified 263 (mostly unvaccinated) patients with IMD of
whom 40 were HIV-positive. HIV-positive cases differed
from HIV-negative patients with IMD in being more often
male, non-white, smokers, and presenting with meningo-
coccal septicaemia rather than meningitis. The relative
risk for IMD amongst HIV patients was overall 10.0 (95%
CI 7.2–14.1), and increased in those with CD4 cell count
<200 cells/lL and viral load >400 copies/mL. Similar
results were obtained from an observational study in
South Africa, which indicated also that patients with HIV
had double the risk of death [5]. HIV infection alone is
not currently an indication for meningococcal vaccina-
tion [6].
13.4 Meningococcus vaccine
Different types of meningococcal vaccine are currently
available including a polysaccharide vaccine (no longer
recommended for routine use), conjugate vaccines, and
multicomponent vaccines. The conjugated vaccines MenC
and MenACWY are directed against group C and groups
A, C W, and Y, respectively. The multicomponent MenB
vaccines are directed against group B. The choice of vac-
cine is related to age, epidemiological circumstances, and
previous vaccination history. The vaccines are given by
parenteral administration. Meningococcal vaccines are
highly immunogenic and effective; they induce ser-
ogroup-specific protection. Fever and injection site reac-
tions are the most common adverse events reported. More
serious complications are very rare.
13.4.1 General indications
Indications for meningococcal vaccination are evolving
rapidly in the UK. MenC is part of the infant vaccination
programme and is also indicated for adults aged
<25 years who have never received the vaccine, received
the last MenC vaccine dose before 10 years of age, or
have an uncertain vaccination history. In March 2015,
the 4CMenB vaccine was included in the UK infant vacci-
nation programme, but no routine use has yet been indi-
cated for those over 11 years of age. In June 2015,
MenACWY was recommended for adolescents and univer-
sity entrants. MenC, MenACWY, and/or MenB are also
indicated for patients at risk of disease, mainly compris-
ing those with asplenia, splenic dysfunction or
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s45
complement disorders (including those on complement
inhibitor treatment). MenACWY is indicated for travellers
that are at recognised risk based on itinerary, duration of
stay and planned activities. In North America, targeted
vaccination of MSM has been recommended in some
states. Vaccination is also used during outbreaks of
meningococcal infection with vaccine serogroups to
reduce the number of secondary cases.
13.5 Meningococcus vaccine in HIV-positive adults
Several reports of adequate serological responses to
meningococcus vaccination are available, generally show-
ing better responses in those with less advanced disease,
and no major adverse reactions [7–11]. The immunogenic-
ity and safety of MenACWY in HIV-positive children and
young adults (aged 2–24) has been reported from the
P1065 study in the USA [8–10]; one study in Brazilian
children reported on the immunogenicity and safety of
the MenC vaccine [11]. In the P1065 study, response rates
to a single vaccine dose varied from 55% to 86% across
the different serogroups, with higher response rates in
younger children and those with higher CD4 cell counts
and lower viral load. Response rates increased with a sec-
ond dose of vaccine. In the Brazilian study, the response
rate to a single dose of MenC vaccine was 72%, increasing
to 81% when non-responders received a second dose. In
both of these studies adverse events were rare and com-
patible with studies in HIV-negative subjects.
13.6 Post-exposure prophylaxis
Close contacts of confirmed cases of meningococcal
infection are offered antibiotic prophylaxis (e.g. cipro-
floxacin) and appropriate vaccination.
13.7 Recommendations for HIV-positive adults
•We recommend that HIV-positive adults follow the
general indications for meningococcal vaccination and
be offered vaccination where indicated [1B]. The cate-
gories and recommended vaccine currently comprise:
oThose aged <25 years of age who have not been
previously vaccinated, have uncertain vaccination
history, or received the last MenC vaccine below the
age of 10 years –MenACWY [1B], and possibly
MenB [1C], according to national guidance.
oHave functional or anatomical asplenia or persistent
complement component deficiency –MenB, and/or
MenACWY, according to vaccination history [1B].
oAre at risk of exposure through travel –MenACWY
[1B].
oAre at risk of exposure through an outbreak –MenB
[1C], or MenACWY [1B], according to the epidemio-
logical scenario, and including MSM who may be
exposed to outbreaks due to residence, travel, or
social interactions.
•We recommend that HIV-positive patients are offered
two vaccine doses at the interval of 2 months in order
to increase immunogenicity [1C].
•We recommend that patients receiving MenACWY are
offered a booster dose every 5 years if at ongoing risk
through travel or due to underlying conditions [2C].
•This guidance should be interpreted in the context of
national epidemiological data and applied according to
the evolving national vaccination programme [GPP].
•We recommend that HIV-positive adults who are close
contacts of meningococcal disease be offered antibiotic
prophylaxis and appropriate vaccination [1C].
13.8 References
1 Public Health England. MenACWY vaccine introduction,
2015. Available at: www.gov.uk/government/
publications/menacwy-vaccine-introduction (accessed
November 2015).
2 Centers for Disease Control and Prevention (CDC). Notes
from the field: serogroup C invasive meningococcal
disease among men who have sex with men –New York
City, 2010–2012. MMWR Morb Mortal Wkly Rep 2013;
61: 1048.
3 Simon MS, Weiss D, Gulick RM. Invasive meningococcal
disease in men who have sex with men. Ann Intern Med
2013; 159: 300.
4 Miller L, Arakaki L, Ramautar A et al. Elevated risk for
invasive meningococcal disease among persons with HIV.
Ann Intern Med 2014; 160:30–37.
5 Cohen C, Singh E, Wu HM et al. Increased incidence of
meningococcal disease in HIV-infected individuals
associated with higher case-fatality ratios in South Africa.
AIDS 2010; 24: 1351–1360.
6 Cohn AC, MacNeil JR, Clark TA et al. Prevention and
control of meningococcal disease: recommendations of the
Advisory Committee on Immunization Practices (ACIP).
MMWR Recomm Rep 2013; 62 (RR-2): 1.
7 Rubin LG, Levin MJ, Ljungman P et al. 2013 IDSA clinical
practice guideline for vaccination of the
immunocompromised hosts. Clin Infect Dis 2014; 58: e44.
8 Siberry GK, Williams PL, Lujan-Zilbermann J et al. Phase I/
II, open-label trial of safety and immunogenicity of
meningococcal (groups A, C, Y, and W-135) polysaccharide
diphtheria toxoid conjugate vaccine in human
immunodeficiency virus-infected adolescents. Pediatr Infect
Dis J 2010; 29: 391–396.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s46 BHIVA Writing Group
9 Lujan-Zilbermann J, Warshaw MG, Williams PL et al.
Immunogenicity and safety of 1 vs 2 doses of quadrivalent
meningococcal conjugate vaccine in youth infected with
human immunodeficiency virus. J Pediatr 2012; 161: 676–
681.
10 Siberry GK, Warshaw MG, Williams PL et al. Safety and
immunogenicity of quadrivalent meningococcal conjugate
vaccine in 2- to 10-year-old human immunodeficiency
virus-infected children. Pediatr Infect Dis J 2012; 31:47–
52.
11 Bertolini DV, Costa LS, van der Heijden IM et al.
Immunogenicity of a meningococcal serogroup C conjugate
vaccine in HIV-infected children, adolescents, and young
adults. Vaccine 2012; 30: 5482–5486.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s47
14. Pertussis (whooping cough)
14.1 Infection and disease
Whooping cough is a highly contagious disease of the
respiratory tract usually caused by the bacterium Borde-
tella pertussis. A similar illness can be caused by
B. parapertussis but this is not preventable with available
vaccines. The infection is transmitted through direct close
contact with a case, and vaccination provides the most
effective prevention strategy. Protection afforded by
vaccination or from past infection is not life-long [1].
Disease severity ranges from mild to life-threatening, and
infants and young children are most at risk of complica-
tions. Older children and adults who have previously had
disease or been vaccinated may still become infected but
usually have mild disease.
14.2 Epidemiology
In the UK the introduction of routine vaccination against
pertussis in 1957 resulted in a marked reduction in
pertussis notifications and deaths, and pertussis control
has been good since the 1990s during a sustained period
of high coverage [2]. Pertussis activity increased consid-
erably from late 2011 leading to a national outbreak
being declared in April 2012. Most cases were in previ-
ously vaccinated adolescents and young adults but the
highest incidence of morbidity and mortality occurred in
unvaccinated infants. Public health action has identified
two target groups: those who are vulnerable to suffering
severe disease (young infants) and those who are at risk
of transmitting the infection to vulnerable individuals [1].
In October 2012 a temporary programme was introduced
to offer pertussis vaccination to pregnant women, ideally
between 28 and 32 weeks of pregnancy, with the aim of
protecting infants through intrauterine transfer of mater-
nal antibodies. In June 2014 the Joint Committee on Vac-
cination and Immunisation (JCVI) advised that this
temporary programme should continue for at least a fur-
ther 5 years as pertussis continues to circulate at height-
ened levels.
14.3. Pertussis in HIV-positive adults
Pertussis has been diagnosed in HIV-positive children
and adults, and should be considered as a cause of respi-
ratory disease in persons with HIV [3–7]. However,
pertussis is not generally considered an opportunistic
infection amongst immunocompromised individuals [1]
and current evidence does not suggest that pertussis is
common among persons with HIV or that they are more
likely to be a reservoir for B. pertussis in the community.
14.4 Pertussis vaccine
Pertussis vaccines licensed in the UK are inactivated acel-
lular vaccines made from highly purified components of
B. pertussis, and are only available as part of combined
products:
(1) diphtheria/tetanus/acellular pertussis/inactivated polio
vaccine/Haemophilus influenzae type b (DTaP/IPV/
Hib) –for primary immunisation in children.
(2) diphtheria/tetanus/acellular pertussis/inactivated polio
vaccine/(DTaP/IPV or dTaP/IPV) –for pre-school
boosters.
(3) diphtheria/tetanus/acellular pertussis/inactivated polio
vaccine (dTaP/IPV) –for adults requiring vaccination,
including pregnant women.
The vaccines are given by parenteral administration.
Pertussis vaccines are safe and immunogenic in immuno-
competent adults. Vaccination does not induce lifelong
immunity, and the possible need for boosters in adoles-
cence is under review. Vaccination is generally well toler-
ated [7,8]. Injection site reactions are common and may
occur more frequently following subsequent doses.
14.4.1 General indications
Pertussis vaccination in not available for individuals aged
≥10 years, except in pregnancy or as part of outbreak
control. For adults, including pregnant women, a vaccine
containing low dose diphtheria and tetanus is preferred.
Since 2014, Boostrix-IPV (dTaP/IPV) is the vaccine
offered for the prenatal programme. Repevax (dTaP/IPV)
may be a suitable alternative, whereas Infanrix-IPV is
used only in exceptional circumstances when neither
Boostrix-IPV nor Repevax (dTaP/IPV) is available. Preg-
nant women are offered a single vaccine dose not earlier
than 28 weeks and ideally between week 28 and week 32
of pregnancy. The vaccine will act as a reinforcing dose
and is offered in every pregnancy regardless of prior vac-
cination status. Vaccination after week 38 is unlikely to
provide passive protection to the infant but would
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s48 BHIVA Writing Group
potentially protect the mother from pertussis infection
and thereby reduce the risk of exposure to her infant.
14.5 Pertussis vaccine in HIV-positive adults
After vaccination, antibody titres are lower in HIV-posi-
tive children compared to HIV-negative children, and
correlate with the CD4 cell count [6]. No data on the effi-
cacy of the pertussis vaccine in HIV-positive adults are
available. There is no evidence of increased risk of side
effects or adverse reactions to vaccination in individuals
with HIV infection.
14.6 Post-exposure prophylaxis
Antibiotic prophylaxis (usually with macrolides) –to be
started within 21 days of onset of cough in the index
patient –is indicated for all asymptomatic household
contacts of a suspected, epidemiologically linked, or con-
firmed pertussis case. Secondary attack rates are high,
even when household contacts are current with vaccina-
tions. Antibiotic prophylaxis may also be indicated for
contacts who are at high risk of severe disease or are
likely to come in contact with a person at high risk (e.g.
pregnant women in the third trimester). Vaccination may
also be considered for those who have been offered
antibiotic prophylaxis.
14.7 Recommendations for HIV-positive adults
•We recommended that HIV-positive adults who meet
general indications for pertussis vaccination and
including HIV-positive pregnant women be offered one
dose of the dTaP/IPV vaccine regardless of CD4 cell
count, ART use, and viral load [1C].
•We recommended that HIV-positive adults who are in
contact with case of pertussis are considered for
antibiotic prophylaxis and vaccination in line with
standard recommendations [1C].
14.8 References
1 Health Protection Agency. Guidelines for the public health
management of pertussis. Available at:
www.gov.uk/government/uploads/system/uploads/
attachment_data/file/323098/HPA_Guidelines_for_the_
Public_Health_Management_of_Pertussis_2012_PB65.01-
_Oct_2012.pdf (accessed November 2015).
2 Amirhalingam G, Gupta S, Campbell H. Pertussis
immunisation and control in England and Wales, 1957 to
2012: a historical review. Euro Surveill 2013; 18: 20587.
3 Ng VL, York M, Hadley WK. Unexpected isolation of Bordetella
pertussis from patients with acquired immunodeficiency
syndrome. JClinMicrobiol1989; 27:337–338.
4 Doebbeling BN, Feilmeier ML, Herwaldt LA. Pertussis in an
adult man infected with the human immunodeficiency
virus. J Infect Dis 1990; 161: 1296–1298.
5 Cohn SE, Knorr KL, Gilligan PH et al. Pertussis is rare in
human immunodeficiency virus disease. Am Rev Respir Dis
1993; 147: 411–413.
6 Colebunders R, Vael C, Blot K et al. Bordetella pertussis as a
cause of chronic respiratory infection in an AIDS patient.
Eur J Clin Microbiol Infect Dis 1994; 13: 313–315.
7 De Martino M, Podda A, Galli L et al. A cellular
pertussis vaccine in children with perinatal human
immunodeficiency virus-type 1 infection. Vaccine 1997;
15: 1235–1238.
8 Halperin SA, Smith B, Russell M et al. An adult
formulation of a 5-component acellular pertussis vaccine
combined with diphtheria and tetanus toxoids is safe and
immunogenic in adolescents and adults. Vaccine 2000;
18: 1312–1319.
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British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s49
15. Pneumococcus
15.1 Infection and disease
Streptococcus pneumoniae, or pneumococcus, is a Gram-
positive bacterium. There are over 90 serotypes and
although all can cause infections, a few serotypes
account for most cases of disease [1]. Infection is
acquired through direct person-to-person contact via res-
piratory droplets and by autoinoculation in persons car-
rying the bacteria in their upper respiratory tract.
Pneumococci may be isolated from the nasopharynx of
healthy persons in the absence of disease. The rate of
asymptomatic carriage varies with age, environmental
factors, and the presence of other infections of the respi-
ratory tract. HIV-positive adults and children tend to
have higher carriage rates. The mechanisms that control
the healthy carrier state vs. invasive disease are poorly
understood. Pneumococci can cause: (i) upper respiratory
tract infections (e.g. otitis media and sinusitis); (ii) pneu-
monia and other lower respiratory tract infections; and
(iii) invasive pneumococcal disease (IPD), including bac-
teraemia and meningitis; the latter is frequently compli-
cated by neurological sequelae. Pneumococcal case
fatality is high, up to 15% in pneumonia and 30% in
meningitis.
15.2 Epidemiology
Pneumococcal disease occurs throughout the world,
although geographically there is wide variation in the
incidence of IPD. The greatest burden of disease is in
developing countries. In the UK infections are more com-
mon during the winter and in early spring. The pneumo-
coccus is the most frequent bacterial co-infection
associated with influenza. Rates of antibiotic resistance
are increasing in many parts of the world and susceptibil-
ity to penicillin, cephalosporin and macrolides can no
longer be assumed. Penicillin resistance is present in 5%
of UK isolates with a similar proportion of macrolide
resistant isolates. This has little impact on management
of respiratory infections, but penicillin cannot be used to
manage meningitis when resistance is present. Pneumo-
coccal infection is a major contributor to mortality
among young children in developing countries. Pneumo-
coccal disease is also common in children in developed
countries, but in these settings mortality is seen predomi-
nantly in those aged ≥65 years and adults with underly-
ing conditions [2], including:
•alcoholism,
•cancer (particularly haematological malignancy),
•chronic cardiovascular disease,
•chronic pulmonary disease (e.g. chronic obstructive
pulmonary disease or emphysema, but not asthma),
•chronic liver disease (cirrhosis),
•chronic renal disease,
•diabetes mellitus,
•absent or non-functioning spleen (e.g. sickle cell dis-
ease),
•hypogammaglobulinaemia,
•malnutrition,
•immunocompromise, including HIV infection.
15.3. Pneumococcus in HIV-positive adults
Pneumococcus infection is a significant cause of pneu-
monia and IPD in HIV-positive persons [3,4]. Disease can
occur early in the course of HIV infection and may recur.
Paediatric serotypes are frequently involved and close
contact with children is a recognised risk factor for infec-
tion. Risk factors for severe disease include low CD4 cell
counts, African race, injecting drug use, smoking, a pre-
vious AIDS-defining diagnosis, previous pneumonia,
chronic illness (i.e. lung, heart, liver, or kidney disease),
and alcoholism [5–8]. The annual attack rate of pneumo-
coccal bacteraemia was as high as 1% among persons
with AIDS [9]. The incidence of IPD has declined with
effective ART [10,11] but HIV-positive adults remain at
an approximately 40-times higher risk of disease com-
pared with age-matched HIV-negative adults. Major risk
factors for IPD are similar to those reported in HIV-nega-
tive individuals and include associated co-morbidity,
prior hospitalisation with alcoholism, and current smok-
ing as prominent [12]. Compared with HIV-negative
adults, HIV-positive persons show an increased risk of
mortality after controlling for age and severity of presen-
tation, and the risk is related to the CD4 cell count. With
an increasing proportion of associated co-morbidities in
ageing HIV-positive populations (e.g. cirrhosis, chronic
pulmonary disease) case-fatality has tended to increase in
recent years.
Universal vaccination with pneumococcal conjugate
vaccine (PCV) was introduced into the UK paediatric vac-
cine schedule in 2006; PCV-7 initially including sero-
types 4, 6B, 9V, 14, 18C, 19F and 23F; and in 2011 PCV-
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s50 BHIVA Writing Group
13 added the serotypes 1, 3, 5, 6A, 7F, 19A. These vacci-
nes have had a dramatic impact on the epidemiology of
pneumococcal disease. Not only have they been highly
effective at presenting disease from the vaccine serotypes
in the vaccinated children, but also there has been a
reduction in disease caused by vaccine serotypes in all
age groups as a consequence of herd protection. This has
however been offset by an increase in disease caused by
non-PCV serotypes. In the US, a net reduction in IPD in
HIV-positive adults of around 25% was attributed to pae-
diatric PCV use with only about 8% of IPD disease caused
by PCV-7 serotypes 5 years after introduction [13]. The
pattern has been similar in the UK with PCV-7 serotypes
dramatically reducing as a cause of disease [8]. Recent
UK surveillance among adults with IPD has also shown a
fall in the six additional serotypes included in PCV-13.
At the present time, the proportion of IPD cases caused
by PCV-13 serotypes in HIV-positive adults is unclear,
although it is likely to be falling. The burden of non-bac-
teraemic pneumococcal pneumonia is believed to be 5- to
10-times greater than the IPD burden. The contribution
of PCV-13 serotypes to this syndrome is less clear due to
difficulties of measurement, but is also likely to be falling
as a result of reduced community transmission.
15.4 Pneumococcal vaccine
Two different vaccines have been developed: the pneu-
mococcal polysaccharide vaccine (PPV) and the pneumo-
coccal protein-conjugated vaccine (PCV). Both vaccine
types have a license in the UK for use in adults and are
given by parenteral administration.
•PPV-23 is composed of purified preparations of pneu-
mococcal capsular polysaccharide from 23 different
serotypes, which has traditionally accounted for
around 90% of cases of IPD. PPV-23 has been avail-
able in the UK for much of the last 30 years. It is given
as a single dose by subcutaneous or intramuscular
injection.
•PCV vaccines were specifically designed for use in
infant populations where pure polysaccharide vaccines
fail to induce protective immune responses. Immuno-
genicity is improved by attaching the pneumococcal
polysaccharide to a “carrier” protein. Two preparations
are available: a 13-valent preparation (PCV-13) and a
10-valent preparation (PCV-10). PCV-13 has been eval-
uated in adult populations. No adult studies have been
reported with PCV-10.
No serious safety concerns have been identified with
either PPV-23 or the PCVs. Injection site reactions occur
in 30–50% of PPV-23 vaccine recipients but usually
resolve within 48 h. Local reactions are reported more
frequently following a second dose of PPV-23 than after
the first dose, especially if fewer than 3 years have
elapsed since the first injection. Systemic reactions with
fever and myalgia occur uncommonly (<1%) and more
serious adverse events are very rare. Reactions to the
PCVs may be more common than with PPV-23 but the
serious adverse event profile is similar. Contraindications
to vaccination include:
•PPV-23: vaccination given within the previous 3 years.
•PCV: previous serious adverse reaction to PCV.
15.5 Vaccine efficacy
The efficacy of pneumococcal vaccines has been the sub-
ject of significant debate. In the case of PPV there have
been a limited number of randomised controlled trials
(RCT) and large number of observational studies with sig-
nificant variation in reports of efficacy, particularly in
those reported from outside the US. In the case of PCV,
there is a much smaller literature, although this includes
two RCTs with consistent results.
15.5.1 PPV-23: immunogenicity
More than 80% of healthy young adults who receive
PPV-23 develop antibodies against the serotypes con-
tained in the vaccine, usually within 2–3 weeks. In older
adults and persons with underlying conditions, responses
are often reduced or absent. HIV-positive adults produce
significantly lower peak levels and durability of response
compared to HIV-negative adults. The functional quality
of antibodies produced in HIV-positive adults in response
to PPV is also significantly impaired in comparison to
HIV-negative adults. ART use has not been shown to
convincingly improve response to PPV-23 [14–19]. The
degree of immunodeficiency as measured by CD4 cell
count may also affect immunogenicity [15,20]. HIV-posi-
tive patients with CD4 cell counts <500 cells/lL have
shown lower responses than patients with higher CD4 cell
counts [21], although this effect is not consistent across
reports [22–24]. Routine boosting is not recommended in
immunocompetent individuals previously vaccinated with
the PPV-23 vaccine. However revaccination after
5–10 years of the first dose is part of general guidance
for the use of PPV-23 in specific risk groups. Repeat
doses of PPV in HIV-positive adults however produce
attenuated antibody responses [25]. Recent studies in tha-
lassaemic patients have suggested a dose-dependent
attenuation in pneumococcal memory responses with
repeat doses of PPV [26]. Importantly, the relationship
between antibody levels and protection from IPD is not
certain in adult populations.
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British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s51
15.5.2 PPV-23: clinical efficacy
Overall, PPV-23 is estimated to be approximately 60%
effective in preventing IPD in otherwise healthy older
adults, but is less or ineffective in those groups that also
have the greatest risk of disease. PPV-23 efficacy against
non-bacteraemic pneumonia has not been demonstrated
unequivocally. Several meta-analyses have shown that
vaccination reduced bacteraemic pneumococcal pneumo-
nia in low-risk adults, but did not show efficacy against
non-bacteraemic pneumonia and in high-risk groups [27–
30]. Studies on the clinical efficacy of pneumococcal vac-
cination in HIV-positive adults have reported inconsistent
findings. Most have been conducted in persons not
receiving ART or receiving suboptimal mono and dual
therapy. In the only randomised controlled trial, the vac-
cine showed no efficacy in reducing the risk of pneumo-
coccal disease among Ugandan HIV-positive persons not
taking ART [31]. Surprisingly, there was a borderline
increase in pneumonia of any cause in vaccine recipients
(HR 1.89, 95% CI 1.1–3.2). Follow-up reports showed a
persistent excess of “all-cause” pneumonia in vaccine
recipients –although a small survival advantage was also
observed in this extremely high mortality study [32].
Ten observational studies of varying size and quality
have been reported evaluating PPV-23 in routine use
against a pneumococcal disease end-point, six from the
USA [5,6,33–36], two from Spain [37,38], one from Brazil
[39], and one from Taiwan [15]. Six studies reported
varying effectiveness (20–79%) against IPD; two studies
reported 20–35% effectiveness against pneumonia. Within
these studies effectiveness was associated with higher
CD4 cell counts (>200 or >500 cells/lL) [5,33,36], non
African-American race [6], and viral load
<100 000 copies/mL [36]. In the six studies able to evalu-
ate ART use, five confirmed this as independently protec-
tive against pneumococcal disease (50–77% effective)
with only one study showing no independent protective
effect [36]. None of the studies was able to demonstrate
an impact of ART use on PPV-23 efficacy. The underly-
ing confounding associated with vaccine receipt and risk
of pneumococcal disease remains problematic when inter-
preting these observational studies. There are no studies
reporting clinical end-point efficacy with repeat PPV-23
use in HIV-positive adults.
15.5.3 PCV
PCV is a highly effective paediatric vaccine, which is
now in use in most developed countries following a series
of successful RCTs. As noted above, the introduction of
these vaccines has led to dramatic changes in pneumo-
coccal disease epidemiology through herd protection
effects. A large-scale trial of PCV-13 in approximately
85 000 over 65-year-old HIV-negative Dutch residents
was recently completed [40]. In this study a single dose
of PCV-13 reduced vaccine serotype IPD by 75%.
15.5.4 PCV: immunogenicity
Serological studies of PCV confirm its immunogenicity in
HIV-positive adults. However responses are reduced when
compared to HIV-negative adults [41,42] and demonstra-
ble superiority of PCV response over PPV response may
be limited to certain serotypes [43–49]. Durability of
serological response appears to be enhanced by ART
usage [50,51] and repeat dosing elicits a better response
than with repeat doses of PPV [52].
15.5.5 PCV: clinical efficacy
The vaccine is effective in HIV-positive children, reducing
the risk of vaccine serotype IPD by 60–65% and the risk
of clinical lower respiratory tract disease by 15% [53]. A
randomised placebo-controlled trial of PCV-7 in HIV-
positive Malawian adults who had recovered from IPD,
reduced vaccine serotype IPD by 74% [54]. In this study
efficacy was unequivocally demonstrated at CD4 cell
counts <200 cells/lL. The study was not powered to
assess the interaction with ART or duration of response.
Most participants received vaccine prior to commencing
ART and efficacy was not measurable 12 months after
vaccination. The study used a two-dose schedule with
vaccinations given 1 month apart. Serological assess-
ments suggest that the second dose of vaccine may pro-
vide little if any benefit over a single dose.
15.5.6 PCV +PPV
Only serological studies are available to inform this
approach to vaccination. Serological responses to PCV
serotypes are increased by boosting with either PCV or
PPV in the majority of published studies [42,43,45,47,48].
There are no studies to support the effectiveness of this
approach to prevent disease end-points.
15.6. Pneumococcal vaccine in HIV-positive adults
The most robust evidence for the use of pneumococcal
vaccines in HIV-positive adults relates to PCV use. The
conjugated vaccines are immunogenic and have proven
to be clinically effective in RCTs including one under-
taken in HIV-positive adults with low CD4 cell counts. A
strong recommendation based on these data would be
justified for vaccine to be given at all CD4 cell counts
with or without ART, and with or without co-morbidities
that would increase pneumococcal disease risk. However,
with the routine use of PCV in the infant vaccine pro-
gramme, the burden of pneumococcal disease attributable
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s52 BHIVA Writing Group
to PCV-13 serotypes is now falling. With a large herd
protection, the clinical effectiveness of this approach may
become increasingly limited as disease burden falls. There
is a clear research need to determine the burden of IPD
and non-bacteraemic pneumonia caused by PCV-13,
PPV-23, and non-vaccine serotypes among HIV-positive
populations in the UK, in order to inform vaccination
practices.
15.7 Recommendations for HIV-positive adults
•We recommend that HIV-positive adults receive a sin-
gle dose of PCV-13 irrespective of CD4 cell count, ART
use, and viral load [1B]. This recommendation will be
reviewed in light of the evolving epidemiology of
PCV-13 type pneumococcal disease in the UK.
oPCV-13 should be given at least 3 months after any
use of PPV-23.
•We suggest that HIV-positive adults who meet the
indications for PPV-23 vaccination within the national
programme (typically aged >65 years or with co-mor-
bidity other than HIV) follow general guidance and
also receive a single dose of PPV-23 [2C].
oPPV-23 should be given at least 3 months after any
PCV-13.
•We recommend against repeat PPV-23 or repeat PCV-
13 dosing [1C].
15.8 References
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pneumococcal serogroups cause the most invasive disease:
implications for conjugate vaccine formulation and use, part
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2 van Hoek AJ, Andrews N, Waight PA et al. The effect of
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invasive pneumococcal disease in England. J Infect 2012;
65:17–24.
3 Miller RF, Foley NM, Kessel D, Jeffrey AA. Community
acquired lobar pneumonia in patients with HIV infection
and AIDS.Thorax 1994; 49: 367–368.
4 Rimland D, Navin TR, Lennox JL et al. Prospective study of
etiologic agents of community-acquired pneumonia in
patients with HIV infection. AIDS 2002; 16:85–95.
5 Dworkin MS, Ward JW, Hanson DL et al. Pneumococcal
disease among human immunodeficiency virus-infected
persons: incidence, risk factors, and impact of vaccination.
Clin Infect Dis 2001; 32: 794–800.
6 Breiman RF, Keller DW, Phelan MA et al. Evaluation of
effectiveness of the 23-valent pneumococcal capsular
polysaccharide vaccine for HIV-infected patients. Arch
Intern Med 2000; 160: 2633–2638.
7 Gilks CF, Ojoo SA, Ojoo JC et al. Invasive pneumococcal
disease in a cohort of predominantly HIV-1 infected female
sex-workers in Nairobi, Kenya. Lancet 1996; 347: 718–723.
8 Yin Z, Rice BD, Waight P et al. Invasive pneumococcal
disease among HIV-positive individuals, 2000–2009. AIDS
2012; 26:87–94.
9 Redd SC, Rutherford GW, Sande MA et al. The role of
human immunodeficiency virus infection in pneumococcal
bacteremia in San Francisco residents. J Infect Dis 1990;
162: 1012–1017.
10 Heffernan RT, Barrett NL, Gallagher KM et al. Declining
incidence of invasive Streptococcus pneumoniae infections
among persons with AIDS in an era of highly active
antiretroviral therapy, 1995–2000. J Infect Dis 2005; 191:
2038–2045.
11 Grau I, Pallares R, Tubau F et al. Epidemiologic changes in
bacteremic pneumococcal disease in patients with human
immunodeficiency virus in the era of highly active
antiretroviral therapy. Arch Intern Med 2005; 165: 1533–
1540.
12 Grau I, Ardanuy C, Linares J et al. Trends in mortality and
antibiotic resistance among HIV-infected patients with
invasive pneumococcal disease. HIV Med 2009; 10: 488–
495.
13 Cohen AL, Harrison LH, Farley MM et al. Prevention of
invasive pneumococcal disease among HIV-infected adults
in the era of childhood pneumococcal immunization. AIDS
2010; 24: 2253–2262.
14 Rodriguez-Barradas MC, Alexandraki I, Nazir T et al.
Response of human immunodeficiency virus-infected
patients receiving highly active antiretroviral therapy to
vaccination with 23-valent pneumococcal polysaccharide
vaccine. Clin Infect Dis 2003; 37: 438–447.
15 Hung CC, Chen MY, Hsieh SM et al. Clinical experience of
the 23-valent capsular polysaccharide pneumococcal
vaccination in HIV-1-infected patients receiving highly
active antiretroviral therapy: a prospective observational
study. Vaccine 2004; 22: 2006–2012.
16 Subramaniam KS, Segal R, Lyles RH et al. Qualitative
change in antibody responses of human immunodeficiency
virus-infected individuals to pneumococcal capsular
polysaccharide vaccination associated with highly active
antiretroviral therapy. J Infect Dis 2003; 187: 758–768.
17 Iyer AS, Leggat DJ, Ohtola JA et al. Response to
pneumococcal polysaccharide vaccination in HIV-positive
individuals on long term highly active antiretroviral
therapy. J AIDS Clin Res 2015; 6: 421.
18 Leggat DJ, Iyer AS, Ohtola JA et al. Response to
pneumococcal polysaccharide vaccination in newly
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diagnosed HIV-positive individuals. J AIDS Clin Res 2015;
6: 419.
19 Rodriguez-Barradas MC, Serpa JA, Munjal I et al.
Quantitative and qualitative antibody responses to
immunization with the pneumococcal polysaccharide
vaccine in HIV-Infected patients after initiation of
antiretroviral treatment: results from a randomized clinical
trial. J Infect Dis 2015; 211: 1703–1711.
20 Loeliger AE, Rijkers GT, Aerts P et al. Deficient
antipneumococcal polysaccharide responses in HIV-
seropositive patients. FEMS Immunol Med Microbiol 1995;
12:33–41.
21 Rodriguez-Barradas MC, Musher DM, Lahart C et al.
Antibody to capsular polysaccharides of Streptococcus
pneumoniae after vaccination of human immunodeficiency
virus-infected subjects with 23-valent pneumococcal
vaccine. J Infect Dis 1992; 165: 553–556.
22 Vandenbruaene M, Colebunders R, Mascart-Lemone F et al.
Equal IgG antibody response to pneumococcal vaccination
in all stages of human immunodeficiency virus disease.
J Infect Dis 1995; 172: 551–553.
23 French N, Gilks CF, Mujugira A, Fasching C et al.
Pneumococcal vaccination in HIV-1-infected adults in
Uganda: humoral response and two vaccine failures. AIDS
1998; 12: 1683–1689.
24 Amendola A, Tanzi E, Zappa A et al. Safety and
immunogenicity of 23-valent pneumococcal polysaccharide
vaccine in HIV-1 infected former drug users. Vaccine 2002;
20: 3720–3724.
25 Tasker SA, Wallace MR, Rubins JB et al. Reimmunization
with 23-valent pneumococcal vaccine for patients infected
with human immunodeficiency virus type 1: clinical,
immunologic, and virologic responses. Clin Infect Dis 2002;
34: 813–821.
26 Papadatou I, Piperi C, Alexandraki K et al. Antigen-specific
B-cell response to 13-valent pneumococcal conjugate
vaccine in asplenic individuals with beta-thalassemia
previously immunized with 23-valent pneumococcal
polysaccharide vaccine. Clin Infect Dis 2014; 59: 862–865.
27 Huss A, Scott P, Stuck AE et al. Efficacy of pneumococcal
vaccination in adults: a meta-analysis. CMAJ 2009; 180:
48–58.
28 Cornu C, Yzebe D, Leophonte P et al. Efficacy of
pneumococcal polysaccharide vaccine in immunocompetent
adults: a meta-analysis of randomized trials. Vaccine 2001;
19: 4780–4790.
29 Moore RA, Wiffen PJ, Lipsky BA. Are the pneumococcal
polysaccharide vaccines effective? Meta-analysis of the
prospective trials. BMC Fam Pract 2000; 1:1.
30 Fine MJ, Smith MA, Carson CA et al. Efficacy of
pneumococcal vaccination in adults. A meta-analysis of
randomized controlled trials. Arch Intern Med 1994; 154:
2666–2677.
31 French N, Nakiyingi J, Carpenter LM et al. 23-valent
pneumococcal polysaccharide vaccine in HIV-1-infected
Ugandan adults: double-blind, randomised and placebo
controlled trial. Lancet 2000; 355: 2106–2111.
32 Watera C, Nakiyingi J, Miiro G et al. 23-Valent
pneumococcal polysaccharide vaccine in HIV-infected
Ugandan adults: 6-year follow-up of a clinical trial cohort.
AIDS 2004; 18: 1210–1213.
33 Gebo KA, Moore RD, Keruly JC, Chaisson RE. Risk factors
for pneumococcal disease in human immunodeficiency
virus-infected patients. J Infect Dis 1996; 173: 857–862.
34 Guerrero M, Kruger S, Saitoh A et al. Pneumonia in HIV-
infected patients: a case-control survey of factors involved
in risk and prevention. AIDS 1999; 13: 1971–1975.
35 Rodriguez-Barradas MC, Goulet J, Brown S et al. Impact of
pneumococcal vaccination on the incidence of pneumonia
by HIV infection status among patients enrolled in the
Veterans Aging Cohort 5-Site Study. Clin Infect Dis 2008;
46: 1093–1100.
36 Teshale EH, Hanson D, Flannery B et al. Effectiveness of
23-valent polysaccharide pneumococcal vaccine on
pneumonia in HIV-infected adults in the United States,
1998–2003. Vaccine 2008; 26: 5830–5834.
37 Lopez-Palomo C, Martin-Zamorano M, Benitez E et al.
Pneumonia in HIV-infected patients in the HAART era:
incidence, risk, and impact of the pneumococcal
vaccination. J Med Virol 2004; 72: 517–524.
38 Penaranda M, Falco V, Payeras A et al. Effectiveness of
polysaccharide pneumococcal vaccine in HIV-infected
patients: a case-control study. Clin Infect Dis 2007; 45:
e82–e87.
39 Veras MA, Enanoria WT, Castilho EA, Reingold AL.
Effectiveness of the polysaccharide pneumococcal vaccine
among HIV-infected persons in Brazil: a case control study.
BMC Infect Dis 2007; 7: 119.
40 Bonten M, Bolkenbaas M, Huijts S et al. Community
acquired pneumonia immunisation trial in adults (CAPITA).
Pneumonia 2004; 3:1.
41 Gordon SB, Kayhty H, Molyneux ME et al. Pneumococcal
conjugate vaccine is immunogenic in lung fluid of HIV-
infected and immunocompetent adults. J Allergy Clin
Immunol 2007; 120: 208–210.
42 Chen M, Ssali F, Mulungi M et al. Induction of
opsonophagocytic killing activity with pneumococcal
conjugate vaccine in human immunodeficiency virus-
infected Ugandan adults. Vaccine 2008; 26: 4962–4968.
43 Feikin DR, Elie CM, Goetz MB et al. Randomized trial of the
quantitative and functional antibody responses to a 7-
valent pneumococcal conjugate vaccine and/or 23-valent
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s54 BHIVA Writing Group
polysaccharide vaccine among HIV-infected adults. Vaccine
2001; 20: 545–553.
44 Kroon FP, van Dissel JT, Ravensbergen E et al. Enhanced
antibody response to pneumococcal polysaccharide vaccine
after prior immunization with conjugate pneumococcal
vaccine in HIV-infected adults. Vaccine 2000; 19: 886–894.
45 Lesprit P, Pedrono G, Molina JM et al. Immunological
efficacy of a prime-boost pneumococcal vaccination in
HIV-infected adults. AIDS 2007; 21: 2425–2434.
46 Crum-Cianflone NF, Huppler Hullsiek K, Roediger M et al. A
randomized clinical trial comparing revaccination with
pneumococcal conjugate vaccine to polysaccharide vaccine
among HIV-infected adults. J Infect Dis 2010; 202: 1114–
1125.
47 Penaranda M, Payeras A, Cambra A et al. Conjugate and
polysaccharide pneumococcal vaccines do not improve
initial response of the polysaccharide vaccine in HIV-
infected adults. AIDS 2010; 24: 1226–1228.
48 Ho YL, Brandao AP, de Cunto Brandileone MC, Lopes MH.
Immunogenicity and safety of pneumococcal conjugate
polysaccharide and free polysaccharide vaccines alone or
combined in HIV-infected adults in Brazil. Vaccine 2013;
31: 4047–4053.
49 Lu CL, Hung CC, Chuang YC et al. Serologic response to
primary vaccination with 7-valent pneumococcal conjugate
vaccine is better than with 23-valent pneumococcal
polysaccharide vaccine in HIV-infected patients in the era
of combination antiretroviral therapy. Hum Vaccin
Immunother 2013; 9: 398–404.
50 Sogaard OS, Schonheyder HC, Bukh AR et al. Pneumococcal
conjugate vaccination in persons with HIV: the effect of highly
active antiretroviral therapy. AIDS 2010; 24:1315–1322.
51 Slayter KL, Singer J, Lee TC et al. Immunization against
pneumococcal disease in HIV-infected patients: conjugate
versus polysaccharide vaccine before or after reconstitution
of the immune system (CTN-147). Int J STD AIDS 2013; 24:
227–231.
52 Lu CL, Chang SY, Chuang YC et al. Revaccination with 7-
valent pneumococcal conjugate vaccine elicits better
serologic response than 23-valent pneumococcal
polysaccharide vaccine in HIV-infected adult patients who
have undergone primary vaccination with 23-valent
pneumococcal polysaccharide vaccine in the era of
combination antiretroviral therapy. Vaccine 2014; 32:
1031–1035.
53 Klugman KP, Madhi SA, Huebner RE et al. A trial of a 9-
valent pneumococcal conjugate vaccine in children with
and those without HIV infection. N Engl J Med 2003; 349:
1341–1348.
54 French N, Gordon SB, Mwalukomo T et al. A trial of a 7-
valent pneumococcal conjugate vaccine in HIV-infected
adults. N Engl J Med 2010; 362: 812–822.
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British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s55
16. Poliomyelitis
16.1 Infection and disease
Poliomyelitis is caused by poliovirus serotypes 1, 2 and
3. Polioviruses are neuroinvasive enteroviruses that are
spread by the faecal-oral and respiratory routes. Most
infections are subclinical, but a minority give rise to neu-
rological manifestations including aseptic meningitis,
encephalomyelitis, and the poliomyelitis syndrome, char-
acterised by the acute onset of flaccid paralysis. The live
attenuated oral poliovirus vaccine (OPV) is shed asymp-
tomatically in the stool of vaccine recipients for several
days; shedding may be prolonged in immunocompro-
mised persons, which may allow reversion to virulence
and give rise to vaccine-associated paralytic polio (VAPP)
in vaccine recipients or their contacts.
16.2 Epidemiology
Poliomyelitis continues to occur in only a few countries
and is now exceedingly rare in the UK. The last indige-
nous case of wild-type infection was in 1984, with the
last imported case in 1993. Travellers going to certain
parts of Africa and Asia may be at risk for polio.
16.3 Poliomyelitis in HIV-positive people
No specific data are available on wild-type poliomyelitis
in HIV-positive persons. HIV-positive children –includ-
ing those who are mildly to moderately symptomatic –
retain the ability to clear enteroviruses, including vac-
cine-related poliovirus, and do not appear to be at
increased risk of prolonged OPV shedding relative to
HIV-negative children [1,2].
16.4 Polio vaccine
Replicating live attenuated OPV is no longer available in
the UK, having been replaced in 2004 with the trivalent
(serotypes 1–3) enhanced inactivated poliovirus vaccine
(IPV) in all routine vaccine schedules. The vaccine is given
to adults in combination with tetanus and diphtheria tox-
oid (Td/IPV). The vaccine is given by parenteral adminis-
tration. IPV is highly immunogenic. Antibodies to all three
poliovirus serotypes develop in >90% of healthy recipients
after two doses and in >99% after three doses. The duration
of immunity conferred by IPV is not known. A total of five
vaccine doses at the appropriate intervals (as per the UK
childhood vaccination schedule) are considered to give
lasting immunity, with reinforcing doses recommended
every 10 years for those at risk. The vaccine is well toler-
ated. Injection site reactions are common but usually self-
limited and may occur more frequently following subse-
quent doses. Fever and other systemic reactions are
uncommon. Severe systemic reactions are rare.
16.4.1 General indications
The aim of the UK national vaccination programme is to
ensure that all individuals receive at least five vaccine doses.
Td/IPV is recommended for vaccination of those aged ≥10
years. Adults who are either unvaccinated or have an uncer-
tain vaccination history are advised to receive primary
immunisation with three vaccine doses at either monthly
intervals or at 0, 1–2, and 6–12 months [3]. Two further
doses are scheduled 5 and 10 years after the last dose.
Adults who have received partial vaccination are advised to
receive the remaining doses, regardless of the interval since
the last dose and type of vaccine previously received. It is
also recommended that travellers to areas that pose a risk of
exposure should ensure they are fully vaccinated.
16.5 Polio vaccine in HIV-positive adults
Both OPV and IPV can elicit neutralising antibody
responses in HIV-positive children and adults, and in
patients with CD4 cell counts <300 cells/lL[4–9]. The
seroprevalence of poliovirus-neutralising antibodies var-
ies among HIV-positive adults. HIV-positive patients born
and resident in the UK since 1962 will have generally
received a complete five-dose vaccine course as part of
routine childhood immunisation. High prevalence rates,
comparable to those in normal controls, have been
reported in some cohorts. However, in a seroepidemiolog-
ical study of Italian drug users, those with HIV infection
were more likely to lack protection, with 34% seronega-
tive for poliovirus type 3 and 11% lacking neutralising
antibodies to all three virus types [10]. OPV is contraindi-
cated in patients with HIV and their contacts. IPV can be
administered safely to immunocompromised adults.
16.6. Post-exposure prophylaxis
Following inadvertent administration of OPV, exposure to
a close contact given OPV, or exposure to wild-type
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s56 BHIVA Writing Group
poliovirus, immunocompromised patients can receive
post-exposure prophylaxis with intramuscular human
normal immunoglobulin (HNIG). A serum should be col-
lected for baseline serology testing, but prophylaxis
should not be delayed pending the results. HNIG is not
indicated if the patient is known to be antibody-positive
to all three poliovirus types. Stool samples are collected
1 week apart for analysis. If poliovirus is detected,
administration of HNIG is repeated at 3-weekly intervals
until two consecutive stool samples test negative. Intra-
venous immunoglobulin may be considered if intramus-
cular injections are contraindicated.
16.7 Recommendations for HIV-positive adults
•We recommend that HIV-positive adults who require
vaccination against diphtheria, tetanus, or polio be
given the Td/IPV vaccine in accordance with general
indications, and regardless of CD4 cell count, ART use,
and viral load [1B].
oWe recommend that individuals who are either
unvaccinated or have an uncertain vaccination his-
tory receive three vaccine doses at monthly interval
(or at 0, 1–2, and 6–12 months) followed by two
reinforcing doses after 5 and 10 years, whereas par-
tially vaccinated individuals should complete the
five-dose vaccine course [1B].
oWe recommend that fully vaccinated individuals
(five doses) receive a booster dose every 10 years if
at risk of exposure, typically through travel [1C].
•We recommend that individuals who may be occupa-
tionally exposed to poliovirus (e.g. laboratory workers)
be tested for specific antibodies 3 months after vacci-
nation to confirm protective immunity and revacci-
nated if required [1C].
•We recommend that HIV-positive patients who are
exposed to OPV or wild-type polio are considered for
post-exposure prophylaxis with HNIG, based on con-
siderations of vaccination history, CD4 cell counts,
viral load, ART status, and poliovirus serology [1C].
16.8 References
1 Troy SB, Musingwini G, Halpern MS et al. Vaccine
poliovirus shedding and immune response to oral polio
vaccine in HIV-infected and -uninfected Zimbabwean
infants. J Infect Dis 2013; 208: 672–678.
2 Khetsuriani N, Helfand R, Pallansch M et al. Limited
duration of vaccine poliovirus and other enterovirus
excretion among human immunodeficiency virus infected
children in Kenya. BMC Infect Dis 2009; 9: 136.
3 Centers for Disease Control (CDC). Poliomyielitis. Available
at: www.cdc.gov/vaccines/pubs/pinkbook/downloads/
polio.pdf (accessed November 2015).
4 Vardinon N, Handsher R, Burke M et al. Poliovirus
vaccination responses in HIV-infected patients: correlation
with T4 cell counts. J Infect Dis 1990; 162: 238–241.
5 Barbi M, Bardare M, Luraschi C et al. Antibody response to
inactivated polio vaccine (E-IPV) in children born to HIV-
positive mothers. Eur J Epidemiol 1992; 8: 211–216.
6 Barbi M, Biffi MR, Binda S et al. Immunization in
children with HIV seropositivity at birth: antibody
response to polio vaccine and tetanus toxoid. AIDS 1992;
6: 1465–1469.
7 Mathisen GE, Allen AD. Inactivated polio vaccine
hyperimmunization in adults with HIV disease: a placebo-
controlled study. AIDS 1992; 6: 737–751.
8 Kroon FP, van Dissel JT, Labadie J et al. Antibody response
to diphtheria, tetanus, and poliomyelitis vaccines in relation
to the number of CD4+T lmphocytes in adults infected with
human immunodeficiency virus. Clin Infect Dis 1995; 21:
1197–1203.
9 Gnanashanmugam D, Troy SB, Musingwini G et al.
Immunologic response to oral polio vaccine in human
immunodeficiency virus-infected and uninfected
Zimbabwean children. Pediatr Infect Dis J 2012; 31: 176–
180.
10 Pregliasco F, Minolfi V, Boschin A et al. A
seroepidemiologic survey of immunity against poliomyelitis
in a group of HIV-positive and HIV-negative drug addicts.
Eur J Epidemiol 1995; 11: 693–695.
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British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s57
17. Rabies
17.1 Infection and disease
Rabies is caused by viruses of the Lyssavirus genus,
including the classic rabies virus genotype 1 and other
related viruses [e.g. European bat lyssaviruses (EBLV) and
Australian bat lyssavirus (ABLV)]. Rabies is transmitted
by contact with a rabid animal, generally as the result of
a bite or scratch [1–3]. Transmission may also occur
when infectious material, such as saliva or aerosolised
secretions from an infected animal, comes into contact
with mucous membranes or abraded skin, or on rare
occasions through inhalation of virus-containing aerosol.
Virus may be present in the saliva of patients with rabies,
but person-to-person spread of the disease has not been
documented, with the exception of a few cases of trans-
plant-associated transmission from donors unsuspected of
having rabies [4]. Rabies classically presents as an acute
encephalomyelitis and less commonly with an ascending
flaccid paralysis. In both forms, coma and death follow
almost invariably although a few cases of survival have
been described [5].
17.2 Epidemiology
Human rabies is common in most developing countries,
where it occurs in both urban and rural areas [1–3]. In
the majority of industrialised countries human rabies is
rare, mainly because of oral vaccination of wildlife and
mandatory vaccination of domestic animals. No case of
indigenous human rabies from terrestrial animals has
been reported in the UK since 1902. An indigenous case
of EBLV infection occurred in 2002 in a bat handler who
was bitten by a bat and did not receive pre- or post-
exposure rabies prophylaxis. Animal rabies is widespread
in every continent except Antarctica. In Asia, Africa, and
parts of Latin America both stray and domestic dogs
remain the principal vector and transmitter of rabies to
humans. Canine rabies is endemic throughout most of
these regions, and 90% of human cases with a defined
source are caused by exposure to dogs, usually in the
form of bites. Rabies reservoir species include wild mam-
mals such as racoons, skunks, foxes, and insectivorous
bats in North America; vampire bats and mongooses in
Central America; jackals, hyenas and mongooses in
Africa; wolves, foxes, and insectivorous bats in Europe;
and fruit bats in Australia. In some parts of the world,
other domestic and wild mammals such as cats and mon-
keys may transmit infection. In the UK, EBLVs have been
detected in Daubenton’s bats [6]. Public Health England
(PHE) provides indications of rabies risk by country [7].
Prevention through vaccination prior to exposure is
available but underused, and disease prevention mostly
relies on rabies post-exposure prophylaxis (rabies-PEP)
[8]. The number of people requiring rabies-PEP has
increased in recent years in the UK, and is almost 900
per year in England and Wales, of which 10% in people
potentially exposed to bats in the UK and 90% potentially
exposed overseas.
17.3 Rabies in HIV-positive adults
It is not known if the natural history of rabies is modified
by HIV infection.
17.4 Rabies vaccine
Human rabies vaccines are inactivated. Vaccines com-
monly available in Europe, North America, Australia,
and New Zealand are cell culture-based and include the
human diploid cell vaccine (HDCV), the purified chick
embryo cell vaccine (PCECV), and the purified Vero cell
rabies vaccine (PVRV) [9]. HDCV and PCECV are avail-
able in the UK. Vaccines of nerve tissue origin are still
in use in some developing countries, but are reactogenic
and some are of low immunogenicity; these are not
generally recommended, although they are still prefer-
able to no vaccine. Rabies vaccines are administered
intramuscularly (or subcutaneously if bleeding disor-
ders); the standard schedule is with three vaccine doses
given at 0, 7, and 28 (or 21) days. Intradermal adminis-
tration of smaller vaccine doses is used in some devel-
oping countries, but is generally not recommended. In
pre-exposure rabies prophylaxis, cell culture-based vac-
cines administered through the intramuscular route
induce a satisfactory antibody response in approximately
95% of healthy recipients, with rare failures; responses
are usually maintained for at least 10 years. Although
associated with mild and transient reactions, cell cul-
ture-derived rabies vaccines are considered safe [10].
Injection site reactions occur in 30–74% of vaccine
recipients, whereas mild systemic reactions are reported
in 5–40%.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s58 BHIVA Writing Group
17.4.1 Serology testing
A rabies-neutralising antibody level ≥0.5 IU/mL, as per
World Health Organization guidelines, is considered the
minimal adequate response indicating unequivocal sero-
conversion [11]. There are strict indications for serologi-
cal testing in order to guide vaccine use, and those
eligible in the UK include vaccine candidates who have
had a severe reaction to a previous vaccine dose, people
with regular and continuous exposure to rabies, and
those in whom vaccine immunogenicity may be reduced
including HIV-positive individuals. Rabies serology is
available at selected UK laboratories and advice can be
obtained through the PHE Rabies clerk on +44 (0) 20
8327 6204 or through the Animal and Plant Health
Agency (APHA) Rabies Help Line (+44 (0) 1932 357345
or (0) 1932 341111).
17.4.2 General indications for pre-exposure rabies
prophylaxis in healthy individuals
Pre-exposure rabies vaccination is offered in the UK to
the following categories:
•At continuous risk of exposure: laboratory workers
(three vaccine doses, serology testing after the primary
course and every 6 months thereafter, booster vaccine
dose if antibody titre falls below 0.5 IU/mL).
•At frequent risk of exposure: bat handlers, persons
who regularly handle imported animals, animal control
and wildlife workers, veterinary staff or zoologists who
travel regularly in rabies enzootic areas, health workers
in rabies enzootic areas who will be at risk of direct
exposure to body fluids or tissue from a patient with
confirmed or probable rabies (three vaccine doses,
booster vaccine dose at 1 year, then a booster vaccine
dose every 3–5 years, or based on serology results
where available).
•At occasional risk of exposure: travellers to rabies
enzootic areas, especially if post-exposure medical care
and rabies biologics at the destination are lacking or in
short supply, or they are undertaking higher risk activ-
ities such as cycling or running, or they are living or
staying for more than 1 month (three vaccine doses,
booster dose considered at 10 years post-primary
course if the risk recurs; serology not generally
offered). It should be noted that an Australian study
called into question such selection criteria, based on a
case series indicating that most injuries occurred
within 30 days of arrival in a rabies-endemic region,
most were injured whilst participating in common
tourist activities, more than a third did not initiate
contact with animals, and the most common injury
sites were hands and fingers –high risk sites for rabies
transmission due to rich nerve supply [12].
17.5 Post-exposure prophylaxis
Management consists of wound treatment and risk assess-
ment for appropriate rabies-PEP, taking into account the
circumstances of the exposure, including the local inci-
dence of rabies in the species involved and the immune
status of the person. Detailed guidance has been pub-
lished by PHE [9]. Contact details for specialist advice in
England, Wales, Scotland, and Northern Ireland are listed
in the Green Book (www.gov.uk/government/uploads/sys-
tem/uploads/attachment_data/file/85762/Green-Book-
Chapter-27-v3_0.pdf). For head and neck bites, treatment
should ideally be started within 12 h of reporting; for
other exposures treatment should be started ideally
within 24 h. Because the incubation period for rabies can
be prolonged, treatment should be considered whatever
the interval from exposure. Rabies-PEP initiated at an
early stage is nearly 100% effective in preventing rabies,
but delayed or incomplete treatment results in human
deaths, often associated with severe lesions on or near
the head or hand.
Rabies vaccine is the mainstay of rabies-PEP, and the
aim is to achieve an antibody titre of ≥0.5 IU/mL, as per
WHO guidelines [11], as quickly as possible. Individuals
with no prior vaccination or with an incomplete or
uncertain vaccination history are offered five vaccine
doses at 0, 3, 7, 14, and 30 days. Individuals that have
received a full primary course of a cell culture-based vac-
cine are offered two vaccine doses at 0 and 3–7 days.
Human rabies immunoglobulin (HRIG) is employed in
selected cases, and is usually given within 7 days post-
initiation of rabies vaccination in individuals who were
not fully vaccinated pre-exposure. The entire HRIG dose
(20 IU/kg) is infiltrated, if anatomically possible, in and
around the site of exposure, with any remaining solution
administered intramuscularly at a site different from that
used for the vaccine. Reactions with HRIG include local
pain and low-grade fever, but no serious adverse reac-
tions have been reported. In developing countries, equine
rabies immunoglobulin (ERIG) is sometimes used, which
has a higher incidence of adverse effects and may vary in
quality.
In the US and Australia the full vaccine course for
rabies-PEP consists of four vaccine doses (at 0, 3, 7, and
14 days), with a fifth dose offered (day 28) only in the
case of immune impairment (through disease or treat-
ment) [12].
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s59
17.6 Rabies vaccine in HIV-positive adults
There are limited data on the immunogenicity and clini-
cal efficacy of rabies vaccines for pre- or post-exposure
prophylaxis in HIV-positive patients. Available evidence
indicates that vaccine immunogenicity is influenced by
the CD4 cell count and viral load, with low or absent
antibody responses reported in some patients with CD4
cell counts <200–250 cells/lL [13–17] or even with CD4
cell counts >500 cells/lL [9]. Effective ART has been
shown to restore antibody responses to vaccination [18].
Approximately 88% of subjects with CD4 cell counts
>450 cells/lL while receiving stably suppressive ART
(6 months) develop a protective antibody response to
three doses of a cell culture-based vaccine [19]. The dura-
tion of responses is reduced relative to HIV-negative per-
sons, and is affected by ART discontinuation [18,19].
Higher (double) and more frequent vaccine doses, and
combined intradermal and subcutaneous vaccine admin-
istration have been proposed as management options for
HIV-positive patients who fail to mount an acceptable
antibody response, but data are limited [12]. Whether the
intradermal route may be more effective at producing an
immune response in HIV-positive patients than intramus-
cular vaccine remains unclear [20]. Current opinion is
that caution is needed in assessing HIV-positive patients
after a potential rabies exposure even when immunocom-
promise is thought to be mild [12]. In the few studies
reported, rabies cell culture-based vaccines were well tol-
erated in HIV-positive persons [12–17], including when
vaccines were used at double the standard dose [12].
17.7 Recommendations for HIV-positive adults
17.7.1 Pre-exposure prophylaxis for travellers.
•We recommend that HIV-positive adults who are at risk
of rabies exposure through travel be counselled about
pre-exposure prophylaxis and offered vaccination with
a cell culture-derived vaccine as indicated [1B].
oWe recommend three vaccine doses be given intra-
muscularly on days 0, 7, and 28. Advancing the
third dose to day 21 is not recommended because it
may curtail the immune response [1B].
oWe recommend that patients be counselled about
the risk of poor vaccine immunogenicity, which is
reduced although not abolished in patients with CD4
cell counts >500 cells/lL who are receiving stably
suppressive ART [1B].
oWe recommend that patients at increased risk of
vaccine failure (based upon CD4 cell count, ART
use, and viral load) undergo rabies serology testing
2–4 weeks after the last vaccine dose, and if the
antibody response is <0.5 IU/mL be offered a boos-
ter vaccine dose, followed by repeat serology testing
[1C]. We suggest that the booster may be given at
double the standard dose to increase immunogenic-
ity [2C].
•We recommend that if the risk of travel-related expo-
sure recurs, a first booster be offered 1 year after com-
pletion of the primary vaccine course, and subsequent
boosters be given every 3–5 years or based on the
results of serology testing where indicated [1C].
•We recommend travellers be advised that vaccination
does not eliminate the need for wound management
and post-exposure vaccination [GPP].
17.7.2 Pre-exposure prophylaxis for those at continuous
or frequent exposure in the occupational setting.
•We recommend that HIV-positive adults with CD4 cell
counts >200 cells/lL and stable viral load suppression
on ART be offered pre-exposure rabies vaccination with
three doses of a cell culture-derived vaccine given intra-
muscularly at 0, 7, and 28 days [1C]. We recommend
that such patients undergo rabies serology testing 2–
4 weeks after the last vaccine dose, and if the antibody
response is <0.5 IU/mL be offered a booster vaccine
dose, followed by repeat serology testing [1B]. We sug-
gest that the booster may be given at double the stan-
dard dose to increase immunogenicity [2C]. Exposure
must be avoided in those who fail to mount an accept-
able antibody response after the booster dose [GPP].
•We recommend that in patients at continuous risk of
exposure who have an initial response to vaccination,
subsequent booster doses are guided by serology test-
ing performed every 6 months as per national guid-
ance [1C].
•We recommend that in patients at frequent risk expo-
sure who have an initial response to vaccination, sub-
sequent booster doses be guided by serology testing
performed at regular intervals [1C]. We recommend
that in such patients the frequency of serology testing
may vary between 1 and 3 years, and be guided by the
CD4 cell count, ART use, and viral load at the time of
vaccination and during follow-up [1C].
•We recommend that patients with CD4 cell counts
<200 cells/lL avoid continuous or frequent exposure
to rabies [1C].
17.7.3 Post-exposure prophylaxis.
•We recommend that each case be assessed individually
following expert advice, because responses to rabies
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s60 BHIVA Writing Group
vaccination may be reduced even in patients with mild
immunodeficiency [1B].
•We recommend that the following patients are
regarded as non-immune and offered five doses of a
cell culture-derived vaccine given intramuscularly at 0,
3, 7, 14, and 30 days, together with HRIG [1C]:
oPreviously unvaccinated.
oPreviously given partial vaccination (<three doses).
oPreviously given complete vaccination (three doses)
not followed by serological evidence of an adequate
antibody response.
oUncertain vaccination history.
oCD4 cell count <500 cells/lL and not receiving sta-
bly suppressive ART.
•We suggest that patients who previously received a
complete vaccine course (three doses) followed by
serological evidence of an adequate antibody response,
and with a CD4 cell count >500 cells/lL and stable
viral load suppression (>6 months) on ART at the time
of vaccination and during subsequent follow-up may
be managed with two intramuscular vaccine doses
given at 0 and 3–7 days and without HRIG [2D].
•We recommend that all patients undergo serology test-
ing 2 weeks after the last vaccine dose to determine
responses to vaccination and that non-responders are
offered double-dose and/or more frequent vaccine
doses accordingly [1C], and are considered for com-
bined intradermal and subcutaneous double-dose vac-
cine administration [1D].
17.8 References
1 World Health Organization. Rabies. Available at:
www.who.int/rabies/en/ (accessed November 2015).
2 Crowcroft NS, Thampi N. The prevention and management
of rabies. Br Med J 2015; 350: g7827.
3 Fooks AR, Banyard AC, Horton DL et al. Current status of
rabies and prospects for elimination. Lancet 2014; 384:
1389–1399.
4 Srinivasan A, Burton EC, Kuehnert MJ et al. Transmission
of rabies virus from an organ donor to 4 transplant
recipients. N Engl J Med 2005; 352: 1103–1111.
5 de Souza A, Madhusudana SN. Survival from rabies
encephalitis. J Neurol Sci 2014; 339:8–14.
6 Fooks AR, Brookes SM, Healy D et al. Detection of
antibodies to EBLV–2 in Daubenton’s bats in the UK. Vet
Rec 2004; 154: 245–246.
7 Public Health England. Rabies risks by country. Available
at: www.gov.uk/government/publications/rabies-risks-by-
country (accessed November 2015).
8 Dodet B, Durrheim DN, Rees H. Rabies: underused vaccines,
unnecessary deaths. Vaccine 2014; 32: 2017–2019.
9 Public Health England. Rabies post-exposure prophylaxis:
management guidelines. Available at: www.gov.uk/
government/publications/rabies-post-exposure-prophylaxis-
management-guidelines (accessed November 2015).
10 Dobardzic A, Izurieta H, Woo EJ et al. Safety review of the
purified chick embryo cell rabies vaccine: data from the
Vaccine Adverse Event Reporting System (VAERS), 1997–
2005. Vaccine 2007; 25: 4244–4251.
11 World Health Organization. Rabies vaccines: WHO position
paper. Wkly Epidemiol Rec 2010; 85: 309–320. Available at:
www.who.int/wer/2010/wer8532.pdf (accessed November
2015).
12 Conroy N, Vlack S, Williams JM et al. Using serology to
assist with complicated post-exposure prophylaxis for rabies
and Australian Bat Lyssavirus. PLoS Negl Trop Dis 2013; 7:
e2066.10.
13 Thisyakorn U, Pancharoen C, Ruxrungtham K et al. Safety
and immunogenicity of preexposure rabies vaccination in
children infected with human immunodeficiency virus type
1. Clin Infect Dis 2000; 30: 218.
14 Thisyakorn U, Pancharoen C, Wilde H. Immunologic and
virologic evaluation of HIV-1-infected children after rabies
vaccination. Vaccine 2001; 8: 1534–1537.
15 Tantawichien T, Jaijaroensup W, Khawplod P, Sitprija V.
Failure of multiple-site intradermal postexposure rabies
vaccination in patients with human immunodeficiency virus
with low CD4 T lymphocyte counts. Clin Infect Dis 2001;
33: E122–E124.
16 Jaijaroensup W, Tantawichien T, Khawplod P et al.
Postexposure rabies vaccination in patients infected with
human immunodeficiency virus. Clin Infect Dis 1999; 28:
913–914.
17 Pancharoen C, Thisyakorn U, Tantawichien T et al.
Failure of pre- and postexposure rabies vaccinations in a
child infected with HIV. Scand J Infect Dis 2001; 33:
390–391.
18 Gelinck LB, Jol-van der Zijde CM et al. Restoration of
the antibody response upon rabies vaccination in HIV-
infected patients treated with HAART. AIDS 2009; 23:
2451–2458.
19 Azzoni L, Foulkes AS, Firnhaber C et al. Antiretroviral
therapy interruptions result in loss of protective humoral
immunity to neoantigens in HIV-infected individuals. AIDS
2012; 26: 1355–1362.
20 Sirikwin S, Likanonsakul S, Waradejwinyoo S et al.
Antibody response to an eight-site intradermal rabies
vaccination in patients infected with human
immunodeficiency virus. Vaccine 2009; 27: 4350–4354.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s61
18. Smallpox
18.1 Infection and disease
Variola virus, a member of the Orthopoxviridae, causes
smallpox. The infection is spread through droplets and
aerosol and the most common mode of transmission is
through face-to-face contact with an infectious individual
[1]. The fatality rate is ~25% overall, and severe compli-
cations such as blindness can occur. Following a world-
wide vaccination campaign, smallpox was declared
eradicated from the world in 1980 and routine vaccina-
tion was stopped. The last naturally occurring case in the
world was in Somalia in 1977. Vaccine programmes were
later restarted in several countries (e.g. in the military or
healthcare workers) in response to a hypothetical threat
from bioterrorism [1–3]. In the UK, people who were vac-
cinated against smallpox prior to national programmes
being discontinued (i.e. most people born before 1971)
will have some level of protection [4,5]; the vaccine is
currently available for selected individuals who may
come in contact with orthopox viruses through their
occupation (e.g. laboratory workers). Some governments
have stockpiled smallpox vaccines for deployment in case
of intentional or accidental release [2,3].
18.2 Smallpox vaccine
Replicating smallpox vaccines such as ACAM2000 are
prepared with live vaccinia virus, which is closely related
to the smallpox virus, and administered percutaneously
via scarification in the skin of the upper arm [2,3]. Virus
replication at the injection site produces a major cuta-
neous reaction or “take”, which indicates a successful
immune response. Primary vaccination is administered in
a single dose; a booster dose is recommended after
3 years. People who have received two doses are likely to
be protected for at least 10 years. A non-replicating vac-
cine based on modified vaccinia Ankara (Imvanex) was
approved in 2013 for use in adults, including HIV-posi-
tive patients [6]. The approval was granted under “excep-
tional circumstances” due to lack of clinical data.
Imvanex is derived from a vaccinia virus strain that was
attenuated through multiple passages in tissue culture
and lost the ability to replicate in mammalian cells. The
primary course for previously unvaccinated individuals
consists of two doses given by subcutaneous administra-
tion at least 1 month apart. Two doses are also recom-
mended for previously vaccinated patients who are
immunocompromised. There are inadequate data to deter-
mine the need for and appropriate timing of further boos-
ter doses. Imvanex does not produce a visible cutaneous
reaction following administration. In healthy persons,
smallpox vaccines are highly effective in inducing
protective immunity [2,3,6]. The protective efficacy of
Imvanex against smallpox has not been studied [6].
18.3 Vaccine safety
Replicating smallpox vaccines have been associated with
side effects ranging from frequent benign events to rare
but life-threatening complications. Among vaccine recipi-
ents, 36% become sufficiently ill to miss work, school, or
recreational activities or to have trouble sleeping [2]. In a
smallpox vaccination campaign conducted in healthcare
workers in Arkansas in 2003, there was a 2% adverse
event rate and a 0.5% hospitalisation rate [7]. Myoperi-
carditis is a recognised complication [8]. It is reported to
occur in 5.7 of 1000 primary vaccine recipients; most
cases are mild and self-limited with few documented
reports of dilated cardiomyopathy [3]. Other serious
adverse events include encephalitis, encephalomyelitis,
encephalopathy, progressive vaccinia, generalised vac-
cinia, severe vaccinial skin infections, erythema multi-
forme major (including Stevens–Johnson syndrome), and
eczema vaccinatum (severe and destructive infection of
skin affected by eczema or other chronic skin disorder
caused by spread of vaccinia virus). Permanent sequelae
or death, ocular complications, blindness, and fetal death
have occurred following either primary vaccination or
revaccination with replicating smallpox vaccines [3].
Inadvertent transfer from the site of inoculation causes
swelling, tenderness and rash at the site of transfer, and
may result in vaccinia keratitis and subsequent corneal
scarring. Progressive vaccinia is characterised by a slow
and uncontrolled growth of vaccinia virus at the site of
inoculation, frequently complicated by viraemia and gen-
eralised infection involving skin and multiple organs,
with a 40–80% risk of mortality; it usually occurs in the
presence of immunodeficiency. Death is most often the
result of encephalitis or progressive vaccinia.
A vaccinated person can transmit the vaccine virus
directly through contact with the injection site and indi-
rectly through objects that come in contact with the area
around the vaccination site, including clothes, bedding,
bandages and furniture. Infectivity lasts until the
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s62 BHIVA Writing Group
vaccination wound has healed and the scab has fallen
off, usually within 14–21 days.
Contraindications to replicating smallpox vaccines
include:
•Pregnancy and breast-feeding. The overall risk associ-
ated with maternal smallpox vaccination appears low.
Fetal vaccinia is a rare consequence but is associated
with a high rate of fetal loss [9].
•Current or past eczema and atopic dermatitis, or a cur-
rent significant skin condition.
•Heart disease, or at least three known major cardiac
risk factors.
•Immunodeficiency caused by disease or treatment (in-
cluding HIV infection).
•The vaccines are generally not recommended for those
>65 years of age.
Imvanex appears to be safe and well tolerated and does
not increase the risk for development of myopericarditis
[3,10]. The most common adverse reactions observed in
clinical trials were injection site reactions and mild to
moderate systemic reactions that resolved without inter-
vention within 7 days following vaccination. Imvanex is
preferable for individuals at increased risk of adverse
events with replicating smallpox vaccines in circum-
stances when the risk for smallpox is minimal and a
delay in the onset of immunity (relative to using the
replicating vaccine) would not increase this risk to an
unacceptable level [3]. As a precautionary measure, use is
avoided during pregnancy and breastfeeding unless it is
considered that the possible benefit in terms of prevent-
ing smallpox would outweigh the potential risk.
18.4 Smallpox vaccine in HIV-positive adults
Although the safety of the replicating vaccine ACAM2000
has not been studied in persons with HIV infection, HIV-
positive persons with low CD4 cell counts are at risk of
progressive vaccinia when vaccinated with replicating
smallpox vaccines [11–13]. In a study of 10 military
recruits with a mean CD4 cell count of 483 cells/lL
(range 286–751) the replicating vaccine was well toler-
ated and immunogenic [13]; however, there is one case
report of progressive vaccinia in a HIV-positive military
recruit who received smallpox vaccination in 1984 with a
CD4 cell count <25 cells/lL [12]. The non-replicating
vaccine Imvanex was well tolerated and highly immuno-
genic in 91 HIV-positive patients with CD4 cell counts
≥350 cells/lL and viral load <400 copies/mL, with no
vaccine-related serious adverse events and an overall
safety profile comparable to that of uninfected subjects
[14]. LC16m8, a replicating smallpox vaccine licensed in
Japan, shows reduced virulence in animal studies and has
been proposed as a potential option for immunocompro-
mised patients [15]. This remains controversial however
as clinical data are lacking [16]. In 2014, the World
Health Organization specifically indicated that Imvanex
should be considered for use, where approved, in individ-
uals for whom replicating smallpox vaccines are con-
traindicated due to immunocompromise [17].
In the past, high doses of intravenous vaccinia
immunoglobulin (VIGIV) derived from immunised indi-
viduals appeared to be effective in halting a proportion
of cases of progressive vaccinia. The experience with
VIGIV for the treatment of progressive vaccinia in per-
sons with AIDS is limited to one reported case [12].
Antiviral drugs such as cidofovir (or others in advanced
stages of development such as liposomal cidofovir,
tecovirimat or brincidofovir) are recommended for the
treatment of complications [3], although clinical data are
scarce.
18.5 Post-exposure prophylaxis
Persons exposed to smallpox are at high risk for develop-
ing smallpox and transmitting the virus to others. Vacci-
nation with replicating smallpox vaccines given within
3 days of exposure prevents disease or reduces its sever-
ity; partial protection is observed if post-exposure pro-
phylaxis is started after 4–7 days of exposure. There are
no absolute contraindications to the use of replicating
smallpox vaccines in this setting [3]. Whilst persons with
atopic dermatitis (eczema), HIV infection with CD4 cell
counts of 50–199 cells/lL, other immunocompromised
states, and persons with vaccine or vaccine-component
allergies are at higher risk for adverse events, replicating
vaccines still are recommended in these groups as the risk
of severe smallpox is considered higher than the risk of
vaccine-related adverse events [3]. Although persons vac-
cinated with Imvanex have a lower risk for serious
adverse events, protection is less certain also considering
the requirement for two doses given at least 1 month
apart. Persons with severe immunodeficiency, including
HIV-positive patients with CD4 cell counts <50 cells/lL,
are not expected to benefit from vaccination and can be
managed with appropriate antivirals, or Imvanex when
antivirals are not immediately available [3].
18.6 Recommendations for HIV-positive adults
•We recommend that all vaccine candidates are
informed that smallpox vaccines might pose a serious
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s63
risk to people with HIV infection, and that HIV testing
is offered prior to vaccination to those who wish to be
tested [1B].
•We recommend that for vaccine candidates who are
HIV-positive, an assessment is made of the risk of con-
tracting smallpox vs. the risk of vaccine-related side
effects, using the CD4 cell count as a guide to inform
vaccine use [1B].
•We recommend that in cases where vaccination is indi-
cated but there is no urgency to induce a rapid immune
response (e.g. most occupational settings) HIV-positive
adults regardless of CD4 cell counts receive the non-
replicating smallpox vaccine Imvanex, with two doses
given subcutaneously at least 1 month apart [1B].
•We recommended that in selected scenarios where
there is urgency to induce a rapid immune response,
patients with CD4 cell counts ≥200 cells/lL may be
offered a replicating smallpox vaccine followed by
close monitoring for adverse events [1C].
•We recommend that following exposure, patients with
CD4 cell counts >50 cells/lL are offered vaccination
with a replicating smallpox vaccine given preferably
within 3 days and up to 10 days after the exposure
[1C]. We suggest that in similar circumstances patients
with CD4 cell counts <50 cells/lL are unlikely to
respond to vaccination and should be managed by
appropriate antiviral therapy, although there is no
absolute contraindication to Imvanex vaccination [2C].
Expert opinion should be sought.
•We recommended that vaccine recipients who experi-
ence vaccine complications should receive VIGIV and/
or appropriate antiviral therapy according to availabil-
ity [1C]. Expert opinion should be sought.
•We recommend that HIV-positive persons avoid close
contact with recipients of replicating smallpox vacci-
nes as they may spread the vaccine virus through
direct or indirect contact with the vaccine reaction site
[1C].
18.7 References
1 Adalja AA, Toner E, Inglesby TV. Clinical management of
potential bioterrorism-related conditions. N Engl J Med
2015; 372: 954–962.
2 Centers for Disease Control and Prevention. Smallpox.
Available at: www.bt.cdc.gov/agent/smallpox/ (accessed
November 2015).
3 Petersen BW, Damon IK, Pertowski CA et al. Clinical
guidance for smallpox vaccine use in a postevent
vaccination program. MMWR Recomm Rep 2015; 64:1–26.
4 Cohen J. Smallpox vaccinations: how much protection
remains? Science 2001; 294: 885.
5 Taub DD, Ershler WB, Janowski M et al. Immunity from
smallpox vaccine persists for decades: a longitudinal study.
Am J Med 2008; 121: 1058–1064.
6 Imvanex. Summary of product characteristics. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/
EPAR_-_Product_Information/human/002596/
WC500147896.pdf (accessed November 2015).
7 Haselow D. Vaccination-related side effects, humoral
immunity, and adverse events during the civilian smallpox
vaccination campaign, Arkansas, 2003. Public Health Nurs
2015; 33: 129–138.
8 Engler RJ, Nelson MR, Collins LC Jr et al. A prospective
study of the incidence of myocarditis/pericarditis and new
onset cardiac symptoms following smallpox and influenza
vaccination. PLoS One 2015; 10: e0118283.
9 Badell ML, Meaney-Delman D, Tuuli MG et al. Risks
associated with smallpox vaccination in pregnancy: a
systematic review and meta-analysis. Obstet Gynecol 2015;
125: 1439–1451.
10 Zitzmann-Roth EM, von Sonnenburg F, de la Motte S et al.
Cardiac safety of modified vaccinia Ankara for vaccination
against smallpox in a young, healthy study population.
PLoS One 2015; 10: e0122653.
11 Freed ER, Duma RJ, Escobar MR. Vaccinia necrosum and its
relationship to impaired immunologic responsiveness. Am J
Med 1972; 52: 411–420.
12 Redfield RR, Wright DC, James WD et al. Disseminated
vaccinia in a military recruit with human
immunodeficiency virus (HIV) disease. N Engl J Med
1987; 316: 673–676.
13 Tasker SA, Schnepf GA, Lim M et al. Unintended
smallpox vaccination of HIV-1-infected individuals in the
United States military. Clin Infect Dis 2004; 38: 1320–
1322.
14 Greenberg RN, Overton ET, Haas DW et al. Safety,
immunogenicity, and surrogate markers of clinical efficacy
for modified vaccinia Ankara as a smallpox vaccine in HIV-
infected subjects. J Infect Dis 2013; 207: 749–758.
15 Yokote H, Shinmura Y, Kanehara T et al. Safety of
attenuated smallpox vaccine LC16 m8 in immunodeficient
mice. Clin Vaccine Immunol 2014; 21: 1261–1266.
16 Danon YL, Sutter G. Use of the LC16 m8 smallpox vaccine
in immunocompromised individuals is still too risky. Clin
Vaccine Immunol 2015; 22: 604.
17 World Health Organization. Meeting of the Strategic
Advisory Group of Experts on Immunization, November
2013: conclusions and recommendations. Wkly Epidemiol
Rec 2014; 18:1–20.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s64 BHIVA Writing Group
19. Tetanus
19.1. Infection and disease
Tetanus is caused by the action of a neurotoxin
(tetanospasmin) released by the Gram-positive, anaerobic
bacterium Clostridium tetani [1,2]. The bacterium and its
spores are found primarily in the soil and intestinal tracts
of animals and humans. Transmission occurs when spores
are introduced into the body, typically through puncture
wounds, burns and scratches, but also through trivial,
unnoticed wounds, injecting drug use and occasionally
abdominal surgery. Tetanus spores are widely distributed
in soil or manure and may be introduced to a wound
easily following an injury. The spores can also be found
on skin surfaces and in contaminated heroin and drug
paraphernalia. In the presence of anaerobic conditions,
the spores germinate and the toxins are produced and
released systemically. Tetanus is not contagious from per-
son to person. Tetanus-prone wounds or burns include
those that require surgical intervention and when that
treatment is delayed for more than 6 h; show a signifi-
cant degree of devitalised tissue; are a puncture-type
injury particularly in contact with soil or manure; con-
tain foreign bodies; are compound fractures; or occur in
patients who have systemic sepsis. In its most common
manifestation, tetanus is characterised by generalised
rigidity and spasms of skeletal muscles and can lead to
respiratory and cardiac failure. The case fatality ratio is
29% overall, but ranges from 8% to 90%. Recovery from
tetanus may not result in immunity, and vaccination fol-
lowing tetanus is indicated.
19.2 Epidemiology
Tetanus occurs worldwide but is most common in densely
populated regions in hot, damp climates with soil rich in
organic matter. Tetanus has occurred only rarely among
persons who had previously received a primary vaccine
course. The proportions of persons lacking protective
levels of circulating antitoxins against tetanus increase
with age; at least 40% of those aged >60 years may lack
protection. Between 2001 and 2012, 88 cases of tetanus
were reported in the UK, mostly in individuals aged
≥45 years who had not been appropriately immunised
[2]. In 2003–2004 a first cluster of cases of tetanus occur-
ring in young injecting drug users (IDUs) was identified
(case fatality 8%). Following this cluster, only sporadic
cases of tetanus were reported in IDUs in England to the
end of 2014 [2,3].
19.3 Tetanus in HIV-positive adults
In a US cohort of HIV-positive patients, 94% of those
born in the US had evidence of tetanus immunity at the
time of HIV diagnosis, whereas only 55% of those born
outside the US had a positive tetanus antibody test [4]. It
is not known whether the natural history of tetanus is
modified by HIV infection.
19.4 Tetanus vaccine
The tetanus vaccine is non-replicating and is made from
cell-free purified toxin extracted from C. tetani and con-
verted into tetanus toxoid. The vaccine is given to adults
in combination with diphtheria toxoid and inactivated
polio vaccine (Td/IPV). The vaccine is given by parenteral
administration. The tetanus vaccine is highly immuno-
genic and effective. Although antitoxin levels decrease
with age, the majority of vaccinated adults maintain pro-
tective antitoxin levels for many years. A total of five
vaccine doses at the appropriate intervals (as per the UK
childhood vaccination schedule) are considered to give
lifelong immunity, with reinforcing doses recommended
every 10 years for those at risk. The vaccine is well toler-
ated. Injection site reactions are common but usually
self-limited and may occur more frequently following
subsequent doses. Fever and other systemic reactions are
uncommon. Severe systemic reactions are rare.
19.4.1 General indications
The aim of the UK national vaccination programme is to
ensure that all individuals receive at least five vaccine
doses. Td/IPV is recommended for vaccination of those
aged ≥10 years. Adults who are either unvaccinated or
have an uncertain vaccination history are advised to
receive primary immunisation with three vaccine doses at
either monthly intervals or at 0, 1–2, and 6–12 months.
Two further doses are scheduled 5 and 10 years after the
last dose. Adults who have received partial vaccination
are advised to receive the remaining doses, regardless of
the interval since the last dose and type of vaccine previ-
ously received. It is also recommended that travels to
areas where access to post-exposure prophylaxis may be
limited ensure they are fully vaccinated.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s65
19.5 Tetanus vaccine in HIV-positive adults
The vaccine has been shown to be immunogenic in a
variety of immunocompromised hosts including HIV-
positive adults, although less so than in HIV-negative
persons [5–10]. In HIV-positive children, serological
response rates are 60–100% after primary vaccination
and 75–90% after booster vaccination [10]. Children
show lower serum antitoxin levels compared to controls,
and antibody levels deteriorate such that non-immune
levels may be reached in <5 years [11]. Adults who
received full primary vaccination before acquiring HIV
infection may have sufficient humoral immunity for sev-
eral years and are likely to develop protective levels of
antitoxin following a booster dose. However, this
response is lower in patients aged >50 years and those
with a history of AIDS [12]. As a general rule, responses
are inversely correlated to the CD4 cell count and immu-
nity improves after successful ART [13]. There is no
reported increased risk of side effects or adverse reactions
in individuals with HIV infection.
19.6 Post-exposure prophylaxis
Tetanus vaccine and human tetanus immunoglobulin
(TIG) are used for post-exposure prophylaxis in cases of
potential exposure, and used according to the vaccination
history and type of wound. Use of TIG is guided by rec-
ommendations set out in the Green Book (www.-
gov.uk/government/uploads/system/uploads/attachment_-
data/file/148506/Green-Book-Chapter-30-dh_103982.pdf).
Efficacy in HIV-positive persons has not been established.
19.7 Recommendations for HIV-positive adults
•We recommend that HIV-positive adults who require
vaccination against diphtheria, tetanus, or polio be
given the Td/IPV vaccine in accordance with general
indications, and regardless of CD4 cell count, ART use,
and viral load [1B].
oWe recommend that individuals who are either
unvaccinated or have an uncertain vaccination
history receive three vaccine doses at 1 month
intervals, followed by two reinforcing doses after
5 and 10 years, whereas partially vaccinated indi-
viduals should complete the five-dose vaccine
course [1B].
oWe recommend that fully vaccinated individuals
(five doses) receive a booster dose every 10 years if
at risk of exposure, typically if they are due to tra-
vel to areas where they may not be able to receive
post-exposure prophylaxis in the event of a tetanus-
prone injury [1C].
oWe suggest that the interval between booster doses
may be shortened to 5 years in patients older than
50 years [2C].
•We recommend that following a potential exposure,
HIV-positive contacts receive post-exposure prophy-
laxis according to the type of exposure, the vaccina-
tion history, and the CD4 cell count [1C].
oSubjects with uncertain or incomplete (fewer than
three doses) vaccination history: three vaccine doses
at monthly intervals, regardless of type of wound
and level of risk.
oSubjects who have previously received at least three
vaccine doses with clean wound and negligible risk:
one vaccine dose if the last dose received was
>10 years previously.
oSubjects who have previously received at least three
vaccine doses with tetanus-prone wound: one vac-
cine dose if the last dose received was >10 years
previously or with CD4 cell count <200 cells/mL.
oSubjects with high-risk tetanus-prone wounds
should also receive TIG, and it is recommended that
a careful assessment is made of the likely immuno-
genicity of vaccination as the sole mechanism of
protection in patients with poor immune function
and a significant risk of exposure [1B].
19.8 References
1 Aronoff DM. Clostridium novyi,sordellii, and tetani:
mechanisms of disease. Anaerobe 2013; 24:98–101.
2 Public Health England. Tetanus: Information for health
professionals. Available at: www.gov.uk/government/
uploads/system/uploads/attachment_data/file/441356/
IMW166.02_Tetanus_information_for_health_professionals_
v1.4__2_.pdf (accessed July 2015).
3 Public Health England. Tetanus in England and Wales.
Available at: www.gov.uk/government/uploads/system/
uploads/attachment_data/file/429677/hpr1815_ttns.pdf
(accessed November 2015).
4 Alagappan K, McGowan J, DeClaro D et al. Tetanus
antibody protection among HIV-infected US-born patients
and immigrants. Int J Emerg Med 2008; 1: 123–126.
5 Kroon FP, van Dissel JT, De Jong JC, Furth RV. Antibody
response to influenza, tetanus and pneumococcal vaccines
in HIV-seropositive individuals in relation to the number of
CD4 lymphocytes. AIDS 1994; 8: 469–476.
6 Janoff EN, Hardy WD, Smith PD, Wahl SM. Humoral recall
responses in HIV infection. Levels, specificity, and affinity
of antigen-specific IgG. J Immunol 1991; 147: 2130–2135.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s66 BHIVA Writing Group
7 Bonetti TC, Succi RC, Weckx LY et al. Tetanus and
diphtheria antibodies and response to a booster dose in
Brazilian HIV-1-infected women. Vaccine 2004; 22: 3707–
3712.
8 Dieye TN, Sow PS, Simonart T et al. Immunologic and
virologic response after tetanus toxoid booster among HIV-
1- and HIV-2-infected Senegalese individuals. Vaccine
2001; 20: 905–913.
9 Rosenblatt HM, Song LY, Nachman SA et al. Tetanus
immunity after diphtheria, tetanus toxoids, and acellular
pertussis vaccination in children with clinically stable HIV
infection. J Allergy Clin Immunol 2005; 116: 698–703.
10 Borkowsky W, Steele CJ, Grubman S et al. Antibody
responses to bacterial toxoids in children infected with
human immunodeficiency virus. J Pediatr 1987; 110: 563–
566.
11 Choudhury SA, Matin F. Subnormal and waning immunity
to tetanus toxoid in previously vaccinated HIV-infected
children and response to booster doses of the vaccine. Int J
Infect Dis 2013; 17: e1249–e1251.
12 Andrade RM, Andrade AFB, Lazaro MA et al. Failure of
highly active antiretroviral therapy in reconstituting immune
response to Clostridium tetani vaccine in aged AIDS patients.
J Acquir Immune Defic Syndr 2010; 54:10–17.
13 Burton CT, Goodall RL, Samri A et al. Restoration of anti-
tetanus toxoid responses in patients initiating highly active
antiretroviral therapy with or without a boost
immunization: an INITIO substudy. Clin Exp Immunol 2008;
152: 252–257.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s67
20. Tick-borne encephalitis
20.1 Infection and disease
Tick-borne encephalitis (TBE) is an acute febrile
syndrome that can become complicated with neurologi-
cal symptoms ranging from mild meningitis to severe
encephalomyelitis [1]. It is caused by the tick-borne
encephalitis virus (TBEV), which is a Flavivirus. TBEV
can be divided into three main subtypes: European
(TBEV-Eu), Siberian (TBEV-Sib), and Far Eastern (TBEV-
Fe). Other types also circulate [2]. The infection is
transmitted to humans by the bite of an infected tick
or, less commonly, by ingestion of unpasteurised milk
from infected animals, mainly goats. Person-to-person
transmission has not been reported. Only about one-
third of those with symptomatic infection develop neu-
rological complications, which may lead to death (1–
2% or higher with certain subtypes) or sequelae (10–
20%).
20.2 Epidemiology
TBE is an emerging international public health problem
[3]. TBE is the most common tick-transmitted disease in
Central and Eastern Europe and Russia, and is endemic in
27 European countries. Infections also occur in the for-
mer Soviet Union and Asia [2]. In the UK, Ireland, Bel-
gium, the Netherlands, Luxembourg, Spain, Portugal and
Malta no autochthonous TBE cases have been registered
to date. Climate, social, economic, and demographic
changes are thought to have promoted the expansion of
the endemic region of TBE viruses [3]. There are two sea-
sonal peaks in Europe, one in May/June and the second
in September/October. Infections are related to either lei-
sure activities such as hiking, walking, and hunting, or
working in agriculture and forestry in warm, rural or
forested parts of endemic regions. Vaccination remains
the most effective protective measure against TBE for
people living in risk zones, occupationally exposed sub-
jects, and travellers to endemic areas [2,4–6]. The risk of
infection among unvaccinated travellers to a highly
endemic region is calculated to be 1/10 000 [2]. For
countries at very high risk of TBE infection, introduction
of universal TBE vaccination in children >1 year of age
onwards has been advocated. For countries with a very
low risk of TBE, vaccine recommendations apply to those
traveling to endemic areas [2,5,6].
20.3 TBE in HIV-positive adults
It is not known whether the natural history of TBE is
modified by HIV infection.
20.4 TBE vaccine
Two non-replicating whole killed vaccines are currently
in use in Europe: FSME-Immun and Encepur, which are
given by parenteral administration. Three doses are rec-
ommended, at 0, 1–3, and 6–12 months [2]. Accelerated
schedules can be implemented in emergency situations (0
and 14 days, followed by a third dose 5–12 months after
the second). Booster doses are indicated every 3–5 years,
although immunity is likely to last for longer [2]. The
two vaccines are interchangeable. TBE vaccines are
highly immunogenic in adults, with seroconversion rates
close to 100% after three doses, and cross-protection
against different subtypes [2,4–7]. The rapid vaccination
schedule has been shown to elicit similar rates of sero-
conversion in healthy individuals and is practical for
travellers; antibody titres are lower and decline more
rapidly than with the conventional schedule and therefore
the rapid schedule is best suited for short-term travellers.
The TBE vaccine is well tolerated. Injection site reactions
are the most frequent side effects. The vaccine however is
contraindicated in those with severe allergy to eggs. The
vaccine has been suspected of causing an exacerbation of
autoimmune diseases, but a cause-and-effect relationship
has not been confirmed; a risk assessment should be
made before administering the vaccine in these condi-
tions.
20.5 TBE vaccine in HIV-positive adults
Two published studies have investigated the immuno-
genicity of TBE vaccination in HIV-positive patients [8,9].
These studies suggest that the vaccine is less immuno-
genic than in HIV-negative persons, particularly at CD4
cell counts <400–500 cells/lL, although a four-dose vac-
cine course (given at 0, 1, 2, and 9–12 months) may
improve responses. The duration of protection in HIV-
positive persons is unknown, but may be reduced com-
pared to healthy individuals; however, there is insuffi-
cient evidence to guide a change in boosting
recommendations. A neutralising antibody response >126
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s68 BHIVA Writing Group
Vienna Units/mL is considered to be protective. Post-vac-
cination testing is not recommended routinely in healthy
individuals, but may be considered in some immunocom-
promised persons at risk of exposure in order to guide
booster requirements. Whether rapid schedules are effec-
tive in HIV-positive persons is unknown. The TBE vaccine
is safe and well tolerated in HIV-positive individuals with
CD4 cell count >200 cells/lL [8,9; H. Kollaritsch and M.
Peallabauer, personal communications].
20.6 Recommendations for HIV-positive adults
•We recommend that HIV-positive patients who intend
to walk, camp, or work in heavily forested regions of
TBE-affected countries during late spring or summer
be offered TBE vaccination, particularly if staying in
areas with heavy undergrowth [1B]. The vaccine is also
recommended for expatriates whose principal area of
residence is an area where TBE is endemic and this
should be according to local vaccination programmes
[1B].
oWe recommend that four vaccine doses be offered
in order to improve responses, and these should be
given at 0, 1, and 2 months (primary course), fol-
lowed by a fourth dose at 9–12 months [1B].
oWe recommend that the decision to offer a rapid
vaccination schedule (two doses 2 weeks apart, fol-
lowed by a third dose 5–12 months later) be based
upon an evaluation of risk of exposure and urgency,
taking into account that responses may be reduced
in patients with CD4 cell counts <400 cells/lL [1C].
•We recommend that a booster vaccine dose is offered
every 3–5 years to those at continued risk, with the
shorter interval preferred for patients with CD4 cell
counts <400 cells/lL [1C].
•We suggest that where available serological testing for
specific antibodies may be used to guide boosting
requirements [2C].
20.7 References
1 Zambito Marsala S, Pistacchi M, Gioulis M et al.
Neurological complications of tick borne encephalitis: the
experience of 89 patients studied and literature review.
Neurol Sci 2014; 35:15–21.
2 Amicizia D, Domnich A, Panatto D et al. Epidemiology of
tick-borne encephalitis (TBE) in Europe and its prevention
by available vaccines. Hum Vaccin Immunother 2013; 9:
1163–1171.
3 Jaenson TG, Hjertqvist M, Bergstr€
om T, Lundkvist A. Why is
tick-borne encephalitis increasing? A review of the key
factors causing the increasing incidence of human TBE in
Sweden. Parasit Vectors 2012; 5: 184.
4 Demicheli V, Debalini MG, Rivetti A. Vaccines for
preventing tick-borne encephalitis. Cochrane Database Syst
Rev 2009; 1: CD000977.
5 Kollaritsch H, Paulke-Korinek M, Holzmann H et al.
Vaccines and vaccination against tick-borne encephalitis.
Expert Rev Vaccines 2012; 11: 1103–1119.
6 Zavadska D, Anca I, Andr
eFet al. Recommendations for
tick-borne encephalitis vaccination from the Central
European Vaccination Awareness Group (CEVAG). Hum
Vaccin Immunother 2013; 9: 362–374.
7 Loew-Baselli A, Poellabauer EM, Pavlova BG et al.
Prevention of tick-borne encephalitis by FSME-IMMUN
vaccines: review of a clinical development programme.
Vaccine 2011; 29: 7307–7319.
8 Panasiuk B, Prokopowicz D, Panasiuk A. Immunological
response in HIV-positive patients vaccinated against tick-
borne encephalitis. Infection 2003; 31:45–46.
9 Wolf HM, Pum M, Jager R et al. Cellular and humoral
immune responses in haemophiliacs after vaccination
against tick-borne encephalitis. Br J Haematol 1992; 82:
374–383.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s69
21. Typhoid fever
21.1 Infection and disease
Salmonella is a Gram-negative bacillus transmitted by the
faecal-oral route [1]. Thousands of serotypes are recognised,
and most cause non-invasive infections of the gastrointesti-
nal tract. Typhoid fever is an invasive infection caused by
S. typhi,S. paratyphi A, B and C, and in HIV-positive indi-
viduals other salmonella species, also cause invasive infec-
tions which may present as enteric fever. Disease severity
varies, but untreated infection carries a 12–30% risk of mor-
tality. Deaths are rare in treated persons (2% or less). Up to
10% of patients with typhoid fever excrete the organism for
3 months following the acute illness. A chronic carrier state,
with excretion of S. typhi for more than 1 year, occurs in
approximately 1–6% of individuals.
21.2 Epidemiology
The incidence of typhoid fever per 100 000 people ranges
from <0.1 cases/year in Central and Eastern Europe and
Central Asia to 725 cases/year in sub-Saharan Africa [2].
Paratyphoid incidence ranges from 0.8 cases/year in North
Africa/Middle East to 77 cases/year in sub-Saharan Africa
and South Asia. The adjusted estimate for the burden of
typhoid fever accounting for the low sensitivity of blood
cultures for diagnosis is about 27 million episodes. In the
UK most cases follow travel to endemic areas; about 7% of
cases occur in individuals with no relevant travel history.
Travellers to Asia, Africa, and Latin America who have
prolonged exposure to potentially contaminated food and
drink are especially at risk of infection [1,3,4]. In these
regions, the attack rate for travellers has been estimated at
10 per 100 000 travellers. Increasing resistance to available
antibiotics, including fluoroquinolones, is being reported.
Multidrug-resistant strains of S. typhi have become com-
mon in the Indian subcontinent, the Middle East and some
African countries [5–7]. Typhoid vaccination is an impor-
tant component of typhoid fever prevention and control,
and is recommended for travels and in public health pro-
grammes in both endemic and outbreak settings. Vaccina-
tion is currently only available against S. typhi.
21.3 Typhoid fever in HIV-positive adults
HIV-positive patients are at increased risk of infection
with Salmonella, and immunodeficiency predisposes
patients to bacteraemia, antibiotic resistance, relapsing
disease, and persistent infection [8–14]. In residents of
endemic countries, particularly in Africa, disease is
predominately due to non-typhoidal Salmonella (NTS),
rather than S. typhi. The burden of NTS in HIV-positive
adults is declining with the roll-out of ART [15]. Whether
the disease manifestations of typhoid fever among HIV-
positive persons differ significantly from those observed
in HIV-negative persons is uncertain.
21.4 Typhoid vaccine
Available vaccines comprise the injectable non-replicat-
ing Vi capsular polysaccharide vaccine (ViCPS), the oral
replicating live attenuated Ty21a vaccine, and the inject-
able non-replicating typhoid conjugate vaccine (TCV)
[16–18]. These vaccines do not protect against S. paraty-
phi or NTS infection. An NTS vaccine is under develop-
ment [17]. TCVs have only recently become available and
experience remains limited [16]. ViCPS is 38–80% protec-
tive in healthy people after a single dose [16,17,19], with
boosters recommended every 3 years for those at risk.
There are no major safety concerns with the ViPS vaccine
in healthy individuals from endemic or non-endemic
countries [16–19]. Injection site reactions occur in up to
7% of ViCPS recipients and usually resolve within 48 h.
Systemic reactions such as headache and fever occur in
up to 20% and 1% of vaccinees respectively. Anaphylaxis
and other serious adverse reactions are rare. There are no
major safety concerns with the Ty21a vaccine in healthy
people. However, the Ty21a vaccine should not be co-
administered with antibacterials or antimalarials as these
may impair efficacy.
21.4.1 General indications
The vaccine is indicated for travellers to areas that pose a
risk of exposure.
21.5 Typhoid vaccine in HIV-positive adults
In HIV-positive persons, the induction of protective anti-
bodies is impaired, particularly in patients with CD4 cell
counts <200 cells/lL [20]. The duration of protection
may also be reduced in HIV-positive persons. None the
less, there is no evidence for dose or interval modifica-
tion. Whether the Vi-conjugate vaccine when it becomes
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s70 BHIVA Writing Group
available will be more effective in this population is cur-
rently unknown. The ViCPS vaccine is safe for HIV-posi-
tive persons. Although there have been no reports of
adverse events [21] the Ty21a vaccine is contraindicated
in immunocompromised persons, including HIV-positive
patients [13].
21.6 Recommendations for HIV-positive adults
•We recommend that HIV-positive patients who are due
to travel to areas in which there is a recognised risk of
exposure to S. typhi be offered the parental ViCPS
vaccine [B1].
oEfforts should be made to offer vaccination to those
at particularly high risk of exposure: visitors to
friends and relatives; long-term travellers; and those
with likely exposure to poor sanitary conditions
[B1].
oThese patients should receive one vaccine dose at
least 2 weeks before expected exposure [C1].
•We recommend a booster vaccine dose is given every
3 years in those who remain at risk [1C].
21.7 References
1 Wain J, Hendriksen RS, Mikoleit ML et al. Typhoid fever.
Lancet 2015; 385: 1136–1145.
2 Buckle GC, Walker CL, Black RE. Typhoid fever and
paratyphoid fever: systematic review to estimate global
morbidity and mortality for 2010. J Glob Health 2012; 2:
10401.
3 Feasey NA, Dougan G, Kingsley RA et al. Invasive non-
typhoidal salmonella disease: an emerging and neglected
tropical disease in Africa. Lancet 2012; 379: 2489–2499.
4 Meltzer E, Schwartz E. Enteric fever: a travel medicine
oriented view. Curr Opin Infect Dis 2010; 23: 432–437.
5 Zaki SA, Karande S. Multidrug-resistant typhoid fever: a
review. J Infect Dev Ctries 2011; 5: 324–372.
6 Feasey NA, Gaskell K, Wong V et al. Rapid emergence of
multidrug resistant, H58-lineage Salmonella typhi in
Blantyre, Malawi. PLoS Negl Trop Dis 2015; 9: e0003748.
7 Wong VK, Baker S, Pickard DJ et al. Phylogeographical
analysis of the dominant multidrug-resistant H58 clade of
Salmonella typhi identifies inter- and intracontinental
transmission events. Nat Genet 2015; 47: 632–639.
8 Gordon MA. Salmonella infections in immunocompromised
adults. J Infect 2008; 56: 413–422.
9 Gordon MA. Invasive nontyphoidal Salmonella disease:
epidemiology, pathogenesis and diagnosis. Curr Opin Infect
Dis 2011; 24: 484–489.
10 Feasey NA, Archer BN, Heyderman RS et al. Typhoid fever
and invasive nontyphoid salmonellosis, Malawi and South
Africa. Emerg Infect Dis 2010; 16: 1448–1451.
11 Gordon MA, Kankwatira AM, Mwafulirwa G et al. Invasive
non-typhoid salmonellae establish systemic intracellular
infection in HIV-infected adults: an emerging disease
pathogenesis. Clin Infect Dis 2010; 50: 953–962.
12 Nga TV, Parry CM, Le T et al. The decline of typhoid and
the rise of non-typhoid salmonellae and fungal infections in
a changing HIV landscape: bloodstream infection trends
over 15 years in southern Vietnam. Trans R Soc Trop Med
Hyg 2012; 106:26–34.
13 Hochberg NS, Barnett ED, Chen LH et al. International
travel by persons with medical comorbidities: understanding
risks and providing advice. Mayo Clin Proc 2013; 88: 1231–
1240.
14 Biggs HM, Lester R, Nadjm B et al. Invasive Salmonella
infections in areas of high and low malaria transmission
intensity in Tanzania. Clin Infect Dis 2014; 58: 638–647.
15 Feasey NA, Houston A, Mukaka M et al. A reduction in
adult blood stream infection and case fatality at a large
african hospital following antiretroviral therapy roll-out.
PLoS One 2014; 9: e92226.
16 Date KA, Bentsi-Enchill A, Marks F, Fox K. Typhoid fever
vaccination strategies. Vaccine 2015; 33 (Suppl 3): C55–C61.
17 Maclennan CA, Martin LB, Micoli F. Vaccines against
invasive Salmonella disease: current status and future
directions. Hum Vaccin Immunother 2014; 10: 1478–1493.
18 Bhutta ZA, Capeding MR, Bavdekar A et al.
Immunogenicity and safety of the Vi-CRM197 conjugate
vaccine against typhoid fever in adults, children, and
infants in south and southeast Asia: results from two
randomised, observer-blind, age de-escalation, phase 2
trials. Lancet Infect Dis 2014; 14: 119–129.
19 Anwar E, Goldberg E, Fraser A et al. Vaccines for
preventing typhoid fever. Cochrane Database Syst Rev 2014;
1: CD001261.
20 Kroon FP, van Dissel JT, Ravensbergen E et al. Impaired
antibody response after immunization of HIV-infected
individuals with the polysaccharide vaccine against
Salmonella typhi (Typhim-Vi). Vaccine 1999; 17: 2941–
2945.
21 Banda R, Yambayamba V, Lalusha BD et al. Safety of live,
attenuated oral vaccines in HIV-infected Zambian adults:
oral vaccines in HIV. Vaccine 2012; 30: 5656–5660.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s71
22. Tuberculosis
22.1 Infection and disease
The Mycobacterium tuberculosis complex includes M.
tuberculosis,M. bovis and M. africanum. Transmission
nearly always occurs through airborne droplets that are
expelled when a person with pulmonary tuberculosis (TB)
coughs, talks, sings, or sneezes. The most infectious persons
are those with cavitary pulmonary disease. Transmission
usually requires prolonged exposure and close contact. In
some cases transmission can occur through unpasteurised
milk or milk products from infected cattle. Depending on
host factors, infection may be cleared, remain latent, or pro-
gress to active disease over a period of weeks or months.
Disease is usually pulmonary (60% of cases), but non-pul-
monary and disseminated disease can occur, especially in
young children and immunocompromised persons, and
almost every tissue and organ can be affected [1]. Latent
infection can re-activate. The lifetime risk of re-activation is
5–15% for immunocompetent adults. The majority of re-
activations occur within 2 years of primary infection.
22.2 Epidemiology
In the UK, cases of TB have increased over the last 10 years.
A large number of cases are in people born abroad, the rate
being higher in certain ethnic groups in the first few years
after they enter the country, and rates remain high in the
children of these immigrants wherever they are born. The
risk of infection is also increased in persons who are close
contacts of infectious persons, have HIV infection, are
homeless, have hazardous alcohol use, or inject drugs. Risk
factors for disease are diabetes mellitus, renal failure,
immunodeficiency, latent infection acquired in infancy or
early childhood, and therapy with immunomodulators
(especially TNF-aantagonists). The mainstay of TB control
is identifying and treating infectious cases to stop transmis-
sion, skin-testing or interferon gamma release assays
(IGRAs) for children and adults who are at high risk for TB,
and (where indicated) administering preventive therapy to
persons with a positive skin-test result. Vaccination con-
tributes to the prevention and control of TB in limited situa-
tions and is contraindicated in HIV infection.
22.3 TB in HIV-positive adults
HIV infection substantially increases the risk of infection
and active TB disease: worldwide, TB is the leading cause
of death among HIV-positive people [2]. HIV also sup-
presses responses to the tuberculin test.
22.4 Bacille Calmette-Gu
erin vaccine
The BCG vaccine is a live attenuated vaccine containing
a strain of M. bovis isolated in 1908 from a cow, which
was sub-cultured 231 times over 13 years resulting in
gradual attenuation. Several laboratories produce vaccine
derived from the original strain and many different BCG
vaccines are available worldwide, with different produc-
tion techniques and characteristics. BCG Vaccine Statens
Serum Institut (SSI) is available in the UK. It is adminis-
tered intradermally in the latter aspect of the left upper
arm. Studies of BCG vaccine are difficult to interpret
because they differ in design, location, strains used, vac-
cine dose, population, presence of mycobacteria in the
environment, and diagnostic approach [3]. Protection
rates vary widely in different trials. The vaccine appears
to prevent the blood-borne spread of M. tuberculosis
from primary pulmonary foci especially in children, but
the protection afforded against pulmonary disease is more
uncertain. There remain limited data concerning the pro-
tective efficacy of vaccination in adults, but overall effi-
cacy appears to be higher in persons vaccinated during
childhood compared with persons vaccinated at older
ages. The efficacy of BCG vaccine in children and adults
who are infected with HIV has not been determined. New
TB vaccines are currently under investigation [4].
22.4.1 General indications
In the UK, a single BCG vaccine dose is given to selected
high-risk infants and children, and previously unvacci-
nated tuberculin-negative close contacts of those with
active respiratory TB. The vaccine is also indicated for
previously unvaccinated tuberculin-negative adults below
the age of 35 years if they are at occupational risk of
exposure (e.g. healthcare workers, laboratory staff, veteri-
narians, prison staff, staff of care homes for the elderly,
staff of hostels for homeless people and facilities accom-
modating refugees and asylum seekers) or intend to live
or work in countries with an annual incidence of TB of
40/100 000 or greater. The BCG vaccine may also be
considered for previously unvaccinated, tuberculin-nega-
tive individuals travelling to high-prevalence countries
for 1 month or longer.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s72 BHIVA Writing Group
22.5 Vaccine safety
The BCG vaccine often causes local adverse effects, but
serious or long-term complications are rare in healthy
individuals. Within 10–14 days, 90–95% of vaccine
recipients develop a tender erythematous papule at the
injection site, which may ulcerate and then slowly sub-
side over several weeks or months leaving a flat scar of
5–15 mm. There may be enlargement (<1 cm) of a regio-
nal lymph node. Severe injection site reactions may
occur, usually as a result of faulty injection technique,
excessive dosage, or vaccinating individuals who are
tuberculin-positive. Other adverse reactions include head-
ache, fever, lymphadenopathy (>1 cm), allergic reactions
(including anaphylaxis) and, rarely, lymphadenitis, and
disseminated BCG (e.g. osteitis or osteomyelitis). Fatal
dissemination has been described in immunocompromised
individuals and the BCG vaccine is contraindicated in
such populations. Case reports indicate that symptomatic
HIV-positive persons are at a greater risk of local and
systemic complications including disseminated BCG dis-
ease than HIV-negative persons or persons with asymp-
tomatic HIV infection [5–12]. These complications can
occur several years after BCG vaccination. Overall, there
is no evidence of a clear benefit of BCG vaccination in
HIV-positive people that may offset the potential risk.
22.6 Recommendations for HIV-positive adults
•We recommend that the BCG vaccine be absolutely
contraindicated in all HIV-positive persons regardless
of CD4 cell count, ART use, virasl load, and clinical
status [1C].
22.7 References
1 Zumla A, Raviglione M, Hafner R, von Reyn CF.
Tuberculosis. N Engl J Med 2013; 368: 745–755.
2 Bruchfeld J, Correia-Neves M, K€
allenius G. Tuberculosis and
HIV coinfection. Cold Spring Harb Perspect Med 2015; 5(7):
a017871.
3 Abubakar I, Pimpin L, Ariti C et al. Systematic review
and meta-analysis of the current evidence on the duration
of protection by bacillus Calmette-Gu
erin vaccination
against tuberculosis. Health Technol Assess 2013; 17:
1–372.
4 Andersen P, Urdahl KB. TB vaccines; promoting rapid and
durable protection in the lung. Curr Opin Immunol 2015;
35:55–62.
5 Centers for Disease Control and Prevention. Disseminated
Mycobacterium bovis infection from BCG vaccination of a
patient with acquired immunodeficiency syndrome. MMWR
Morb Mortal Wkly Rep 1985; 34: 227–228.
6 Ninane J, Grymonprez A, Burtonboy G et al. Disseminated
BCG in HIV infection. Arch Dis Child 1988; 63: 1268–
1269.
7 Boudes P, Sobel A, Deforges L, Leblic E. Disseminated
Mycobacterium bovis infection from BCG vaccination and
HIV infection. JAMA 1989; 262: 2386.
8 Reynes J, Perez C, Lamaury I et al. Bacille Calmette-Guerin
adenitis 30 years after immunization in a patient with AIDS.
J Infect Dis 1989; 160: 727.
9 Armbruster C, Junker W, Vetter N, Jaksch G. Disseminated
Bacille Calmette-Guerin infection in an AIDS patient 30 years
after BCG vaccination. J Infect Dis 1990; 162: 1216.
10 Lumb R, Shaw D. Mycobacterium bovis (BCG) vaccination:
progressive disease in a patient asymptomatically infected
with the human immunodeficiency virus. Med J Aust 1992;
156: 286–287.
11 Smith E, Thybo S, Bennedsen J. Infection with
Mycobacterium bovis in a patient with AIDS: a late
complication of BCG vaccination. Scand J Infect Dis 1992;
24: 109–110.
12 Talbot EA, Perkins MS, Silva SF et al. Disseminated Bacille
Calmette-Guerin disease after vaccination: case report and
review. Clin Infect Dis 1997; 24: 1139–1146.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s73
23. Varicella zoster virus
23.1 Infection and disease
VZV is a herpes virus that after primary infection estab-
lishes latency within neurons. Primary infection causes
varicella or chickenpox. Reactivation causes herpes zoster
or shingles. Chickenpox is highly infectious and can be
transmitted by respiratory droplets and aerosols up to
48 h prior to the onset of the rash. The skin lesions of
both chickenpox and shingles are infectious until crusted.
Chickenpox is usually benign and self-limiting in healthy
children; healthy adults are more likely to develop severe
and even life-threatening infections. Complications may
include severe cutaneous rashes, secondary bacterial
infections, visceral involvement (e.g. pneumonia, hepati-
tis), and neurological disease (meningitis, encephalitis,
myelitis). All adults with chickenpox, and especially preg-
nant women, are at risk of VZV pneumonia. Occasionally,
infection in pregnancy leads to fetal injury (congenital
varicella syndrome). Shingles is usually self-limiting,
although persistent debilitating pain is a frequent compli-
cation, particularly in the elderly (post-herpetic neuralgia,
PHN); eye involvement may lead to permanent visual
impairment.
23.2 Epidemiology
In temperate climates, primary infection with VZV occurs
most commonly during childhood. At least 90% of adults
in England and Wales are VZV IgG seropositive [1], con-
firming prior infection. In tropical and sub-tropical
climates, the mean age of primary VZV infection may be
delayed. As a result, a significant proportion of adults
raised in those regions remain VZV IgG seronegative and
susceptible to primary infection in adulthood. Among
HIV-positive adults in the UK, 1.5% lack evidence of
VZV IgG [2]. Shingles is common in the general popula-
tion, with an overall rate of 2–4 cases per 1000 person-
years and higher incidence rates in adults ≥50 years of
age and in immunocompromised people, including HIV-
positive individuals [3–5].
23.3 VZV in HIV-positive adults
HIV-positive patients who acquire chickenpox are at
increased risk of severe and even fulminant disease [6–8].
Cell-mediated immunity plays a major role in controlling
VZV reactivation, and impaired cellular immunity also
increases the risk of shingles in people with HIV [9].
Before the introduction of effective ART, incidence rates
of shingles were 10- to 20-times higher in HIV-positive
adults than in the age-matched general population [5,10–
13]. While disease burden has been reduced by ART, it is
has remained 3–5-times higher than in HIV-negative peo-
ple [5,13–17]. Shingles may occur and may recur at any
time during HIV infection, although a low CD4 cell count
and a viral load >400 copies/mL have been associated
with a higher risk [5,12,18]. Additional risk factors may
include a prior episode of shingles, crack cocaine use,
and age >60 years (>40 years in crack cocaine users)
[16,18]. Complications of shingles are also more common
in HIV-positive subjects than in the age-matched general
population (27–28% vs.10–13%) [5,12], and may include
cutaneous dissemination, chronic atypical skin lesions,
ocular and neurological complications, or visceral dis-
semination. Acute retinal necrosis and neurological syn-
dromes can occur as a result of VZV reactivation in the
absence of rash. Both shingles and VZV-mediated cere-
bral vasculitis causing stroke have also been recognised
as a manifestation of the immune reconstitution inflam-
matory syndrome [19,20].
23.4 Chickenpox vaccine
Two varicella vaccines are available in the UK: Varilrix
and Varivax. Both contain replicating live attenuated
VZV (OKA strain). The vaccine strain can establish latent
infection in some vaccine recipients, and can reactivate
to cause shingles, although less commonly than with
wild-type virus. Varilrix should only be administered by
deep subcutaneous injection. Varivax can be administered
by either intramuscular or deep subcutaneous injection.
In healthy adults, two doses give 75% protection against
any disease and 95% protection against severe disease.
Waning immunity over time is manifested by mild break-
through infections with wild-type virus. The need for
booster doses is currently under investigation. The vac-
cine is safe, although up to 10% of healthy adults
develop a vaccine-associated rash, localised at the site of
injection or generalised, within 1 month of immunisation
[21]. Transmission of vaccine virus from vaccine recipi-
ents has been documented only rarely and only from
individuals with vaccine-associated rashes. Vaccination is
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s74 BHIVA Writing Group
not contraindicated and is in fact recommended for close
contacts of HIV-positive persons.
23.4.1 General indications
In the UK, the varicella vaccine is currently recommended
for susceptible healthcare workers and close contacts of
immunocompromised patients. Contraindications include
pregnancy and significant immunocompromise.
23.5 Chickenpox vaccine in HIV-positive adults
The chickenpox vaccine has been shown to be safe and
immunogenic in susceptible children with asymptomatic or
mildly symptomatic HIV infection, and a suppressed viral
load on ART is associated with improved immunogenicity
[22–27]. Severe, but non-fatal vaccine-associated disease
has been reported in some children with undiagnosed
immunodeficiency [28]. There are limited data in HIV-posi-
tive adults. Among VZV IgG seropositive persons with CD4
cell counts >400 cells/lL and stable on ART for
≥3 months, the vaccine has been shown to boost VZV-spe-
cific cellular immune responses, without safety concerns
[29]. Expert opinion in the US advises VZV vaccination in
susceptible HIV-positive adults with CD4 cell counts
>200 cells/lL, based upon evidence of safety and immuno-
genicity in children, the highly contagious nature of the
infection, and the significant risk of severe disease result-
ing from primary VZV infection [30]. Furthermore, patients
who develop complications from the vaccine strain can be
managed with antiviral therapy (e.g. aciclovir 800 mg
five-times daily, or valaciclovir 1 g three-times daily).
23.6. Shingles vaccine
The available shingles vaccine (Zostavax) contains high
dose, replicating live attenuated VZV (Oka/Merck strain).
The shingles vaccine is at least 14 times more potent than
the chickenpox vaccine [31]. It is given as a single dose
by subcutaneous injection and is licensed for immuno-
competent adults aged ≥50 years [32]. Vaccination of
immunocompetent adults aged ≥60 years boosts natural
immunity and reduces the incidence of shingles by half
and the incidence of PHN by two-thirds [33]. The vaccine
is also efficacious in immunocompetent adults aged 50–
59 years, and protection against shingles lasts for at least
5 years [34–36]. The need for boosting doses has not
been clearly determined. A systematic review concluded
that there is a clear benefit in vaccinating elderly
patients, with no major safety concerns [36]. Inactivated
subunit vaccines based on the VZV glycoprotein E (gE)
antigen are in clinical development [37].
23.6.1 General indications
In the UK, shingles vaccination is recommended for
adults without a history of immunodeficiency aged
70 years, and a “catch-up” programme currently targets
those aged 70–79 years. Contraindications include preg-
nancy and breast feeding and significant immunocom-
promise.
23.7. Shingles vaccine in HIV-positive adults
The shingles vaccine was safe and immunogenic in a ran-
domised trial (ACTG 5247) of 392 HIV-positive patients
who were VZV IgG seropositive and receiving ART with a
CD4 cell count >200 cells/lL. There was a greater inci-
dence of injection site reactions in the vaccine group
(42%) versus the placebo group (12%). The greatest anti-
body response was observed in patients with CD4 cell
counts >350 cells/lL [38]. Duration of response and clini-
cal effectiveness are unknown. Although these data are
promising, further studies are required to define the cost-
effectiveness of shingles vaccination in HIV-positive
adults, including the appropriate age cut-off. Expert
opinion is that it is reasonable to vaccinate patients
≥60 years of age (provided the CD4 cell count is
>200 cells/lL) [39]. Meanwhile, efforts are required to
overcome barriers to the vaccination of HIV-positive peo-
ple with good immune status who meet age-related indi-
cations for vaccination based upon general indications
[40]. As a future alternative to a replicating vaccine, a
recent phase 1/2, randomised, placebo-controlled study
evaluated the immunogenicity and safety of a non-repli-
cating adjuvanted subunit shingles vaccine in 123 HIV-
positive adults who were predominantly on ART with
CD4 cell counts ≥200 cells/lL [37]. After two doses, the
vaccine proved to be strongly immunogenic; no vaccina-
tion-related serious adverse events were reported.
23.8 Post-exposure prophylaxis
Protective immunity develops within 4 days of chicken-
pox vaccination, and Varivax (but not Varilrix) is
licensed for post-exposure prophylaxis in susceptible
individuals exposed to VZV, when it should be adminis-
tered within 3 days and up to 5 days post-exposure in
order to prevent or attenuate the infection. Available evi-
dence supports the use of vaccination as post-exposure
prophylaxis in healthy individuals [41,42]. There are
currently no data in HIV infection, where the risk of any
vaccine-related adverse event must be balanced against
the risk of severe complications resulting from natural
infection. Varicella-zoster immune globulin (VZIG) is
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s75
indicated for susceptible immunocompromised patients
(and pregnant women) who have had a significant expo-
sure to VZV, and this includes symptomatic HIV-positive
patients and asymptomatic patients with CD4 cell count
<400 cells/lL. VZIG should be given within 7 days and
up to 10 days after exposure by intramuscular injection.
The duration of protection is 3 weeks. In the event of a
second exposure after 3 weeks, repeat administration is
recommended. Where intramuscular injection is con-
traindicated in individuals with bleeding disorders, intra-
venous immunoglobulin may be given instead. VZIG
given within 3 weeks of a live attenuated vaccine (except
yellow fever) may interfere with the vaccine immuno-
genicity. Replicating vaccines should likewise be post-
poned until 3 months after the administration of VZIG.
Published evidence for the efficacy of aciclovir as post-
exposure prophylaxis indicates that chickenpox may be
prevented or attenuated in children by administration of
aciclovir starting between 7 and 10 days after exposure,
for a total of 7 days [43,44]. The equivalent dose of aci-
clovir in adults is 800 mg four-times daily. There are no
published controlled trials comparing antiviral prophy-
laxis directly with VZIG.
23.9 Recommendations for HIV-positive adults
•We recommend HIV-positive adults with a negative or
uncertain history of chickenpox or shingles undergo
VZV IgG testing to determine susceptibility to primary
infection and reactivation [1B].
•We recommend VZV IgG seronegative patients who
have a CD4 cell count >200 cells/lL and preferably are
established on ART are offered two doses of the chick-
enpox vaccine 3 months apart [1B].
oSerological testing for evidence of VZV IgG sero-
conversion should be performed 4–6 weeks after the
second vaccine dose [GPP].
•We recommend VZV IgG seropositive patients who have
a CD4 cell count >200 cells/lL and preferably are estab-
lished on ART be offered one dose of the shingles vac-
cine in line with national age-related indications [1B].
oWe recommend prior serological testing for evidence
of VZV IgG seropositivity in those lacking a reliable
history of chickenpox or shingles [1C].
oWe recommend efforts be made to overcome barri-
ers to the vaccination of HIV-positive people with
CD4 cell count >200 cells/lL who meet the age-
related indications for shingles vaccination based
upon national guidance [1B].
•We suggest that VZV IgG seropositive patients who
have a CD4 cell count >200 cells/lL and preferably are
established on ART may benefit from shingles vaccina-
tion from the age of 60 years [2B].
•We recommend HIV-positive recipients of replicating
VZV vaccines be advised to report post-vaccine rashes
or other symptoms promptly, and following medical
evaluation, be offered appropriate antiviral therapy
against VZV if required [1B].
•We recommend that following a significant exposure
to VZV, the VZV IgG status of the HIV-positive contact
be ascertained regardless of vaccination history
(although prophylaxis should not be delayed waiting
for the results) and VZV IgG seronegative patients be
considered for post-exposure prophylaxis and moni-
tored closely for symptoms to facilitate prompt institu-
tion of antiviral therapy [1A].
oWe recommend VZV IgG seronegative contacts with
CD4 cell counts <400 cells/lL receive post-exposure
prophylaxis with VZIG as soon as possible, prefer-
ably within 7 days and not later than 10 days after
exposure [1B].
oWe recommend that where VZIG is not available
VZV IgG seronegative contacts be offered antiviral
prophylaxis with aciclovir (800 mg four-times daily)
[1B] or valaciclovir (1 g three-times daily) [1C]
starting from day 7 after exposure and continuing
for 7 days.
oWe suggest VZV IgG seronegative contacts with
CD4 cell count <200 cells/lL be considered for both
VZIG and antiviral prophylaxis with aciclovir
(800 mg four-times daily) or valaciclovir (1 g three-
times daily) [2C] starting from day 7 after exposure
and continuing for 7 days.
oWe recommend VZV IgG seronegative contacts with
CD4 cell counts >400 cells/lL receive post-exposure
prophylaxis with the Varivax vaccine within 3 and
up to 5 days after exposure [1C]. The second dose
should normally be scheduled after 3 months.
•We recommend that VZV seronegative close contacts of
HIV-positive adults with CD4 cell count <200 cells/lL
are proactively offered chickenpox vaccination [1B].
•We recommend that whenever possible HIV-positive
patients receiving VZV replicating vaccines are not
given treatment doses of antiviral drugs with anti-her-
petic activity (e.g. aciclovir) at the time of vaccination
and for 4 weeks subsequently as it may reduce vaccine
immunogenicity [1D].
23.10 References
1 Vyse AJ, Gay NJ, Hesketh LM et al. Seroprevalence of
antibody to varicella zoster virus in England and Wales in
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children and young adults. Epidemiol Infect 2004; 132:
1129–1134.
2 Molton J, Smith C, Chaytor S et al. Seroprevalence of
common vaccine-preventable viral infections in HIV-
positive adults. J Infect 2010; 61:73–80.
3 Brisson M, Edmunds WJ. Epidemiology of varicella-zoster
virus in England and Wales. J Med Virol 2003; 70 (Suppl
1): 9–14.
4 Yawn BP, Saddier P, Wollan PC et al. A population-based
study of the incidence and complication rates of herpes
zoster before zoster vaccine introduction. Mayo Clin Proc
2007; 82: 1341–1349.
5 Blank LJ, Polydefkis MJ, Moore RD, Gebo KA. Herpes zoster
among persons living with HIV in the current antiretroviral
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6 Perronne C, Lazanas M, Leport C et al. Varicella in patients
infected with the human immunodeficiency virus. Arch
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7 Grilli E, Baiocchini A, Del Nonno F et al. Fulminant VZV
infection in an adult AIDS patient treated with steroids: a
case report. J Clin Virol 2014; 60:63–66.
8 Maves RC, Tripp MS, Dell TG et al. Disseminated vaccine-
strain varicella as initial presentation of the acquired
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9 De Castro N, Carmagnat M, Kern
eis S et al. Varicella-zoster
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10 Buchbinder SP, Katz MH, Hessol NA et al. Herpes zoster
and human immunodeficiency virus infection. J Infect Dis
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11 Veenstra J, Krol A, van Praag RM et al. Herpes zoster,
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12 Glesby MJ, Moore RD, Chaisson RE. Clinical spectrum of
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14 Gebo KA, Kalyani R, Moore RD, Polydefkis MJ. The
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15 Vanhems P, Voisin L, Gayet-Ageron A et al. The incidence
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17 Grabar S, Tattevin P, Selinger-Leneman H et al. Incidence
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et al. Varicella zoster as a manifestation of immune
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20 Teo S, Raha D, Warren D et al. Central nervous system-
immune reconstitution inflammatory syndrome presenting
as varicella zoster virus-mediated vasculitis causing stroke.
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with varicella-zoster virus. N Engl J Med 2005; 352: 439–
440.
22 Levin MJ, Gershon AA, Weinberg A et al. Immunization of
HIV-infected children with varicella vaccine. J Pediatr
2001; 139: 305–310.
23 Levin MJ, Gershon AA, Weinberg A et al. Administration of
live varicella vaccine to HIV-infected children with current
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24 Armenian SH, Han JY, Dunaway TM, Church JA. Safety and
immunogenicity of live varicella virus vaccine in children
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25 Bekker V, Westerlaken GHA, Scherpbier H et al. Varicella
vaccination in HIV-1-infected children after immune
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26 Son M, Shapiro ED, LaRussa P et al. Effectiveness of
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27 Taweesith W, Puthanakit T, Kowitdamrong E et al. The
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28 Galea S, Sweet A, Beninger P et al. The safety profile of
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29 Weinberg A, Levin MJ, MacGregor RR. Safety and
immunogenicity of a live attenuated varicella vaccine in
VZV-seropositive HIV-infected adults. Hum Vaccin 2010; 6:
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30 Rubin LG, Levin MJ, Ljungman P et al. IDSA clinical
practice guideline for vaccination of the
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31 Harpaz F, Ortega-Sanchez IR, Seward JF. Centers for Disease
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32 Centers for Disease Control and Prevention (CDC). Update
on herpes zoster vaccine: licensure for persons aged 50
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33 Oxman MN, Levin MJ, Johnson GR et al. A vaccine to
prevent herpes zoster and postherpetic neuralgia in older
adults. N Engl J Med 2005; 352: 2271–2284.
34 Schmader KE, Oxman MN, Levin MJ et al. Persistence of
efficacy of zoster vaccine in the shingles prevention study
and the short-term persistence study. Clin Infect Dis 2012;
55: 1320–1328.
35 Schmader KE, Levin M, Gnannet JW et al. Efficacy, safety
and tolerability of herpes zoster vaccine in persons aged
50–59 years. Clin Infect Dis 2012; 54: 922–928.
36 Gagliardi AMZ, Gomes Silva BN, Torloni MR, Soares BGO.
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37 Berkowitz EM, Moyle G, Stellbrink HJ et al. Safety and
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randomized, placebo-controlled study. J Infect Dis 2015;
211: 1279–1287.
38 Benson C, Hua L, Anderson J et al. Zostavax is generally
safe and immunogenic in HIV+ adults virologically
suppressed on ART: results of a Phase 2, randomized,
double-blind, placebo-controlled trial. 19th Conference on
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39 Aberg JA, Gallant JE, Ghanem KG et al. Primary care
guidelines for the management of persons infected with
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58: e1.
40 Aziz M, Kessler H, Huhn G. Providers’ lack of knowledge
about herpes zoster in HIV-infected patients is among
barriers to herpes zoster vaccination. Int J STD AIDS 2013;
24: 433–439.
41 Macartney K, McIntyre P. Vaccines for post-exposure
prophylaxis against varicella (chickenpox) in children
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42 Souty C, Boos E, Turbelin C et al. Vaccination against
varicella as post-exposure prophylaxis in adults: a
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43 Asano Y, Yoshikawa T, Suga S et al. Post exposure
prophylaxis of varicella in family contacts by acyclovir.
Pediatrics 1993; 92: 219–222.
44 Suga S, Yoshikawa T, Ozaki T, Asano Y. Effect of oral
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incubation period of varicella. Arch Dis Child 1993; 69:
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©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s78 BHIVA Writing Group
24. Yellow fever virus
24.1 Infection and disease
Yellow fever virus (YFV) is a flavivirus spread by the bite
of an infected Aedes aegypti mosquito. Severity varies.
Most infections are asymptomatic or cause a non-specific,
self-limited influenza-like illness. Severe cases are char-
acterised by hepatitis, jaundice, and haemorrhage, and
carry a risk of mortality of up to 50% in non-immune
adults travelling to endemic areas [1–3]. There is no
specific antiviral treatment available.
24.2 Epidemiology
YFV is prevalent in tropical and sub-tropical regions of
Africa and South America, where it is endemic and inter-
mittently epidemic. It does not occur in Asia. Two forms
of YF –urban and jungle –are epidemiologically distin-
guishable. In South America, sporadic infections occur
almost exclusively as a result of occupational exposure in
or near forested areas. In Africa, YFV is transmitted
mainly in the moist savannah zones of west-central
Africa, especially during the late rainy and early dry sea-
son (July–October). For travellers to endemic areas the
risk of acquiring YF has been estimated to be 0.4–4.3
cases per million travellers [2]. The risk of disease is ~10-
times lower in South America than in rural West Africa,
but varies greatly according to specific location and sea-
son. Under regulations set out by the World Health Orga-
nization, anyone travelling to a country or area where
the Aedes aegypti mosquito is found must have an Inter-
national Certificate of Vaccination or Prophylaxis, which
is compulsory for entry to several countries in these
regions. The certificate is valid for 10 years from the
tenth day after primary vaccination and immediately
after revaccination [1].
24.3 Yellow fever in HIV-positive adults
It is not known whether the natural history of YF is mod-
ified by HIV infection.
24.4 YFV vaccine
YF vaccine is a replicating live attenuated preparation of
the YFV 17D strain grown in embryonated chick eggs.
The YF vaccine is given as a single dose by deep
subcutaneous or intramuscular injection. In healthy recip-
ients, a single dose of the YF vaccine has a protective
efficacy of 90% after 10 days and 99% after 30 days [3].
The protection lasts for at least 10 years (for which dura-
tion the certificate of vaccination is valid), after which a
booster is required for those at continued risk. However,
with some exceptions, immunity is thought to persist for
at least 35 years and probably for life. The Green Book
gives recommendations about selected boosting indica-
tions (www.gov.uk/government/uploads/system/uploads/
attachment_data/file/306941/Green_Book_Chap-
ter_35_v3_3.pdf).
24.4.1 General indications
The YF vaccine is offered to travellers to specific regions.
Vaccination can only be given at designated vaccination
centres as established by the International Health Regula-
tions of WHO.
24.5 Vaccine safety
Adverse reactions are generally mild with headache,
myalgia, low-grade fever and/or soreness at the injection
site occurring in 10–30% of vaccine recipients. More seri-
ous adverse events are very rare and more likely to occur
in persons who have no prior immunity to YFV. These
are principally urticarial, bronchospasm or anaphylaxis
(occurring in one per 130 000–250 000 vaccine doses),
which may be related to reactions to the egg protein in
the vaccine. Yellow fever vaccine-associated neurological
disease (YEL-AND) has an estimated incidence overall of
0.4–0.8 per 100 000 with a higher rate in person aged
over 60 years (1.4–1.8 per 100 000) [1]. Presentation is
with fever and headache progressing to confusion, focal
neurological deficits, coma, and Guillain–Barr
e syndrome;
complete clinical recovery is the usual outcome. Yellow
fever vaccine-associated viscerotropic disease (YEL-AVD)
was first described in 2001 and has an estimated inci-
dence of 0.4 per 100 000, increasing to 1–2.3 per
100 000 in persons aged ≥60 years [1,4,5]. It resembles
naturally acquired YF clinically and pathologically, and
is characterised by multi-organ involvement and 50%
risk of mortality. Studies are being conducted to clarify
the cause and risk factors for these rare adverse events
associated with the YF vaccines. A history of thymic dys-
function may be a risk factor.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s79
The main groups of adult people for whom the vaccine
is contraindicated are:
•People with severe egg allergy or previous anaphylac-
tic reaction to a previous YF vaccine or to any compo-
nents of the vaccine.
•Those with a thymus disorder.
•Persons with immunodeficiency caused by disease or
treatment.
People with any of these conditions can obtain a
waiver letter prior to travel, although some countries may
not accept waiver documents. Since it is recognised that
older recipients are more at risk of developing YF vac-
cine-associated neurotropic and viscerotropic disease,
older travellers are usually advised not to undergo vacci-
nation and instead receive a certificate of exemption
when the absolute risk of infection is low. In selected,
individual cases, pregnant and breastfeeding women may
be offered vaccination after careful risk assessment,
where the risk of unavoidable exposure is greater than
any potential risk associated with vaccination.
24.6 YFV vaccine in HIV-positive adults
A Cochrane review evaluated the risk and benefits of
YFV vaccination in HIV-positive patients [6]. The review
included three cohort studies [7–9] and reported that vac-
cination can produce protective levels of neutralising
antibodies in HIV-positive people, although immuno-
genicity is less than in HIV-negative people. In one of
the included studies, 83% of HIV-positive people had
protective YFV neutralising antibodies titres (NT) 1 year
after vaccination, compared with 97% of HIV-negative
people [8]. NT were significantly lower and declined more
rapidly during follow-up in HIV-positive patients.
Another study demonstrated high NT 1 year after immu-
nisation (98%) with a marginal decrease after 10 years
(92%) [9]. Having a higher CD4 cell count (>200 cells/lL)
and lower viral load at the time of vaccination were key
associations with development of NT. The Cochrane
review reported that none of the 484 HIV positive persons
included in the review suffered serious adverse events as
a result of vaccination [6]. The data cautiously support
the safety of YF vaccination in HIV-positive patients with
CD4 cell counts >200 cells/lL and following viral load
suppression on ART. The small numbers of patients
included limit conclusions, particularly the very low
numbers (n=21) with a CD4 cell count <200 cells/lL.
There has been only one report of death after receiving
YF 17D vaccine in a Thai man with symptomatic HIV
infection and a CD4 cell count of 108 cells/lL, probably
from YEL-AND [10].
24.7 Recommendations for HIV positive adults
•We recommend that HIV-positive persons aged
<60 years and with CD4 cell counts >200 cells/lL who
are due to travel to countries in which there is a recog-
nised risk of exposure to YFV should be offered the
choice of vaccination [1C].
oWe recommend patients receive counselling about
the benefits and risks of vaccination in relation to
the risk of exposure, emphasising that a high CD4
cell count and a suppressed viral load on ART are
likely to maximise safety and efficacy of vaccina-
tion [1C].
oIf international travel requirements and not true
exposure risk are the only reasons to vaccinate, a
certificate of exemption can be given (some coun-
tries may not accept waiver certificates) [1C].
oWe recommend one vaccine dose at least 2 weeks
before travel. Vaccine recipients should be moni-
tored closely after vaccination [1C].
•We recommend a booster after 10 years for those at
continued risk, providing the recipient remains aged
<60 years, the CD4 cell count is >200 cells/lL, and fol-
lowing risk assessment and counselling [1C].
oWe suggest that a serological test may precede vac-
cination and guide boosting requirements in those
at greater risk of side effects [2C].
•We recommend that until more data are available on
vaccine safety, HIV-positive adults with CD4 cell
counts <200 cells/lL or >60 years of age and pregnant
women should not receive YFV vaccination, and
should be discouraged from travel to destinations that
present a true risk of infection [1C].
24.8 References
1 Monath TP. Review of the risks and benefits of yellow fever
vaccination including some new analyses. Expert Rev
Vaccines 2012; 11: 427–448.
2 Centers for Disease Control and Prevention. Yellow fever
vaccination: recommendations of the Advisory Committee
on Immunization Practices (ACIP). MMWR Recomm Rep
2010; 59 (RR-7): 1–27.
3 Lang J, Zuckerman J, Clarke P et al. Comparison of the
immunogenicity and safety of two 17D yellow
fever vaccines. Am J Trop Med Hyg 1999; 60: 1045–
1050.
4 Khromava AY, Eidex RB, Weld LH et al. Yellow fever
vaccine: an updated assessment of advanced age as a risk
factor for serious adverse events. Vaccine 2005; 23: 3256–
3263.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
s80 BHIVA Writing Group
5 Martin M, Weld LH, Tsai TF et al. Advanced age as risk
factor for illness temporally associated with yellow fever
vaccination. Emerg Infect Dis 2001; 7: 945–951.
6 Barte H, Horvath TH, Rutherford GW. Yellow fever vaccine
for patients with HIV infection. Cochrane Database Syst Rev
2014; 1: CD010929.
7 Sibailly TS, Wiktor SZ, Tsai TF et al. Poor antibody
response to yellow fever vaccination in children infected
with human immunodeficiency virus type 1. Pediatr Infect
Dis J 1997; 16: 1177–1179.
8 Veit O, Niedrig M, Chapuis-Taillard C et al. Immunogenicity
and safety of yellow fever vaccination for 102 HIV-infected
patients. Clin Infect Dis 2009; 48: 659–666.
9 Pacanowski J, Lacombe K, Campa P et al. Plasma HIV-RNA is
the key determinant of long-term antibody persistence after
yellow fever immunization in a cohort of 364 HIV-infected
patients. J Acquir Immune Defic Syndr 2012; 59: 360–367.
10 Kengsakul K, Sathirapongsasuti K, Punyagupta S. Fatal
myeloencephalitis following yellow fever vaccination in a case
with HIV infection. J Med Assoc Thai 2002; 85:131–149.
©2016 British HIV Association HIV Medicine (2016), 17 (Suppl. 3), s2--s81
British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults 2015 s81
