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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Interventions to improve adherence to antiretroviral
therapy: a rapid systematic review
Krisda H. Chaiyachati
a
, Osondu Ogbuoji
b
, Matthew Price
b
,
Amitabh B. Suthar
c
, Eyerusalem K. Negussie
c
and Till Ba
¨rnighausen
b,d
Introduction: Access to antiretroviral treatment (ART) has substantially improved over
the past decade. In this new era of HIV as a chronic disease, the continued success of
ART will depend critically on sustained high ART adherence. The objective of this
review was to systematically review interventions that can improve adherence to ART,
including individual-level interventions and changes to the structure of ART delivery,
to inform the evidence base for the 2013 WHO consolidated antiretroviral guidelines.
Design: A rapid systematic review.
Methods: We conducted a rapid systematic review of the global evidence on
interventions to improve adherence to ART, utilizing pre-existing systematic reviews
to identify relevant research evidence complemented by screening of databases for
articles published over the past 2 years on evidence from randomized controlled trials
(RCTs). We searched five databases for both systematic reviews and primary RCT
studies (Cochrane Library, EMBASE, MEDLINE, Web of Science, and WHO Global
Health Library); we additionally searched ClinicalTrials.gov for RCT studies. We
examined intervention effectiveness by different study characteristics, in particular,
the specific populations who received the intervention.
Results: A total of 124 studies met our selection criteria. Eighty-six studies were RCTs.
More than 20 studies have tested the effectiveness of each of the following interven-
tions, either singly or in combination with other interventions: cognitive-behavioural
interventions, education, treatment supporters, directly observed therapy, and active
adherence reminder devices (such as mobile phone text messages). Although there is
strong evidence that all five of these interventions can significantly increase ART
adherence in some settings, each intervention has also been found not to produce
significant effects in several studies. Almost half (55) of the 124 studies investigated the
effectiveness of combination interventions. Combination interventions tended to have
effects that were similar to those of single interventions. The evidence base on
interventions in key populations was weak, with the exception of interventions for
people who inject drugs.
Conclusion: Tested and effective adherence-enhancing interventions should be
increasingly moved into implementation in routine programme and care settings,
accompanied by rigorous evaluation of implementation impact and performance.
Major evidence gaps on adherence-enhancing interventions remain, in particular,
on the cost-effectiveness of interventions in different settings, long-term effectiveness,
and effectiveness of interventions in specific populations, such as pregnant and
breastfeeding women. ß2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
AIDS 2014, 28 (Suppl 2):S187–S204
Keywords: antiretroviral adherence, interventions, randomized controlled
trials, systematic review
a
Yale School of Medicine, New Haven,
b
Department of Global Health and Population, Harvard School of Public Health, Boston,
USA,
c
HIV Department, World Health Organization, Geneva, Switzerland, and
d
Wellcome Trust Africa Centre for Health and
Population Science, University of KwaZulu-Natal, Mtubatuba, South Africa.
Correspondence to Till Ba
¨rnighausen, 665 Huntington Avenue, Boston 02115, Boston, MA.
Tel: +1 617 379 0372; fax: +1 617 432 6733; e-mail: tbaernig@hsph.harvard.edu
DOI:10.1097/QAD.0000000000000252
ISSN 0269-9370 Q2014 Wolters Kluwer Health | Lippincott Williams & Wilkins S187
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Background
Antiretroviral treatment (ART) has converted a highly
fatal HIV infection into a chronic condition that requires
lifelong care [1]. Within the past decade, worldwide
access to ART has improved significantly, with almost
10 million people receiving ART by the end of 2012 [2].
In addition to its life-prolonging effects, ART can also
reduce HIV transmission to uninfected people [3,4].
In this new era of HIV treatment, the continued
success of ART will depend on improving our under-
standing of when to initiate therapy, creating continuity of
care, and ensuring high treatment adherence. Adherence
is the extent to which a person uses a medication
according to medical recommendations, inclusive of
timing, dosing, and consistency. Arguably, adherence is
the most critical factor in ensuring ART success, because
without good adherence, treatment failure is likely,
leading to avoidable HIV-related morbidity and mortality.
Additionally, imperfect adherence increases the risk
of developing resistant HIV strains and transmitting the
virus to others [5 –7]. Because adherence behaviours
and patterns can profoundly affect an individual’s
treatment response and potentially narrow future
therapeutic options, improving and sustaining ART
adherence is a critical component and priority of public
health efforts.
People living with HIV and their care providers often
face challenges in ensuring good adherence. A 2011
meta-analysis, which pooled ART adherence of 33 199
adults in 84 observational studies, reports that only 62%
of individuals took at least 90% of their prescribed
ART doses [8]. Given these adherence difficulties,
effective, feasible and acceptable interventions to
enhance ART adherence are urgently needed to ensure
the continued success and clinical and financial sustain-
ability of the global ART scale-up [9–11]. Multiple
systematic reviews and meta-analysis of ART adherence-
enhancing interventions have been conducted over
the past few years, but these studies have often been
limited to particular interventions, populations, or
settings [12–16].
To inform the evidence base for the 2013 WHO
consolidated guidelines on the Use Antiretroviral
Drugs for Treating and Preventing HIV Infection [17],
we conducted a rapid systematic review synthesizing
the research results on ART adherence-enhancing
interventions across intervention types, populations,
and settings. Our review advances the existing literature
in three ways: first, it is the most comprehensive
compilation of the evidence on adherence-enhancing
interventions to date; second, it allows evaluation of
robustness of interventions across settings; and third,
we indicate studies that focus on specific populations of
particular interest because of comorbidities and other
vulnerabilities that may interfere with their ability to
adhere to ART. In addition to the contribution to the
WHO 2013 consolidated guidelines, our review aims
to provide a guide for ART programme managers,
policy makers, and researchers to the portfolio of ART
adherence-enhancing interventions for practice, policy
and further study.
Methods
General methodology of rapid systematic
reviews
We conducted a rapid systematic review of the global
evidence on interventions to improve ART medication
adherence. Rapid systematic reviews differ from
traditional systematic reviews in that they utilize pre-
existing systematic reviews to identify relevant research
evidence in addition to screening databases for recent
primary studies [18 – 21]. This practice is useful for
making health policy decisions, because it allows
examination of the evidence while ensuring that
information is assimilated as fast as possible given prior
work [18– 24].
Using pre-existing systematic reviews to identify relevant
primary articles reduces the time needed to identify the
relevant body of evidence on a particular topic. However,
given that the time required to conduct, complete, and
publish a systematic review typically ranges from 1 to
2 years [20,22], synthesis solely based on pre-existing
systematic reviews runs the danger of failing to
incorporate evidence that has accrued over the most
recent few years. We thus supplement our systematic
review of systematic reviews, with a complete screening
of databases of primary evidence, but – in order to
maintain rapidity in the identification of primary studies
– we constrained these searches to the past 2 years (2010–
2012) and to randomized controlled trials (RCTs).
Search strategies
To identify systematic reviews, we conducted searches
in the Cochrane Library, EMBASE, MEDLINE, Web
of Science, and WHO Global Health Library (which
includes both regional and global indices). The search
algorithms are shown in Boxes A1 and A2 in the appendix
(http://links.lww.com/QAD/A499). Abstracts from
conferences and meetings were excluded because they
do not undergo the same level of peer review as published
full-text articles and they do not provide the necessary
references for extracting study-level data. Publications
on adherence interventions were excluded if they
were letters to the editor, editorials, commentaries, or
opinion articles. We further excluded systematic
reviews of interventions studying programme retention,
efficacy of combination antiretrovirals (fixed or multiple
medications), dosing strategies, or use of antiretrovirals
for pre-existing or post-exposure prophylaxis. We did not
S188 AIDS 2014, Vol 28 (Suppl 2)
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
limit our search to particular times, locations, or
languages. Additionally, we searched ClinicalTrials.gov,
Cochrane Central Register of Controlled Trials,
EMBASE, MEDLINE, Web of Science, and WHO
Global Health Library for RCTs published between 1
September 2010 and 31 August 2012 that investigated
interventions targeted towards improving ART adher-
ence. To be included in this review, RCTs could report
an adherence intervention as the primary or secondary
aim or simply report adherence measurements in the
presence of an intervention. Studies comparing or
validating adherence measurement approaches without
reporting on an adherence-enhancing intervention were
excluded. We followed the reporting standards described
in the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) statement [25].
Study selection
Three investigators (K.C., M.P., and O.O.) worked
independently, completing separate screenings of the
literature. We screened titles and abstracts of studies
that were identified in previous systematic reviews on
the effectiveness of interventions aimed at increasing
antiretroviral adherence; as well as titles and abstracts of
records identified in the search of databases for RCTs
investigating adherence interventions. All records were
screened by two of the three reviewers; two reviewers
have been found to be sufficient to carry out a high-
quality systematic review [26]. The same reviewers used
the inclusion and exclusion criteria to independently
assess the full eligibility of studies identified in the
databases. Reviewers were not blinded to study authors,
conclusions, or outcomes, because blinding is compli-
cated to implement and has been shown to have little
effect on the quality of systematic reviews [27]. Once all
potentially relevant full-text articles and abstracts were
identified, the three reviewers achieved consensus
regarding eligibility and extracted data onto a standar-
dized extraction form. Where consensus was not possible,
a fourth reviewer (T.B.) served as arbiter. After relevant
systematic reviews were identified, we searched for the
primary studies featured in these reviews and extracted
the data from the studies. Data entry was compared, and
discordant information was resolved by consensus
through data checks and discussion between the data
extractors. When necessary, the further reviewer (T.B.),
who guided but was not directly involved in the primary
data extraction process, was asked to mediate. Figures 1
and 2 show flowcharts of the study selection processes.
Data extraction
We organized the synthesis of results by adherence
intervention type, that is, the actual intervention activity,
such as directly observed therapy (DOT) or depression
Improving adherence to antiretroviral therapy Chaiyachati et al. S189
773 reviews excluded based on
screening titles
923 systematic reviews identified
by database searches
150 reviews screened
90 reviews after duplicates removed
35 full-text reviews assessed for
eligibility
32 full-text systematic reviews for
study extraction
488 studies available for full-text
review and extraction
105 full studies included in final
review
60 duplicate reviews excluded
55 reviews excluded based on
screening abstracts
383 studies excluded
• 138 Duplicates
• 86 No described intervention
• 50 No comparison group
• 42 Conference abstracts
• 36 No adherence measure
• 14 Descriptive reports
• 10 Letters or magazine articles
• 3 Studies on drug effects
• 3 Other
• 1 Non-ART intervention
3 reviews excluded
• 1 Not a systematic review
• 2 Not about HIV/AIDS
Fig. 1. Flowchart of study selection process based on systematic reviews of ART adherence-enhancing interventions.
ART, antiretroviral therapy.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
treatment. In addition to the intervention types, we
extracted from the studies the following data: author and
year of publication, study period, study design, country of
study, population, source of information, and healthcare
setting, in which the study took place; study duration,
sample size, loss to follow-up, intervention, control
group, adherence measure, and study results. Web
Appendix, http://links.lww.com/QAD/A506 shows
the study characteristics; Table 1 provides an overview
of the different adherence-enhancing interventions that
were tested in the studies and reports the results by
outcome measure. We report on results for subjective
adherence measures (self-report by patients), objective
adherence measures (pill count, pharmacy refill, and
electronic monitoring), and the biological correlates of
adherence (viral load, CD4
þ
cell count, and change in
body weight). A few studies report composite adherence
indices incorporating information from several outcome
measures. We do not include the results in terms of
these outcome measures in our review, because the use
of these indices is usually particular to one study, and
all studies using indices also report results in terms of
outcome based on individual measures.
Results
A total of 124 studies met our selection criteria (Figures 1
and 2). These studies included 86 RCTs, 6 non-
randomized controlled trials (NRCT), 19 before-after
studies, 8 cohort studies, 4 case-control studies, and 1
cross-sectional study. Seventy-five studies were carried
out in North America, 30 in Africa, 11 in Europe,
4 in Asia, 3 in Central and South America, and 2 in
Australia. Publication intensity in studies testing ART
adherence-enhancing interventions increased over time;
each year before 2003 three or fewer articles were
published, whereas in 2003 and thereafter, at least six
articles were published each year and in many years more
than 10 articles (Web Appendix, http://links.lww.com/
QAD/A506).
Almost half (55) of the 124 studies investigated the
effectiveness of combination interventions, that is,
interventions that were composed of several clearly
identifiable components. The most commonly tested
interventions were cognitive-behavioural therapy (CBT)
(60), followed by education (28), treatment supporters
(26), DOT (20) and active reminder devices (20). The less
commonly tested intervention types included structural
interventions (such as changes in the person delivering
ART, or in the location where ARTwere provided) (10),
counselling (8), nutritional support (7), financial incen-
tives (5), passive reminder devices (5), and drug use
treatment (4). Active reminder devices included both
telephone reminders and other technologies, such as
pagers and pillboxes with in-built timers and alarms.
Passive reminder devices included pillboxes and diary
cards. Detailed information on intervention types and
the interventions are shown in Table 1. Commonly (in 29
studies), CBT, education or counselling were combined
with other interventions. DOT, passive reminder devices,
treatment supporters, nutritional support, and financial
incentives were combined with other interventions
in more than two-fifths of the studies, whereas the
other interventions were less likely to be investigated in
combination.
The synthetic picture that emerges becomes even more
complex when the success of particular interventions is
considered across different outcomes. Table 2 shows the
S190 AIDS 2014, Vol 28 (Suppl 2)
825 RCTs identified by database
searches
690 RCTs excluded based on
screening titles
57 RCTs excluded based on review
of abstracts
135 RCTs after screening
78 RCTs after screening
38 full-text RCTs assessed for
eligibility
19 RCTs for data extraction
40 RCTs excluded based on review
of abstracts
19 RCTs excluded after review
• 10 Duplicates
• 6 Descriptive reports
• 2 No comparison group
• 1 Non-ART intervention
Fig. 2. Flowchart of study selection process of randomized controlled trials of ART adherence-enhancing interventions. RCTs,
randomized controlled trials. ART, antiretroviral therapy.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Improving adherence to antiretroviral therapy Chaiyachati et al. S191
Table 1. Adherence-enhancing interventions and results.
Authors and year (review
authors) Intervention type Intervention
Results
SR PC PR EM VL CD4
þ
WC O
Blank et al., 2011 [28] Structural intervention Advanced practice nurse for monitoring and managing ART – – – – Y N – –
Berg et al., 2011 [29] DOT, other ART DOT and methadone maintenance therapy – Y – Y Y – – –
Chung et al., 2011 [30] Counselling, ARD Intensive adherence counselling, pocket alarm device, or both – Y Y – Y N – –
da Costa et al., 2012 [31] ARD SMS messages before last scheduled medication for the day (Y) (Y) – (Y) – – – –
de Bruin et al., 2010 [32] Counselling, CBT Adherence counselling, brief motivational interviewing utilizing
EM results
–––YY – ––
Duncan et al., 2012 [33] CBT Mindfulness-based stress reduction strategies for reducing ART
symptoms and stress related to ART side effects
N–––– – ––
Fisher et al., 2011 [34] CBT, education Interactive computer-based antiretroviral adherence promotion
programme consisting of educational materials, goal selection,
and targeted interventions focused on motivational and
behavioral strategies for improving adherence
Y–– –N – ––
Hardy et al., 2011 [35] ARD Personalized mobile phone reminder system for adherence Y Y – N – – – –
Holstad et al., 2011 [36] CBT Motivational interviewing group sessions involving exploring
day-to-day experiences, identifying barriers to adherence,
exploring motivations and adherence strategies
–––YY N – –
Kalichman et al., 2011a [37] CBT, education Counselling about effective decision-making, providing education,
and developing skills to avoid drug use, unsafe sexual practices,
and improve adherence
–Y––N – – –
Kalichman et al., 2011 [38] Counselling Counselling sessions via mobile phones Y Y – – – – – –
Leon et al., 2011 [39] Counselling, structural
intervention
Home care monitoring through an internet-based clinical system
that provides consultation, telepharmacy, access to a library of
resources, and a community of other individuals with HIV
N–N– N N – –
Pyne et al., 2011 [40] Depression treatment Depression treatment through a clinical team consisting of a
psychiatrist, a case manager, and pharmacist
N–––– – ––
Ramirez-Garcia and Cote
2012 [41]
CBT Nurse-led counselling sessions seeking to stimulate development
and use of skills needed for proper treatment-taking behaviour,
enhancing self-efficacy, and reinforcing positive attitudes toward
treatment-taking in the participant
Y–– – Y N – –
Ruiz et al., 2010 [42] Treatment supporters,
education
Peer-led treatment with baseline psycho-educational component N – – – N – – –
Sabin et al., 2010 [43] ARD EM feedback – – – Y N Y – –
Safren et al., 2012 [44] CBT Cognitive-behavioural therapy for adherence and depression – – – Y N N – –
Uzma et al., 2011 [45] ARD Phone call reminders as memory aids Y – – – Y – – Y
Zubaran et al., 2012 [46] CBT Motivational interviews with information to promote motivation for
adherence
––––– – –N
DiIorio et al., 2003 [47]
(Amico et al., [48])
CBT, education, other Nurse counsellor-led motivational interview sessions, alcoholics
anonymous videotape, education materials
N–––– – ––
Fairly et al., 2003 [49] (Amico
et al. [48])
ARD, PRD, CBT,
education
Nurse-led education about HIV and adherence, telephone-based
support; medication planners, SMS text messages, medication
box, and medication alarms
Y–– –N N ––
Goujard et al., 2003 [50]
(Amico et al. [48])
CBT, PRD, education Personalized educational diagnoses made for each patient,
planning cards, pill boxes
(Y) – – – N N – N
Lyon 2003 [51] (Amico et al.
[48])
CBT, education,
nutritional support
Education on medication choices, side effects, and nutrition
treatments
Y – – – (Y) (Y) – –
Mann, 2001 [52] (Amico et al.
[48])
Other Future writing N – – – – – – –
Margolin et al., 2003 [53]
(Amico et al. [48])
CBT Manual-guided group therapy sessions with harm reduction skills
training, adherence training, and exploration of barriers to
adherence
Y–– – Y – – –
(continued)
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
S192 AIDS 2014, Vol 28 (Suppl 2)
Table 1 (continued )
Authors and year (review
authors) Intervention type Intervention
Results
SR PC PR EM VL CD4
þ
WC O
McPherson-Baker et al., 2000
[54] (Amico et al. [48])
CBT, PRD, counselling,
education
Medication counselling, pill boxes, education on problem solving
strategies
––Y–N N –Y
Molassiotis et al., 2003 [55]
(Amico et al. [48])
CBT, ARD, education Individual education sessions about antiretroviral medication and
side effects, weekly counselling, and follow-up phone calls
Y–– –N Y –Y
Murphy et al., 2002 [56]
(Amico et al. [48])
CBT Intervention sessions by cognitive-behavioural therapist and
psychiatric nurse
N–––– – ––
Powell-Cope et al., 2003 [57]
(Amico et al. [48])
ARD Timer, pager, or pillbox with timer integrated into box N – – – – – – –
Pradier et al., 2003 [58] (Amico
et al. [48])
Counselling, education Individual educational and counselling sessions with a trained
nurse
Y–– – Y – – –
Rawlings et al., 2003 [59]
(Amico et al. [48])
CBT, education Education modules, focused on patient empowerment, HIV
pathogenesis and treatment, and medication management or
adherence; and education modules focused on names and
physical description of medications, dosage instructions, use of
MEMS, importance of adherence, and side-effects
–––NN N – –
Rigsby et al., 2000 [60] (Amico
et al. [48])
Financial incentives,
ARD
Customized medication schedules, daily reminders, with or without
cash incentives
–––YN – ––
Safren et al., 2001 [61] (Amico
et al. [48])
CBT Life-Steps protocol, a single-session intervention utilizing cognitive-
behavioural, problem-solving, and motivational interviewing
techniques to enhance motivation, rehearse adherence-related
behaviours, and solve problems that interfere with adherence to
HIV medications, with one follow-up telephone review
Y–––– – ––
Safren et al., 2003 [62] (Amico
et al. [48])
ARD Daily pill diary, paged electronic reminders through www.
medimom.com
–––Y– – ––
Smith et al., 2003 [63] (Amico
et al. [48])
CBT, education Feedback on adherence, rooted in social cognitive theory,
education and assistance with medication self-management
skills
–––YN – ––
Stenzel et al., 2001 [64]
(Amico et al. [48])
DOT, counselling,
other
Nurse-led DOT and adherence support, side effects information
relayed to physician for follow-up
(Y) – – – (Y) (Y) – –
Tuldra et al., 2000 [65] (Amico
et al. [48])
CBT, education,
counselling
Psycho-education, education material, counselling support N – – – Y – – –
Berrien et al., 2004 [66]
(Bain-Brickley et al. [67])
Treatment supporters,
education
Structured home-based support for education and identifying
barriers for intervention group
N–Y – Y N – –
Funck-Brentano et al., 2005
[68] (Bain-Brickley et al.
[67])
Treatment supporters,
CBT
Peer support sessions, in which ART patients discuss their feelings,
fears and attitudes about ART
N– – – N N – –
Wamalwa et al., 2009 [69]
(Bain-Brickley et al. [67])
Treatment supporters,
CBT
Medication diaries and counselling N – – – N N – –
Cantrell et al., 2008 [70]
(Ba
¨rnighausen et al. [71])
Nutritional support Food rations (individual rations if patient is not the primary income
earner in his/her family; rations for a total of seven household
members if patient is primary income earner)
––Y–– N ––
Chang et al., 2010 [72]
(Ba
¨rnighausen et al. [71])
Treatment supporters Home visits by treatment supporters to promote adherence through
questions and pill count, and to discuss treatment benefits and
side effects
NN – – Y N – –
Idoko et al., 2007 [73]
(Ba
¨rnighausen et al. [71])
DOT DAOT, TWOT, or WOT; provided by patient-selected treatment
supporters (from the community or the patient’s family)
––––N N ––
Kabore et al., 2010 [74]
(Ba
¨rnighausen et al. [71])
Treatment supporters,
nutritional support
Treatment supporter and/or nutritional support within a
community-based model of ART care
YY––– N ––
Lester et al., 2010 [75]
(Ba
¨rnighausen et al. [71])
ARD SMS from study clinicians asking ‘How are you?’ requiring a
response within 48 h
Y–– – Y – – –
Mugusi et al., 2009 [76]
(Ba
¨rnighausen et al. [71])
Treatment supporters,
other
Calendar for record-keeping of dose intake, or treatment supporters N – – – – N N –
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Improving adherence to antiretroviral therapy Chaiyachati et al. S193
Nachega et al., 2010 [77]
(Ba
¨rnighausen et al. [71])
DOT, education,
treatment supporters
DAOT by a treatment supporter chosen using a personal network
inventory instrument, one baseline education session for
treatment supporter, four additional baseline education sessions
and refresher course every three months for patients and
treatment supporter
–N– –N Y – –
Ndekha et al., 2009 [78]
(Ba
¨rnighausen et al. [71])
Nutritional support Supplementary feeding with ready-to-use fortified, energy-dense,
lipid paste
N– – – N N – –
Ndekha et al., 2009 [79]
(Ba
¨rnighausen et al. [71])
Nutritional support Supplementary feeding with ready-to-use fortified, energy-dense,
lipid paste
N– – – N N – –
Pearson et al., 2007 [80]
(Ba
¨rnighausen et al. [71])
DOT, treatment
supporters, education
Treatment supporter-delivered DAOT, patient education about
treatment, identification and mitigation of adherence barriers
Y–– – – N ––
Pienaar et al., 2006 [81]
(Ba
¨rnighausen et al. [71])
Structural intervention Five different models of ART delivery; three
community-based models (doctor-led primary care clinic,
nurse-led primary care clinic, integrated primary care clinic) and
two hospital-based models (rural district hospital, hospital-based
specialist service)
N– – – – Y – –
Pop-Eleches et al., 2011 [82]
(Ba
¨rnighausen et al. [71])
ARD Different types of SMS (short daily reminders, long daily messages,
short weekly reminders, or long weekly reminders)
–––Y– – ––
Roux et al., 2004 [83]
(Ba
¨rnighausen et al. [71])
PRD Diary cards with calendars showing medication dosing schemes N – – – – – – –
Sarna et al., 2008 [84]
(Ba
¨rnighausen et al. [71])
DOT TWOT at nearby clinics, pill counting, and treatment support Y N – – N N Y –
Sherr et al., 2010 [85]
(Ba
¨rnighausen et al. [71])
Structural intervention Assignment to non-physician clinicians – – Y – – Y – Y
Stubbs et al., 2009 [86]
(Ba
¨rnighausen et al. [71])
Treatment supporters Treatment supporters (from the community or the patient’s family)
provided psycho-social support
––Y–– – ––
Taiwo et al., 2010 [87]
(Ba
¨rnighausen et al. [71])
Treatment supporters,
DOT
Treatment supporters provided DOT, assisted in reporting and
managing adverse effects, and reminded patients of drug pick-up
––Y–Y N – –
Thurman et al., 2010 [88]
(Ba
¨rnighausen et al. [71])
Structural intervention Case managers (nurses or social workers) identified patients’ needs,
linked patients to community service providers, and coordinated
care with medical staff and community health workers
(Y) – – – – – – –
Torpey et al., 2008 [89]
(Ba
¨rnighausen et al. [71])
Treatment supporters Treatment supporters followed up with patients in the community
and provided support to improve adherence
N– – – – – – –
Antoni et al., 2006 [90] (Brown
et al. [91])
CBT Cognitive medication adherence and management training N – – N N N – –
Creswell et al., 2009 [92]
(Brown et al. [91])
CBT A mindfulness-based stress reduction meditation programme – – – – N N – –
Johnson et al., 2011 [93]
(Brown et al. [91])
CBT Individually tailored CBT sessions designed to improve HIV
treatment coping skills and medication adherence
Y–– – – – – –
Weiss et al., 2011 [94] (Brown
et al. [91])
Drug use treatment, CBT,
education
Cognitive stress management with expressive-supportive therapy
and educational material
Y–– –Y Y – –
Jaffar et al., 2009 [95] (Brown
et al. [91])
Structural intervention Home-based ART delivery N – – – N N – –
Wall et al., 1995 [96] (Fogarty
et al. [97])
DOT Nurse-supervised DAOT N N – N – – – Y
Knobel et al., 1999 [98]
(Haddad et al. [16])
CBT, education Individual advise and education on ART adherence, addressing
lifestyle issues, by pharmacist at first ART dispensing interaction
YY– – N – – –
Altice et al., 2007 [99], Maru
et al., 2009 [100] (Hart et al.
[101])
DOT, treatment
supporters, CBT
Enhanced community-based DOT, beeper reminders, mobile vans
with on-site clinician, drug treatment coordinator, case manager,
outreach workers, methadone co-management
N– – – Y Y – –
Gross et al., 2009 [102] (Hart
et al. [101])
DOT DOT by a healthcare professional – – – N N N – –
Lucas et al., 2006 [103] (Hart
et al. [101])
DOT, drug use treatment DOT by nurse or medical assistant and prepackaged doses on
non-DOT days
––––Y Y ––
Macalino et al., 2007 [104]
(Hart et al. [101])
DOT DOT by trained outreach worker, prepackaged pills Y – – – Y Y – –
(continued)
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
S194 AIDS 2014, Vol 28 (Suppl 2)
Table 1 (continued )
Authors and year (review
authors) Intervention type Intervention
Results
SR PC PR EM VL CD4
þ
WC O
Munoz et al., 2010 [105] (Hart
et al. [101])
DOT, treatment
supporters, nutritional
support
DOT by lay healthcare worker who also monitored side effects and
provided social support; financial aid for tests, medication,
transportation; nutritional support
Y–– – Y N – –
Tinoco et al., 2004 [106] (Hart
et al. [101])
DOT DOT by lay healthcare worker who also monitored side effects and
provided social support; financial aid for tests, medication,
transportation; nutritional support
––––Y Y ––
Wohl et al., 2006 [107] (Hart
et al. [101])
DOT, treatment
supporters, financial
incentive
DOT by community health worker who also discussed adherence
problems with the patient, financial incentives, or intensive
adherence case management
N– – – N N – –
Andrade et al., 2005 [108]
(Haynes et al. [109])
ARD Disease Management Assistance system (DMAS), an electronic
reminder message system to remind patients to take medications
N– –NY N – –
Collier et al., 2005 [110]
(Haynes et al. [109])
ARD Serial, supportive phone calls using a standardized script, side effect
management
N– – – N – – –
Remien et al., 2005 [111]
(Haynes et al. [109])
Treatment supporters,
CBT, education
A couple-focused adherence programme to provide support and
education about coping strategies and the medical impact of
adherence
–––YN N ––
Samet et al., 2005 [112]
(Haynes et al. [109])
CBT Assessment of alcohol use and readiness for behaviour change,
enhancement of perceived medication efficacy, individualized
HIV counselling and exploration
N– –NN N – –
Van Servellen et al., 2005
[113] (Haynes et al. [109])
Treatment supporters,
CBT, education
Educational sessions with nurse practitioners, motivational
interviewing, problem-solving skills strategy, and support groups
N – – – Y (N) – –
Weber et al., 2004 [114]
(Haynes et al. [109])
CBT Psychotherapy sessions based on concepts of cognitive-behavioural
therapy
Y–– YN – ––
DiIorio et al., 2008 [115] (Hill
and Kavookjian [116])
CBT Motivational interviewing – – – N N N – –
Parsons et al., 2007 [117] (Hill
and Kavookjian [116])
CBT Motivational interviewing and cognitive-behavioural skills training Y – – – Y Y – –
Mitty et al., 2005 [118]
(Kenya et al. [119])
DOT DAOT by peer outreach workers – – – – (Y) (Y) – –
Purcell et al., 2007 [120]
(Kenya et al. [119])
Treatment supporters,
CBT
Peer-led sessions on HIV care, adherence, and risk behaviours N – – – – – – –
Simoni et al., 2007 [121]
(Kenya et al. [119])
Treatment supporters Peer-led sessions to identify barriers, create coping strategies, and
peer-directed phone calls
N– –NN – – –
Visnegarwala et al., 2006 [122]
(Kenya et al. [119])
DOT, treatment
supporters, CBT
Care management team consisting of social worker, peer
caseworker, and pharmacist, or peer DAOT and social support
––––Y N – –
Williams et al., 2006 [123]
(Kenya et al. [119])
Treatment supporters,
CBT
Home visits by nurses and community support workers to discuss
barriers to adherence and propose solutions
–––YN N ––
Golin et al., 2006 [124]
(Leeman et al. [125])
CBT Motivational interviewing focused on adherence, including
audiotape and booklet, one-on-one sessions with a health
educator, mail follow-up after each session
NN – N N – – –
Harwell et al., 2003 [126]
(Leeman et al. [125])
DOT DAOT by outreach worker – – – – (Y) (Y) – –
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Improving adherence to antiretroviral therapy Chaiyachati et al. S195
Holzemer et al., 2006 [127]
(Leeman et al. [125])
CBT Individually tailored, nurse-delivered adherence intervention
programme with a range of interventions, including teaching and
discussions about adherence, self-care management of
perceived side-effects, role performance, and improvement in
the client-provider relationship
NNNN N N – –
Javanbakht et al., 2006 [128]
(Leeman et al. [125])
Financial incentives, drug
use treatment,
treatment supporters
Individualized case management with treatment supporters and
monetary reinforcement
––––Y Y ––
Johnson et al., 2007 [129]
(Leeman et al. [125])
CBT Individually cognitive-behavioural interventions Y – – – – – – –
Jones et al., 2007 [130]
(Leeman et al. [125])
CBT, education Group cognitive-behavioural stress management sessions and
expressive supportive therapy intervention with education on a
healthier lifestyle
N–––– – ––
Koenig et al., 2008 [131]
(Leeman et al. [125])
Treatment supporters,
CBT
Structured interviews (to help patients identify adherence barriers,
generate possible solutions, select strategies to overcome the
barriers, and evaluate how strategies are working) treatment
supporter, MEMS providing electronic adherence cues
–––YY N – –
Levin et al., 2006 [132]
(Leeman et al. [125])
ARD, PRD Printed cards with information about each drug, pill boxes, and
bimonthly postal reminders
N– – – N N – –
Ma et al., 2008 [133] (Leeman
et al. [125])
DOT DOT (Y) – – – (Y) – – –
Milam et al., 2005 [134]
(Leeman et al. [125])
CBT Printed and verbal adherence information, self-efficacy and skill
building, behavioural cues
Y–– –N N ––
Parsons et al., 2005 [135]
(Leeman et al. [125])
CBT Motivational interviewing and cognitive-behavioural therapy (Y) – – – – – – –
Reynolds et al., 2008 [136]
(Leeman et al. [125])
ARD Structured telephone calls by specifically trained nurse Y – – – N – – –
Rosen et al., 2007 [137]
(Leeman et al. [125])
Financial incentives, drug
use treatment, CBT
Reinforcement of medication taking with prizes or monetary
rewards
N– –NN – – –
Sorenson et al., 2007 [138]
(Leeman et al. [125])
Financial incentives Medication coaching and voucher reinforcement for opening
MEMS devices on time
Y (Y) – (Y) – – – –
Wagner et al., 2006 [139]
(Leeman et al. [125])
CBT Cognitive-behavioural adherence intervention with or without
practice ART
Y––NN N – –
Jones et al., 2003 [140]
(Manias and Williams
[141])
CBT Cognitive-behavioural stress management and expressive
supportive therapy
N–––– – ––
Rathbun et al., 2005 [142]
(Manias and Williams
[141])
CBT, education Visit and phone follow-up to provide education about ART, food
restrictions, adverse-event management strategies, and
monitoring of patient progress after therapy initiation
N– –NY N – –
von Servellen et al., 2003 [143]
(Manias and Williams
[141])
CBT Instructional support programme to enhance health literacy with
follow-up with case management
N–––– – ––
Wyatt et al., 2004 [144]
(Manias and Williams
[141])
CBT, education Sessions guided by cognitive-behavioural principles, psycho-
education
N–––– – ––
Levy et al., 2004 [145] (Rueda
et al. [15])
CBT, education Adherence education programme, individualized counselling,
adherence tools (dosette boxes for antiretroviral pills and
electronic alarms)
Y–– –N N ––
Mannheimer et al., 2006 [146]
(Saberi and Johnson, 2011
[147])
CBT Medication manager involving research staff member providing
tailored adherence support in a protocol-guided manner, or
electronic medication reminder system using a small
portable alarm for all antiretroviral doses, or both
Y–– –N
a
Y––
(continued)
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S196 AIDS 2014, Vol 28 (Suppl 2)
Table 1 (continued )
Authors and year (review
authors) Intervention type Intervention
Results
SR PC PR EM VL CD4
þ
WC O
Murphy et al., 2007 [148]
(Saberi and Johnson, 2011
[147])
CBT Sessions focused on role-playing, problem-solving, coaching,
reinforcement strategies
–Y–Y – – ––
Simoni et al., 2009 [149]
(Saberi and Johnson, 2011
[147])
ARD, treatment
supporters
Pager messaging with a reminder device or phone, or peer support
with group meetings, or both
N
a
––NN N ––
Simoni et al., 2011 [150]
(Saberi and Johnson, 2011
[147])
ARD, CBT Electronic reminder device, or counselling on cognitive-
behavioural and problem-solving approaches, or both
Y––NN N – –
Wu et al., 2006 [151] (Saberi
and Johnson, 2011 [147])
ARD, CBT, education Prompting device that verbally reminds patients at medication times
and electronically records doses, adherence education session
–––(Y)– – ––
Frick et al., 2006 [152] (Saberi
et al., 2012 [153])
CBT, education One-on-one sessions with a pharmacist, dietician, and social
worker focused on ART education, ART readiness, and
identification and mitigation of adherence barriers
––N–Y N – –
Hirsch et al., 2011 [154]
(Saberi et al., 2012 [153])
Structural intervention Pharmacist-provided ART medication management – Y Y – – – – –
Horberg et al., 2007 [155]
(Saberi et al., 2012 [153])
CBT Care at clinics employing an HIV clinical pharmacist – – Y – Y N – –
March et al., 2007 [156]
(Saberi et al., 2012 [153])
Structural intervention Pharmacist-provided ART medication management – – – – Y Y – –
Pirkle et al., 2009 [157] (Saberi
et al., 2012 [153])
DOT DOT with weekly follow-up visits from pharmacists or adherence
counsellors
– – – – (Y) – – –
Rotheram-Borus et al., 2004
[158] (Simoni et al., [159])
ARD, CBT Phone or in-person sessions focused on improving physical health,
reducing sexual and drug use acts, and improving mental health
N–––– – ––
Byron et al., 2008 [160]
(Tirivayi and Groot [161])
Nutritional support Food support programme (Y) – – – – (Y) – –
Feaster et al., 2010 [162]
(Wechsberg et al. [163])
CBT, other Family-based interventions therapy, emphasizing the female
patient’s interaction with her family and other social groups
N–––– – ––
Ingersoll et al., 2011 [164]
(Wechsberg et al. [163])
CBT, education Motivational interviewing and counselling sessions, educational
hand-outs
Y–– –N – – –
Page et al., 2003 [165] (Wong
et al. [166])
Structural intervention HIV services provided by general practitioners N – – – N N – –
Igumbor et al., 2011 [167]
(Wouters et al. [168])
Treatment supporters Patient advocates, a community-based adherence support
programme provided by adherence supporters
––Y–Y – ––
Kunutsor et al., 2011 [169]
(Wouters et al. [168])
Treatment supporters,
education
Treatment supporter initiative designed to improve access,
adherence diaries, and education
–N––– – ––
Rich et al., 2012 [170]
(Wouters et al. [168])
Structural intervention Community-based treatment programme providing nutritional
support, financial assistance, patient support groups, and
transportation
– – – – (Y) (Y) (Y) –
ART, antiretroviral therapy; CBT, cognitive and/or behavioural therapy; CD4
þ
,CD4
þ
cell count; DAOT, daily DOT; DOT, directly observed therapy; EM, electronic monitoring; MEMS, medication event monitoring system; O, other; PC, pill
count; PR, pharmacy refill; PRD, passive reminder devices; RD, active reminder devices; SR, self-report; TWOT, twice weekly DOT; VL, viral load; WC, weight change; WOT, weekly DOT.
Y means significantly better outcome in the intervention group (at least at one time point);N means not significantly better outcome in the intervention group; results (Y, N) are shown in parentheses if an effect size is reported and the authors draw a
conclusion as to whether the intervention has improved adherence or not but without reporting significance levels.
a
The study showed that the intervention decreased adherence as assessed by this outcome measure.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
distribution of outcome measures used across the
124 studies. Two-fifths of studies followed the general
recommendation to use both outcomes that capture
adherence (subjective measures-self-reported adherence
levels, or objective measures – pill count, pharmacy refill,
etc.), as well as those that capture the biological outcomes
determined by adherence behaviour (viral load, CD4
þ
cell count, body weight). However, 16% of the studies
measured adherence using only subjective outcomes.
Overall, 72 of the 124 studies were found to generate
significant positive effects as assessed by at least one
outcome measure. But only 24 studies (or one-fifth)
found significant positive effects in at least one
biological and one (objective or subjective) ART-
adherence measure. Combination interventions were
not more or less likely to succeed in significantly
improving outcomes than single interventions (P¼0.80
for having at least one positive effect across all outcomes;
P¼0.55 for having at least one positive effect each for
a biological and a subjective or objective adherence
outcome).
Table 3 shows a synthesis of the study results by
intervention type. In the case of combination interven-
tions, each component intervention is counted separately.
The table shows that for most interventions, at least three-
fifths of the studies found a positive result for at least
one outcome, but the proportion of studies finding
positive results for both at least one biological and one
subjective or objective adherence outcome is less than
50%.
Most studies (87) investigated adherence-enhancing
interventions in the general population; the remainder
focused on particular sub-populations. The most
commonly researched sub-populations were persons
who use drugs (PWUD), with 22 studies, followed by
women (8 studies), children (4 studies), and persons with
mental health disorders (2 studies). It is an important
finding that despite overall small sample sizes, there
were significant effects in 12 out of the 22 studies in
PWUD. Syntheses of results by outcome measure are
presented in Table 1.
Discussion
A large global evidence base on ART adherence-
enhancing interventions – a total of 124 studies including
86 RCTs – provides important information for ART
programming and planning. The field of ART adherence
intervention research is developing rapidly and relatively
more rapidly than research into ART access, linkage to
care, and retention. The reason for this differential
in research intensity within the overall field of HIV
operations and health services research plausibly reflects
the importance of ART adherence – we would prefer
only to initiate patients on ART once we are able to
ensure good ART adherence. It could also reflect the f act
that ART adherence is more easily conducted than
research into other aspects of ART services, because
unlike studies of access, linkage, and retention, it only
requires data collection in clinical cohorts and not in
HIV-infected populations in communities. Whatever
the reason for the intensity of the research on ART
adherence-enhancing interventions, the speed of study
implementation, analysis, and publication means that
evidence syntheses will rapidly grow out of date. Our
review provides an updated synthesis on the body of
knowledge on the effectiveness of ART adherence-
enhancing interventions.
Each of the following interventions has been tested
in more than 20, mostly rigorous studies, either singly
or in combination with other interventions: CBT,
education, treatment supporters, DOT, and active
adherence reminder devices (such as mobile phone text
messages). Whereas there is strong evidence that all
five of these interventions can significantly increase
ART adherence in some settings, each intervention
has also been found not to produce significant effects in
several studies.
The 2013 WHO consolidated guidelines on the use of
antiretroviral drugs for treating and preventing HIV
infection describe the portfolio of adherence-enhancing
interventions and recommends that ‘[M]obile phone text
messages could be considered as a reminder tool for
promoting adherence to ART as part of a package of
adherence interventions’. This recommendation, as well
as the descriptions of the evidence on other adherence-
enhancing interventions in the guidelines, have been
informed and are broadly supported by this systematic
review. In addition – and with the caveats regarding
context-specificity of findings discussed below – our
review suggests that the other four interventions which
have been widely tested in rigorous studies – CBT,
education, treatment supporters, and DOT – warrant
consideration by ART programme managers. Given the
critical importance of adherence for the long-term
individual and population-level success of ART, routine
implementation of adherence-enhancing interventions
should be considered.
Whereas the current evidence base provides a portfolio of
interventions that have been shown to be effective in
high-quality studies at least in some settings, adherence is
a behaviour and as such is affected by culture and
circumstance. The standard approaches to synthesizing
evidence on effectiveness take on a different meaning
when considering behavioural interventions as opposed
to biological interventions. For behavioural inter-
ventions, consistency of causal effects across studies
is an indicator of the degree of generalizability of an
intervention effect to other settings rather than a measure
Improving adherence to antiretroviral therapy Chaiyachati et al. S197
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
of the degree to which an effect is ‘true’ as in the case of
biological interventions.
We would expect that behavioural interventions that
have been truly successful in one setting may not be
effective in another one with different economic, social
and behavioural barriers to adherence. Thus, health
policy makers and programme planners need to carefully
consider which adherence intervention to choose for
routine implementation in a particular setting based on
socio-cultural context, feasibility, acceptability, and health
systems organization. The adherence-enhancing inter-
ventions identified in this review are likely to differ
widely in implementation-relevant aspects, such as costs,
human resources requirements, and scalability. Thus,
other factors than the effectiveness evidence covered in
this review will likely guide implementation decisions.
For instance, DOT is labour-intensive and expensive, but
it may be a good strategy for particular settings, for
example, where patients can be easily reached, such as in
hospitals or prisons. In contrast, some types of mobile
phone text messaging interventions are comparatively
inexpensive and do not require substantial human
resources investment. As such, they may be a good
option for general populations with high individual
mobile phone coverage. Future meta-analyses of the
contextual predictors of success of particular types of
ART adherence interventions can further inform these
choices. Additionally, it will be critical to monitor the
performance of an adherence-enhancing intervention
as it is introduced into routine ART services. Quasi-
experimental designs, such as stepped wedge scale-up
of adherence interventions across HIV clinics, might
offer ‘natural’ opportunities for rigorous confirmation of
effectiveness of the five interventions that the currently
available body of evidence can increase adherence.
Whereas the global evidence on effectiveness of
adherence-enhancing interventions is rich, our review
has identified several important knowledge gaps that will
be relevant for implementation decisions and should
increasingly be filled with evidence from implementation
science research. First, more evidence is needed to
examine interventions that have shown promise in a few
studies, but have only been tested in a limited range
of settings. Our review finds that these interventions
include the following: alternative health system structures
for ART delivery, nutrition support, financial incentives,
passive reminder devices (such as diary cards and
compartmentalized pill boxes), drug use treatment, and
anti-depressive treatment.
Second, comparative information on costs and cost-
effectiveness of different effective adherence interventions
is largely lacking, and when it is available, it is unclear in
how far the costs assessed in a research setting are
transferable to routine implementation situations. More
cost-benefit studies as part of routine care are needed
to provide this critical component for deciding between
alternative effective adherence-enhancing interventions.
Whereas several studies investigated combination
interventions (see Table 1), differential effectiveness of
alternative combination portfolios and interaction effects
between different intervention components were rarely
examined. It would seem plausible that combination
adherence interventions will be particularly successful
in increasing ART adherence because they commonly
work through different pathways. However, our synthesis
shows that combination interventions tend to be similarly
likely to succeed in increasing ART adherence as single
interventions. One reason for this finding could be that
S198 AIDS 2014, Vol 28 (Suppl 2)
Table 2. Distribution of outcome measures.
Type of outcome measure
% of studies
(N¼124)
Subjective adherence measure only 16
Objective adherence measure only 6
Subjective and objective adherence measure 4
Biological measure only 10
Biological measure and subjective and/or
objective adherence measure
63
Other 1
Table 3. Summary of effects of adherence-enhancing interventions.
Intervention component
Number of
studies
% with positive
results for at least
one outcome measure
% with positive results for at least one
positive effect each for a biological and
a subjective or objective adherence outcome
CBT 60 67 20
Education 28 79 21
Treatment supporter 26 62 19
DOT 20 85 30
ARD 20 75 25
Structural 10 70 10
Counselling 8 88 63
Nutrition support 7 71 43
PRD 5 60 0
Financial incentives 5 60 0
Drug use treatment 5 80 40
Depression treatment 1 0 0
ARD, active reminder device; CBT, cognitive-behavioural therapy; DOT, directly observe therapy; PRD, passive reminder device.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
there is usually one dominant intervention within the
combination, and the other interventions merely
moderately enhance the effectiveness of the dominant
intervention. Another reason could be that combination
interventions are more difficult to implement than
single interventions, and the achieved effects reflect
these implementation difficulties. Future experimental
research should increasingly use factorial designs that
allow precise determinations of component intervention
and interaction effects.
Third, the majority of studies establishing the effective-
ness of adherence-enhancing interventions have lasted
2 years or less. Antiretroviral therapy, however, requires
life-long adherence, spanning several decades for many
patients. Long-term studies of ART adherence are
urgently needed, and several teams are currently
conducting follow-up studies, which will generate these
important results [171–174]. Fourth, many studies are
internally inconsistent in their findings, establishing
significant effects on some outcomes (e.g. self-reported
adherence), but not on other, related outcomes (e.g.
immunological recovery). Technological improvements
in capturing ART adherence could substantially improve
the strength of the evidence regarding adherence
behaviours, which tend to be unreliably reported [175]
and may also not be accurately measureable with objective
approaches, such medication event monitoring systems
(MEMS), pill counts, or observation of pharmacy refill.
Finally, as ART initiation is moving into earlier disease
stages, average effects of ART adherence-enhancing
interventions may change, because the population
composition of people on ART changes. For instance,
people initiating in earlier stages of HIV infection are
less likely to have experienced recovery from advanced
HIV-related disease and may thus require different
cognitive and behavioural strategies and different
technological support to ensure good adherence than
people who initiated in late stages of the infection [176].
Our study has several limitations. Although it was a
systematic review, it was ‘rapid’ in the methodological
sense that it utilized existing systematic reviews to identify
studies on adherence-enhancing interventions. Some of
these systematic reviews may have missed relevant studies
related to their objective and timeframe, and these studies
could have also been missed in our review. In particular,
the reliance on previous systematic reviews and our
focused search of recent published results from RCTs
imply that our synthesis is largely based on experimental
studies, and that an additional review of quasi-
experimental and non-experimental evidence may
provide important additional insights. Additionally, our
selection of reviews to identify primary studies under
the rapid review methodology we employed excluded
reviews that were not systematic, for example, narrative
reviews; and our identification of records reporting
primary RCT-based results was limited to studies
whose primary aim was to enhance ART adherence.
These selection criteria may have led to the exclusion
of some interventions that can be of use in enhancing
ART adherence, in particular, approaches to optimize
ART regimens [177]. One example of such an intervention
is single-tablet ART regimens, which have not been
included in our review. Recently published reviews
concluded that single-tablet regimens improve adherence
and quality of life among ART patients in comparison to
multi-tablet regimens [178,179].
Another unavoidable limitation of a systematic review
based on formally published studies in a fast moving
research field is that evidence that is emerging
informally but has not yet been formally published
will likely have been ignored, because academic
writing, review and publication times in global health
can last several years. These delays would have been
particularly limiting if they led to the exclusion of
completely novel interventions, for example, based on
new technologies.
Although some studies were identified related to PWUD,
data on other key populations were scarce. Given
that these populations are disproportionately affected
by the HIV epidemic and commonly face multiple
challenges in ART adherence, future research focused on
ART adherence-enhancing interventions tailored to
key populations will be important, in particular, in
sub-Saharan Africa, where such focused studies have been
especially scarce.
In conclusion, we find a large and overall strong evidence
base to support the claim that five interventions – CBT,
education, treatment supporters, DOT, and active
reminder devices – can improve ART adherence at least
in some settings. These tested and effective adherence-
enhancing interventions should increasingly be con-
sidered for routine implementation in ART programmes
and health systems. However, rigorous on-going
evaluation of the impact and performance of these
interventions will be critical, because all interventions
that proved effective in at least one setting were also found
not to significantly increase adherence in at least one
other setting. Significant evidence gaps on adherence-
enhancing interventions need to be closed, including
on cost-effectiveness, long-term effectiveness, and effec-
tiveness in specific key populations.
Acknowledgements
Conflicts of interest
There are no conflicts of interest.
TB and KC were the lead authors, designing the study in
close collaboration with EN and AS. KC, OO and MP
Improving adherence to antiretroviral therapy Chaiyachati et al. S199
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
scrutinized identified studies for eligibility and extracted
data. TB and KC wrote the first draft of the manuscript; all
authors contributed to the interpretation of the extracted
data and critically reviewed the manuscript before
submission.
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