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Journal of Antimicrobial Chemotherapy (2006) 57, 815–818
doi:10.1093/jac/dkl068
Advance Access publication 23 March 2006
Management of chronic hepatitis B and C in
HIV-coinfected patients
Vincent Soriano*, Pablo Barreiro and Marina Nun
˜ez
Department of Infectious Diseases, Hospital Carlos III, Calle Sinesio Delgado 10, 28029 Madrid, Spain
One-third of HIV-infected individuals worldwide suffer from chronic hepatitis C virus (HCV) infection, but
chronic hepatitis C affects more than 75% of HIV-positive subjects infected parenterally, such as haemo-
philiacs and intravenous drug users. Chronic hepatitis B virus (HBV) infection, on the other hand, occurs in
10% of HIV-infected persons, coinfection being more prevalent in Southeast Asia. There are two main
reasons for considering HCV and HBV therapy as a priority in HIV-coinfected patients: first, the more
rapid liver disease progression seen in this population, leading to end-stage liver disease complications,
including hepatocellular carcinoma, at younger ages; and second, the higher risk of developing hepato-
toxicity following the initiation of antiretroviral therapy in subjects with underlying chronic hepatitis than in
HIV-monoinfected individuals. As highly active antiretroviral therapy (HAART) has dramatically improved
the prognosis of those with HIV disease, the consequences of associated illnesses such as hepatitis B and
C, which are currently among the leading causes of hospital admission and death in the HIV-infected
population, have become more relevant. Therefore, the adequate management of viral hepatitis should
now be considered a priority in HIV-coinfected patients. Several guidelines have recently been released in
response to this demand. In this article, we discuss the most critical issues highlighted in these documents.
Keywords: HIV, HBV, HCV, interferon, antiretroviral therapy, lamivudine, tenofovir, liver
Introduction
HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV) share
similar routes of transmission, with sexual, parenteral and peri-
natal transmission being the most frequent modes of acquiring
these infections. In contrast, exposure to these viruses is followed
by an immune response which differs markedly in its ability to
clear the infection. Clearance is maximal for adults exposed to
HBV, much lower for HCV and negligible (or non-existent) for
HIV. Taking into consideration these two facts, it comes as no
surprise that there is a high worldwide prevalence of coinfection
with these agents. Figure 1 shows the estimated burden of the
population currently living with each of these viruses and the
number of coinfected persons.
Hepatitis C
One-third of HIV-infected individuals worldwide suffer from
chronic hepatitis C, but HCV affects more than 75% of HIV-
positive subjects infected parenterally, such as haemophiliacs and
intravenous drug users.
1
End-stage liver disease complications
have emerged as one of the leading causes of hospital admission
and death in HIV-infected patients in developed countries, where
the use of highly active antiretroviral therapy (HAART) has
halted the progression of HIV-associated immunodeficiency.
As a result, classical opportunistic infections are now only rarely
seen in HIV-infected individuals in regular clinical care, whereas
liver complications due to viral hepatitis coinfections have
become more evident.
2–4
In the past few years, several
guidelines
5,6
and reviews
7–10
have highlighted this problem
and have provided recommendations about how best to manage
patients coinfected with HIV and HCV.
Screening for HCV antibodies is key to an effective strategy
against hepatitis C, and should be mandatory for all HIV-infected
individuals. HCV-seropositive subjects should be tested for
serum HCV RNA. Around 15% will have cleared HCV spontan-
eously. For the rest, quantitative serum HCV RNA measurement
using sensitive tests (lower limit of detection in 10–50 IU/mL)
and HCV genotyping should be performed before considering
any therapeutic intervention against HCV.
The treatment of choice for hepatitis C is a combination of
pegylated interferon and ribavirin. Unfortunately, HCV therapy
is associated with poorer response and a higher incidence of
side effects in HIV/HCV-coinfected patients than in HCV-
monoinfected individuals.
11,12
However, recent studies suggest
that when adequate HCV therapy is administered (using higher
doses of ribavirin than in earlier trials, with satisfactory drug
compliance and for at least 12 months irrespective of the
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*Corresponding author. Tel: +34-91-4532500; Fax: +34-91-7336614; E-mail: vsoriano@dragonet.es
............................................................................................................................................................................................. ..................................................................................................................................................................................................... ...........................
815
ÓThe Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: journals.permissions@oxfordjournals.org
JAC
antiviral
HCV genotype), and to the most appropriate candidates (exclud-
ing active intravenous drug users, alcoholics and subjects with
very low CD4 counts), treatment response rates may improve
significantly in HIV/HCV-coinfected patients and can approach
what is achieved in HCV-monoinfected individuals.
13–18
The best
coinfected responders are individuals with the following profile:
infection with HCV genotypes 2 or 3, low HCV viral load, no
cirrhosis, age less than 40 years, elevated ALT concentrations,
preserved CD4 counts and low or undetectable plasma HIV RNA.
Using the data already available from HCV monoinfection, it is
time to design trials in coinfected patients in which therapy is
tailored on the basis of individual characteristics. As an example,
using variables such as baseline HCV RNA, genotype and week 4
virological clearance, patients could be allowed to complete
different lengths of therapy (see Figure 2) in an attempt to
balance efficacy and tolerance of the medication.
Treatment should be considered early in antiretroviral-naive
coinfected patients with stable HIV infection. In patients already
on antiretroviral therapy, HCV therapy should not be admin-
istered before ensuring that didanosine is not taken, given the
increased risk of mitochondrial toxicities (i.e. pancreatitis and
lactic acidosis). If possible, zidovudine should be avoided as
well, given the higher risk of anaemia. Treatment adherence is
key to maximizing the chances of success, and side effects of the
HCV medication should be managed expertly before discontinu-
ing HCV therapy.
The histological information obtained using either non-inva-
sive procedures (FibroScan, Fibro-test, etc.)
19–21
or liver biopsy is
useful but these tests should not be considered mandatory before
prescribing HCV therapy.
22
Progression of liver fibrosis to
cirrhosis and hepatocellular carcinoma occurs more rapidly
23,24
and liver toxicity following initiation of HAART is more fre-
quent
25,26
in HCV/HIV-coinfected patients. Thus, virological
rather than histological findings justify the provision of therapy
in this population.
22
In patients with evidence of more advanced
liver fibrosis, HCV therapy should be considered a real priority.
However, patients with decompensated cirrhosis should not be
treated with interferon, given the serious risk of liver failure. On
the other hand, in patients with CD4 counts <200 cells/mm
3
and/
or plasma HIV RNA >100 000 copies/mL, it is advisable to
suppress HIV replication and increase the CD4 counts before
beginning HCV therapy, as the APRICOT trial showed that
side effects of the HCV medication occurred more often in
patients with lower CD4 counts.
11
Individuals with a history of neuropsychiatric disorders should
be seen by an experienced psychiatrist before being considered as
candidates for HCV therapy. The psychiatrist may advise about
the possibility of interferon-based therapy and/or the usefulness
of any co-medication. In patients with mild depression, prophy-
lactic treatment with anti-depressant drugs has proven benefit.
10
Subjects who consume a great deal of alcohol and/or are addicted
to illegal drugs generally should not be considered suitable for
HCV treatment, and medical efforts should concentrate on
detoxification.
In summary, liver disease associated with HCV is a growing
problem in HIV-positive individuals. The relatively low efficacy
of the current medication and its low tolerability should prompt
the discovery of new drugs with a direct antiviral activity against
HCV. In contrast to antiretroviral drugs, which need to be used
indefinitely against HIV, the biology of HCV (which fortunately
is not integrated into cellular DNA) provides the chance for
limited treatment duration. This opportunity should be much
appreciated by both coinfected patients and their doctors.
Thus, the provision of HCV treatment should be encouraged
without unnecessary delay in the absence of clear contraindica-
tion in the coinfected population. A further recent stimulus for the
therapeutic intervention is the demonstration of a lack of clinical
progression of liver disease in HIV-infected individuals who
cleared HCV with therapy: their hepatitis C is cured!
27
Hepatitis B
Approximately 10% of the HIV-infected population worldwide
suffers from chronic hepatitis B (Figure 1). This figure may
approach 20% in Southeast Asia, whereas it is 5% in North Amer-
ica and Western Europe. Unlike with HCV, infection with HBV is
not eradicable and the main goal of therapy is to suppress HBV
replication as much as possible and for as long as possible. This
translates into histological and clinical benefit. Guidelines for the
adequate management of chronic hepatitis B in HIV-coinfected
individuals have recently been released,
6,28,29
and several reviews
30
Pos
Neg
High
Pos
NegLow
1,4
Pos
NegHigh
Pos
NegLow2,3
Negative
HCV-RNA
week 4
Baseline
HCV-RNA
HCV
genotype
10–15%
55–65%
25–30%
Length HCV therapy
6 mo
12 mo
18 mo
Figure 2. Preferred treatment duration of HCV therapy taking into account
different patient characteristics. Percentages represent estimates of the number
of HIV/HCV-coinfected patients in each category in the PRESCO trial.
16
HCV
HBV
HIV
4
40
350
1
2
17
5
1
0
.
5
Figure 1. Estimated number (in millions) of subjects infected with HIV, HBV
and HCV worldwide.
Leading article
816
have updated the knowledge on this topic, providing useful
information about how to manage HBV/HIV-coinfected patients.
Four drugs have been approved so far for the treatment of
chronic hepatitis B: interferon alpha (standard or pegylated),
lamivudine, adefovir and, more recently, entecavir. However,
other drugs with anti-HBV activity such as tenofovir and emtricit-
abine are already approved for the treatment of HIV infection and
therefore are frequently used in coinfected patients as anti-HBV
agents. In ACTG A5127, the efficacy and safety of tenofovir and
adefovir were prospectively compared in 52 HBV/HIV-coinfected
individuals, 75% of whom had already failed on lamivudine.
31
At
48 weeks, the mean reduction in serum HBV DNA was 3.2 logs in
the adefovir arm and 4.4 logs in the tenofovir arm. The study was
powered only to show the non-inferiority of tenofovir with respect
to adefovir, but the results support the general belief that tenofovir
300 mg/day is much more potent than adefovir 10 mg/day against
HBV. The widespread use of tenofovir in HBV/HIV-coinfected
patients has demonstrated that HBV can become resistant to
tenofovir, although this seems to occur very slowly.
32
The prescription of treatment for chronic hepatitis B and the
drug of choice are still controversial and may vary in different
situations. Four main variables should guide the selection of
patients to be treated for HBV and of the drug(s) of choice:
transaminase levels, serum HBV DNA viral loads, presence of
serum HBV e antigen (HBeAg) and liver fibrosis staging. Given
that chronic hepatitis B patients with elevated transaminase levels
tend to have liver damage, they should generally be considered
primary candidates for treatment (Figure 3), especially in the
context of HIV coinfection, since HBV-related liver damage
tends to progress faster in HIV-coinfected patients than in
HBV-monoinfected patients.
33,34
While HBeAg-positive chronic
hepatitis B patients tend to show better responses to interferon
therapy provided for 6–12 months, HBeAg-negative individuals
should preferentially be treated with nucleoside/nucleotide
analogues (Figure 4). In HBV/HIV-coinfected patients, a
problem arises when no antiretroviral therapy is required but
HBV therapy is considered to be necessary. Although some
authors have favoured the prescription of adefovir monotherapy
in this situation, concern about the selection of the K65R resist-
ance mutation in HIV has precluded this treatment in some cases.
Recent data, however, suggest that this risk is negligible.
35
In this
specific situation, drugs such as entecavir or in the future
telbivudine or clevudine, which are potent anti-HBV agents lack-
ing any HIV activity, will likely be the first choice. The 24 week
results of the ETV-038 trial were presented at the 2005 Confer-
ence on Retroviruses and Opportunistic Infections.
36
This
trial assessed prospectively the efficacy and safety of entecavir
1.0 mg/day against a placebo in 68 HBV/HIV-coinfected indi-
viduals, all of whom had failed prior lamivudine therapy. The
virological response was significantly better in the entecavir arm.
Even though entecavir acts in patients with lamivudine-resistant
HBV, some cross-resistance between these two drugs exists, and
therefore the greatest efficacy of entecavir will be obtained in
patients without prior exposure to lamivudine.
In summary, substantial progress has been made in the treat-
ment of hepatitis B in HIV-positive individuals in recent years.
This subset of patients, who typically show more rapid and severe
liver damage, now have more treatment options that can be more
easily administered and have fewer adverse effects. The achieve-
ment and maintenance of HBV suppression (despite the lack
of eradication) by judicious use of current HBV therapies will
permit prevention of liver complications in most HBV/HIV-
coinfected patients.
Transparency declarations
None to declare.
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