Indian J Med Res 121, April 2005, pp 424-450
424
Hepatitis B/HIV co-infection
Hepatitis B virus (HBV) infection is one of the
most common infections in the world with
approximately 2 billion people infected with it1. Of
these, approximately 5 per cent suffer from chronic
liver disease1. Also, over two-thirds of all cases of
liver cancers world wide are also caused by HBV2.
While chronic HBV infection in the setting of HIV
infection is not listed as an opportunistic infection by
the US Centers for Diseases Control, it is a common
co-existing infection seen in HIV infected individuals
because of the shared modes of transmission of HBV
and HIV. HIV positive individuals, particularly those
with suppressed immune systems, are less likely to
respond to vaccination against HBV and are more
likely to develop chronic disease after being exposed
to HBV. Moreover, individuals co-infected with HBV
and HIV more frequently present with atypical
serologies, have higher HBV DNA levels, and
experience more profound liver disease as a result of
chronic infection3.
Virology: HBV belongs to the family of DNA viruses
that preferentially infect hepatocytes and are referred
to as hepadnaviridae4. Each complete virion consists
of an inner core (nucleocapsid or hepatitis core
antigen, HBcAg) surrounded by an outer protein coat
or envelope (the hepatitis B surface antigen,
HBsAg)4. The HBV genome is a circular, partially
double-stranded DNA of approximately 3,000 base
pairs. There are four overlapping open reading frames
(ORF), which encode for the envelope, precore/core,
polymerase, and X proteins. The envelope ORF
encodes for the large middle and small surface
glycoproteins of HBsAg. The precore/core ORF is
translated into a precore polypeptide, which is
secreted as hepatitis B ‘e’ antigen, which is detectable
in the blood as HBeAg and HBcAg, which is only
detected in the liver. Upon entering the hepatocytes,
Key words HBV - HCV - HIV - highly active antiretroviral therapy  (HAART)
Hepatitis B & hepatitis C in HIV-infection
Shyam Kottilil, Julia O. Jackson & Michael A. Polis
Laboratory of Immunoregulation, National Institute of Allergy & Infectious Diseases
National Institutes of Health, Bethesda, MD 20892, USA
Accepted February 2, 2005
Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) are
the three most common chronic viral infections seen in the world. All three viruses share modes
of transmission and hence co-exist in the same host at significantly high rates. HIV-induced
immunosuppression has deleterious effects on the natural history, pathophysiology, diagnosis,
therapeutic responses to hepatitis viruses. Responses to HBV vaccination are impaired in persons
with HIV infection. Co-infection with the hepatitis viruses and HIV is likely to become a major
health care catastrophe in the coming years. This review discusses the current trends in the
understanding of the biology of co-infection and implications for treating these viruses effectively.
425
the HBV genome is transported to the nucleus and is
converted into closed circuit circular DNA
(cccDNA). The HBV cccDNA serves as a template
for transcription of mRNA and the RNA pregenome4.
Once transferred to the cytoplasm, HBV polymerase
uses reverse transcription to convert the RNA
genome into new circular genomic DNA 4. Most
virologists consider HBV as a non-cytopathic virus.
Replicative HBV, either during the acute or chronic
stages of infection, causes liver disease because of
vigorous cytotoxic T lymphocyte (CTL) and/or
cytokine-mediated elimination of HBV-infected
hepatocytes.
Epidemiology: Chronic hepatitis B infection causes
chronic liver disease and hepatocellular cancer.
World-wide, it is estimated that more than one million
people infected with HBV will die every year and
approximately 25 per cent of all patients with chronic
HBV infection will die of liver disease 5. The
prevalence of chronic hepatitis B is higher in China
and sub-Saharan Africa (20%) than in North America,
Western Europe and in Australia (0.5%) 6.
Transmission of HBV is predominantly via parenteral
means, even though this infection is also transmitted
by sexual contact and acupuncture. Mother-to-child
transmission and occupational transmission from
HBV infected patients to health care workers are
also major modes of transmission. One of the major
distinctive features of HBV infection is that risk of
developing chronic liver disease varies greatly with
age of acquiring the infection7. For neonates and
infants who acquire HBV, the risk of chronicity is
almost 90 per cent, while it decreases to 30 per cent
for children 1-5 yr, and up to 2 per cent for older
children and adults7.
Natural history/clinical features
Acute HBV infection: HBV infection can manifest
as an asymptomatic infection, acute hepatitis and
rarely fulminant liver failure. Asymptomatic infection,
which is the most common presentation, begins with
active HBV replication within the hepatocytes 4.
Detectable levels of HBV DNA in the peripheral
blood may be present even before elevations in the
levels of serum transaminases. HBsAg and HBeAg
become detectable in blood within two weeks before
the core antigen can be detected and may persists
for up to 8 wk. IgM antibodies to HBcAg occur early
and decrease after six months; however, total anti-
HBc remains for life. Anti-HBs become positive after
loss of active replication, usually after six months.
Anicteric infection is typically associated with a flu-
like illness without jaundice. Icteric infection is
associated with symptoms ranging from mild jaundice
to non-fatal subacute hepatic necrosis to fatal
fulminant hepatitis in <1 per cent of symptomatic
cases. In those with acute hepatitis, HBV DNA levels
and serum transaminases are usually higher and
persist longer. Outcome of acute HBV infection is
largely determined by host factors, particularly age
and immune competence at the time of exposure.
Regardless of the clinical course, most HBV-
infected adults are capable of mounting broad-based
CTL and antibody responses to the virus. With the
development of a protective immune response and
serological evidence of immunity, infection becomes
latent and usually remains so for the life of the patient.
If the patient with latent infection becomes
immunosuppressed at a later date such as after an
organ transplantation, HBV can reactivate, as intact
virions may be hidden from the immune system in the
nucleus of hepatocytes as cccDNA.
Chronic HBV-infection: Three phases of chronic
hepatitis B infection are widely recognized. Children
and adolescents may have a long period of immune
tolerance phase with near normal liver histology, high
concentrations of HBV DNA, and HBeAg positivity;
the immune clearance phase with seroconversion from
HBeAg to antibody against HBeAg accompanied by
active hepatic inflammatory response and fibrosis and
fluctuating serum alanine transaminase (ALT)
concentrations, and lastly, the residual phase with low
concentrations of HBV DNA and normal
concentrations of ALT6. For Caucasians who acquire
the disease during adolescence or adulthood, there is
no immune tolerance phase. Instead, the disease
progresses directly to the immune clearance phase
and is of short duration, which probably accounts for
the better response to immunomodulatory therapy in
Caucasian patients than in those from other ethnic
origins6. By contrast, those who acquire infection
during the neonatal period and early childhood (mainly
KOTTILIL et al: HEPATITIS B & C IN HIV INFECTION
426 INDIAN J MED RES, APRIL  2005
seen within Asians and African populations), the
response to immunotherapy is worse. The disease
continues to progress after HBeAg seroconversion.
Although Asian patients who are HBeAg negative,
have lower levels of HBV DNA than those who are
HBeAg positive, the course of their disease is marked
by frequent exacerbations8. Severe exacerbations
occur with equal frequency in patients who are
HBeAg positive and in those who have antibodies to
HBeAg9. Also, precore mutations, those associated
with mutations in the core promoter region and
absence of HBeAg in serum with elevated HBV
DNA and ALT, can be detected in about 44 per cent
of patients who are HBeAg positive10. Furthermore,
disease activity after HBeAg seroconversion has no
relationship to the presence or absence of precore
and core promoter mutants11.
Hepatitis B genotypes: There are seven different
genotypes (A-G) of HBV recognized worldwide. Of
these, A is pandemic, B and C are seen predominantly
in Asia, D in Southern Europe, E in Africa, F in the
USA, and G in the USA and France 12. A newly
discovered genotype H is seen predominantly in
Central America. B genotype is further divided into
Bj, seen in Japan, and Ba, seen in rest of Asia13. Unlike
HCV, HBV genotypes may affect disease profiles
but not treatment responses12. Caucasians infected
with genotype A have a higher likelihood of clearance
of HBV DNA and HBeAg, sustained remission after
HBeAg seroconversion and a better histologic activity
index (HAI) compared with patients infected with
genotype D12.  Asian patients with genotype B when
compared to those infected with genotype C, have
HBeAg seroconversion at an earlier age, less serious
liver disease, and a better response to interferon  8,14,15.
Pathophysiology: Recent studies using chimpanzees
and acute HBV infection in man have clearly
unraveled several mechanisms by which HBV is
eliminated during the acute phase of HBV infection.
These studies have clearly shown that the elimination
of virus is mainly through non-cytolytic mechanism
mediated through cytokines released by CD8+ T cells.
Tumor necrosis factor-?  (TNF-?  ) and interferon-?
(INF-? )are the major cytokines involved in the
clearance of HBV in chimpanzees. In the chronic
phase of HBV infection, the immune clearance phase
is triggered by a decrease in host tolerance to HBV
antigens with a concomitant increased expression of
class I HLA molecules, resulting in a decrease of
HBV DNA and an increase in ALT. The process of
liver fibrosis and cirrhosis continues with low level of
viremia even after HBeAg seroconversion. However,
the notion of non-cytolytic CD8+ T cell response
occurring in acute infection might also be true for
chronic infection18,19.
Diagnosis: Of all the viral hepatitides, HBV is the
most complicated infection with respect to
interpretation of serologic tests4. Co-infection with
HIV results in even more atypical serologies. Both
acute and chronic HBV infections are characterized
by the presence of hepatitis B surface antigen
(HBsAg) and the absence of antibodies to HBsAg
(anti-HBs)4. Most often, antigen disappearance is
associated with a resolved infection. However,
transplanting a liver from someone with a resolved
infection into a HBV naďve individual, rarely, may
result in an acute HBV infection. This suggests that
HBV infection is most probably latent and not
resolved, and immunocompromised individuals are
unable to control re-activation of latent HBV DNA
in the liver. HBeAg in his serum reflects high levels
of HBV replication in the liver with elevated levels
of ALT 4. The presence of anti-HBe indicates either
that there is no viral replication and normal ALTs or
the presence of pre-core mutants with high levels of
HBV replication and elevated ALTs. Anti-HBV
treatment can be discontinued if HBeAg to an anti-
HBe seroconversion is maintained for over 6 months.
However, those with a precore mutant do not have
HBeAg from the beginning and anti-HBV therapy
should be continued indefinitely in these individuals4.
In HIV-positive individuals, the interpretation of
serologies is often complicated. Many of these
patients often present with anti-HBc alone20. During
a median of 31 months between the first and the last
samples collected, anti-HBc remained the sole marker
for HBV infection in over 98 per cent of patients20.
HBV DNA encoding for the surface and core
antigens was detected in 63 and 60 per cent
respectively of all 202 samples tested. Over time HBV
DNA was detectable in over 89 per cent of all patients.
Those patients who had HBVDNA and no anti-HBV
427
antibodies (36%) had necroinflammatory liver disease
attributable to HBV infection20. These data indicate
that HIV positive patients with anti-HBc antibodies
are more likely to have active HBV infection than
their HIV negative counterparts with anti-HBc
antibodies.
HBV DNA: There are two commonly used commercial
qualitative assays for detecting HBV DNA in the
serum: one is a branched chain DNA assay and the
other is a hybrid capture test21. The lower limits of
detection in these two assays are 700,000 and 140,000
copies/ml respectively21. Another PCR-based assay6
allows for detection of 200 copies of HBV DNA/ml.
Recent studies have indicated that after six months
of lamivudine treatment, 64 per cent of patients with
HBV DNA concentrations of more than 103 copies/
ml will develop lamivudine resistance, compared with
13 per cent of persons with HBV DNA levels less
than 103 copies/ml6. Thus, quantitative PCR (qPCR)
is the preferred assay to monitor the progression of
disease and the effectiveness of treatment. Recently,
there has been new interest in following the levels of
cccDNA. The cccDNA is super-coiled DNA that
does not replicate, it is resistant to nucleoside analog
treatment and is considered as the probable source
for DNA rebound once therapy is stopped 9. One must
consider the cost of these assays and thereby the
applicability to developing countries. Commercial
HBV DNA assays are extremely expensive in the
$200 range per test. Use of serologies is still more
cost effective for following the clinical course of HBV
infection than HBV DNA assays.
Liver biopsy: Liver biopsy is indicated for
assessment of the severity of liver disease in chronic
HBV infection. However, biopsy is not essential for
determining whether treatment is needed, even though
it is preferable to have a baseline histological
assessment. Treatment decisions are made based on
the clinical information like elevations of ALTs more
than 1.5 times the normal limits and detection of HBV
DNA by sensitive assays.
Treatment
General principles: The primary goals of treatment
in chronic HBV infection are to arrest the progression
of liver disease by suppressing HBV replication. Even
though HBV is not considered a cytopathic virus,
immune responses directed against HBV epitopes will
continue to cause hepatic damage in the presence of
viraemia. Once viral replication is shut off, surface
antigen is lost and there will be
no evidence of viral peptides on the surface of
hepatocytes. However, the cccDNA will still be
in the nucleus and potentially lead to relapse
of HBV infection in the presence of immune
suppression induced by chemotherapy, steroids or
immunosuppressive drugs associated with
transplantation.
Therapeutic end points that are used to assess
treatment response include normalization of ALT
levels, inability to detect HBV DNA in the peripheral
blood by qualitative assays, loss of HBeAg with or
without emergence of anti-HBe, and improvements
in liver histology22,23. Some of these assays are
expensive for many developing countries and following
ALT levels is probably the best single clinical
parameter that can be used to follow therapeutic
response. Baseline ALT levels are also good predictors
of therapeutic responses. High levels of ALT indicate
that there is an immune response directed against
HBV occurring in the liver and combined with antiviral
therapy may lead to clearance of virus-infected
hepatocytes. Baseline ALT levels higher than two
times the upper limit of normal carry a good prognostic
value in treating HBV with nucleoside analogs 24.
However, current consensus suggests that low levels
of viral replication can lead to continued progression
of liver disease therefore use of quantitative HBV
DNA assays are considered optimal as treatment end
points22.
There are two modes of anti-HBV treatment
available (Table I). One is immunomodulation using
INF-?  and the other, viral suppression using
nucleoside/nucleotide analogs. Since chronic HBV is
unlikely to be eradicated, an adequate therapeutic
response to anti-HBV treatment is defined as
suppression of HBV re-application, normalization of
ALT levels and/or HBeAg and HBsAg
seroconversion. Liver transplantation is effective and
should be considered in patients with end-stage
disease not responding to treatment.
KOTTILIL et al: HEPATITIS B & C IN HIV INFECTION
428 INDIAN J MED RES, APRIL  2005
Interferons: INF-?  used at a dose of 5 million units
per day or 10 million units three times a week is
associated with HBeAg clearance in approximately
30 per cent and HBsAg clearance in 10 per
cent of immmunocompetent patients 25. INF-?
monotherapy is also effective in reducing HBV DNA
levels and normalizing levels of ALT.  However, it is
associated with a high degree of relapse 25. INF-?
monotherapy is less effective in patients with high
baseline HBV DNA levels and patients with normal
ALT levels prior to treatment, as is often seen with
HIV co-infected HBV patients. Interferon is also
associated with significant adverse events including
fever, myalgias, thyroid dysfunction, bone marrow
suppression, and psychiatric disturbances. When used
in persons with cirrhosis, interferon therapy may be
associated with immune enhancement in the liver that
may lead to decompensation. Unfortunately, several
studies have demonstrated that an effective response
to interferon therapy is seen only with those
HIV/HBV co-infected individuals  with CD4+ T cell
counts greater than 350 cells/µ l25,26.
Recent studies using pegylated interferons have
been promising. A recent study using pegylated
interferon  ? -2a vs  conventional interferon  ? -2a
indicated superior therapeutic response rates for
pegylated interferon ? -2a with greater HBV DNA
suppression, greater loss of HBeAg, and ALT
normalization (24 vs 12%)27. In summary, interferon
is an acceptable therapy for those HIV patients with
higher CD4+ T cell counts, normal synthetic function,
normal haematological profile, elevated
transaminases, and no clinical evidence of hepatic
decompensation.
Lamivudine: Lamivudine, first approved for treatment
of HIV infection, was approved for the treatment of
HBV infection in 1998. The treatment of HBV
infection  is with 100mg of lamivudine once daily  vs
300 mg once daily for HIV infection. HIV/HBV
co-infected patients should be treated with the
higher dose.
One year of lamivudine treatment of HBeAg-
positive chronic HBV infection with persistent
ALT elevations resulted in HBeAg seroconversion
in about 16-18 per cent of patients compared with
4-6 per cent of untreated controls28-30. Improvement
is liver histology was seen with 49-56 per cent of
lamivudine treated patients and only in 23-25 per cent
of controls. HBeAg negative chronic HIV infected
individuals with elevated ALT levels treated with
lamivudine for 24 wk, resulted in a 63 per cent
virologic and biochemical response compared to 6 per
cent response in the control group31. Of those who
completed one year of treatment, 39 per cent had
no detectable HBV DNA by PCR assay, and
60 per cent had improvement in hepatic histology31.
Similar findings were seen with other studies as well32
indicating long term therapy with lamivudine
increases the possibility of HBeAg seroconversion.
Follow-up data of these clinical trials have
indicated that lamivudine resistance mutations
occurred in 15 to 32 per cent of patients treated with
lamivudine for 52 wk and as many as 67 per cent of
HBV-mono-infected patients6. As many as 90 per
cent of HIV/HBV co-infected patients 33  treated
with lamivudine for over 4 yr develop lamivudine
resistance mutations. These resistance mutations
generally fall within the YMDD motif, a highly
conserved domain of HBV reverse transcriptase.
Interestingly, patients with lamivudine resistance
mutations continue to experience HBeAg
seroconversion, partial suppression of HBV DNA,
and biochemical and histologic parameters, probably
because of decreased fitness or replicative
capacity of the mutant strain 32. However, HBV
can develop compensatory mutations in the
DNA polymerase genes (V173L and L180M)
that can restore the replicative capacity and can
cause HBV DNA levels to return to pre-treatment
levels.
Table I. Various modes of anti-HBV thearpy
A. Antiviral agents B. Immunomodulators
Lamivudine Interferon (Peg-IFN)
Adefovir dipivoxil Thymosin-? 1
Tenofovir Steroid withdrawal
Entecavir Therapeutic vaccines
Clevudine (L-FMAU) Interleukin-12
Emtricitabine (FTC)
Famciclovir C. Liver Transplantation
429
Adefovir dipivoxil: Adefovir was recently approved
in the US by the Food and Drug Administration (FDA)
for treatment of HBV infection at a dose of 10mg
once daily. Daily doses of 60mg and greater evaluated
for the treatment of HIV infection were associated
with unacceptable rates of renal toxicity (proximal
renal tubular necrosis). Adefovir has shown activity
against both the wild type and lamivudine resistant
HBV. Several phase I and II studies demonstrated
that adefovir is associated with a 4-log reduction in
HBV DNA as well as seroconversion rates from
HBeAg to anti-HBe antibodies in the range of 20 to
27 per cent34-36.
A recent double-blind, placebo controlled phase
III clinical trial37 evaluating the safety and efficacy
of adefovir once daily versus placebo in patients with
HBeAg-positive chronic HBV infection established
the efficacy of adefovir in treatment of HBV
infection. After 48 wk of treatment of patients who
received 10 mg and 30 mg daily and placebo, there
was significant improvement in liver histology in 53,
59 and 25 per cent of patients respectively. There
was significant reduction in the levels of HBV DNA
in the treatment groups when compared with placebo
(3.52 log copies/ml for 10 mg; 4.76 log copies/ml for
30 mg; and 0.55 log copies/ml for placebo). At the
end of 48 wk, there were also significantly higher
number of patients with no detectable HBV DNA
(<400 copies/ml) in the adefovir groups (21 and 39%)
compared to placebo (0%); 48 per cent of patients
receiving 10mg of adefovir and 55 per cent of those
receiving 30mg of adefovir had normalization of ALT
when compared to the placebo (15%). HBeAg
seroconversion also occurred more frequently with
the treatment groups (12 and 14%) compared to the
placebo (6%). No adefovir-associated mutations were
identified during the 48 wk of therapy, and the safety
profile for the 10 mg dose group was similar to that
of the placebo37.
Another recent international, industry-sponsored,
multi-center double-blind placebo controlled phase III
clinical trial also reported favourable data for the use
of adefovir among HBeAg-negative chronic HBV
infected individuals without evidence of hepatic
decompensation38. After 48 wk of treatment with
10 mg of adefovir, 64 per cent had significant histologic
improvements compared to 33 per cent in the placebo
group; 51 per cent in the treatment arm had no
detectable HBV DNA levels at the end of 48 wk
compared to the placebo arm (0%); and 72 per cent
of all patients treated with adefovir had normalization
of ALT values compared to 29 per cent of those
receiving placebo.
A recent study reported efficacy of adefovir in
the treatment of lamivudine resistant HBV39. Patients
receiving lamivudine as part of their antiretroviral
regimen were started on 10mg of adefovir daily.
Significant reductions in median HBV DNA levels
3.97 log (48 wk), 4.80 log (96 wk), 5.55 log (144 wk)
and 5.62 log copies/ml (192 wk) were seen, indicating
a continued effect on HBV viraemia. Similar results
were also observed with regards to the percentage
of patients with undetectable levels of HBV DNA
(6% at 48 wk, 27% at 96 wk, 46% at 144 wk and
59% at 192 wk). Rates of ALT normalization were
also significant (19% after 48 wk, 37% after 96 wk,
64% after 144 wk, and 67% 192 wk). There were no
reports of adefovir-resistant mutations in this study.
Adefovir resistance can occur  in vivo with a
N236T mutation in the D domain of HBV
polymerase6. However, it does not seem to occur
nearly as frequently as HBV resistance to lamivudine.
Adefovir resistance is only seen with extended
therapy and even then, only in a small percentage of
patients, particularly in those with HBeAg negative,
precore mutant HBV infection.
Tenofovir: Tenofovir, a nucleotide analog recently
approved as a treatment for HIV infection, also has
activity against HBV. However no large, controlled
study addresses the efficacy of tenofovir in the
treatment of HBV infection. Some sub-studies have
evaluated the efficacy of tenofovir for HIV/HBV co-
infection within the context of two, large, phase III
randomized controlled studies involving HIV infected
patients40. In a study involving therapy-experienced
HIV-infected patients, the mean decrease in HBV
DNA was 4.9 log copies/ml 24 wk after receiving
tenofovir (N=10) compared with a mean increase of
1.2 log copies/ml in the placebo group (N=2). In
another study41 involving ARV-naďve HIV infected
patients, the mean decrease in HBV DNA was 3 log
KOTTILIL et al: HEPATITIS B & C IN HIV INFECTION
430 INDIAN J MED RES, APRIL  2005
copies/ml after 48 wk of therapy with lamivudine
(N=6) , compared with a  mean decrease of 4.7 log
copies/ml among those who received both lamivudine
and tenofovir (N=5). A follow up of this study showed
that combined therapy with tenofovir and lamivudine
had greater sustained anti-HBV activity than
lamivudine alone and a greater number of subjects
who had normalization of ALT values without
evidence of emergence of resistance mutations to
tenofovir41.
When considering the use of tenofovir for the
treatment of HBV infection, it should be noted that
the safest and most effective anti-HBV dose has not
been established. Randomized controlled clinical trials
to address this question have not been performed.
Further, no clinical trials have been completed so far
to address the safety and efficacy among HIV
negative HBV positive individuals.
Cross resistance of anti-HBV agents: It is clear from
early clinical trials that lamivudine resistance is
associated with mutations in the YMDD motif and
adefovir resistance is associated with a N236T
mutation in the DNA polymerase6. However, there
has not been any evidence of cross resistance
between these two agents in clinical trials. Adefovir
is active against HBV strains with YMDD mutations
and lamivudine is active against mutants with N236T
mutations. However, it is not known whether either
lamivudine or adefovir resistance mutations can lead
to cross resistance to newer anti-HBV agents under
development like entecavir, emtricitabine and
telbivudine. In vitro, YMDD mutants are less sensitive
to entecavir, but remain sensitive to this drug
in vivo42. N236T mutants are also less sensitive to
entecavir in vitro42 but the in vivo results are not yet
available. Emtricitabine appears to be less active
against YMDD mutants but fully active against
strains with N236T mutants. In vivo data are not yet
available. Telbivudine is not active against YMDD
mutants both in vitro and in vivo, and there is no
data on the activity of this drug against HBV strains
with a N236T mutation.
Treatment of HIV/HBV infection: All HIV-infected
individuals should be screened for the presence of
HBV infection, given their shared routes of
transmission. The most appropriate time to initiate
anti-HBV therapy is always difficult to determine.
For co-infected individuals, most experts recommend
that when therapy for HIV infection is initiated, HBV
should also be treated. For those HIV/HBV co-
infected patients who do not meet the guideline
requirements to initiate therapy for HIV infection,
treatment of HBV infection should still be considered.
Patients with active liver disease as indicated by
elevated ALT and necroinflammatory liver disease,
and those with high HBV DNA levels (over 100,000
copies/ml for HBeAg positive patients and over 10,000
copies for precore mutants) should initiate therapy.
This recommendation is mainly based on the fact that
those who are infected with the precore mutants tend
to have more aggressive and prolonged liver disease.
Liver biopsies are often helpful to assess the severity
of liver disease, but are used mainly for patients with
atypical clinical presentations such as individuals with
normal ALT levels, high HBV DNA levels, or those
with elevated ALTs and low HBV DNA levels. Unlike
immmunocompetent patients, it is not uncommon to
see significant necroinflammatory liver disease in
HIV/HBV co-infected individuals with normal ALTs
and HBV DNA levels.
The emergence of HBV resistant to lamivudine
or adefovir generally takes a much longer time than
does the emergence of resistant HIV. Hence, it is
general practice to continue these drugs in a HIV/
HBV co-infected patient even after genotypic and/
or phenotypic tests show resistance to HIV. In patients
with chronic HBV infection who were receiving
lamivudine, rebound in HBV replication leading to
severe liver disease has been seen, even in patients
with no detectable HBsAg prior to discontinuation of
therapy43-45. Such patients must be closely
monitored44-46. Due to its potent activity against HBV,
a similar approach should be followed when
discontinuing tenofovir. Continuing either lamivudine
or tenofovir as a single agent to prevent such a
rebound runs the risk of inducing resistance by HIV
to that agent, unless resistance by HIV has been
previously documented (e.g., presence of the M184V
mutation in a patient receiving lamivudine). Adefovir
at doses approved for HBV infection can potentially
be used to prevent or control such rebounds, since
the low dose used for treatment of HBV infection
does not have activity against HIV and does not
appear to select for virus resistant to tenofovir47. Thus,
431
consensus is to treat HBV with one of the three drugs,
regardless of the HIV drug resistance profile.
HIV/HBV co-infected individuals are more likely
to develop severe hepatotoxicity due to antiretroviral
regimens. All agents used to treat HIV can cause
severe hepatotoxicity, however, among the non-
nucleoside reverse transcriptase inhibitor analogs
(NNRTI) nevirapine is associated with severe
hepatotoxicity, as is ritonavir among the protease
inhibitors48,49. Hepatic steatosis, most commonly
associated with the nucleoside analogs (NRTI),
didanosine, stavudine and zalcitabine can lead to
severe hepatotoxicity in HIV/HBV co-infected
patients.
The goal of treatment should be suppression of
HBV for as long as possible and to stop progression
of liver fibrosis. Most HIV/HBV co-infected patients
require therapy indefinitely. However, if an HBeAg-
positive patient undergoes rarely seen seroconversion
while on anti-HBV therapy, therapy can be stopped
after six months.
Unlike interferon, nucleoside analogs can be used
to treat both compensated and decompensated liver
disease. Combination therapy (e.g., lamivudine with
tenofovir), although most probably more efficient in
HBV suppression, has yet to be tested in larger
clinical trials to validate their use in the context of
treatment of HIV/HBV patient.
HBV vaccination: Vaccination against HBV is
strongly recommended for all HIV infected individuals
who have not been exposed to HBV. It should be
noted that the success rate of vaccination are much
lower in HIV infected individuals, particularly those
with lower CD4+ T cell counts50. Brugera et al49
showed that standard HBV vaccination schedules
induce anti-HBV protective immunity in 30 to 40 per
cent of HIV infected individuals. Patients with CD4+
T cell counts lower than 200 cells/ µ l have poor
response rates while those with higher CD4+ T cell
counts should expect a protective antibody response
in 70 per cent of cases. At least one study 51
subsequent to this has tested whether doubling the
dose of standard HBV vaccination would increase
the antibody response rates among HIV infected
individuals. The overall response rates were 55 per
cent  and those with lower CD4+ T cells (200-500
cells/µ l) having a lower response rates of 33 per cent
and compared to 87.5 per cent in those individuals
with a CD4+ T cell counts > 500cells/µ l. However,
one year after vaccination, only 58 per cent of these
patients had persistent protective antibody titres.
Hence, it is less likely that repeated vaccination can
induce persistent protective antibody titres in HIV
infected individuals. Currently, several strategies are
being employed to augment the efficacy of HBV
vaccine in HIV infected individuals by using cytokines
as adjuvants.
Relevance to India: Hepatitis B is a major public
health problem in India52,53. The average carrier rates
of HBV in the general population are considered to
be approximately 4 per cent 52. Among these,
professional blood donors constitute a major risk
factor group with a prevalence rate of 14 per cent 52.
Thallassemic and renal dialysis patients also have a
high risk of acquiring HBV infection 52,54. These
studies have indicated that HBV infection is
established in early childhood, probably associated
with crowded living conditions and poor hygiene.
However, HBV is also associated with acute and
sub acute liver failure in adults as well as with a
significant proportion of chronic hepatitis, cirrhosis,
and hepatocellular carcinoma52,55. Community based
epidemiological studies have indicated a slightly
higher rates of chronic HBV infection in a south
Indian tribal population53. Several tribal customs
including scarification, tribal treatment practices like
blood-letting and other practices like tattooing, ear
and body-piercing are all suggested to be contributing
to the high prevalence rates of HBV 53. However, it
should be noted that many of these studies have very
small sample sizes and may have selection biases
and may not accurately reflect the real prevalence
of HBV infection in India. Use of molecular
diagnostics have indicated a higher prevalence rate
of HBV infection among the general population in
India, surprisingly slightly higher among rural than
urban population56. In summary HBV infection
remains a significant public health hazard in India
and will probably remain so until nationwide
vaccination programs and other control measures
are fully implemented.
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432 INDIAN J MED RES, APRIL  2005
Management of hepatitides is expensive, especially
when one needs lifelong treatment. Testing for
resistance mutations, assays to monitor disease
progression and treatment progress and the drugs that
are required to treat the infection are all expensive.
Availability of new generic drugs in India would
definitely be important in the management of HBV/
HIV co-infected individuals. There are several
obstacles one could envision in the management of
HBV infection in developing countries like India. One
major obstacle is the cost and availability of assays
that monitor HBV DNA levels in blood as well as of
anti-HBV therapy.
For those patients who are infected with HIV and
HBV, proper diagnosis of chronic HBV is important.
Measuring HBeAg is a more cost-effective assay than
HBV DNA assays in detecting HBV in chronic HIV
infected individuals. HBV DNA assays should be
restricted to those who are suspected of having
precore mutants. Following HBeAg and anti-HBe is
sufficient to monitor patients who undergo treatment.
Monitoring of ALT is also a very sensitive and cost-
effective assay to diagnose and monitor those patients
undergoing treatment. Normalization of ALT in
someone with elevations prior to initiation of therapy
is a good indication of adequate suppression of HBV
replication. Monitoring of ALT is probably sufficient
for monitoring of those with precore mutants with
elevated ALT prior to therapy. Liver biopsy and
evaluation of necroinflammatory scores in hepatic
histology would be useful in the management of these
individuals with precore mutants.
There have been recent reports from India of
successful treatment of HCV patients using interferon
á and ribavirin57-59. This is a promising trend and as
clinicians gather more experience in managing
patients for interferon associated toxicities and
managing the adverse events in a timely fashion,
interferons will also be used to treat HBV in India.
Lamivudine, which has already been widely used in
India, is easily the best option to treat HBV infection.
Adefovir and tenofovir are not yet available in India;
however, both could potentially add to the
armamentarium to treat HBV. Inclusion of lamivudine
in the initial HIV regimen of all those individuals
coinfected with HBV is the best therapeutic strategy
that can be recommended. Monitoring of these
patients with ALT and hepatitis serologies is important
to ensure adequate HBV suppression.
Vaccination of all individuals is probably the most
cost-effective way to control HBV infection in India.
Even though HBV is not a predominant cause of acute
liver failure in India60, it could potentially lead to
chronic liver disease and decompensation over time,
particularly in HIV infected individuals. Immunization
of HIV infected individuals may not have great
success, as seen with the studies conducted in the
US50. However, it is recommended that all HIV
infected patients, particularly those with higher CD4+
T cell counts, should be offered immunizations.
Currently, there are no strong clinical data to routinely
recommend repeated immunization to achieve
protective immunity against HBV.
In conclusion, screening all HIV infected patients
for HBV, vaccination of all patients who have not
been exposed to HBV, and careful scrutiny of atypical
HBV serologies, and consideration of treatment with
a nucleoside analog against HBV are some of the
recommendations for management of HBV infection.
When newer medications are validated in clinical
trials, we will be able to treat HBV with combination
therapy and extend the duration of HBV suppression
in HIV infected individuals.
HCV and HIV co-infection
Over 170 million people worldwide are suffering
from chronic HCV infection61. Recent WHO reports
indicate that chronic liver disease is responsible for
over 1.4 million deaths due to cirrhosis and primary
liver malignancies1. It is estimated that HCV is
responsible for at least one-fifth of these deaths1,62.
HIV infection is found in approximately 40 million
individuals. Both HCV and HIV are transmitted by
blood and blood products, but HCV is ten times more
infectious than HIV. Co-infection with HCV is more
common in people with high exposure to contaminated
blood and both viruses infect approximately 60-90 per
cent of haemophiliacs and 50-70 per cent HIV positive
intravenous drug users (IDUs) in the US and
Europe63,64.
433
Epidemiology: Chronic HCV is a major cause of
chronic liver disease associated morbidity and
mortality around the world1,61,62. The eradication rates
with treatment of  individuals infected with HCV alone
can approach 60 per cent; however, due to lack of
detection and the cost and difficulty of treatment,
mortality rates associated with HCV are on the rise
in most countries65,66. With the advent of routine blood
screening for HCV, transfusion-related transmission
has almost disappeared in most countries. By contrast
with HBV, sexual transmission of HCV is less
efficient, though patients with high risk sexual
behaviour still have a high risk of acquiring HCV
infection sexually66. HCV is detectable in 2-4 per cent
of infants born to HCV infected mothers. Co-infection
with HIV increases the rate of transmission of both
viruses and high HCV viral levels in mothers increase
the risk of perinatal transmission67. The perinatal risk
of HCV transmission can be significantly reduced to
<1 per cent in infants born to HIV/HCV co-infected
mothers if the mother is on ART and undergoing
caesarean section delivery68. Occupational
transmission of HCV among health care workers is
also a major mode of transmission.
Natural history
(i) Acute HCV infection: Acute HCV infection is
often asymptomatic with resolution in approximately
two-thirds to one-half of all patients69-71. Although
incidence of acute HCV has significantly declined in
many developed nations through routine screening of
blood and blood products, it does occur through shared
needles, sexual transmission and as a nosocomial
infection in health care professionals66. The incubation
period for acute HCV infection is 2 to 26 wk and the
most common clinical presentation is with jaundice
(in about 20-30%)72. The symptoms resolve and a
significant proportion (30-80%), in contrast to HBV
infection, progress to chronicity73. A recent study has
provided overwhelming cure rates (98%) for treating
acute HCV infection within four months of
seroconversion74. However, many acutely infected
individuals will go on to clear the virus and hence
may not require any intervention75. Spontaneous
resolution of acute HCV infection is more common
with children, women and those who are symptomatic
with jaundice during the acute stage of infection69,76.
Several ongoing clinical trials treating acute HCV
infection will probably be able to answer whether and
when we need to treat acute HCV infection.
(ii) Chronic HCV infection: Chronic HCV infection
leads to cirrhosis, oesophageal varices, portal
hypertension, hepatic decompensation, and hepatic
malignancies. HCV is currently the major cause for
liver transplantation in Europe and the US. Recent
evidence suggests that the increase in the number of
deaths from hepatocellular carcinoma in most
countries is due to HCV infection62. Cirrhosis is the
end-stage of progressive liver fibrosis. Chronic HCV
infection leads to cirrhosis among HCV mono-infected
individuals in approximately 30 yr72-79. There are
several factors that may affect the rate of liver
disease progression77,80,81 (Table II).
HCV infection can also present with extrahepatic
manifestations which usually manifest much earlier
than hepatic manifestations. Recent studies have
indicated that three-fourths of all HCV infected
individuals have at least one extra hepatic
manifestation82-84. These include rheumatic (mylagias,
arthralgias, paraesthesias), mucocutaneous (pruritus,
sicca syndrome, Raynaud’s phenomenon), vasculitic
(cryoglobulinemia) and psychiatric (depression and
anxiety) symptoms82-84. Extrahepatic manifestations
also include biochemical abnormalities like the
presence of anti-nuclear antibodies, cryoglobulins,
anti-Sm antibodies, and abnormal thyroid tests82-84.
Even though mixed cryoglobulinaemia is relatively
common in chronic HCV patients, associated
vasculitis is rare (2%). The clinical significance of
these biochemical abnormalities is not yet clearly
understood.
Natural history of HCV/HIV co-infection: Since the
advent of ART, the outcome of HIV infection has
been dramatically altered. Maximal suppression of
HIV replication has led to effective restoration of
immune function, resulting in a dramatic reduction in
mortality associated with HIV infection. Recently
causes other than opportunistic infections have been
implicated in affecting the morbidity and mortality of
HIV infected individuals. These include long-term
toxicities of antiretroviral therapy such as metabolic
abnormalities and cardiovascular events and
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434 INDIAN J MED RES, APRIL  2005
hepatotoxicity and progressive liver disease due to
both ART and chronic hepatitides. In developed
countries, liver disease has already emerged as a
major cause of mortality85.
Effect of HCV on HIV: HCV does not appear to have
a direct effect on HIV viral levels. However, in
patients with progressive liver disease, portal
hypertension and splenomegaly, the peripheral CD4+
T cell counts may be lower, giving the clinical picture
of a more severe immunodeficiency state than is
actually present86. Large cohorts have provided
conflicting results regarding risk of progression of
HIV infected individuals to AIDS in the presence or
absence of HCV co-infection. In the Swiss cohort
study, patients who were co-infected with both HIV
and HCV had a more rapid progression to AIDS than
those who did not have HCV coinfection 87.
Interestingly, this study also found that CD4+ T cell
count increased less in patients with HCV than those
without HCV after effective ART was instituted,
suggesting that HCV infection may blunt immune
recovery of HIV infected individuals on ART. Another
large study88 failed to show an increase in progression
of HIV infected individuals to AIDS among those
who were coinfected with HCV. It is reasonable to
believe that HIV/HCV coinfected patients differ in
many important aspects from those with mono-
infection. It has been suggested that decreased
compliance with ART across the entire group could
dilute the ability to discern differences in progression
to AIDS. Understanding how HCV infection modifies
the outcome of HIV infection is also complicated by
the dramatic effects of ART on the natural history of
HIV infected individuals.
Effect of HIV on HCV: HIV-associated
immunosuppression has striking effects on several
aspects of the natural history of HCV. First, the
presence of HIV appears to be associated with higher
HCV viral loads in serum and in liver tissue 89,90.
Although one would assume that this is probably due
to the immunosuppression associated with HIV
infection, clinical trials have failed to demonstrate a
clear relationship between the CD4+ T cell counts
and HCV RNA levels. Moreover, HCV viral kinetic
modeling does not support the hypotheses of higher
viral production among HIV infected patients 91.
However, higher HCV viral loads definitely will have
a negative impact on therapeutic response among
HIV/HCV patients to anti-HCV therapy. Second, co-
infected patients are less likely to clear HCV virus
spontaneously73,92,93. Third, HIV infected individuals
are more likely to have false positive and false negative
tests for serologic assays to detect HCV94. This is
more likely due to the presence of non-specific
hypergammaglobulinaemia seen in HIV infected
patients with lower CD4+ T cell counts. Finally, HIV/
HCV co-infection is associated with a more rapid
progression of liver disease to cirrhosis, liver failure
and hepatocellular carcinoma80,95-98. Benhamou et al80
estimated the annual rate of fibrotic progression by
dividing the METAVIR score by estimated duration
of infection. Multivariate analysis of this study
indicated that a low CD4+ T cells count (< 200 cells/
µ l) and alcohol consumption in excess of 50 g/day
were highly associated with increased risk of disease
progression (Table II). A subsequent study comparing
patients on ART, a less effective ART, or no treatment,
clearly indicated that effective suppression of HIV
viral levels was associated with a decrease in liver-
associated mortality99. In a haemophiliac cohort94,
there was a higher risk for mortality from hepatic
decompensation and hepatoma in persons with HIV
co-infection than in mono-infected individuals. The
overall risk of development of liver-related mortality
for those who were exposed to HCV alone was 1.4,
Table II. Factors that predict liver fibrosis progression among
HCV infected individuals
1. Stage of liver fibrosis
2. Age at infection
3. Duration of HCV infection
4. Age at biopsy
5. Consumption of alcohol >50 g per day
6. HIV co-infection
7. CD4 count <200/µ l
8. Male sex
9. Necrosis seen in liver biopsy
10. Body-mass index, diabetes, steatosis
11. Absence of protease inhibitors in antiretroviral
therapy regimen
Source: References 77,80,81
435
compared with 6.5 among those who were infected
with both viruses over those individuals who were
negative for both viruses95. It is conceivable that as
survival of HIV infected individuals increases with
potent viral suppressive therapies and appropriate
prophylaxis of opportunistic pathogens, HCV-related
morbidity and mortality will be more prevalent100. In
many developed countries, HCV-related liver disease
is already among the predominant causes for death
among HIV infected individuals101.
Effect of HCV on ART: ART has been associated
with hepatotoxicity leading to multiple interruptions
causing significant morbidity and mortality48,49,102.
Several studies have demonstrated that
hepatotoxicities associated with ART are more
common in people coinfected with HCV and HIV,
particularly those taking protease inhibitors 48,49.
Several cohort studies have demonstrated a higher
proportion of elevated transaminase levels among
those with HCV infection48,49. Management of liver
toxicities in the presence of underlying liver disease
is often cumbersome. Severe hepatotoxicities are
more commonly associated with HBV and HCV
infection. A recent review on the manifestations and
current management trends of hepatotoxicity
associated with ART in HIV/HCV co-infection
covers the topic in greater depth103.
Effect of ART on HCV : Several studies have
suggested that initiation of ART leads to an increase
in HCV viral levels104-106. This increase is transient,
and the viral load returns to baseline levels within six
months of initiation of ART106. Chung et al 104 recently
showed that even though the viral loads increased in
all patients, it continued to increase only in those with
lower CD4+ T cell counts. Most studies used multiple
ART regimens that makes it difficult to conclude any
treatment-specific differences. Serum HCV RNA
level increases are associated with increases in ALT
and Aspartate transaminase (AST) increases as well.
The mechanism of HCV RNA level increase in
association with ART-associated immune
reconstitution is not clearly established. This may be
true in the case of HBV co-infection, where the
increases in ALT coincides with a decrease in HBV
DNA levels, suggesting an immune-mediated viral
clearance as a mechanism for this phenomenon.
However, the paradoxical increase in HCV RNA
levels seen with HCV co-infection may reflect
increased replication in some extrahepatic reservoirs
or an altered immune-mediated HCV clearance in
these patients107.
Pathogenesis: Both HCV and HIV are RNA viruses
whose genomes are transcribed frequently, producing
greater than 1010 virions in a day78. Since both viruses
replicate by means of a polymerase enzyme lacking
the ability to proofread error, the replication results
in the accumulation of a swarm of variants108,109. The
HIV genome is reverse transcribed and the
complementary DNA strand is integrated into the
DNA of latently infected CD4+ T cells contributing
to the persistence of a HIV reservoir 110. HCV
infection, on the other hand, is maintained by ongoing
replication. In other words, since the HCV genome
does not integrate into the host cell genome, but rather
replicates in the cytoplasm, it is possible to eradicate
HCV infection with effective therapy.
HCV predominantly replicates in hepatocytes111.
HCV is not considered as a cytopathic virus
(Poynard), and chronic HCV is generally considered
to be the result of an intermediate immune response
that is large enough to induce hepatic cell destruction
and fibrosis but not enough for eradication of HCV112.
HCV-specific humoral and cellular responses are
weaker in the chronic phase than in the acute phase
of the infection113. Also, patients with poor immune
responses in the acute phase are often asymptomatic
and are more likely to become chronic carriers than
those with good immune responses against HCV. It
is arguable that one of the mechanisms by which
immunomodulatory therapy (interferons) eradicates
HCV infection is by restoration of a specific immune
response.
HCV genotypes: HCV consists of six genotypes:
genotypes 1a and 1b are prevalent in the US 114,
genotype 1, 2, and 3 are common in Europe115,116 and
Australia117, genotype 4 is common in the middle east
and North Africa118,119, genotypes 1b, 2a and 2b are
common in Japan120 genotypes 1b and 2a in China120,
genotype 6 in Hong Kong , Macau and Vietnam120
genotype 5 in Sub-Saharan Africa  and genotype 3 in
Thailand, Malaysia and Singapore 121. In India
genotype 1b is predominant in southern India53,122 and
3 and 2b are common in northern India123-126.
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436 INDIAN J MED RES, APRIL  2005
Knowledge of genotypes is helpful for prediction
of therapeutic response and the choice of treatment
duration127, 128. Response rates to therapy for
genotypes 2 and 3 with pegylated interferon and
ribavirin is around 88 per cent, but only 48 per cent
for genotypes 1, 4, 5, and 678. Genotypes do not change
during the course of infection. Genotyping all HCV
patients for the purpose of management without
treatment is recommended. Interestingly, no studies
have shown any relationship between genotypes and
severity of liver disease129.
Diagnosis: There are currently two types of tests
available to detect HCV: one is a serologic assay for
the presence of antibodies and the other is a molecular
test for detection of viral particles. Initial screening
is done by detection of antibodies against HCV in the
serum. Antibodies against HCV are often detected
by using enzyme immunoassays (EIAs) that are very
sensitive and specific. The third generation EIA
currently used can detect both the core proteins and
the non-structural proteins enabling diagnosis of HCV
within 4 to 10 wk of infection. False positive results
can be expected for immunosuppressed individuals,
like those with HIV infection, chronic renal failure,
and essential cryoglobulinemia78.
Molecular assays for detection of HCV RNA are
of two types. One is the qualitative assay, based on a
PCR technique and has a lower limit of detection of
100 HCV RNA copies/ml. This test is particularly
useful when transaminase levels are normal, when
other causes of liver disease are present, in
immunosuppressed individuals and in the acute stage
of HCV infection. The second type of assay is the
quantitative type and there are two different assays
currently available. One is a qPCR assay and the other
a bDNA assay. The HCV RNA viral levels from
different assays are reported as standardized
international units in order to make it clinically relevant
for routine use in clinical practice130,131. Knowledge
of HCV viral load is important as a predictor of
therapeutic response and relapse. Patients with high
HCV viral loads prior to therapy will experience
higher rates of treatment relapses. Also, patients with
less than two-log reduction in baseline viral levels at
12 wk after initiation of therapy have been shown to
have a very low likelihood of achieving sustained
virologic response130,131. However, baseline HCV viral
loads have not been shown to correlate with the
severity of liver disease130,131.
All HIV infected individuals should be screened
for the presence of HCV infection132. Screening is
done with EIA followed by a confirmatory test or
qualitative RNA test for positive patients72. Detection
of HCV RNA along with a positive antibody test
indicates active HCV infection. It should be noted
that HCV antibody titres decrease to levels below
the level of detection in persons co-infected with HIV
and HCV, particularly in those with CD4+ T cell counts
< 200/ml94. Therefore, it is recommended that HCV
RNA tests be done in persons with negative anti-HCV
results and elevated ALT levels.
Liver biopsy: A liver biopsy for HCV patients is
usually recommended for evaluation of the severity
of liver disease. It is useful to stage the fibrosis and
grade the degree of inflammation133,134. Biopsy is also
helpful in diagnosing other causes for liver disease
like autoimmune hepatitis, non-alcoholic
steatohepatitis (NASH), alcoholic liver disease,
haemochromatosis and drug toxicities. One of the
major limitations of liver biopsy is sampling error. The
co-efficient of variation of the staging of 15 mm biopsy
sample is around 55 per cent135. Liver biopsy is also
associated with several serious adverse events and
carries a mortality rate of 0.3 per 1000136.
Recently, a number of studies have attempted to
validate the utility of non-invasive tests such as serum
biochemical markers to predict the extent of HCV-
induced liver disease. These markers, which include
? 2-macroglobulin, haptoglobin, ? -glutamyl
transpeptidase (GGT), total bilirubin and
apolipoprotein A1, have been shown to have high
predictive value for the diagnosis of significant fibrosis
when combined with ALT 137, 138. However, their utility
in detecting early hepatic fibrosis has not been proven.
Such markers, if validated, would be extremely helpful
in assessing and monitoring liver disease among
HCV/HIV coinfected patients.
Management of HCV infection
General principles: HCV does not integrate into the
host genome, but replicates in the cytoplasm. Hence,
it is conceivable that HCV can be eradicated with
437
adequate suppressive therapy. However, to date we
do not have HCV-specific antiviral therapy available.
Current treatment regimens include interferon-á,
(standard or pegylated) and ribavirin. Although
interferon may have some direct effects on HCV
replication, the exact mechanism of action of both
these agents is not yet clearly understood. It is
believed that the antiviral effects of combination
therapy include suppression of HCV replication in
hepatocytes, enhancement of immune-mediated
elimination of HCV infected hepatocytes, and
prevention of new infection of hepatocytes. Some
genotypes of HCV confer resistance to interferon and
are less responsive to treatment (e.g., genotype 1, 4,
5 and 6). Until newer HCV-specific drugs are
available, treatment for HCV is recommended for
persons with chronic HCV who are at the greatest
risk of developing cirrhosis. The risk is estimated by
several biochemical, viral and histologic factors,
including portal or bridging fibrosis or moderate degree
of necroinflammatory response139,140. Since liver
fibrosis progression is more rapid in HIV/HCV co-
infected patients, and the life expectancy of HIV
infected individuals has significantly improved, it is
recommended that these patients should be
considered for anti-HCV treatment140. Factors that
are associated with a poor prognosis to achieve
sustained virologic response (SVR) are summarized
in Table III.
There are four potential benefits for treating HCV
in HIV/HCV co-infected patients (Table IV). First,
treatment of HCV could lead to viral eradication or
SVR, as defined as undetectable HCV RNA at the
end of treatment and 6 months later (See definitions
of treatment responses in Table V). SVR is
considered a cure in HCV mono-infected individuals,
as several studies with 3 to 13 yr of follow up have
shown that viral clearance is durable141,142. Second,
suppression of HCV can lead to a reduction in the
risk of liver failure and hepatoma143. Although only a
few available data link HCV treatment to long-term
clinical benefits, it is noteworthy that such benefits
are not restricted to those with SVR. These studies
have treated patients who are at the greatest risk of
developing liver failure and hepatoma, without regard
to SVR. Such approaches are relevant to HIV/HCV
infected individuals who have lower rates of achieving
a SVR, and limited access to liver transplantation
compared to monoinfected individuals. Third, the
treatment of HCV among HIV/HCV co-infected
individuals may allow these individuals to better
tolerate antiretroviral therapy for HIV. Many HIV/
HCV co-infected patients have multiple interruptions
of ART, due to higher rates of severe hepatotoxicity
following initiation of ART 48,49. Treatment of
underlying HCV infection can lead to normalization
of transaminases and enable these patients to tolerate
ART without interruptions103. Finally, patients who
Table III. Factors associated with poor sustained virologic response to combination therapy
A. Viral factors B. Host factors
 HCV genotype 1 Age
 HCV pre-treatment viral load > 2 million copies/ml Male sex
 Chronicity of infection Race- African American
Alcohol consumption
Liver fibrosis > grade 3
HIV co-infection
CD4 T cell count <500 cells/µ l
Prior treatment with interferon
Body mass index (BMI)
Ribavirin usage
Source: References 81,127,128
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438 INDIAN J MED RES, APRIL  2005
show no decline in plasma HCV levels may derive
clinical benefit from therapy as evidenced by a
decrease in the elevated transaminase levels,
improved tolerance of antiretroviral therapy, and the
decreased inflammation on the repeat liver biopsies103
(Fig.). Whether this benefit will be durable following
discontinuation of therapy is uncertain. Long-term
follow up of co-infected patients in a clinical trial
setting to examine hepatic histologic response after
discontinuation of therapy is needed to determine the
durability of such benefit.
It should be noted that while no therapies have
been specifically approved by the US FDA for the
treatment of chronic HCV in HIV infected individuals,
there are several treatments approved for HCV
mono-infected individuals: monotherapy with
interferon-?  2b, interferon alfacon-1, pegylated
interferon-?  2b, and pegylated interferon-?  2a and
combination therapy with interferon-?  2b, pegylated
interferon-?  2b, or pegylated interferon-?  2a with
ribavirin.
Interferon-?  monotherapy: Interferon-?
monotherapy has been used to treat both HCV
monoinfected and HIV/HCV co-infected
individuals144-147. The results of interferon- ?
monotherapy are disappointing, although HCV mono-
infected individuals fare better than HIV/HCV co-
infected individuals. One study treated147 90 HIV/
HCV co-infected individuals with CD4+ T cell counts
> 200 cells/µ l with interferon-?  for 12 months. In an
intent to treat analysis, 20 per cent of these individuals
achieved SVR: better responses were associated with
a pretreatment CD4+  T cell count of >500 cells/
cmm147,148.
Addition of polyethylene glycol to the interferon-?
molecule allows once-weekly administration and
provides continuous exposure to interferon-? . Studies
have shown that in HCV mono-infected patients
pegylated interferon-?  2a, a branched 40 kDa PEG
and pegylated interferon ? 2b, a linear 12 kDa PEG
are more effective than standard interferon alone and
have a similar tolerability profiles149, 150.
Combination therapy with interferon-?  and
ribavirin: Several randomized controlled trials have
shown that interferon-?  with ribavirin is a more
effective therapy than interferon monotherapy in
HCV mono-infected individuals151,152. Many
studies153-156 have suggested that combination therapy
with interferon-?  and ribavirin is well tolerated by
HIV/HCV co-infected patients and may eradicate
HCV in a small percentage of patients.
Two large multi-center international clinical drug
registration trials in HCV-monoinfected individuals
have clearly demonstrated that combination therapy
with pegylated interferons (both ?  2a or ?  2b) is
superior to that of combination therapy with standard
interferon plus ribavirin127,128, with SVR of 54 per cent
(pegylated interferon-?  2b) and 56 per cent (pegylated
interferon-?  2a). Given the ease of administration
(weekly  vs three times a week for standard
interferons) and its superior efficacy, combination
therapy with pegylated interferons and ribavirin has
largely replaced the use of standard interferon-?  with
ribavirin140.  There are four major clinical trials which
have used pegylated interferon plus ribavirin for the
treatment of HIV/HCV infected individuals157-160. The
Spanish study was an open label study using pegylated
interferon-?  and ribavirin to treat HIV/HCV co-
infected patients158. This study had a significantly
higher proportion of HCV genotype 3 patients (35%),
Table IV. HIV/HCV co-infection: therapeutic objectives
Eradication of HCV infection
Delay histologic progression of HCV-related hepatic fibrosis
Delay clinical progression to ESLD, hepatocellular carcinoma,
and death
Reduce risk of ART-related hepatotoxicity and increase
tolerability to antiretroviral therapy
ESLD, end stage liver disease
Table V. HIV/HCV co-infection: definition of therapeutic
responses
Early virologic response (EVR): Decrease in HCV viral load in
plasma of  >2 logs by week 12 on therapy
End of treatment response (ETR): Absence of detectable HCV in
plasma at the completion of therapy
Sustained virologic response (SVR): Absence of detectable HCV
in plasma 24 wk after the completion of therapy
439
Fig. Liver biopsy slides showing necroinflammatory and fibrotic process in liver of an HIV/HCV patient who underwent successful
treatment with pegylated interferon and ribavirin. (A) The necroinflammatory score (H & E staining) shows marked improvement
from baseline biopsy (i) at the end of one year of treatment  (ii).
(B). On the other hand, the liver fibrosis scores (Masson staining) shows no significant change from baseline  (i) after one year of
treatment (ii) despite eradication of HCV.
A. H & E staining, i. Baseline, ii.  After treatment
B. Masson staining, i. Baseline, ii.  After treatment
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440 INDIAN J MED RES, APRIL  2005
investigators to speculate that higher SVR could have
been achieved in the ACTG trial, if higher doses of
ribavirin were used with initiation of treatment107. The
other key difference is the trial population, (US vs
other countries). Baseline weight of US participants
seems to be higher than those from other countries
who participated in these trials and obesity is
associated with decreased interferon response.
Moreover, African-Americans appear to have lower
response rates to interferon treatment than patients
from other races that were represented at a higher
proportion in ACTG 5071 than in APRICOT.
Furthermore, liver pathology was more advanced in
the ACTG study, which could have had a negative
effect on treatment response.
Special consideration should be given to those
patients with advanced liver disease. Persons with
hepatic decompensation are not optimal candidates
for interferon therapy. Hence, persons with advanced
liver disease need to be screened for evidence of
ascites, hepatoma, portal hypertension, and
encephalopathy. Liver transplantation for HIV/HCV
co-infected individuals is being explored as a feasible
option in many centers in the US 161. Current
guidelines recommend treating patients who are co-
infected with HIV and HCV prior to development of
severe liver disease81. Given the high rates of relapse
among HIV/HCV co-infected patients with genotype
2 and 3, current recommendations suggest these
patients should be treated for 48 wk instead of 24 wk
as with HCV mono-infected individuals81. Also, HIV/
HCV co-infected individuals have a higher relapse
rate after stopping treatment for 48 wk when
compared with that of HCV mono-infected
individuals81. Studies are currently addressing the need
for prolonged, 48 wk treatment regimens for HIV/
HCV co-infected patients in order to improve the rate
of SVR.
Adverse events associated with anti-HCV
treatment: Immunomodulatory therapy with
interferon-?  has many adverse events 162. Most
persons experience flu-like symptoms with initial
doses, such as fatigue and malaise and other side
effects such as anorexia, weight loss, hair loss, and
skin rash. Neuropsychiatric disturbances (depression,
irritability, insomnia, and cognitive changes) are
who appear to respond better to the combination
therapy than individuals with genotype 1. Despite this
advantage, overall SVR rates were only 28 per cent,
which is much lower than rate seen with monoinfected
patients158. The second trial, ACTG 5071, a multi-
center, randomized clinical trial, enrolled 134 patients
in the US. Patients were randomized to receive
pegylated interferon-?  2a in doses of 180 µ g weekly
along with escalating doses of ribavirin (600 mg to
1000 mg/d),159 or standard interferon-?  2a using an
induction regimen (6 million units three times a week
to 3 million units three times a week) plus ribavirin
(as escalating doses). This study reported an SVR of
27 per cent for the pegylated interferon-?  2a with
ribavirin group, lower than the other that seen with
HCV monoinfected patients who underwent similar
treatment. The RIBAVIC study160, sponsored by the
French National Research Group, treated 412 patients
and compared responses in HIV/HCV co-infected
individuals receiving pegylated interferon-?  2b with
ribavirin or standard interferon-?  2b with ribavirin.
The SVR for this study was only 26 per cent
(pegylated interferon arm) vs 18 per cent (interferon
arm). The fourth study, the AIDS Pegasys Ribavirin
International Co-infection Trial (APRICOT) was a
multi-center, international, industry sponsored
randomized controlled study that used three arms157.
Patients received pegylated interferon-?  2a 180 µ g/
wk with or without ribavirin (800mg daily) or
interferon-?  2a (3 million units three time s a week)
with ribavirin (800 mg/day). Of the 868 patients who
completed the trial, SVR was attained in 40 per cent
of the pegylated interferon-?  2a with ribavirin arm,
20 per cent of the pegylated interferon-?  2a alone
arm, and 12 per cent of the interferon- ?  2a with
ribavirin arm.
Overall efficacy of pegylated interferon-?  2a with
ribavirin in HIV/HCV co-infected patients is modest
compared to HCV mono-infected individuals. Subtle
yet significant differences between these trials could
be key factors to why the response rates are different
between these trials. ACTG 5071 used a dose-
escalation regimen for ribavirin initiating at a lower
dose (600 mg) and then increased this to 1000mg
within the first twelve weeks159. On the other hand,
APRICOT study used a fixed dosing schedule for
ribavirin at 800 mg/day157. This approach has led
441
reported in over 50 per cent of patients162. Depression
can be severe and suicides have been reported with
use of interferon for the treatment of HCV 162.
Interferon can also lead to thyroid dysfunction in less
than 5 per cent of patients and can also cause dose-
dependent cytopenias, including leucopenia and
thrombocytopenia. Lymphopenia that follows is
usually associated with a decrease in absolute CD4+
T cell counts; however, the percentage of CD4+ T
cells remains unchanged, and there is no apparent
additional risk for opportunistic infection163.
Ribavirin is associated with haemolytic anaemia
and interferon also induces bone marrow suppression
leading to anaemia152,164. This may be a more serious
problem with HIV infected individuals because of the
high prevalence of anaemia and limited myeloid
reserves due to comorbid diseases and /or associated
drug toxicity165. Ribavirin can also cause birth defects
and hence should not be administered to pregnant
women. Both men and women should be advised to
use effective measures of contraception during
therapy and for six months after the drug is
discontinued.
Since combination therapy has been used for
treating HIV/HCV co-infected patients, newer
adverse events have been reported. A recent study166
reported loss of colour vision and other ophthalmologic
changes in  patients undergoing therapy with
pegylated interferon-?  2b and ribavirin. These findings
suggest that all patients undergoing therapy for HCV
should undergo complete ophthalmologic examination
at baseline and at regular intervals while undergoing
treatment166. Another concern has been drug
interactions that may be involved with the use of
ribavirin with other nucleoside analogs. Several years
ago, it was shown that ribavirin, which is a guanosine
nucleoside analog has antagonistic activity in vitro
against the anti-HIV activity of pyrimidine nucleoside
analogs: zidovudine, stavudine and zalcitabine167,168.
However, many small clinical trials have failed to
detect any clinically significant antagonism when
ribavirin was used along with pyrimidine nucleoside
analogs156,169. In contrast, ribavirin inhibits inosine 5’
phosphate dehydrogenase, which facilitates the
intracellular conversion of didanosine to its inactive
metabolite. This enhances HIV activity in vitro but
may also increase  in vivo toxicity, including
mitochondrial effects167,170. Further, symptomatic
hyperlactetaemia has been reported in some patients
co-infected with HIV and HCV and receiving
ribavirin and didanosine concomitantly. Therefore it
is not recommended that those two drugs be used
concomitantly.
Prevention: Compared to HCV mono-infection, co-
infection with both HIV and HCV results in
accelerated liver fibrosis, hepatocellular carcinomas,
intolerability to ART, multiple interruptions in ART,
lack of adequate response to existing anti-HCV
treatment and problems associated with orthotopic
liver. Overall, the best strategy in fighting HCV among
HIV co-infected individuals is to prevent acquiring
HCV infection. Unlike HBV, we do not have an
effective HCV vaccine that prevents infection. All
these factors reiterate the significance of developing
efficient preventive strategies to thwart HIV infected
persons from acquiring HCV infection. First, persons
with HIV infection who are not yet infected with HCV
should undergo counselling to stop using injection
drugs; those unable to do so should pursue safe
injection practices72 (Table VI). Second, use of
barrier methods of contraception must be employed
to adequately prevent sexual transmission of HCV.
Third, pregnant mothers who have risk factors to
acquire HCV infection must be screened for the
presence of HCV. It should be noted that interferon-
?  and ribavirin are contraindicated in pregnancy.
Elective caesarian section prior to rupture of
membranes has shown to reduce maternal fetal
transmission rates of HCV (and HIV) significantly,
but is still not routinely recommended by the experts.
Finally, although post- exposure prophylaxis with ART
is recommended for all HIV infection, it is not
recommended to prevent HCV infection.
Relevance to India: There have been a few studies
in India that provided information on prevalence of
HCV infection. A community-based study using
serologic assays indicated a HCV prevalence rate of
0.87 per cent172. The prevalence increased from 0.31
per cent for children <10 yr to 1.85 per cent among
those who are older than 60 yr172. Although these
percentages are far below what has been projected
world-wide, these represent a significant reservoir of
KOTTILIL et al: HEPATITIS B & C IN HIV INFECTION
442 INDIAN J MED RES, APRIL  2005
infection calling for public health measures to address
the magnitude of this problem. Another study from a
tertiary care hospital173 in southern India demonstrated
an overall 6 per cent prevalence of HCV infection
and a 21 per cent seroprevalence of HCV among
HIV infected individuals. These numbers probably do
not represent that in the general population, but are
of concern. Surprisingly, a study evaluating the
knowledge of HCV among family physicians in one
of the provinces in northern India indicated that there
were deficiencies in the awareness about HCV, its
detection and transmission174. However, this study had
a low physician response rate and probably does not
represent the practice of family physicians over the
entire country. These results reiterate the need for
health education for health care providers regarding
all aspects of health care (Table VII).
Several studies52,122-126 have evaluated the
prevalence of HCV genotypes in India. HCV
genotype 3 is more common in northern and western
parts of India123,125,126 whereas, genotype 1 is more
common in the southern region53,122. Genotype 3
infections have a greater response to treatment and
HIV-negative individuals require 24 wk of therapy,
compared to 48 wk for genotype 1127,128,151,152.  Unlike
HBV treatment, several studies reported treatment
of HCV patients with interferon with or without
ribavirin57-59.  These studies have been done in cohorts
which are predominantly genotype 3 and have
reported excellent SVR rates57,59. These data indicate
that it is conceivable to diagnose and treat HCV
patients and obtain cure rates similar to that seen with
larger clinical trials reported worldwide127,128,149-152.
These clinical trials also demonstrated excellent
adherence and follow up of patients who underwent
48 wk of treatment. Overall, these data suggest it is
very possible to successfully manage HCV infection
in a resource-limited setting. However, it should be
noted that management of HCV patients in settings
with limited resources like community hospitals and
Table VI. Who should we screen for HCV?
A. Based on increased risk for infection B. Based on need for exposure management
Prior use of injected illegal drugs Healthcare, emergency, public safety workers after needle stick/mucosal
exposures to HCV-positive blood
Received clotting factors made before 1987 Children born to HCV-positive women
Received blood/organs before July 1992
Previously on chronic haemodialysis
Evidence of liver disease
Source : Reference 72
Table VII. Methods to reduce risk of acquiring HCV infection
Screen and test donors for blood, blood products and organs
Virus inactivation of plasma-derived products
Risk-reduction counseling and services:
Obtain history of high-risk drug and sex behaviours
Provide information on minimizing risky behaviour,
including referral to other supportive services
Vaccinate against hepatitis A and/or hepatitis B
Safe injection and infection control practices
Identify persons at risk for HCV and test to determine infection
status:
Routinely identify at risk persons through history, record
review
Provide HCV-positive persons:
Medical evaluation and management
Counselling
Prevent further liver damage
Prevent transmission to others
Source : Reference 72
443
clinics is going to be extremely challenging. Anti-
HCV therapy is not without severe adverse events
and has high drop out rates outside of clinical trials
settings. Monitoring these patients and managing
adverse events can be challenging. Also, the studies
mentioned above only represent a very small portion
of the total number of patients infected with HCV in
the Indian subcontinent, reiterating the need for
prioritizing limited resources. Further, the response
rates of the majority of patients with genotype 1 are
not going to be as high as those seen with genotype
3. Finally, HIV/HCV co-infected individuals are
unlikely to respond to treatment to the same degree
as HCV mono-infected individuals157-160.
Management of these individuals will obviously be
challenging. HIV infected individuals are susceptible
to opportunistic infections associated with a high
degree of morbidity and mortality. Management of
HIV infection should be prioritized for control of
ongoing HIV replication using ART, prophylaxis and
specific therapy for opportunistic infections. With
regards to HCV infection, prompt diagnosis and
counselling of these patients is the most effective
strategy (Tables VI & VII). Vaccination of these
patients against HBV and hepatitis A virus is
recommended72 (CDC). Moreover, these patients
should be advised to avoid alcohol and other
hepatotoxic agents like acetaminophen, as these
agents can worsen the underlying liver disease.
In summary, HCV co-infection is an emerging
opportunistic infection that could have a catastrophic
effect on the morbidity and mortality of HIV infected
patients. Screening susceptible individuals and
offering counselling are the first steps in the
management of HCV infection. Treatment for HCV
in HIV infected individuals is expensive, associated
with severe side effects, and has only modest cure
rates. Availability of resources may require that
treatment be reserved for select patients until less
expensive and more effective therapies are available.
Conclusion
HCV and HIV co-exist in a large proportion of
patients due to their shared modes of transmission.
HIV accelerates HCV-associated liver fibrosis and
HCV leads to higher rates of discontinuation of
HAART due to severe hepatotoxicity. HCV treatment
responses to the current standard of care are only
modest in HIV co-infected individuals. Moreover,
current treatments are associated with significant side
effects. HCV treatments that are more effective, less
expensive, associated with fewer side effects, and
preferably not immune-based are required to eradicate
HCV. Current research is focused on defining the
optimal management of chronic HCV patients
including the role of liver transplantation. Future
studies should focus on the pathogenesis of HCV in
HIV infected individuals, thereby enabling clinicians
to develop novel therapeutic approaches to impede
liver disease progression.
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