J Antimicrob Chemother 2010; 65: 10 17

doi:10.1093/jac/dkp414 Advance publication 8 November 2009

HIV/hepatitis B virus co-infection: current challenges

and new strategies
K. Lacombe1 3*, J. Bottero3, M. Lemoine4,5, A. Boyd1,2 and P. M. Girard1 3
1

INSERM UMR-S707, Paris, France; 2UPMC, Pierre and Marie Curie School of Medicine, Paris, France;
3
Department of Infectious and Tropical Diseases, Saint-Antoine Hospital, AP-HP, Paris, France;
4
Hepatology Department, Saint-Antoine Hospital, AP-HP, Paris, France; 5INSERM U938, CDR Saint-Antoine, Paris, France
*Corresponding author. Service de maladies infectieuses, Hopital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France.
Tel: 33-1-49-28-24-38; Fax: 33-1-49-28-21-49; E-mail: karine.lacombe@sat.aphp.fr

Keywords: immunodeficiency, chronic viral hepatitis, epidemiology, prevention, qualitative systematic review

Recent trends in epidemiology

tattoos (Africa).3 In these settings, the prevalence of HBV infection is often close to 15%, regardless of HIV co-infection.4

Global prevalence
Since HIV and hepatitis B virus (HBV) share common routes of
transmission, the prevalence of hepatitis B markers [antihepatitis B core antibodies (anti-HBcAb) or hepatitis B surface
antigen (HBsAg)] in HIV-infected patients is remarkably high.
Around the world, 90% of HIV-infected persons have biological
signs of prior HBV infection (defined by the presence of serum
anti-HBcAb) and 5%15% suffer from chronic infection
(defined by the presence of serum HBsAg).1 As a consequence,
2 4 million of the 33 million people living with HIV globally are
also co-infected with chronic hepatitis B.2 Modes of transmission
can be characterized by the geographical origin of infected
patients. In areas with low HBV prevalence (,2% HBsAgpositive), such as the USA and Western Europe, injecting drug
practices and unprotected sex are the primary mode of transmission, and affect essentially the adult population. The main
consequence is a prevalence of co-infection of between 5%
and 10%, 10 times higher than that of the general population.
In contrast, in Africa and Asia, where HBV endemicity is high
(.8% and often approaching 15% HBsAg-positive), most HBV
infections occur within the first 5 years of life through perinatal
transmission (Asia) or close contact within households and
medical or cultural procedures, such as scarification and

Impact of co-infection on morbidity and mortality

In the era of broad-use of combined antiretroviral therapy
(cART), the mortality and incidence of AIDS-defining diseases
have dramatically declined.5 Liver diseases, notably those associated with HBV, have consequently emerged as a major cause of
morbidity and mortality in HIV-infected persons.6 8 A recent
meta-analysis performed on 12 382 patients living in Europe
found a significant 36% excess risk of all-cause mortality attributed to the effect of HIV/HBV co-infection (pooled effect estimate, 1.36; 95% CI, 1.12 1.64).9
The outcome of HBV infection varies according to age
at acquisition and host immune status. Compared with
HIV-uninfected adults, of whom ,5% acquire chronic HBV infection,10 HBV infection persists in 25% of HIV-infected adults and
in 50% 90% of persons infected at birth or in early childhood.
Once chronic, HBV infection might evolve within decades
towards end-stage liver diseases (ESLD), such as decompensated
cirrhosis and/ or hepatocellular carcinoma (HCC), and all the
more rapidly if HBV replication is uncontrolled.11,12 In HIV
co-infection, a more severe and critical progression is reported,13
and the occurrence of HCC becomes a major concern.14

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Chronic hepatitis B virus (HBV) infection, which affects 7%10% of HIV-infected patients, is associated with an
increased frequency of AIDS-related and non-AIDS-related clinical endpoints, such as end-stage liver diseases including cirrhosis and hepatocellular carcinoma. Broad access to a very efficient antiviral therapy containing nucleos(t)ide
analogues with dual activity against HBV and HIV reverse transcriptases has initiated a transition in the paradigm of
HBV control in the context of HIV-induced immunosuppression. The control of viral replication is not currently such a
problem, but preventing the emergence of HBV polymerase and surface gene mutants after prolonged exposure to
nucleos(t)ides and their consequences in terms of HBV vaccine escape are the next long-term challenges. Another
challenge is the prevention of end-stage liver disease in an ageing population, in whom non-invasive markers of
liver fibrosis, although used more frequently as a substitute for liver biopsy, are not the panacea. Finally, access
to prevention, diagnosis, care and treatment of HBV infection remains a major issue in developing countries, including most regions of Africa and Asia, where HBV is endemic and the epidemic of HIV infection is still thriving.

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Multiple hepatitis virus infection

Common routes of transmission are also shared with hepatitis C
virus (HCV) and Delta virus (HDV), and co-infection with HIV and
HBV occurs relatively frequently (29.9% of HIV/HBV/HCV triple
infections in the Eurosida Cohort;7 7.8% of HDV co-infection
either in triple HIV/HBV/HDV or quadruple HIV/HBV/HCV/HDV
infections in the French HIV/HBV Cohort).15 In HIV/HBV
co-infected patients, the additional effect of HCV and HDV on
liver fibrosis has been associated with myriad liver-related complications, such as increased risk of hepatic decompensation and
cirrhosis defined as F3 and F4 METAVIR fibrosis score.16,17 Tri- and
quad-infected patients are also more likely to demonstrate constant replication of other hepatitis viruses, which is most apparent in additional HDV infections, despite treatment.18

Impact of HIV and antiretroviral treatment

on liver injury
Profibrogenic effect of HIV
HIV tropism for hepatic stellate cells and hepatocytes
There is increasing evidence of a direct cytopathic effect of HIV
on liver tissue, independent of viral hepatitis co-infection. HIV
RNA and p24 antigen were detected in hepatocytes as early as
the 1990s.19 Pathways of HIV pathogenic action are likely to be
numerous and are not yet completely elucidated. One of these
pathways is related to CCR5 and CXCR4, the two major
co-receptors required for HIV entry into host cells. They are
expressed on the surface of hepatocytes and hepatic stellate
cells (HSC), involved in fibrogenesis.20 Recent data suggest
that HIV and/or the HIV glycoprotein gp120 ligation of CXCR4
receptors present on hepatocytes selectively up-regulate
tumour necrosis factor (TNF)-related apoptosis-inducing ligand
(TRAIL) R2 expression and confer an acquired sensitivity to
TRAIL-mediated apoptosis.21 According to the authors, HIV
infection renders hepatocytes more susceptible to liver injury
during disease states associated with enhanced TRAIL production, such as HBV infection. Recent experimental data
suggested the ability of HIV to infect HSC and to promote their
myofibroblastic differentiation leading to the production of
a-smooth muscle actin, collagen and monocyte chemoattractant protein 1.22

Altered innate and adaptive immune response

Immune response to HBV is suboptimal in the context of HIV,
leading to a decreased frequency of hepatitis B envelope (HBe)
and HBs seroconversion.23 Causes for an altered immune
response are also multifactorial and not all have been fully
explained. Toll-like receptors (TLRs) are pathogen-recognition
receptors that initiate inflammatory responses orchestrated by
innate immune cells, such as dendritic cells. It has been
suggested that their course of expression might be modified
when in contact with either HIV24 or HBV,25 inducing a
pro-inflammatory signalling cascade with consequences for
liver fibrosis. Alongside TLRs, the role of natural killer and dendritic cells in HIV and HBV disease progression is presently being
debated.26,27

The mechanisms underlying adaptive immune responses to

HBV in HIV-co-infected patients may also be helpful in understanding the control of HIV/HBV disease progression. The activation of HBV-specific CD8 T cells, which play a key role both
in the control of HBV replication and in the pathogenesis of
liver disease,28 is clearly impaired during concomitant HIV infection. This might explain why acute HBV infection tends to frequently evolve towards chronicity in HIV-infected patients.29

HBV immune restoration and HBV reactivation

Hepatic flares in the setting of HIV/HBV co-infection are caused
by multifarious factors and are frequent, with an incidence rate
of cytolysis over twice the normal value at 13.4 per 100
patient years (95% CI, 9.5 17.3), as observed in a cohort of
308 patients over a 3 year period.30 Immune restoration
disease (IRD) is a troubling complication of restoring the adaptive
anti-HBV immune response while under antiretroviral (ARV) treatment. Recent data suggest that IRD is mediated by proinflammatory and antiviral cytokines, such as TNF-a and
interferon-d (IFN-d), which in turn can induce the production of
several chemokines.31 These chemokines include CXCL-10, a
protein whose concentration has been proved to be positively
correlated with biochemical scores of liver fibrosis and liver
enzymes levels in HIV/HCV co-infected patients.32
HBV reactivation is another feared complication of either
unplanned interruption of HIV drugs with HBV activity or emergence of HBV resistance, which might lead to major hepatic
flares and increases the risk of fulminant hepatitis and the
need for urgent orthotopic liver transplantation (OLT).33,34

Hepatotoxicity and metabolic syndrome

Hepatotoxicity associated with ARVs is a common aetiology of
hepatic flares and worsening of liver fibrosis. The role that ARVs
play in drug-induced elevations of transaminases arouses particular controversies. The mere process of prescribing ARVs is
driven by the necessity of balancing potential toxic effects with
the need for increasing the CD4 cell count and controlling HBV
replication alongside that of HIV. With respect to HBV, mechanisms for hepatotoxicity are not much different from those seen in
HCV:35,36 mitochondrial toxicity associated with certain nucleoside analogues (zalcitabine, stavudine and didanosine); idiosyncratic hypersensitivity reaction with nevirapine and abacavir;
and alteration of metabolism with certain protease inhibitors
(tipranavir and ritonavir).
Alongside hepatotoxicity, a set of metabolic alterations,
known as non-alcoholic fatty liver disease (NAFLD), has
emerged in HIV-infected patients treated with cART, including
lipodystrophy syndrome closely associated with insulin resistance and dyslipidaemia.37 39 NAFLD and insulin resistance are
now widely recognized as major co-factors of fibrosis progression
in patients already chronically infected with viral hepatitis. Experimental data also suggest a direct role of HIV in nuclear transcription involved in insulin resistance and fibrogenesis, by
altering insulin sensitivity through suppression of peroxisome
proliferator-activated receptor type gamma activity, a major
transcription factor involved in lipid metabolism, insulin sensitivity, inflammatory processes and fibrogenesis.40 Attention
should also be brought to the early detection of HIV portal

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obliteration with nodular regenerative hyperplasia, a new manifestation of liver disease recently described41 and responsible
for non-cirrhotic portal hypertension. Although not specific to
HBV infection, it might aggravate the prognosis of liver disease
in the presence of chronic hepatitis infection.

Diagnostic and follow-up tools

Frequency of periodic screening
There is an overall agreement among recommendations
to screen HIV-monoinfected patients annually for the presence
of serum HBsAg (alongside HCV antibodies) and to screen
for this antigen in cases of hypertransaminasaemia.42 In
HBsAg-negative patients without evidence of anti-HBc-positive
serology, immunization schedules must be adapted to antiHBsAb response. Isolated HBcAb seropositivity is common in
HIV-infected patients and could be a marker of occult HBV infection, whose prevalence varies across subgroups of patients.43 45
HBV DNA and liver function tests should therefore be systematically assessed in patients with such a serologic pattern. If acute
HBV infection is suspected, anti-HBc immunoglobulin M (IgM)
should also be tested.

Initial liver assessment

When HBsAg presence in serum is detected and confirmed,
patients should be systematically evaluated for physical signs
of chronic liver disease. Other liver disorders, as well as extrahepatic signs of HBV infection (such as arthritis, neuropathy and
rash), should be sought. Identification of liver co-morbidities is
of the utmost importance, as they accelerate liver damage progression. Liver co-morbidities include multiple viral hepatitis
infections,16 obesity, metabolic syndrome (hypertension, diabetes and/or hyperlipidaemia) and lipodystrophy.38 Alcohol consumption and use of hepatotoxic drugs should be avoided.
Initial laboratory tests should include liver enzymes, complete
blood count, coagulation tests, albumin, creatinine, a-fetoprotein
(AFP), HBV markers of replication (HBe antigen, anti-HBe and HBV
DNA), and hepatitis A (HAV), HCV and HDV antibodies. Other
hepatic diseases, such as Wilson disease, auto-immune hepatitis
and haemochromatosis, should be ruled out if necessary.
Patients with negative HAV serology must be vaccinated
because of the risk severe hepatitis A confers in the context of
other hepatic co-infections.46
Grading and staging of liver disease is the next most important
step after biological evaluation of chronic hepatitis B. Although
most ARV combinations now include drugs with dual HIV and
HBV activity, assessment of liver fibrosis remains a necessity in
order to prevent evolution towards ESLD. Liver biopsy is still the
gold standard for evaluating fibrosis severity in HIV co-infected
patients, because of its ability to diagnose overlapping hepatic
conditions (steatosis, mitochondrial cytotoxicity and granulomatous disease) that may compromise HBV treatment efficacy and
tolerance, and accelerate fibrosis progression.47 However, the
need for a more easy-to-use and easily repeated tool has
prompted the development of several non-invasive methods for
assessing fibrosis. In the context of HIV/HBV co-infection, noninvasive methods can be used to accurately define an appropriate
time for anti-HBV treatment initiation in non-cART-treated

12

patients. They can also assist in evaluating the use of certain

ARV drugs contraindicated for severe liver fibrosis. Lastly, they
can help monitor and assess the therapeutic efficacy of antiviral
treatments according to the level of liver fibrosis and cirrhosis.
In this respect, some biochemical scores have proved to detect
bridging fibrosis and cirrhosis accurately in the specific context
of HIV/HBV co-infection.48 The use of Fibroscanw, a promising noninvasive tool validated in HCV monoinfection,49 and to a lesser
extent with lower performance in HBV monoinfection50 and HIV/
HCV co-infection,51 might be more limited in HIV/HBV co-infection.
Its performance still needs to be established for this indication.

Follow-up and prevention of ESLD

Due to the increased risk of progression towards ESLD in the
context of HIV infection, close and careful clinical and biological
follow-up is advised. In patients with advanced fibrosis or liver cirrhosis, physical examination, liver ultrasonography and serum AFP
should be assessed every 6 months, and an upper gastrointestinal
tract endoscopy should be planned annually. Complications of
portal hypertension should be treated.52 As HCC is likely to occur
among HBV-infected patients without evidence of liver cirrhosis,
it is recommended to repeat clinical, biological and radiological
liver evaluation every 6 months in patients with pre-cirrhotic fibrosis (F3 according to the METAVIR classification). Doppler ultrasonography has a good performance for HCC screening and is also
useful for the diagnosis of portal vein thrombosis,53 which is a
common complication of cirrhosis and an underestimated event
in HIV infection.54,55 Magnetic resonance imaging might also be
a useful tool in the early detection of HCC, but its use still needs
to be integrated in guidelines for HCC screening and treatment.56

Advances in therapeutic management

Treatment
Clinicians caring for HIV/HBV co-infected patients are facing
several issues in terms of therapeutic management: the efficacy
of antiviral drugs is generally lower than in HBV monoinfected
patients; the emergence of viral resistance and consequent
viral failure is a constant concern; and drugs with dual activity
prove to be beneficial in terms of treatment simplification, but
are more difficult to manage when HIV or HBV resistance occurs.
Is there still any room for IFN or pegylated IFN (Peg-IFN) in the
treatment regimens of HIV/HBV co-infected patients? Much disappointment has been generated over the use of standard IFN
in HIV/HBV co-infected patients.57,58 The higher efficacy of
Peg-IFN in HBV monoinfection59 has led to its evaluation in
small groups of co-infected patients; however, this has been
without much success, except in isolated cases.60 Combined
treatment with adefovir61 has not led to satisfactory results
either. In a pilot study, sequential treatment with Peg-IFN for
6 months and then tenofovir led to a drop of ,3 log HBV-DNA
in 7 of 10 patients.62 Another sequential algorithm (tenofovir
for 6 months and then Peg-IFN) is currently being tested and
results are expected in 2010. Thus, the profile of patients who
might benefit from a treatment with Peg-IFN still remains to
be determined.
The availability of nucleos(t)idic inhibitors of HBV reverse transcriptase with dual anti-HIV and anti-HBV activity has initiated

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a transition in the paradigm of HBV treatment in the context of

HIV, along with many advantages and drawbacks. The use of
treatment combinations (emtricitabine/tenofovir) and of dual
activity drugs (tenofovir, lamivudine and emtricitabine) help to
simplify both HIV and HBV management, but the onset of resistance warrants a strict viral follow-up. Owing to their high potential to rapidly generate multiple pol mutations,63 lamivudine and
emtricitabine must not be used alone. When released in 2002,
adefovir was promising because of its high genetic barrier to
resistance,64 but its lower potency does not make this treatment
an ideal candidate among HIV-infected patients, in whom HBV
viral load is usually high. Tenofovir also exhibits a high genetic
barrier to resistance, with a rapid and long-lasting decline in
HBV DNA when used as single anti-HBV agent in the context of
HIV,65 even in patients with lamivudine-resistant HBV strains.66
Newer, very potent nucleosides, such as entecavir67,68 and telbivudine,69 have been marketed in HBV monoinfection. However,
these treatments cannot be used as single agents in HIV/HBV
co-infection, because of their capacity to suboptimally inhibit
HIV replication70,71 and select M184V mutations in HIV reverse
transcriptase.70 Clevudine was purportedly another treatment
alternative after its efficacy and safety had been confirmed by
Phase III randomized clinical trials.72,73 However, its clinical
evaluation has been recently stopped due to cases of mitochondrial myopathy after a mean 8 13 months of exposure.74

Timely initiation of treatment

Several important issues should drive the decision as to when
antiviral therapy should be initiated in HIV/HBV co-infected
patients.42,75 A balance should be found between a combination
of factors, including the necessity of starting a lifelong treatment, the need to manage treatment in conjunction with HIV,
the commitment to viral resistance prevention and the requirement for optimal tolerability.
The severity of liver fibrosis and the risk of rapid evolution
towards increased cirrhosis and ESLD merit an early introduction
of ARVs in patients with chronic hepatitis, probably before the
CD4 cell count threshold of 500 cells/mm3, as indicated for
HIV.76 When HIV treatment is initiated, tenofovir is the preferred
choice regarding its high potency and the possibility of a simplified therapeutic strategy active on both HBV and HIV when combined with emtricitabine. If tenofovir is contraindicated,
entecavir or telbivudine can be prescribed if HIV viral load is controlled. In the event of lamivudine resistance, the dose of entecavir needs to be doubled and telbivudine might not be as
effective.77 Adefovir still remains an option in patients with
lamivudine-resistant virus.78 Data are very scarce on whether
or not it is more beneficial to start treatment with an anti-HBV
combination. In treatment-naive patients, the adjunction of lamivudine did not prove to be superior to tenofovir alone in a small, 36
patient clinical trial in Thailand,79 whereas lamivudine-experienced
patients from a retrospective AustralianAmerican cohort seemed
to have benefitted from a tenofovir/lamivudine combination in
terms of HBV DNA load undetectability.80
Very few options are available if HIV treatment is postponed,
because of the dual HIV and HBV activity of most available drugs.
Guidelines for HBV monoinfection could be extended to
HIV-infected patients for treatment with Peg-IFN if the determinants for a positive response are present: low HBV DNA load; age

,40 years; ALT .5 normal value; and genotype A or B. Otherwise, adefovir is the only remaining option. The paucity of
options must incite clinicians to start HIV therapy earlier.

New challenges
Clinicians and healthcare providers throughout developed and
developing countries are facing new and multiple challenges,
some of which could become a serious threat to public health.
Three major concerns that could affect future generations of
co-infected patients arise from the impact of emerging HBV
viral mutants on immunization strategies, the access to innovative HCC treatment and liver transplantation in a population
more prone to succumb to fatal outcomes from ESLD. Finally,
certain pitfalls of HIV/HBV co-infection in resource-limited
countries must be addressed.

Genotypes, viral mutants and long-term impact

on public health
Genotypes and mutations on one of the P, S and C genes constitutive of the HBV genome have recently been associated
with differences in HBV disease evolution and treatment
response. The peculiarity specific to HIV/HBV co-infection
resides in the fact that most mutations are induced by long
exposure to nucleos(t)ides that have been largely used to
treat HIV.
Genotype distribution is linked to the geographical origin of
patients81 and is not influenced by HIV or treatment (except
when mixed patterns are present82). Cohort studies have found
an association between some genotypes and the risk of severe
liver fibrosis (genotype G in HIV/HBV co-infected patients15) or
HCC (genotype C in HBV monoinfected patients83). Whether or
not these results should elicit routine genotyping of HBV strains
in daily practice still remains to be evaluated.
Since the molecular structure of the HBV genome consists of
four long overlapping open reading frames that encode for
various antigens and proteins,84 mutations in one of these
regions may induce mutations in the neighbouring gene. pol
mutations selected by exposure to nucleos(t)ides indeed
induce mutations on the S gene, conferring decreased HBsAg
antigenicity.85 A recent study conducted on chimpanzees
also attributed HBV vaccine failure to the presence of
E164D I195M S gene mutations selected when triple pol
173 180204 mutations occur (mainly after exposure to lamivudine).86 Data on HIV/HBV co-infection are very scarce and
cross-sectional;87 thus, rendering it difficult to determine the
involvement that HIV treatment has with these mutations or
the consequences for disease progression. The public health
impact attributed to such mutations must be continuously evaluated in a co-infected population likely to be treated and immunization strategies must be adapted accordingly.

New markers of treatment efficacy

Most HIV/HBV co-infected patients effectively treated with
potent anti-HBV drugs, such as tenofovir, exhibit an undetectable
plasma HBV DNA load. However, they very rarely clear HBeAg or
HBsAg and are still at risk of developing cirrhosis and ESLD,

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despite a controlled HBV replication. New markers of treatment

efficacy are currently being assessed, whose performance in predicting the evolution towards ESLD may be increased compared
with HBV DNA load.
The covalently closed circular DNA molecule is an interesting
marker, because of its role in HBV persistence within the hepatocytes by maintaining a stable intranuclear pool of transcriptional
templates.88 Its decline is predictive of long-term control of HBV
replication and HBsAg clearance under nucleotides such as adefovir.89,90 It is also strongly correlated to HBsAg concentration in
plasma, whose predictive value was established as a strong
marker of viral replication in 1992.91 Contrary to HBV DNA load,
serum HBsAg level is an accurate predictor of HBsAg seroconversion and HBV clearance, and a threshold of HBsAg of 10 IU/mL at
the end of Peg-IFN treatment has also been defined as a strong
predictor of complete cure within 3 years post-treatment.92 In
the context of HIV where nucleos(t)ides are more frequently
used, HBsAg quantification could help tailor HBV treatment
more precisely and assist in the early detection of nonresponding patients whose anti-HBV treatment could consequently be more rapidly maximized.

Access to liver transplantation and innovative

procedures for HCC treatment
As highlighted by a recent retrospective cohort study conducted
in France on 898 HIV-infected patients, of whom 15.4% died
from a liver-related cause, HCC is rising as an aetiology of
ESLD14 and is likely a harbinger of an emerging problem for
persons living with hepatic co-infection in regions with access
to potent ARV regimen.93
Innovative procedures for HCC treatment and OLT should no
longer be excluded from HIV-infected patients. As HIV disease
is being more easily controlled than ever, patients with decompensated cirrhosis should be referred earlier for OLT because of
the increased risk of death whilst waiting for a transplant
(higher Model for End-stage Liver Disease score at inclusion).94
The outcome of OLT in HIV/HBV co-infected patients is very
reassuring, with 100% survival at a median 3 year follow-up.95
For patients with HCC, systemic treatment, such as sorafenib,
transarterial chemoembolization or radiofrequency thermal
ablation, should be discussed similar to non HIV-infected
patients, according to official recommendations.96,97 Sorafenib
(Nexavarw) is the first oral multikinase inhibitor of the vascular
endothelial growth factor receptor and the platelet-derived
growth factor receptor. Its use has led to a significantly
increased survival rate in patients with HCC98 and is currently
being evaluated in the context of HIV because of its potential
interactions with protease inhibitors.99

HBV co-infection in resource-limited countries

ARV scaling-up strategies will inaugurate a new era of HIVrelated co-morbidities in resource-limited countries, where the
prevalence of opportunistic infections will progressively decrease
and non-AIDS-related pathologies will become predominant.
One must expect a greater incidence of ESLD in conjunction
with a higher prevalence of chronic hepatitis B, and limited
access to treatments with dual anti-HBV and anti-HIV activity.

14

So far, HBV and HCV screening is included as a part of the

initial clinical and biological package recommended by WHO
when initiating ARVs,100 but is not often applied due to financial
constraints. In HBsAg-negative patients, immunization is strongly
advised, but two factors limit its efficacy. First, patients are often
diagnosed at a late stage of HIV infection, when immunodeficiency is too profound to induce a vaccine response. Second,
the burden of immunization cost falls on patients (except children, for whom national immunization programmes provide
HBV vaccines free of charge).
When HIV-infected patients are diagnosed with chronic hepatitis B, a first-line ARV regimen should include lamivudine and
tenofovir, as recommended by WHO.101 However, access to
tenofovir still remains problematic in many countries and, if contraindicated, other treatment options are typically unavailable.
Broader and cheaper access to HBV screening and a first-line
TDF-containing therapy should be advocated so as to prevent
the emergence and spread of drug-resistant strains.4,102
HBV mother-to-child transmission (HBV-MTCT) is another
important issue. Guidelines recommend preventing transmission
through newborn immunization and the administration of
immunoglobulins (HBIg), although this is rarely employed
because of its high cost. Furthermore, this procedure might
also fail if the maternal HBV DNA load is high,103,104 which is
often the case in HIV co-infection. Lamivudine has been successfully evaluated in the prevention of HBV-MTCT,105 but optimal
results are obtained when combined with HBIg. Results from
clinical trials using tenofovir and emtricitabine in this particular
setting are strongly anticipated.
Finally, the HBV and HIV epidemics are entangled with that of
HCC (200000 deaths every year in sub-Saharan Africa).106 One
substantial fear is that the risk of developing HCC will increase
in parallel with life expectancy, as a consequence of broader
access to ARVs. Diagnosis and treatment of HCC is unfortunately
out of reach for most healthcare centres in resource-limited settings. Campaigns for the prevention of HBV transmission through
immunization, effective screening and access to drugs with a
high potency and high genetic barrier (such as tenofovir and,
hopefully, entecavir) must be promoted.

Conclusions
Despite the broader use of very potent drugs with dual anti-HIV
and anti-HBV activity, under which a decrease in the risk of liver
fibrosis progression and the occurrence of liver-related complications would be expected, many challenges are still faced by
HIV/HBV co-infected patients and their caregivers. Future research
should focus on the following aspects of HBV infection in the
context of HIV: natural history (through a better understanding
of the direct effect of HIV on liver injury); prevention (of HBV transmission through efficient immunization and MTCT strategies,
emergence and spreading of resistant HBV strains, and ESLD);
screening and follow-up (by developing easy-to-use tools and
increasing quality of care); and, eventually, treatment (by maximizing efficacy and minimizing side effects). Knowledge on
prevention, follow-up and treatment strategies is constantly evolving in developed countries, but it should not be forgotten that
HBV infection is still a burden in resource-constrained settings,
where these strategies still need to be successfully implemented.

Review

Acknowledgements
The authors thank Prof F. Zoulim for his continuous support and
invaluable expertise regarding HBV diversity and variability in the HIV
context.

Funding
K. L. has received fundings from SIDACTION and ANRS (Agence Nationale
de Recherche sur le Sida).

Transparency declarations
None to declare.

References
1 Alter M. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol
2006; 44: S6 9.
2 Report
UG.
http://data.unaids.org/pub/Report/2009/jc1736_2008_
annual_report_en.pdf (12 October 2009, date last accessed).
3 Adewole OO, Anteyi E, Ajuwon Z et al. Hepatitis B and C virus
co-infection in Nigerian patients with HIV infection. J Infect Developing
Countries 2009; 3: 36975.
4 Hoffmann C, Thio C. Clinical implications of HIV and hepatitis B
co-infection in Asia and Africa. Lancet Infect Dis 2007; 7: 4029.

JAC
15 Lacombe K, Massari V, Girard P et al. Major role of hepatitis B
genotypes in liver fibrosis in HIVHBV co-infection. AIDS 2005; 20:
41927.
16 Lacombe K, Boyd A, Desvarieux M et al. Impact of chronic hepatitis C
and/or D on liver fibrosis severity in patients co-infected with HIV and
hepatitis B virus. AIDS 2007; 21: 2546 9.
17 Sheng WH, Hung CC, Kao JH et al. Impact of hepatitis D virus infection
on the long-term outcomes of patients with hepatitis B virus and HIV
coinfection in the era of highly active antiretroviral therapy: a matched
cohort study. Clin Infect Dis 2007; 44: 988 95.
18 Boyd A, Lacombe K, Miailhes P et al. Longitudinal evaluation of viral
interactions in treated HIV-hepatitis B co-infected patients with
additional hepatitis C and D virus. J Viral Hepat 2009; doi: 10.1111/
j.1365-2893.2009.01153.x.
19 Housset C, Lamas E, Brechot C. Detection of HIV1 RNA and p24
antigen in HIV1-infected human liver. Res Virol 1990; 141: 1539.
20 Feng H, Ana T, Ting Fang L et al. Hepatic stellate cells express
functional CXCR4: role in stromal cell-derived factor-1a-mediated
stellate cell activation. Hepatology 2009; 49: 2055 67.
21 Babu CK, Suwansrinon K, Bren GD et al. HIV induces TRAIL sensitivity
in hepatocytes. PLoS ONE 2009; 4: pe4623.
22 Tuyama A, Hong F, Mosoian A et al. HIV entry and replication in
stellate cells promotes cellular activation and fibrogenesis: implications
for hepatic fibrosis in HIV/HCV co-infection. 15th Conference on
Retroviruses and Opportunistic Infections, Boston, MA, 2008. Abstract
57.
http://www.retroconference.org/2008/Abstracts/32362.htm
(12
October 2009, date last accessed).

5 Palella FJ Jr, Baker RK, Moorman AC et al. Mortality in the highly active
antiretroviral therapy era: changing causes of death and disease in the
HIV Outpatient Study. J Acquir Immune Defic Syndr 2006; 43: 27 34.

23 Piroth L, Sene D, Pol S et al. Epidemiology, diagnosis and treatment of

chronic hepatitis B in HIV-infected patients (EPIB 2005 STUDY). AIDS
2007; 21: 1323 31.

6 Mocroft A, Brettle R, Kirk O et al. Changes in the cause of death among

HIV positive subjects across Europe: results from the EuroSIDA study.
AIDS 2002; 16: 1663 71.

24 Thibault S, Fromentin R, Tardif M et al. TLR2 and TLR4 triggering exerts

contrasting effects with regard to HIV-1 infection of human dendritic
cells and subsequent virus transfer to CD4 T cells. Retrovirology 2009;
6: 42.

7 Konopnicki D, Mocroft A, de Wit S et al. Hepatitis B and HIV: prevalence,

AIDS progression, response to highly active antiretroviral therapy and
increased mortality in the EuroSIDA cohort. AIDS 2005; 19: 593 601.
8 Lewden C, May T, Rosenthal E et al. Changes in causes of death among
adults infected by HIV between 2000 and 2005: the Mortalite 2000 and
2005 surveys (ANRS EN19 and Mortavic). J Acquir Immune Defic Syndr
2008; 48: 5908.
9 Nikolopoulos GK, Paraskevis D, Hatzitheodorou E et al. Impact of
hepatitis B virus infection on the progression of AIDS and mortality in
HIV-infected individuals: a cohort study and meta-analysis. Clin Infect
Dis 2009; 48: 1763 71.
10 Hyung Joon Y, Lok ASF. Natural history of chronic hepatitis B virus
infection: what we knew in 1981 and what we know in 2005.
Hepatology 2006; 43: S173 81.
11 Chen C-J, Yang H-I, Su J et al. Risk of hepatocellular carcinoma across
a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;
295: 65 73.

25 Jun W, Zhongji M, Min J et al. Hepatitis B virus suppresses toll-like

receptor-mediated innate immune responses in murine parenchymal
and nonparenchymal liver cells. Hepatology 2009; 49: 1132 40.
26 Morsica G, Tasca S, Biswas P et al. Natural killer-cell cytotoxicity
in HIV-positive and HIV-negative patients with and without
severe course of hepatitis B virus infection. Scand J Immunol 2005; 62:
31824.
27 Op den Brouw ML, Binda RS, van Roosmalen MH et al. Hepatitis B virus
surface antigen impairs myeloid dendritic cell function: a possible
immune escape mechanism of hepatitis B virus. Immunology 2009;
126: 2809.
28 Chang JJ, Sirivichayakul S, Avihingsanon A et al. Impaired quality of
the hepatitis B virus (HBV)-specific T-cell response in human
immunodeficiency virus type 1-HBV coinfection. J Virol 2009; 83:
7649 58.

12 Iloeje U, Yang H, Su J et al. Predicting cirrhosis risk based on the level

of circulating hepatitis B viral load. Gastroenterology 2006; 130: 67886.

29 Thimme R, Wieland S, Steiger C et al. CD8() T cells mediate viral

clearance and disease pathogenesis during acute hepatitis B virus
infection. J Virol 2003; 77: 6876.

13 Thio CL, Seaberg EC, Skolasky J et al. HIV-1, hepatitis B virus, and risk
of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet
2002; 360: 1921 6.

30 Chauvel O, Lacombe K, Bonnard P et al. Risk factors for acute liver

enzyme abnormalities in HIV-hepatitis B virus-coinfected patients on
antiretroviral therapy. Antivir Ther 2007; 12: 1115 26.

14 Salmon-Ceron D, Rosenthal E, Lewden C et al. Emerging role of

hepatocellular carcinoma among liver-related causes of deaths in
HIV-infected patients: the French national Mortalite 2005 study.
J Hepatol 2009; 50: 73645.

31 Crane M, Oliver B, Matthews G et al. Immunopathogenesis of hepatic

flare in HIV/hepatitis B virus (HBV)-coinfected individuals after the
initiation of HBV-active antiretroviral therapy. J Infect Dis 2009; 199:
97481.

15

Review

32 Roe B, Coughlan S, Hassan J et al. Elevated serum levels of

interferon-g-inducible protein-10 in patients coinfected with hepatitis C
virus and HIV. J Infect Dis 2007; 196: 1053 7.

51 de Ledinghen V, Douvin C, Kettaneh A et al. Diagnosis of hepatic

fibrosis and cirrhosis by transient elastography in HIV/hepatitis C
virus-coinfected patients. J Acquir Immune Defic Syndr 2006; 41: 175 9.

33 Bellini C, Keiser O, Chave J et al. Liver enzyme elevation after

lamivudine withdrawal in HIV-hepatitis B virus co-infected patients: the
Swiss HIV Cohort Study. HIV Med 2009; 10: 12 8.

52 Bruix J, Sherman M. Management of hepatocellular carcinoma.

Hepatology 2005; 42: 1208 36.

34 Bonacini M, Kurz A, Locarnini S et al. Fulminant hepatitis B due to a

lamivudine-resistant mutant of HBV in a patient coinfected with HIV.
Gastroenterology 2002; 122: 2445.
35 Sulkowski MS. Management of hepatic complications in HIV-infected
persons. J Infect Dis 2008; 197: S279 93.
36 Vogel M, Rockstroh JK. Hepatotoxicity and liver disease in the context
of HIV therapy. Curr Opin HIV AIDS 2007; 2: 306 13.
37 Sutinen J, Hakkinen AM, Westerbacka J et al. Increased fat
accumulation in the liver in HIV-infected patients with antiretroviral
therapy-associated lipodystrophy. AIDS 2002; 16: 2183 93.
38 Lemoine M, Barbu V, Girard PM et al. Altered hepatic expression of
SREBP-1 and PPARg is associated with liver injury in insulin-resistant
lipodystrophic HIV-infected patients. AIDS 2006; 20: 387 95.
39 Ingiliz P, Valantin MA, Duvivier C et al. Liver damage underlying
unexplained transaminase elevation in human immunodeficiency
virus-1 mono-infected patients on antiretroviral therapy. Hepatology
2009; 49: 43642.
40 Shrivastav S, Kino T, Cunningham T et al. Human immunodeficiency
virus (HIV)-1 viral protein R suppresses transcriptional activity of
peroxisome proliferator-activated receptor fgg and inhibits adipocyte
differentiation: implications for HIV-associated lipodystrophy. Mol
Endocrinol 2008; 22: 234 47.
41 Mallet VO, Varthaman A, Lasne D et al. Acquired protein S deficiency
leads to obliterative portal venopathy and to compensatory nodular
regenerative hyperplasia in HIV-infected patients. AIDS 2009; 23:
1511 8.
42 Rockstroh JK, Bhagani S, Benhamou Y et al. European AIDS Clinical
Society (EACS) guidelines for the clinical management and treatment
of chronic hepatitis B and C coinfection in HIV-infected adults. HIV Med
2008; 9: 82 8.
43 Piroth L, Binquet C, Vergne M et al. The evolution of hepatitis B virus
serological patterns and the clinical relevance of isolated antibodies to
hepatitis B core antigen in HIV infected patients. J Hepatol 2002; 36:
6816.
44 Perez-Rodriguez MT, Sopena B, Crespo M et al. Clinical significance of
anti-HBc alone in human immunodeficiency virus-positive patients.
World J Gastroenterol 2009; 15: 123741.
45 Neau D, Winnock M, Jouvencel AC et al. Occult hepatitis B virus
infection in HIV-infected patients with isolated antibodies to hepatitis B
core antigen: Aquitaine cohort, 2002 2003. Clin Infect Dis 2005; 40:
7503.
46 Keeffe EB. Acute hepatitis A and B in patients with chronic liver
disease: prevention through vaccination. Am J Med 2005; 118: 21 7.
47 Don CR, Stephen HC, Zachary DG et al. Liver biopsy. Hepatology 2009;
49: 1017 44.
48 Bottero J, Lacombe K, Guechot J et al. Performance of 11 biomarkers
for liver fibrosis assessment in HIV/HBV co-infected patients. J Hepatol
2009; 50: 1074 83.
49 Ziol M, Handra-Luca A, Kettaneh A et al. Noninvasive assessment of
liver fibrosis by measurement of stiffness in patients with chronic
hepatitis C. Hepatology 2005; 41: 48 54.
50 Marcellin P, Ziol M, Bedossa P et al. Non-invasive assessment of liver
fibrosis by stiffness measurement in patients with chronic hepatitis B.
Liver Int 2009; 29: 242 7.

16

53 Maruyama H, Yoshikawa M, Yokosuka O. Current role of ultrasound for

the management of hepatocellular carcinoma. World J Gastroenterol
2008; 14: 1710 9.
54 Chang P-E, Miquel R, Blanco J-L et al. Idiopathic portal hypertension in
patients with HIV infection treated with highly active antiretroviral
therapy. Am J Gastroenterol 2009; 104: 1707 14.
55 Mallet V, Blanchard P, Verkarre V et al. Nodular regenerative
hyperplasia is a new cause of chronic liver disease in HIV-infected
patients. AIDS 2007; 21: 18792.
56 Zech CJ, Reiser MF, Herrmann KA. Imaging of hepatocellular
carcinoma by computed tomography and magnetic resonance
imaging: state of the art. Dig Dis 2009; 27: 114 24.
57 Brook MG, McDonald JA, Karayiannis P et al. Randomised controlled
trial of interferon a 2A (rbe) (Roferon-A) for the treatment of chronic
hepatitis B virus (HBV) infection: factors that influence response. Gut
1989; 30: 1116 22.
58 Di Martino V, Thevenot T, Colin JF et al. Influence of HIV infection on
the response to interferon therapy and the long-term outcome of chronic
hepatitis B. Gastroenterology 2002; 123: 1812 22.
59 Marcellin P, Lau GK, Bonino F et al. Peginterferon a-2a alone,
lamivudine alone, and the two in combination in patients with
HBeAg-negative chronic hepatitis B. N Engl J Med 2004; 351: 1206 17.
60 Gozlan J, Lacombe K, Gault E et al. Complete cure of HBV HDV
co-infection after 24 weeks of combination therapy with pegylated
interferon and ribavirin in a patient co-infected with HBV/HCV/HDV/HIV.
J Hepatol 2009; 50: 4324.
61 Ingiliz P, Valantin MA, Thibault V et al. Efficacy and safety of adefovir
dipivoxil plus pegylated interferon-a2a for the treatment of
lamivudine-resistant hepatitis B virus infection in HIV-infected patients.
Antivir Ther 2008; 13: 895 900.
62 Johnson RM, Ristig MB, Overton ET et al. Safety and tolerability of
sequential pegylated IFN-a2a and tenofovir for hepatitis B infection in
HIV() individuals. HIV Clin Trials 2007; 8: 173 81.
63 Benhamou Y, Bochet M, Thibault V et al. Long-term incidence of
hepatitis B virus resistance to lamivudine in human immunodeficiency
virus-infected patients. Hepatology 1999; 30: 1302 6.
64 Benhamou Y, Bochet M, Thibault V et al. Safety and efficacy of
adefovir dipivoxil in patients co-infected with HIV-1 and
lamivudine-resistant hepatitis B virus: an open-label pilot study. Lancet
2001; 358: 71823.
65 Peters MG, Andersen J, Lynch P et al. Randomized controlled study of
tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG
A5127. Hepatology 2006; 44: 1110 6.
66 Lacombe K, Gozlan J, Boelle PY et al. Long-term hepatitis B virus
dynamics in HIV-hepatitis B virus-co-infected patients treated with
tenofovir disoproxil fumarate. AIDS 2005; 19: 90715.
67 Lai CL, Shouval D, Lok AS et al. Entecavir versus lamivudine for
patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006;
354: 1011 20.
68 Chang TT, Gish RG, de Man R et al. A comparison of entecavir and
lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006;
354: 1001 10.
69 Lai CL, Gane E, Liaw YF et al. Telbivudine versus lamivudine in patients
with chronic hepatitis B. N Engl J Med 2007; 357: 2576 88.

Review

JAC

70 McMahon MA, Jilek BL, Brennan TP et al. The HBV drug entecavir effects on HIV-1 replication and resistance. N Engl J Med 2007; 356:
2614 21.

89 Werle-Lapostolle B, Bowden S, Locarnini S et al. Persistence of cccDNA

during the natural history of chronic hepatitis B and decline during
adefovir dipivoxil therapy. Gastroenterology 2004; 126: 1750 8.

71 Low E, Cox A, Atkins M et al. Telbivudine has activity against HIV-1.

AIDS 2009; 23: 5467.

90 Maynard M, Parvaz P, Durantel S et al. Sustained HBs seroconversion

during lamivudine and adefovir dipivoxil combination therapy for
lamivudine failure. J Hepatol 2005; 42: 27981.

72 Yoo BC, Kim JH, Kim TH et al. Clevudine is highly efficacious in hepatitis
B e antigen-negative chronic hepatitis B with durable off-therapy viral
suppression. Hepatology 2007; 46: 1041 8.
73 Yoo BC, Kim JH, Chung YH et al. Twenty-four-week clevudine therapy
showed potent and sustained antiviral activity in HBeAg-positive chronic
hepatitis B. Hepatology 2007; 45: 1172 8.
74 Fleischer RD, Lok AS. Myopathy and neuropathy associated
with nucleos(t)ide analog therapy for hepatitis B. J Hepatol 2009; 51:
78791.
75 Soriano V, Puoti M, Peters M et al. Care of HIV patients with chronic
hepatitis B: updated recommendations from the HIV-Hepatitis B Virus
International Panel. AIDS 2008; 22: 1399 410.
76 Vogel M, Rockstroh JK. Liver disease: the effects of HIV and
antiretroviral therapy and the implications for early antiretroviral
therapy initiation. Curr Opin HIV AIDS 2009; 4: 171 5.
77 Pessoa MG, Gazzard B, Huang AK et al. Efficacy and safety of entecavir
for chronic HBV in HIV/HBV coinfected patients receiving lamivudine as
part of antiretroviral therapy. AIDS 2008; 22: 1779 87.
78 Benhamou Y, Thibault V, Vig P et al. Safety and efficacy of adefovir
dipivoxil in patients infected with lamivudine-resistant hepatitis B and
HIV-1. J Hepatol 2006; 44: 627.
79 Matthews GV, Avihingsanon A, Lewin SR et al. A randomized
trial of combination hepatitis B therapy in HIV/HBV coinfected
antiretroviral naive individuals in Thailand. Hepatology 2008; 48:
1062 9.
80 Matthews GV, Seaberg E, Dore GJ et al. Combination HBV therapy is
linked to greater HBV DNA suppression in a cohort of
lamivudine-experienced HIV/HBV coinfected individuals. AIDS 2009; 23:
1707 15.
81 Kao JH. Hepatitis B viral genotypes: clinical relevance and molecular
characteristics. J Gastroenterol Hepatol 2002; 17: 64350.
82 Jardi R, Rodriguez-Frias F, Schaper M et al. Analysis of hepatitis B
genotype changes in chronic hepatitis B infection: influence of antiviral
therapy. J Hepatol 2008; 49: 695 701.
83 Chan HL, Tse CH, Mo F et al. High viral load and hepatitis B virus
subgenotype ce are associated with increased risk of hepatocellular
carcinoma. J Clin Oncol 2008; 26: 177 82.
84 Ganem D, Prince AM. Hepatitis B virus infectionnatural history and
clinical consequences. N Engl J Med 2004; 350: 1118 29.
85 Torresi J. The virological and clinical significance of mutations in the
overlapping envelope and polymerase genes of hepatitis B virus. J Clin
Virol 2002; 25: 97106.
86 Kamili S, Sozzi V, Thompson G et al. Efficacy of hepatitis B vaccine
against antiviral drug-resistant hepatitis B virus mutants in the
chimpanzee model. Hepatology 2009; 49: 1483 91.
87 Sheldon J, Ramos B, Garcia-Samaniego J et al. Selection of hepatitis B
virus (HBV) vaccine escape mutants in HBV-infected and HBV/
HIV-coinfected patients failing antiretroviral drugs with anti-HBV
activity. J Acquir Immune Defic Syndr 2007; 46: 27982.
88 Tuttleman JS, Pourcel C, Summers J. Formation of the pool of
covalently closed circular viral DNA in hepadnavirus-infected cells. Cell
1986; 47: 45160.

91 Zoulim F, Mimms L, Floreani M et al. New assays for quantitative

determination of viral markers in management of chronic hepatitis B
virus infection. J Clin Microbiol 1992; 30: 1111 9.
92 Brunetto MR, Moriconi F, Bonino F et al. Hepatitis B virus surface
antigen levels: a guide to sustained response to peginterferon a-2a in
HBeAg-negative chronic hepatitis B. Hepatology 2009; 49: 1141 50.
93 Sulkowski M. Hepatocellular carcinoma in HIV-infected patients
comes of age: the convergence of epidemiology and treatment
effectiveness. J Hepatol 2009; 50: 6558.
94 Subramanian A, Sulkowski M, Barin B et al. MELD is the best predictor
of pre-transplant mortality in HIV-infected liver transplant candidates.
15th Conference on Retroviruses and Opportunistic Infections, Boston,
MA, 2008. Abstract 64. http://www.retroconference.org/2008/Abstracts/
31927.htm (12 October 2009, date last accessed).
95 Tateo M, Roque-Afonso A-M, Antonini TM et al. Long-term follow-up of
liver transplanted HIV/hepatitis B virus coinfected patients: perfect
control of hepatitis B virus replication and absence of mitochondrial
toxicity. AIDS 2009; 23: 1069 76.
96 Verslype C, Van Cutsem E, Dicato M et al. The management of
hepatocellular
carcinoma.
Current
expert
opinion
and
recommendations derived from the 10th World Congress on
Gastrointestinal Cancer, Barcelona, 2008. Ann Oncol 2009; 20: vii1 6.
97 El-Serag HB, Marrero JA, Rudolph L et al. Diagnosis and treatment of
hepatocellular carcinoma. Gastroenterology 2008; 134: 1752 63.
98 Llovet JM, Ricci S, Mazzaferro V et al. Sorafenib in advanced
hepatocellular carcinoma. N Engl J Med 2008; 359: 378 90.
99 Deeken JF, Pantanowitz L, Dezube BJ. Targeted therapies to treat
non-AIDS-defining cancers in patients with HIV on HAART therapy:
treatment considerations and research outlook. Curr Opin Oncol 2009;
21: 44554.
100 WHO. Essential Prevention and Care Interventions for Adults and
Adolescents Living with HIV in Resource-limited Settings. http://
www.who.int/hiv/pub/plhiv/plhiv_treatment_care.pdf (12 October 2009,
date last accessed).
101 WHO. HIV/AIDS Prevention, Treatment and Care in the Health Sector.
http://www.who.int/entity/hiv/pub/priority_interventions_web.pdf
(12
October 2009, date last accessed).
102 Lessells RJ, Main J, Cooke GS. HIV and hepatitis B co-infection in
Africa. Lancet Infect Dis 2008; 8: 2101.
103 Wiseman E, Fraser MA, Holden S et al. Perinatal transmission of
hepatitis B virus: an Australian experience. Med J Aust 2009; 190:
48992.
104 Liu S-L, Dong Y, Zhang L et al. Influence of HBV gene heterogeneity
on the failure of immunization with HBV vaccines in eastern China. Arch
Virol 2009; 154: 43743.
105 Xu WM, Cui YT, Wang L et al. Lamivudine in late pregnancy to
prevent perinatal transmission of hepatitis B virus infection: a
multicentre, randomized, double-blind, placebo-controlled study. J Viral
Hepat 2009; 16: 94 103.
106 Parkin DM. The global health burden of infection-associated cancers
in the year 2002. Int J Cancer 2006; 118: 3030 44.

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