Review
Management of patients co-infected with hepatitis B virus and HIV

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Summary

The management of chronic hepatitis B virus (HBV) infection poses specific problems in the presence of HIV co-infection, since therapeutic approaches have to consider both HBV and HIV infections. There are currently four drugs approved for the treatment of chronic HBV infection (interferon α, lamivudine, adefovir, and entecavir); the dual antiviral activity of tenofovir and emtricitabine broadens the armamentarium against HBV in HBV/HIV co-infected patients. Nucleotide analogues—eg, adefovir and tenofovir—have the advantage of a higher genetic barrier to the development of resistance compared with nucleoside analogues—eg, lamivudine and emtricitabine. Fortunately, the two families do not share resistance mutations, allowing salvage therapy and the possibility of combination therapy for drug-naive individuals. Although response to interferon α is poorer in HBV/HIV co-infected patients compared with HIV-negative individuals, especially in hepatitis B e antigen-negative HBV infection, the more potent pegylated forms of interferon α have brought new hope.

Introduction

The prevalence of co-infection with hepatitis B virus (HBV) and HIV varies according to geographic region and risk category. In western countries, chronic HBV infection is ten-fold more frequent among HIV-positive individuals than in the general population. Men who have sex with men show the highest rates of co-infection (6–10%); rates of co-infection are slightly lower among intravenous drug users and much lower among people infected through heterosexual contacts.1, 2, 3, 4

HIV infection has a deleterious effect on the outcome of chronic viral hepatitis infections, and greatly complicates their management. HIV-positive individuals with chronic hepatitis—caused by either HBV or hepatitis C virus (HCV)—have greater liver mortality than those with HIV alone; the highest reported mortality is among those with multiple hepatitis infections.5 In one study conducted before lamivudine was available, HBV/HIV co-infection was associated with nearly 13-fold higher risk of liver mortality in HIV-positive patients, and this negative impact was more prominent in people with low CD4 counts.2 There are scarce data on the outcome of HBV infection in the era of highly active antiretroviral therapy (HAART).6

The reciprocal interactions between HIV and HBV infections result in specific problems for the management of HBV/HIV co-infection.6 For example, poorer response to interferon and faster selection of HBV-resistant strains with lamivudine have been reported in co-infected individuals. Moreover, the risk of selecting drug-resistant HIV and/or HBV argues against monotherapy with nucleoside/nucleotide analogues. Thus, the management of both infections should be carefully coordinated.

Ideally, any anti-HBV therapy should aim to cure the infection—defined as the disappearance of serum hepatitis B s antigen (HBsAg) and development of antibodies against HBsAg (anti-HBs). However, this goal is only rarely achieved, since the pool of the major transcriptional template of HBV in the liver—covalently closed circular DNA (cccDNA)—escapes the antiviral effect of most anti-HBV drugs. A less ambitious objective is to halt liver disease progression, to prevent the evolution to liver cirrhosis and the development of hepatocellular carcinoma.6, 7 To achieve this goal, maximal and sustained suppression of HBV replication should be pursued. Clearance of serum HBV DNA is currently considered an accepted surrogate marker for anti-HBV treatment success.8 In hepatitis B e antigen (HBeAg)-positive individuals with chronic HBV, the development of antibodies against HBeAg (anti-HBe) is also considered to be a marker of treatment response.

For a long time, lamivudine was the only available oral drug with dual activity against HIV and HBV. However, since the approval of tenofovir disoproxil fumarate and emtricitabine for the treatment of HIV infection, chronic HBV infection in HBV/HIV co-infected patients may also benefit from using these new drugs, even though they have not yet been approved for the treatment of HBV mono-infection. In addition, the new pegylated forms of interferon α, which may be administered subcutaneously once a week, have attracted much attention for the treatment of HBV infection.

Section snippets

Efficacy of anti-HBV drugs in HBV/HIV co-infected patients

Four drugs have been approved for the treatment of chronic HBV infection: interferon α, lamivudine, adefovir dipivoxil, and entecavir. However, other compounds showing anti-HBV activity have already been approved as therapy against either HIV (eg, tenofovir and emtricitabine) or HCV (eg, pegylated interferon α). Although not approved for use against HBV, these drugs are often used in HIV-infected patients. Table 1 summarises the current therapeutic armamentarium against HBV, including drugs

HBV resistance to nucleoside/nucleotide analogues

Because of the short duration of responses, together with the correlation between HBeAg seroconversion and duration of treatment, lamivudine had the potential to be used for the prolonged treatment of HBV mono-infected individuals. Anti-HBe seroconversion was seen in 29% of patients after 2 years of therapy, and in 40% after 3 years.46, 47 However, the selection of resistance mutations limited the long-term efficacy of the drug to a great extent. On average, mutations in the catalytic site of

Combination therapy for chronic HBV infection

In theory, the use of multiple drugs to treat HBV will result in better suppression of HBV replication and the prevention of selection pressure for drug resistance mutations. However, the combination of pegylated interferon α and lamivudine does not seem to confer any benefit over monotherapy with pegylated interferon α.18, 19 Combination therapy with pegylated interferon α and adefovir is currently being investigated in HIV-negative patients, although preliminary results have not shown any

Who should be treated, what drug to use, and for how long?

All HIV-positive individuals should be screened for HBsAg. Full serological assessment of the HBV infection should be done in those who test postive for HBsAg, including detection of HBeAg and anti-HBe, and plasma HBV DNA quantification. HBV treatment is generally indicated for those patients with active disease and viral replication. Until recently, the indication for therapy in HBV mono-infected people often relied on histological findings. With the advent of new oral drugs and measurement of

Conclusions

The management of chronic HBV infection poses specific problems in the setting of HBV/HIV co-infection, since therapeutic approaches have to address both HBV and HIV infections. Response to interferon α is lower than in HIV-negative subjects, especially in patients at advanced stages of immune deficiency. So far, there are no data on the performance of the new pegylated forms of interferon α in HBV/HIV co-infected individuals, but results in patients infected with HBV alone are encouraging.

Search and selection strategy

A search of the most recent English language medical literature (2000–2005) on HBV and HBV/HIV co-infection was done via Medline, using the following key words: “HBV”, “HIV”, “treatment”, “guidelines”, “interferon”, “lamivudine”, “emtricitabine”, “adefovir”, “tenofovir”, “entecavir”, and “resistance”. We also reviewed some references identified in the reviewed articles, and the abstract books of recent conferences (2000–2004).

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