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Strategies for managing coinfection with hepatitis B virus and HIV

May 1, 2009|Cleveland Clinic Journal of Medicine
Morris Sherman, MD, PhD
Author and Disclosure Information

Morris Sherman, MD, PhD
Associate Professor of Medicine, University of Toronto University Health Network, Toronto, ON, Canada

Correspondence: Morris Sherman, MD, PhD, Toronto General Hospital EN9-223, 200 Elizabeth Street, Toronto, ON, M5G2C4 Canada; Dr.Morris.Sherman@uhn.on.ca

Dr. Sherman reported that he has received consulting fees and honoraria for teaching and speaking from Bristol-Myers Squibb Company, Gilead Sciences, Inc., and Roche Laboratories, Inc.

This article was developed from an audio transcript of Dr. Sherman’s lecture at the “Seventh Annual Liver Update 2008,” a CME course. The transcript was formatted and edited by the Cleveland Clinic Journal of Medicine staff for clarity and conciseness, and was then reviewed, revised, and approved by Dr. Sherman.

Dr. Sherman received honoraria for contributing to this supplement and the CME course on which it was based. The honoraria were paid by the Cleveland Clinic Center for Continuing Education from educational grants provided by Bristol-Myers Squibb Company and Gilead Sciences, Inc., that supported the course and this supplement. These grantors had no input on the content of the course or this supplement.

ABSTRACT

Hepatitis B virus (HBV) infection is more aggressive in individuals coinfected with human immunodeficiency virus (HIV): in the presence of HIV, HBV carrier rates and viremia levels are higher, episodes of activation are more frequent, cirrhosis progresses more quickly, and hepato­cellular carcinoma occurs more often than with HBV infection alone. As in HBV monotherapy, the objective of treatment is suppression of viral replication. Standard or pegylated interferon may be appropriate treatment for chronic HBV infection for patients who have not yet started highly active antiretroviral therapy (HAART) for their HIV. When treatment is required for both diseases, the use of a combination of nucleoside and nucleotide analogues is prudent, with careful selection of therapy to reduce the risk of antiviral resistance—a particular concern for patients receiving antiretroviral therapy for both HIV and HBV. HBV DNA levels should be monitored every 3 months; the frequency can be extended to every 6 months once the viral load becomes stable or undetectable.

KEY POINTS

  • Patients with HBV/HIV coinfection are at relatively high risk of frequent HBV activation, progression to cirrhosis, and death from liver-related causes.
  • If the patient does not yet require HAART but requires treatment for HBV, this is itself an indication for HAART, since monotherapy for HBV is associated with development of resistance to HIV therapy.
  • Nucleoside and nucleotide analogues should not be used as monotherapy in the HBV/HIV-coinfected patient because of the risk of inducing HIV resistance.

TREATMENT OPTIONS

The potential therapies for HBV in the coinfected patient are the same as those for the patient infected with HBV alone (see “Hepatitis B treatment: Current best practices, avoiding resistance”), with the addition of tenofovir and emtricitabine in combination.

Interferon

Early studies of interferon for the treatment of chronic HBV infection included many patients who were also HIV positive. These early studies revealed a lower rate of HBeAg seroconversion in HIV-positive patients compared with HIV-negative patients. Di Martino et al11 found that approximately half (26 of 50) of HIV-negative patients treated with interferon seroconverted at 6 years, compared with only 4 of 26 interferon-treated patients with chronic HBV who were coinfected with HIV. Based on results such as these, interferon therapy in the HBV/HIV-coinfected patient should be limited to patients who are likely to seroconvert: ie, those who are female and younger than 40 years with high ALT levels, low serum HBV DNA levels, and active liver histology (a subgroup that is more likely to undergo spontaneous seroconversion than other HBV-infected groups).

Standard or pegylated interferon is a treatment option for coinfected patients who do not yet require HAART, especially patients who have high ALT levels, low viral loads, and positive HBeAg status without liver decompensation.12

Nucleoside and nucleotide analogues

The nucleoside and nucleotide analogues used for HBV therapy have different degrees of effectiveness against HIV polymerase, but none can be used as monotherapy because of the risk of inducing HIV resistance. Lamivudine and tenofovir are used as part of the standard cocktail for the treatment of HIV (see “Case: HIV/HBV with resistance to tenofovir”). Entecavir is now recognized as a partial inhibitor of HIV replication. Both lamivudine and entecavir induce the YMDD mutation, an indication of resistance to therapy, in HIV polymerase. Tenofovir also may select for resistance mutations in HIV polymerase.

At dosages used for the treatment of HBV infection, adefovir has weak activity against HIV, and therefore HIV would not be under significant selective pressure to develop resistance mutations. In HIV polymerase, the mutations that confer resistance to adefovir also confer resistance to tenofovir, and therefore use of adefovir may induce tenofovir resistance.

Telbivudine has not been studied in HIV-infected patients, but its resistance profile is similar to that of lamivudine.

Treating both infections

When both HBV and HIV infections require treatment, HAART is necessary for HIV.12 The treatment strategy for coinfection is to use standard therapy for HIV, selecting two agents that are effective against HBV infection.

The need to avoid antiviral resistance complicates the selection of active agents. Resistance to HIV therapy limits the choices for treatment of HBV infection. The immediate aim of therapy, an undetectable level of HBV DNA, eliminates the use of less potent agents. The best choice for therapy is the most potent agent that can be used, such as tenofovir plus lamivudine or tenofovir plus emtricitabine.

Antiviral resistance

For the coinfected patient who develops resistance to lamivudine, the recommendation is to treat with tenofovir plus entecavir (the preferable choice because of absence of cross-reactivity between the two agents) or tenofovir plus lamivudine or emtricitabine. There is some evidence that lamivudine resistance predisposes to entecavir resistance, but the studies that generated these results were conducted in patients who had very high baseline viral loads13; the effectiveness of entecavir in patients with low baseline viral loads is unknown. Presumably, when entecavir is used in combination with another potent nucleoside analogue in coinfected patients, the sensitivity of HBV will be more durable than when entecavir is used as monotherapy.

Long-term monitoring

Long-term monitoring for the coinfected patient is similar to that for the patient infected with HBV only. HBV DNA levels should be monitored every 3 months for signs of resistance until levels have plateaued or become undetectable. Once the HBV DNA level is stable or undetectable, the monitoring interval can be extended. Ultrasonographic screening for hepatocellular carcinoma should be conducted every 6 months. Patients with cirrhosis should be screened for esophageal varices.

SUMMARY

HBV in the setting of HIV is more aggressive than in a patient infected with HBV only, and treatment must be comparably aggressive and carefully selected. The primary goal of HBV treatment in a coinfected patient is the same as in a patient with HBV infection only: reduction of viral load to undetectable levels. Treatment decisions are based on viral load, ALT level, findings on liver biopsy, the need for HAART, and the drug’s resistance profile. None of the nucleoside or nucleotide analogues can be used as monotherapy in the coinfected patient because of the risk of inducing resistance to HIV therapy. When the patient requires HAART, then the general recommendation is to select a combination of two drugs that have activity against HIV. If resistance develops, the preferred strategy is treatment with tenofovir plus entecavir. Monitoring includes measurement of HBV DNA levels every 3 months and ultrasonographic screening for hepatocellular carcinoma every 6 months.

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