Drug warning prompts treatment changes for those infected with hepatitis B and HIV

Cross-resistance alarms raised earlier this year by Johns Hopkins researchers about a widely used antiviral therapy for hepatitis B liver infections have prompted swift treatment revisions by the drug's maker and governmental agencies.

Findings by a team of Hopkins infectious disease specialists, to be published in the latest issue of The New England Journal of Medicine online June 21, showed that entecavir should not be used on its own in patients co-infected with HIV. Use of the drug led to cross-resistance to certain antiviral drugs used to treat the AIDS virus.

As a result of the study's initial presentation in February at the 2007 Conference on Retroviruses and Opportunistic Infections (CROI), Bristol-Myers Squibb, the drug's manufacturer, changed its product labeling to warn of the potential for HIV drug resistance, notified prescribing physicians and informed the U.S. Food and Drug Administration. The U.S. Department of Health and Human Services (HHS) also revised its treatment guidelines. HHS now recommends against using entecavir, better known by its brand name Baraclude, as the first option in treating hepatitis B in co-infected patients who are not already using drugs to suppress HIV.

"Many co-infected patients and their physicians are justifiably concerned about whether or not to use the drug," says senior study author Chloe Thio, M.D. She notes that more than 4 million people worldwide are believed to be infected with both viruses.

"Patients contending with both diseases should consult with their physician to see if entecavir is the right drug to treat their hepatitis B in the first place, because the drug still works against the liver disease, or if they should refrain from taking it because of the potential for HIV drug resistance," says Thio, an associate professor of medicine at The Johns Hopkins University School of Medicine.

Hepatitis B infection attacks the liver and can lead to cirrhosis, liver cancer or even death from liver failure.

"Co-infected patients already on entecavir should consult with their physician before stopping therapy and about having blood testing done to monitor for any signs of drug resistance that could potentially compromise subsequent anti-HIV therapy," she says.

In the published study, researchers documented three cases of co-infected patients from Baltimore and San Diego who were only on entecavir therapy, yet also had decreased amounts of HIV in their blood, an indication that the drug could possibly be having some impact on their HIV disease. Detailed blood analysis of two patients showed that entecavir was interfering with HIV replication and confirmed that one patient had developed the so-called M184V mutation in HIV. This mutation is known to prevent two key drugs used to fight the immune-system disease from working. Anti-HIV drugs compromised by the mutation include lamivudine, better known as 3TC, and emtricitabine.

Since the results were presented at CROI, researchers have substantiated their findings with several more cases from across the United States, including some patients whose blood has tested positive for the presence of the M184V.

Researchers say their next step is to better understand the mechanism by which entecavir interferes with the enzyme, called reverse transcriptase, which is involved in viral replication. Their goal is to better understand how drug resistance develops, including the M184V mutation. They also plan to look for evidence of any other HIV mutations.