Treating hepatitis B patients with the drug Baraclude® (entecavir) can cause those who are also infected with HIV to become resistant to two vital HIV drugs, according to a new report in the New England Journal of Medicine.
In a brief report published in the June 21 issue of the Journal, Chloe Thio, MD, and Robert Silicano, MD, of Johns Hopkins University School of Medicine and colleagues reported a patient infected with both hepatitis B and HIV who was treated with Baraclude and subsequently developed a strain of HIV that is resistant to the antiretrovirals lamivudine (branded as Epivir® and also used in Combivir® and Trizivir®) and emtricitabine (branded as Emtriva® and also used in Truvada® and Atripla®).
The group's initial report, presented at the 14th Conference on Retroviruses and Opportunistic Infections, prompted Bristol-Myers Squibb – the manufacturer of Baraclude – to change its product labeling to warn of the potential for HIV drug resistance. The United States Department of Health and Human Services now recommends against using Baraclude as the first option in treating hepatitis B in coinfected patients who are not already using drugs to suppress HIV.
The researchers emphasized that finding drug resistance in this setting underscores the need to test all antiviral drugs for possible activity against HIV before they are approved for use.
Baraclude is a chemically altered version of a chemical called a nucleoside. The drug blocks viral replication by plugging itself into a polymerase enzyme in the hepatitis B virus that helps produce new viral DNA. However, the hepatitis B polymerase closely resembles the reverse transcriptase enzyme that HIV uses to copy its genome inside an infected cell. Thus, there was a possibility that treating co-infected patients for hepatitis B with Baraclude might also have an effect on HIV.
Earlier tests by Bristol-Myers Squibb using techniques available at the time did not detect such an effect on HIV. However, Dr. Thio and co-authors Robert Hegarty, MD, and Braden Hale, MD, of the Naval Medical Center in San Diego recently identified three HIV/HBV-coinfected patients in whom Baraclude treatment did inhibit HIV replication.
Dr. Siliciano's group analyzed Baraclude's effects on HIV using a more sensitive test they had developed to measure inhibition of HIV replication. Consequently, they found that Baraclude does inhibit HIV's reverse transcriptase. They also reported that one of the patients treated with Baraclude developed a mutant form of HIV containing the M184V mutation in its reverse transcriptase gene, thereby rendering the virus highly resistant to lamivudine and emtricitabine.
The finding offers a broader lesson for drug development, explained Dr. Siliciano. "I think we need very careful screening of new antiviral agents that have activity against other viruses to make sure that they are not doing the same thing; that is, selecting for HIV resistance," he said.
Source:
McMahon MA, Jilek BL, Brennan TP, et al. The HBV drug entecavir – effects on HIV-1 replication and resistance. N Engl J Med 356:2614-21, 2007.
