CROI 2007: Another Report of Drug-resistant HIV in a Patient Treated with Entecavir (Baraclude) for Hepatitis B

At the 14th Conference on Retroviruses and Opportunistic Infections (CROI) in February 2007, researchers reported that the hepatitis B drug entecavir (Baraclude) is also active against HIV, and can select for the M184V mutation that confers resistance to the antiretroviral drugs lamivudine (3TC; Epivir) and emtricitabine (Emtriva).

Entecavir had previously been recommended for use by HIV-HBV coinfected patients who did not yet require antiretroviral therapy, since most drugs approved or under study for the treatment of chronic hepatitis B demonstrate activity against both HBV and HIV, and using these dually-active agents alone to treat HBV could select for drug-resistant HIV.

Detailed reports of 3 HIV-HBV coinfected patients taking entecavir who experienced HIV viral load decreases suggestive of anti-HIV activity were published in the June 21, 007 issue of the New England Journal of Medicine.

Based on these findings, U.S. federal HIV treatment guidelines were modified to recommend that all HIV-HBV coinfected individuals who require treatment for HBV should receive a combination antiretroviral regimen that includes agents active against both HIV and HBV.

Now, as reported in the May 1, 2008 advance online edition of Clinical Infectious Diseases, Danish researchers have identified the emergence of the M184V resistance mutation in an antiretroviral-naive HIV-HBV coinfected individual after 26 weeks on entecavir

The 66-year-old man tested positive for hepatitis B in 1985 and for HIV in 1994. From 1997 through 2006, his CD4 cell count remained high and his HIV viral load remained stable, so he did not require antiretroviral therapy. Although a biopsy in 1986 showed only minor liver damage, he developed cirrhosis by 2002. At that point, he started adefovir (Hepsera) to treat HBV. In late 2005, his HBV DNA rose, indicating emergence of adefovir resistance, and in late 2006 he added entecavir (since he still did not require HAART). His HBV DNA was then suppressed to an undetectable level and his HIV RNA level also fell.

After the findings about the anti-HIV activity of entecavir were presented at CROI, the Danish team performed genotypic testing and found that their patient harbored HIV carrying the M184V mutation. By looking at stored serum samples, they determined that HIV with the M184V mutation rapidly emerged after entecavir was initiated and dominated the virus population after only 6 months.

This case differed from those previously reported in that this patient was previously untreated with antiretroviral therapy, and therefore developed a new mutation while taking entecavir. The earlier patients, by contrast, had a history of prior use of lamivudine before starting entecavir, and thus resistance might have been attributable to re-emergence of an "archived" mutation.

Based on their findings, the report authors confirmed the recommendation that "entecavir should only be used for coinfected patients who simultaneously receive suppressive therapy against HIV infection."



MR Jakobsen, H Arildsen, HB Krarup, and others. Entecavir Therapy Induces de Novo HIV Reverse-Transcriptase M184V Mutation in an Antiretroviral Therapy-Naive Patient. Clinical Infectious Diseases 46: e88-e91. May 1, 2008 [Epub ahead of print].

MA McMahon, BL Jilek, TP Brennan, and others. The HBV Drug Entecavir - Effects on HIV-1 Replication and Resistance. New England Journal of Medicine 356(25): 2614-2621. June 21, 2007.