Troubling news from the 2007 Conference on Retroviruses and Opportunistic Infections: The most powerful drug used to treat hepatitis B (HBV) can lead to the emergence of drug-resistant HIV in people infected with both viruses, under certain circumstances.

The drug is entecavir (Baraclude), which the Federal Drug Administration (FDA) approved in March 2005, and which quickly became the drug of choice in treating HBV because it strongly suppresses the virus and leads to a greater number of patients being “cured;” in other words, they can stop therapy.

Equally amazing is that, according to an ongoing study of patients treated with entecavir, not a single case of HBV resistance emerged in those who continued to use it for at least three years. Resistance only emerged in the portion of patients who first used other HBV drugs, became resistant to them and switched to entecavir.

Until recently, it was thought that entecavir had no affect on HIV. However, Johns Hopkins University researcher Chloe Thio, M.D., was intrigued by the cases of two patients infected with both HBV and HIV who began using entecavir to treat their HBV. The patients were not on highly active antiretroviral therapy (HAART) because their HIV viral load was sufficiently low and their CD4 count sufficiently high.

When they started entecavir, not only did their HBV viral load drop, their HIV viral load also dropped, by about one log. But then, after a period of time, their HIV viral load began to creep back up, a pattern often seen with the emergence of viral resistance to therapy. Thio suspected an underlying cause and went looking for it.

Using cell cultures and new ultra-sensitive tests in the lab, Thio was able to demonstrate that entecavir did in fact show activity against HIV. Not surprisingly, HIV quickly developed resistance to this monotherapy.

“In one patient that we studied in depth, [the drug] selected for the M184V mutation confers resistance to lamivudine and emtricitabine, making them ineffective for treating HIV,” she said. The resistance point also impacts use of the combination drugs Combivir, Truvada and Atripla.

During the question portion of the session, Bristol-Myers Squibb vice president Rich Colonno, Ph.D., said, “We have studied this drug for over 10 years, we have assayed it against HIV probably thousands of times now…. The only time we can see any activity is when we use extremely low viral inoculates.” Those results were at the sub-micromolar level and were not reproducible.

Robert “Chip” Schooley, M.D., University of California, San Diego, called Thio’s finding “very significant. The thought had been that it was safe to use to treat HBV in patients that are coinfected with HIV. This changes that.”

The company and the FDA have changed the label of entecavir to take note of these incidents and that clinical trials of entecavir in HIV/HBV coinfected patients have only been conducted in patients who also were on HAART.

Two matters complicate our understanding of this issue. The first is that the number of HIV/HBV coinfected patients is relatively small, and the portion that requires treatment for HBV but not HIV is smaller still. The drop in HIV viral load does not have any noticeable clinical signs in these patients, so the only way to identify it is by monitoring HIV viral load at the appropriate times to catch the decline before it rebounds back to the initial baseline.

The fact that Thio made the initial association from single patients in San Diego and Baltimore suggests the difficulty in studying this in patients.

The scientific question “remains contentious and unresolved,” as does the frequency with which it occurs, said Jules Levin, executive director of the community-based National AIDS Treatment Advocacy Project. “It is important to resolve them quickly because entecavir is an important option for treating hepatitis B.”