New risk with hepatitis B drug

The most powerful drug used to treat hepatitis B (HBV) can lead to the emergence of drug resistant HIV in persons who are co-infected with both viruses under certain circumstances. The news was one of the more troubling things to emerge from the 14th retroviral conference, held last month in Los Angeles.

The drug is entecavir (Baraclude), which was approved by the Food and Drug Administration in March 2005 and quickly became the drug of choice in treating HBV. It strongly suppresses the virus and leads to a greater portion of patients being “cured;” they can stop therapy. Baraclude is made by Bristol-Myers Squibb.

More amazingly, for those who continued to use it, after three years, not a single case of HBV resistance to the drug has emerged in an ongoing study in patients who first started treatment with entecavir. Only a small portion of those who first started on other HBV drugs, became resistant to them, and switched to entecavir have seen resistance emerge.

Entecavir had been thought to have no activity against HIV. However, Johns Hopkins University researcher Dr. Chloe Thio was intrigued by the cases of two co-infected patients who began treatment for HBV. Their HIV viral load was sufficiently low and their CD4 count sufficiently high that they were not on highly active antiretroviral therapy, or HAART.

When they started entecavir, not only did their HBV viral load drop, their HIV viral load also dropped, by about one log. 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 causation 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 have 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 that 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.

Dr. Robert “Chip” Schooley of the 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 co-infected with HIV. This changes that,” Schooley said.

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 co-infected patients have only been conducted in patients who also were on HAART.

Two matters complicate the understanding of this issue. The first is that the number of HIV/HBV co-infected 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.”

Taken From : www.ebar.com