HONOLULU — The future of chronic hepatitis B therapy will look much like HIV treatment today: multidrug combinations aimed at thwarting development of resistant viral strains, Dr. Paul J. Pockros predicted at the annual meeting of the American College of Gastroenterology.
“All of us in gastroenterology are going to have to deal with antiviral resistance. I think we're headed this way both for hepatitis B and hepatitis C. We're going to be akin to the HIV doctors. There are 21 HIV drugs available, and their resistance profiles dictate how they're used, with drugs in different classes being used together. And that's really what many of us have started doing in dealing with hepatitis B,” said Dr. Pockros, head of the division of gastroenterology/hepatology at the Scripps Clinic in La Jolla, Calif.
One of the major lessons hepatologists have learned from the HIV treatment experience is that sequential antiviral monotherapy is not the way to go. It results in creation of drug-resistant strains that can be transmitted to other individuals. That lesson was strikingly brought home by the experience with lamivudine, a nucleoside analog that was the first oral antiviral agent approved for chronic hepatitis B.
When lamivudine (Epivir) received marketing approval in 1998, it was quickly adopted as a first-line therapy because it is orally administered and has far fewer side effects than subcutaneous interferon-alfa-2b (Intron-A), then the only other treatment option.
Unfortunately, as the years went by, the full scope of the lamivudine resistance problem became apparent. After 1 year, 20% of treated patients developed viral resistance to the drug. After 2 years, it was 38%. After 3 years, 49%. And after 4 years on lamivudine, 67% of treated patients had resistant virus. The clinical consequences include rebound of serum hepatitis B DNA, a reduced seroconversion rate, elevated serum liver enzymes, and reversal of histologic improvement.
Viral resistance has been much less of a problem with the two oral antiviral agents approved since lamivudine. The rate of resistance after 4 years on adefovir dipivoxil (Hepsera) monotherapy is 18%. The resistance rate after 1 year on the nucleoside analog entecavir (Baraclude) is 0% in lamivudine-naive patients and 7% in lamivudine-resistant individuals.
“My own view is that lamivudine will drop out of the picture because we have a better nucleoside analog now. It's not cheaper, but it's certainly better in its efficacy, and it causes less resistance,” said Dr. Pockros, who is on the speaker's bureaus for Gilead Corp., Bristol-Myers Squibb Co., Idenix Corp., and Roche.
With the 2005 marketing approval of pegylated interferon-alfa-2a, physicians can now choose from five agents for the treatment of hepatitis B. Many more are in the developmental pipeline.
“I think we'll end up with 10 drugs for hepatitis B, possibly even more, and we'll use combination therapy—either a combination of a nucleoside and a nucleotide analog, like adefovir and lamivudine, to minimize resistance, or a combination of one of those drugs and pegylated interferon,” he predicted.
Four drugs are in or have completed phase III clinical trials for hepatitis B. Two—emtricitabine (Emtriva) and tenofovir (Viread)—are already marketed for HIV. The others are the nucleotide analog telbivudine and pegylated interferon-alfa-2b. In addition, at least 11 agents are in phase II trials.
American patients and physicians clearly prefer oral therapy even though the approved agents must often be prescribed indefinitely, but in Europe, pegylated interferon-alfa-2a has become the leading first-line hepatitis B therapy.
'I think we'll end up with 10 drugs for hepatitis B, possibly even more, and we'll use combination therapy.' DR. POCKROS