HCV therapy changes course

In May, the FDA approved two new drugs for the treatment of hepatitis C genotype 1 — the first major therapeutic advance in more than a decade. The medications, boceprevir (Victrelis) and telaprevir (Incivek), greatly increase the chance of clearing the virus in difficult-to-treat patients.

Clinical cure rates with standard therapies — pegylated interferon alfa-2a or alfa-2b plus ribavirin — are 40 to 50 percent. Adding either boceprevir or telaprevir to this regimen may raise sustained viral response rates up to 70 percent for most people with genotype 1 infection. That includes those who have never been treated as well as those who failed previous therapy. For select patients who respond quickly, the new triple regimen may also shorten treatment time from 48 to 24 weeks.

The HCV antiviral pipeline

Boceprevir and telaprevir are protease inhibitors and the first approved antivirals that directly target the life cycle of the hepatitis C virus, explains Hugo E. Vargas, M.D., Division of Hepatology chair at Mayo Clinic in Arizona. "Now that we better understand how the virus replicates, we can follow the HIV model and halt its growth by disrupting critical viral enzymatic functions."

He adds, "Right now, more than 40 new agents and regimens for treating hepatitis C are in various stages of development. Some are next-generation protease inhibitors. Others are polymerase inhibitors, which may make combination treatment more effective or even aid the transition away from interferon and perhaps ribavirin. Our group is currently testing six different compounds — newer generations of protease inhibitors as well as other agents that impair replication of the virus in novel ways. With the vast number of new drugs, the treatment course for hepatitis C will look very different in the next five to 10 years."

Dr. Vargas says Mayo researchers are especially interested in mixing and matching different antiviral mechanisms in order to arrive at three or four therapeutic modalities that will allow the virus to be cleared in the majority of patients. "Actually," he says, "We hope we can clear everyone."

Issues remain

At the same time, problems remain. One is the side effect profile of the new antiviral regimen, which can complicate treatment.

"Interferon and ribavirin therapy itself is difficult, causing flu-like symptoms, skin problems, irritability, occasionally depression, and anemia. The protease inhibitors add to red blood cell suppression, so anemia is much deeper in the first 12 weeks of triple therapy," Dr. Vargas explains.

Boceprevir alone can cause taste distortion, impaired appetite and unintended weight loss. A small percentage of patients taking telaprevir get a rash, though it usually isn't severe enough to stop treatment. Telaprevir is also associated with anal or rectal irritation and pain.

Even so, Dr. Vargas says treatment-experienced patients are willing to undertake the new therapy. "They know that the side effects will be worse, but are encouraged by the greater chance for a cure."

Another problem is drug resistance. Cross-resistance has already been noted between telaprevir and boceprevir. Dr. Vargas says diverse antiviral mechanisms are important because they provide different resistance profiles — one reason Mayo is investigating a wide range of new compounds. "We must have a full armamentarium to counter resistant strains," he notes.

The biggest challenge, though, is people who are especially difficult to treat — post-transplantation and dialysis patients, people with HIV coinfection, and those with psychiatric problems who cannot use interferon.

"There is no approved drug for treating most of these populations," Dr. Vargas says. "But so many compounds are under development; it's simply a matter of testing them in people who haven't been widely tested before. We are conducting a large number of clinical trials at Mayo Clinic, and I'm certain there will be new options for these patients in the future."

Future trends

Developments in hepatitis C therapy are unfolding at an unprecedented pace. Dr. Vargas recommends that people who are treatment naive or failed previous therapy consult with their doctors.

"Now isn't the time to wait," he says. "The search is on for agents that provide better tolerability, further increase cure rates and shorten duration of therapy as well as for all-oral regimens — even once-a-day antivirals that free patients from complicated dosing schedules. These will no doubt be found sooner than anyone thinks."

He also suggests that physicians grappling with the complexities of the new combination therapy contact Mayo Clinic. "We have been conducting clinical trials on direct-acting antivirals since the early days and are currently treating 70 patients with interferon, ribavirin and protease inhibitors. We understand how to make this therapy work and are happy to help others with innovative methods such as the Mayo Accelerated Viral Referral Clinic (MAVR)."