Abstract & Commentary

Triple Therapy for Hepatitis C — Boceprevir vs. Telaprevir

By Alan D. Tice, MD, FACP, Infectious Disease Consultants, John A. Burns School of Medicine, University of Hawaii, Honolulu, is Associate Editor for Infectious Disease Alert.

Dr. Tice reports no financial relationship to this field of study.

Synopsis: These two new direct-acting antivirals bring a new dimension to the therapy of hepatitis C. Both are protease inhibitors that nearly double the sustained viral response rate at 6 months after therapy that is added to a standard regimen. The adverse effects are somewhat different and will compound the problems and management encountered with the usual pegylated interferon and ribavirin course — and at considerable added expense. Both are oral medications but with the prospect of developing resistance. It is hoped that these new drugs will help lead to a transition to safe and effective oral therapy.

Sources: Fred Poordad; and the SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1195-1206; Bacon BR; and the HCV RESPOND-2 Investigators. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1207-1217.

The April 14 issue of the New England Journal of Medicine contains two articles on boceprevir, a new designer molecule that has demonstrated a dramatic improvement in outcomes for patients with genotype 1 hepatitis C. It is a protease inhibitor that binds reversibly to the non-structural 3 (NS3) site. It was given orally three times daily together with standard pegylated interferon (alpha 2b from Merck) and ribavirin to avoid the development of resistance, which occurs rapidly with monotherapy. It was not started until 4 weeks after standard therapy.

Poordad and collaborators treated more than 1,000 people with genotype 1 infection who had not been previously treated before and found sustained viral response (SVR) rates for non-blacks of 67% after 24 weeks of therapy and 68% for those treated for 44 weeks compared with a 40% response of controls. Blacks were separately studied and found to have SVR rates of 42% and 53% compared with controls of 23%.

Bacon and others from a large clinical trials group treated 403 patients who had failed prior interferon-based treatment. Boceprevir boosted the SVR rate from controls on standard pegylated interferon and ribavirin therapy from 20% to 59% for those receiving 32 weeks and 66% for 44 weeks of therapy. The speed with which the RNA viral load can be brought down is also a consistent indicator of success, especially when it is undetectable at 4 weeks. Rates of early discontinuation of therapy were comparable to standard therapy. The major adverse effect was anemia that occurred in 21% (vs. 13% of controls).

Commentary

The therapy for chronic hepatitis C infection has long been a difficult one: 48 weeks of pegylated interferon and ribavirin with many associated serious adverse effects, with less than half a chance of eliminating the virus, as indicated by SVR 6 months following the last dose. There have been incremental improvements with the addition of ribavirin to interferon, then pegylated interferon; however, failure rates remain high (> 50%) and serious side effects over 48 weeks of therapy are common with this combination.

On May 12, FDA approved boceprevir for the treatment of chronic hepatitis C virus genotype-1 infection combined with peginterferon alfa and ribavirin in adult patients with compensated liver disease previously untreated or who have failed previous therapy. It is believed by many that telepravir will soon also receive approval. Whether the response rates are really better with one drug vs. another is not clear and there are no head-to-head studies pending.

Which one of the two HCV protease inhibitors is better is not clear, but the adverse effects are different — a serious rash with telaprevir and anemia with boceprevir. The pill burdens are also different with twice daily dosing of 6 pills with telapravir and three times daily dosing of 12 pills with bocepravir.

Unfortunately, these new drugs carry a problem with resistance of apparent mutants that break through on therapy with rates of 5%-10%. The mutants can be characterized by amino acid sequencing, as opposed to interferon and ribavirin, which cannot be tested other than by clinical failure; we still do not understand their mechanism of action. The spectrum of mutants that can develop is not yet known, but it may lead to resistance testing and an increase in knowledge of the patterns as has evolved with HIV. Combinations of oral agents are already in clinical trials. Whether ribavirin or other agents will be able to suppress resistance is uncertain.

What happens when telaprevir and boceprevir are released to compete in the marketplace will be interesting to watch. A lot of money is at stake, with estimates of $10,000-$40,000 for the new drugs on top of $50,000-$70,000 for standard therapy. This is something payers will balk at and likely create lengthy and complex prior authorization requirements. Perhaps the costs and patient misery can be lessened by shorter courses of therapy.

These new antivirals offer a new approach to a problem that faces 3.2 million U.S. residents, even though the majority are not even aware they have this insidious virus circulating in their blood. With the economic incentives, many companies are designing and trialing other protease inhibitors, polymerase inhibitors, and other molecules for a better answer.

Let us hope the day will soon arrive when we can prescribe pills that are as effective against hepatitis C as are available for hepatitis B.