A Better Way to Unbind Prometheus? Boceprevir for the Treatment of Chronic Hepatitis C Infection

Published - Written by John Staples

(copyright 2006, Scott Eaton)

What do Mickey Mantle, Evel Knievel, and Pamela Anderson have in common? Infamy, certainly, but all three are also reported to have battled chronic hepatitis C virus (HCV) infection. And they aren’t alone: Including a sizable list of celebrities, it is estimated that 160 million people worldwide have the disease, putting them at risk of hepatic cirrhosis, hepatocellular carcinoma, and death. Current treatments with peginterferon plus ribavirin are poorly tolerated and result in sustained virologic response (SVR) rates below 50% in HCV genotype 1 infection. Some patients feel like the mythical Prometheus, their hands bound as they helplessly watch the virus ravage their liver day after day. Can anything more reliably loosen these chains?

Two randomized, double-blind, multi-center trials published in this week’s NEJM suggest there is significant cause for hope. They examine boceprevir, an oral HCV-protease inhibitor, and its effect on SVR in two distinct populations of patients infected with HCV genotype 1.

HCV_prevalence_1999In the first trial, the SPRINT-2 Investigators enrolled 938 non-black and 159 black adult patients with previously untreated HCV genotype 1 infection (blacks and non-black cohorts were enrolled and analyzed separately as blacks are known to have a much lower response rate to standard therapy). After undergoing a 4-week lead-in with peginterferon alfa-2b plus ribavirin, patients were randomized to one of the following groups:

1) Peginterferon/ribavirin/placebo for 44 weeks (“standard therapy”)

2) Peginterferon/ribavirin/boceprevir for 24 weeks, with an additional 20 weeks of peginterferon/ribavirin/placebo if HCV RNA was detected between weeks 8 and 24 (“response-guided therapy”)

3) Peginterferon/ribavirin/boceprevir for 44 weeks (“48-week therapy”)

The results on the primary outcome were encouraging: For both black and non-black cohorts, SVR measured 24 weeks after completion of therapy were significantly better for the arms that included boceprevir than with standard therapy (see Table). Adverse events were reported in greater than 98% of subjects in each arm, with anemia prompting erythropoietin use occurring in 43% of boceprevir recipients and in 24% of standard therapy recipients.

In the second trial, the HCV RESPOND-2 enrolled 403 subjects with HCV genotype 1 infection that had not responded to or had relapsed after prior treatment with standard peginterferon/ribavirin therapy. Subjects were randomized to three arms very similar to those described for SPRINT-2: Standard therapy, response-guided therapy (here after 32-weeks of triple therapy), or 48-week therapy. On the primary endpoint, subjects receiving boceprevir (i.e. those in the response-guided and 48-week therapy arms) again had significantly higher rates of SVR measured at 24 weeks after completion of therapy (see Table). Just as in SPRINT-2, adverse events were common in all groups, and anemia prompting erythropoietin administration occurred about twice as often in those receiving boceprevir.

In an accompanying editorial, Dr. Donald Jensen of the University of Chicago reflects on the dawning of an exciting new era in HCV therapy, citing the recent publication of trials studying boceprevir (SPRINT-2 and HCV RESPOND-2) and telapravir (PROVE1 and PROVE3), another orally-available HCV protease inhibitor. However, he points out that the “major advance” of HCV protease inhibitors comes at a cost of logistical complexity, and that boceprevir does not address non-genotype 1 HCV infection.

“The ultimate goal for HCV treatment is a therapy that is simple, perfectly effective, has no adverse effects, and is accessible to the populations that HCV affects,” says NEJM deputy editor Dr. Mary Beth Hamel. “Although we’re a long way from that goal, the new data on HCV protease inhibitors is a substantial step toward greater efficacy.”

While HCV protease inhibitors don’t fully accomplish the Herculean feats of ideal HCV treatment, they’re likely to soon help break the Promethean chains of a significant number of patients. And that should be a cause for celebration – for celebrities and non-celebrities alike.