Published in Journal Watch Gastroenterology January 2, 2013
Several regimens with polymerase or protease inhibitors plus ribavirin achieved high sustained virologic response rates without interferon.
A major drawback of current therapies for chronic hepatitis C virus (HCV) infection is poor tolerability of adverse effects, mainly caused by peginterferon. Previous studies of interferon-free HCV regimens were early phase trials (JW Gastroenterol Jan 18 2012 and JW Gastroenterol Sep 30 2011); now results are available from two industry-sponsored, open-label, phase 2a trials in patients with HCV genotypes 1, 2, and 3.
In the first study, investigators randomized 40 treatment-naive patients with genotype 2 or 3 in a 1:1:1:1 ratio to four groups, all of which received sofosbuvir — an oral nucleotide HCV polymerase inhibitor — (400 mg daily) and ribavirin (1000–1200 mg daily) for 12 weeks. Three groups also received peginterferon (180 µg weekly) for 4, 8, and 12 weeks, respectively. Subsequently added study groups included the following: 10 patients with genotypes 2 or 3 who received sofosbuvir monotherapy for 12 weeks; 10 patients with genotypes 2 or 3 who received sofosbuvir, ribavirin, and peginterferon for 8 weeks; and 25 genotype 1, treatment-naive patients and 10 genotype 1 null responders to previous peginterferon/ribavirin treatment who received sofosbuvir and ribavirin for 12 weeks. The primary end point of sustained virologic response at 24 weeks post-therapy was achieved by all 40 patients who received sofosbuvir plus ribavirin with or without peginterferon, 6 of the 10 patients who received sofosbuvir monotherapy, 21 of the 25 genotype 1, treatment-naive patients who received sofosbuvir and ribavirin, and only 1 of the 10 genotype 1, treatment-experienced patients who received sofosbuvir and ribavirin. No mutations were observed in the other 9 patients. Adverse effects were mild.
In the second study, investigators sequentially enrolled patients with HCV genotype 1. All patients received ABT-333 — a nonnucleoside NS5B polymerase inhibitor — (400 mg twice daily), ribavirin (1000–1200 mg daily), and one of two daily doses of ABT-450/r (ABT-450, an NS3 protease inhibitor, combined with 100 mg of ritonavir daily) for 12 weeks. Groups of 19 and 14 treatment-naive patients received 250 mg and 150 mg of ABT-450/r, respectively, and a third group of 17 treatment-experienced patients received 150 mg of ABT-450/r. The primary end point was extended rapid virologic response (undetectable HCV RNA from weeks 4 through 12), which was achieved in 89%, 79%, and 59% of the three groups, respectively. Sustained virologic response was achieved in 95%, 93%, and 47%, respectively. Resistant variants in NS3 and NS5B were observed in 8 of the 9 patients who had virologic failure in group three. Side effects were mild.
Comment: These findings suggest that we are close to realizing the ideal HCV treatment — an interferon-free, simple regimen of short duration with minimal adverse effects and low resistance rates. Patients with genotypes 2 or 3 and treatment-naive patients with genotype 1 will be the first to benefit. Ribavirin seems to be here to stay, at least for now. Unfortunately, difficult-to-treat patients such as genotype 1, treatment-experienced patients will likely continue to require interferon as part of their regimens.
Gane EJ et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013 Jan 3; 368:34.
Poordad F. Exploratory study of oral combination antiviral therapy for hepatitis. N Engl J Med 2013 Jan 3; 368:45.