A Promising First Step for Combination Oral Therapy Against HCV

In a short-term study, use of a protease inhibitor and a polymerase inhibitor together rapidly lowered HCV RNA levels.

Oral hepatitis C virus (HCV) protease inhibitors are expected to be approved in 2011. Adding these agents to standard HCV treatment (peginterferon plus ribavirin) improves the likelihood of sustained virologic response, but the interferon component must be given subcutaneously and has substantial side effects. In the industry-funded INFORM-1 study, researchers explored whether an interferon-free regimen containing two new oral anti-HCV agents — the protease inhibitor danoprevir, plus the nucleoside polymerase inhibitor RG7128 — could successfully suppress HCV replication.

Patients with chronic HCV genotype 1 infection but not cirrhosis or HIV infection were randomly assigned to receive placebo (n=14) or one of six different doses of danoprevir plus RG7128 (n=74) for 13 days. Treatment was directly observed in a clinical research unit.

At day 14, patients who received danoprevir plus RG7128 had marked declines in HCV RNA, with the median reduction ranging from 3.7 to 5.2 log10 IU/mL in the different dose groups; some patients achieved undetectable HCV RNA levels. At the highest doses tested, reductions in viral load were similar between patients who were treatment naive and those who had not responded to previous standard-of-care treatment. No phenotypic drug resistance was detected, although one patient with viral rebound did have a clone containing a danoprevir-resistance mutation.

Comment: This study shows that a combination of two oral investigational agents effectively suppresses HCV replication, at least in the short term. There has been an explosion of new direct-acting anti-HCV agents, and promising trial results were reported for many of them at the Liver Meeting this month in Boston. If longer-term studies show that combination therapy with new oral agents can eliminate viral replication, we may be able to cure HCV with pills alone. As an editorialist notes, we are "on the eve of a new era in HCV treatment."

— Rajesh T. Gandhi, MD

Published in Journal Watch Infectious Diseases November 17, 2010

Citation(s):

Gane EJ et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): A randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 2010 Oct 30; 376:1467.
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Thomas DL. Curing hepatitis C with pills: A step toward global control. Lancet 2010 Oct 30; 376:1441.
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