Thursday, July 4, 2013

Hepatitis C Triple Therapy Scores in Large Clinical Trial

Infectious disease special edition

Hepatitis C Triple Therapy Scores in Large Clinical Trial

by Christina Frangou

Patients with the most prevalent type of hepatitis C virus (HCV) infection have a substantially higher likelihood of achieving a sustained virologic response (SVR) with a triple therapy that includes an HCV protease inhibitor, a recent report confirmed. The findings validate triple therapy as the first-line treatment for genotype 1 hepatitis C (Ann Intern Med 2013;158:114-123).

Donald M. Jensen, MD, a professor of medicine and the director of the Center for Liver Diseases at the University of Chicago Medicine, said that the Annals study confirms previous research and an FDA review. “Triple therapy with a protease inhibitor is the current standard of care,” Dr. Jensen said.

After the drugs were approved in 2011, triple therapy quickly became the general practice in urban centers throughout the United States and the regimen has been adopted slowly as standard treatment throughout the rest of the country, added Paul Pockros, MD, the director, Center for Liver Diseases, Scripps Clinic, San Diego. “I think [triple therapy] is widely adopted now,” said Dr. Pockros, who was not involved in the study.

In the report, lead author Roger Chou, MD, from the Division of General Internal Medicine and Geriatrics at Oregon Health & Science University, in Portland, and his colleagues assessed 379 studies identified by searching multiple databases dating between 1947 and August 2012. Their analysis revealed that, for HCV genotype 1 infection, “fair-quality trials” demonstrated that triple therapy with pegylated interferon (PEG-IFN), ribavirin and either boceprevir or telaprevir increases the likelihood for achieving SVR by between 22% and 31% compared with dual therapy not including a protease inhibitor.

Triple therapy for HCV genotype 1 infection also was associated with a shorter duration of treatment, “an important consideration given the high frequency of adverse effects associated with interferon-based therapy,” the authors said.

Their findings also confirm the well-documented increase in adverse events (AEs) for triple-therapy regimens. Compared with dual therapy, triple therapy including boceprevir was associated with a greater risk for hematologic AEs, and triple therapy including telaprevir was linked to higher rates of anemia and rash.

The authors said their findings have important implications for treatment as well as screening because “screening benefits depend in part on the effectiveness of available treatments.”


Further reviewing the trial results, the investigators reported that no study in the past 70 years has focused on long-term clinical outcomes after treatment. Instead, studies rely on SVR as the primary outcome measure. The authors said that it is difficult to evaluate long-term clinical outcomes other than SVR because HCV infections develop over many years.”

50% Mortality Risk Reduction

However, the authors said evidence suggested that SVR is associated with a lower risk for all-cause mortality. The strongest evidence comes from a cohort study published in 2011 that showed SVR was associated with a 30% to 50% reduction in mortality risk, after adjusting for confounders (Clin Gastroenterol Hepatol 2011;9:509-516). Dr. Chou and his colleagues said the study provides “strong evidence” that virologic and clinical outcomes are linked.

That may be the most important finding in the report, commented Andrew J. Muir, MD, MHS, the clinical director of hepatology, Department of Medicine at Duke University in Durham, N.C. “This has been an area of controversy in the field for a number of years,” Dr. Muir said. “With the slow natural history of hepatitis C, it was difficult to demonstrate the benefits in accepted clinical outcomes. The lack of clear clinical benefit also kept some [practitioners] from accepting the value of hepatitis C treatment.”

The investigators also reported that dual therapy with PEG-IFN alfa-2b was associated with a reduced rate of SVR by about 8% compared with PEG-IFN alfa-2a. However, PEG-IFN alfa-2b was associated with a lower risk for serious AEs, “suggesting potential trade-offs between benefits and harms,” said the authors. For patients with HCV genotype 2 or 3 infection, dual therapy for 12 to 16 weeks was associated with a lower likelihood for achieving SVR than was therapy for 24 weeks, and lower doses of PEG-IFN alfa-2b were less effective than standard doses, according to evidence from two to four fair-quality trials.

Across all regimens, absolute SVR rates were lower in older patients, black patients, patients with more advanced fibrosis and patients with higher viral load, the researchers noted.

The study was supported by the Agency for Healthcare Research and Quality. The authors reported no relevant conflicts of interest.

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