The development of direct acting antivirals has led to significant improvement in treatment outcomes for many patients with hepatitis C. New research has also improved management of treatment-related anemia, helped streamline standard therapy, and identified promising new approaches to interferon-free treatment.
The treatment landscape for hepatitis C has changed rapidly recently, and is poised to change even more profoundly in the next several years, according to Raymond Chung, MD, who provided an overview on recent progress and lessons from new clinical trials at The Liver Meeting, the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).
The advances have come through better understanding of the viral lifecycle, which has allowed development of a large number of new agents, collectively called “direct acting antivirals,” or DAAs. The first two approved agents, telaprevir and boceprevir, target the viral protease.
Their use has led to an approximately 30% improvement in SVR12 (sustained virologic response 12 weeks post-treatment) in patients with HCV genotype 1 infection, from 45% to 75%, said Chung, who is from Massachusetts General Hospital in Boston.
“This is now our ground-level standard ofcare. But this doesn't come without a cost,” with increases in adverse events, and an increase in the incidence of “relatively profound” anemias of approximately 40% between the two drugs. “There are certainly bumps in the road,” he said.
Neither does the benefit extend to all patient subgroups. Those who do best on the new therapies are those who have relapsed after a good response to ribavirin and peginterferon. Those with only a partial response to prior therapy do less well, and null responders, or those with advanced fibrosis or cirrhosis, do worst. “These are the neediest of our patients, but their response rates are as low as 15%,” he said.
Treatment practice is also being refined by better understanding of how to deal with the complication of anemia. A randomized, controlled trial comparing ribavirin dose reduction to erythropoietin therapy has shown that dose reduction is equally effective in treating anemia, with no loss of viral control. “Dose reduction had no adverse effect compared to erythropoietin, no sacrifice of efficacy. We think we've settled the issue on that particular question,” said Chung.
Progress has also come in simplifying current therapy for those patients with low viral loads and rapid response to standard therapy. Recent data supports the concept that standard double therapy may be adequate for these patients, rather than triple therapy. “On-treatment response in general supersedes baseline characteristics. That is to say, phenotype trumps genotype in terms of response,” said Chung.
However, he cautioned, real-world response rates to the new therapies may not match the high rates seen in clinical trials. Up to 21% of patients discontinue in clinical practice prior to week 12, and thus receive incomplete treatment. Chung said, “The on-the-ground experience doesn't mirror the clinical trials.”
Finally, he noted, there are a very large number of Phase II trials now reporting top-line results, showing that second-generation DAAs have high potential to offer all-oral therapy to most HCV patients. These interferon-free trials have showcased a large variety of individual agents, targeting one or another of the steps in viral replication. Many of the trials have combined a protease inhibitor with a nucleoside or non-nucleoside inhibitor of replication complexes NS5A and NS5B.
Key issues in evaluating these therapies over the coming years will include their drug interaction potential, the height of the barrier each poses for development of resistance, and their dosing and adverse effect profiles.
Chung said, “There has been an extraordinarily exciting menu of offerings” in this field, with a rich and growing pool of data on patient- and virus-specific effects from each compound. “Differential behavior appears to be the case.”