As the rapidly evolving field of hepatitis C virus (HCV) treatment progresses, clinicians can look to an expanding array of clinical trials to guide and individualize treatment decisions.
As the rapidly evolving field of hepatitis C virus (HCV) treatment progresses, clinicians can look to an expanding array of clinical trials to guide and individualize treatment decisions. K. Rajendar Reddy, MD, professor of medicine and medicine in surgery and director of hepatology at the University of Pennsylvania outlined the brief but busy history of clinical trials of one DAA, sofosbuvir, to a packed auditorium at The Liver Meeting 2014.
The discussion began with a review of drug classes and actions. DAAs for HCV, Reddy explained, fall into one of three broad categories, with a naming system that identifies the category. The protease inhibitors, such as simeprevir, all end in “previr;” polymerase inhibitors such as sofosbuvir have the “buvir” ending, while NS5A protein inhibitors such as daclatasvir end with “asvir.”
Examining the efficacy and safety of adding the polymerase inhibitor sofosbuvir to the previously accepted regime of RBV + pegylated interferon (PEG), the NEUTRINO study examined a treatment duration shortened from 24 to 12 weeks for treatment-naïve patients with HCV genotype (GT) 1 and GT4. Sustained virologic response at 12 weeks (SVR12) exceeded 90 percent for most treatment groups; further, the study produced a higher response for individuals with cirrhosis and for African Americans (>80 percent for each) than had previously been seen.
The POSITRON study examined an all-oral regime of sofosbuvir + RBV for 12 weeks in HCV positive GT2 and GT3 individuals who were ineligible for or intolerant to interferon, or who were unwilling to take it (most reasons of ineligibility were related to history of psychiatric disease). The GT2 group did well, with SVR12 rates over 90 percent for individuals with and without cirrhosis. The GT3 non-cirrhotic patients had an SVR12 rate of just 68 percent, while those with GT3 and cirrhosis saw just 21 percent reach SVR12.
The FUSION study addressed sofosbuvir-based treatment for HCV GT2 and GT3 individuals who had been prior null responders to treatment, and compared 12 to 16 weeks of treatment with sofosbuvir + RBV for this group. Overall, the GT2 group fared similarly with 12 vs. 16 weeks of treatment, with SVR12 rates for both treatment arms over 80 percent. Just 30 percent of GT3 patients reached SVR12 with 12 weeks of treatment, but 16 weeks increased that figure to 62 percent.
FISSION was a study directly comparing a 12-week course of the all-oral sofosbuvir + RBV regime to 24 weeks of the PEG+RBV standard of care for treatment-naïve GT2 and GT3 patients. This study saw overall similar performance between the two treatment courses for GT3 patients, but GT2 patients fared slightly better with the sofosbuvir + RBV regime.
The VALENCE trial extended the duration of sofosbuvir + RBV treatment to 24 weeks for both treatment naïve and treatment-experienced GT3 patients, and saw SVR12 rates of about 90 percent for the treatment-naive group, including those with cirrhosis. SVR12 for treatment-experienced GT 3 patients was lower, but still exceeded 80 percent for those without and 60 percent for those with cirrhosis.
A small group of GT2 and GT3 patients who had failed treatment with PEG/RBV were trialed on 12 weeks of sofosbuvir + PEG/RBV in the LONESTAR-2 trial. About half of patients had cirrhosis. Over 80 percent of this group achieved SVR12, regardless of cirrhosis status.
Moving to studies that use DAA combinations, Reddy discussed the design of COSMOS, which used sofosbuvir and simeprevir with and without RBV in HCV GT1, for durations of 12 and 24 weeks. Cohorts included prior null responders and treatment-naïve individuals; cohorts were also stratified by disease severity. A uniformly high SVR12 rate ranging from about 80 percent to 100 percent was seen for all treatment arms. COSMOS, said Reddy, represented a good proof-of-concept study of addition of a protease inhibitor demonstrating a high response rate.
Daclatasvir in combination with sofosbuvir has shown high SVR12 rates in GTs 1, 2 and 3; however, daclatasvir is not available in the United States.
The ION studies examine the combination of lepidasvir + sofosbuvir with and without RBV for 12 and 24 weeks in treatment-naïve GT1 patients. SVR12 rates were between 90 percent and 100 percent in all treatment arms when those with and without cirrhosis were pooled. However, for the difficult-to-treat group of treatment-experienced patients with cirrhosis, SVR12 rates climbed dramatically with 24 vs. 12 weeks of treatment. For this group, SVR12 went from 86 percent with the two-drug regime and 82 percent with the addition of ribavirin at 12 weeks of therapy to 100 percent of both treatment groups achieving SVR12 with 24 weeks of therapy.