A 6-month course of the antiviral drug sofosbuvir plus low-dose ribavirin was effective against chronic hepatitis C type 1 in a phase II study predominantly involving patients who had unfavorable predictors of treatment response.
The combination therapy yielded sustained virologic response rates ranging from 48% to 68% in a study population with high prevalences of black race, HCV genotype 1a, advanced liver fibrosis, and obesity, said Dr. Anuoluwapo Osinusi of the National Institute of Allergy and Infectious Diseases, Bethesda, Md., and her associates.
Betty Partin/CDC
The combination therapy yielded sustained virologic response rates ranging from 48% to 68% in a study population with high prevalences of black race, HCV genotype 1a, advanced liver fibrosis, and obesity.
The findings of the small, single-center, open-label study, published online Aug. 27 in JAMA, "are preliminary in nature and require further evaluation in larger studies," the investigators noted.
Several recent studies have demonstrated that interferon-free drug regimens composed solely of directly acting antiviral agents can be effective against chronic HCV type 1, but patients who have certain unfavorable host and viral traits have been underrepresented in these studies.
Noting that it is crucial for such research to involve the "populations most affected by the disease," Dr. Osinusi and her colleagues assessed the safety and efficacy of sofosbuvir in a two-part randomized, controlled trial involving patients who had newly diagnosed, liver biopsy–proven chronic HCV type 1 for which they had never been treated (JAMA 2013 Aug. 27 [doi:10.1001/jama.2013.109309]).
In the study’s proof-of-concept portion, 10 patients who had early to moderate liver fibrosis were treated for 24 weeks with 400 mg/day of sofosbuvir plus weight-based daily doses of ribavirin. In the second, randomized portion of the study, 50 patients with any stage of fibrosis, including compensated cirrhosis, were randomly assigned to receive the same dose of sofosbuvir plus either weight-based ribavirin or low-dose ribavirin for 24 weeks.
Fifty patients (83%) were black, and 29 (48%) were obese. Fourteen (23%) had advanced liver disease and 37 (62%) had high HCV RNA levels at baseline. In comparison, in previous studies the prevalence of black race was 7%-15%, that of obesity was 22%, and that of advanced liver disease was 9%-20%, the researchers said.
All the patients showed a rapid decline in HCV RNA with treatment, and 24 patients in each group achieved total viral suppression within 1 month of beginning treatment. That was accompanied by a rapid improvement in alanine aminotransferase levels, with 77% of patients showing normalized levels within 1 week and 98% showing normalized levels within 2 weeks. The pattern was similar for aspartate aminotransferase levels.
The primary study endpoint was the proportion of patients who had an undetectable HCV viral load 6 months after completing treatment. That endpoint was reached by 68% of patients who took sofosbuvir plus weight-based doses of ribavirin, and by 48% of those who took sofosbuvir plus low doses of ribavirin, the investigators said.
Twenty-nine patients underwent liver biopsy before and after treatment, and 27 of them (93%) showed a large improvement in inflammation. On a 15-point scale of inflammation, the median decline was 5 points.
There were no cases of viral breakthrough during therapy, and HCV deep sequencing in a subgroup of patients detected none of the genetic mutations known to be associated with resistance to sofosbuvir.
"The combination of sofosbuvir and ribavirin was safe and well tolerated, with no death or discontinuation of treatment due to adverse events. The most frequent adverse events were headache, anemia, fatigue, and nausea, the severity of which ranged from mild to moderate," Dr. Osinusi and her associates said.
In an exploratory analysis of viral kinetics-pharmacodynamics, patients who subsequently relapsed showed a significantly slower loss rate of infectious virus at the beginning of treatment. "The mechanism of viral relapse in these participants remains elusive, and future research will be focused on identifying the biological basis for incomplete clearance of HCV in [such] patients," they added.
"This study demonstrates the efficacy of an interferon-free regimen in a traditionally difficult-to-treat population," Dr. Osinusi and her colleagues said. That is encouraging, because HCV treatment is now evolving from interferon-based combination therapy to "an all-oral, interferon-free, directly acting antiviral agent regimen," they added.
The National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the German Research Foundation funded the study. Pharmasset Pharmaceuticals and Gilead Sciences provided the sofosbuvir and scientific assistance. Dr. Osinusi reported no financial conflicts of interest; her associates reported ties to Abbott, Gilead, Merck, Novartis, Roche Pharma, and Vertex Pharmaceuticals.