Hepatitis C treatment with a two-drug, interferon-free regimen was effective at maintaining a sustained virologic response in patients deemed unlikely to respond to treatment, researchers found.
A 24-week regimen of sofosbuvir in tandem with weight-based or low-dose ribavirin was associated with a sustained virologic response to treatment of 68% and 48%, respectively, in those with a "high prevalence of unfavorable traditional predictors of treatment response," according to Shyamasundaran Kottilil, MD, PhD, of the National Institute of Allergy and Infectious Diseases in Bethesda, Md., and colleagues.
A separate, smaller population of patients with early to moderate liver fibrosis showed a 90% sustained virologic response at 24 weeks to sofosbuvir with weight-based ribavirin, they wrote online in the Journal of the American Medical Association.
Hepatitis C is common to large urban areas in the U.S. that are comprised of populations with unfavorable traditional predictors of treatment response, such as black race, advanced liver fibrosis, IL28B CT or TT genotypes, high baseline viral loads, and prior treatment experience, the authors noted in their introduction.
Interferon-alfa and ribavirin are two direct-acting antiviral agents that have improved sustained virologic response, but carry risks of adverse reactions, high pull burdens, and drug interactions. Recent trials have shown efficacy of interferon-free, direct-acting antiviral agent-only regimens in sustained virologic response, but these data have not been collected as frequently in populations with poorer treatment outcomes.
The authors studied the efficacy and safety of a sofosbuvir and weight-based or low-dose ribavirin regimen through a two-part study of 60 hepatitis C patients in various stages of liver fibrosis to a primary endpoint of undetectable viral load at 24 weeks following treatment completion.
Participants were infected with hepatitis C genotype 1, had liver biopsy-proven chronic disease, were treatment-naive, and tested negative for hepatitis B and HIV. Additionally, they had absolute neutrophil counts of 750 cells/uL or greater, platelet counts of 50,000 cells/uL, and hemoglobin of 11 g/dL or greater in women and 12 g/dL in men.
The first part of the study included 10 patients with early to moderate liver fibrosis who were treated for 24 weeks with 400 mg daily of sofosbuvir and weight-based ribavirin (at 400 mg in the morning and 600 mg in the evening if they weighed less than 75 kg, or 600 mg in the morning and evening if they weighed 75 kg or more).
The second part of the study randomized on a one-to-one basis 50 participants at all stages of liver fibrosis, including compensated cirrhosis, to 400 mg daily sofosbuvir with weight-based or a low dose (600 mg) of ribavirin daily for 24 weeks.
Hepatitis C viral loads were measured through a plasma RNA measure. Adherence to treatment was measured by pill counts at each visit and during patient interviews.
Study endpoints included undetectable viral load after 24 weeks of treatment, the proportion of patients with undetectable viral load at various points during and after the study, frequency and severity of adverse events, and discontinuation due to adverse events.
The majority of participants were black (83%) and male (66%), and 48% were obese. By disease characteristic, 81% had the IL28 CT or TT genotype, 70% had the GT-1a genotype, 23% had advanced liver disease, and 62% had a baseline viral RNA level above 800,000.
In the second trial, 96% of each study group achieved viral suppression by week four, while four participants discontinued therapy by week eight due to nonadherence, and another stopped after week 12 but maintained an undetectable viral load at 24 weeks after stopping treatment.
Relapse occurred in 28% of those in the weight-based group and in 40% of the low-dose group. Differences in sustained virologic response between groups were not significant. Relapse was significantly more likely in males (OR 6.09, 95% CI 1.17-31.6), patients with advanced fibrosis (OR 4.27, 95% CI 1.10-16.54), and among patients with a baseline viral RNA load of 800,000 IU/mL (OR 5.74, 95% CI 1.35-24.38).
In an evaluation of viral kinetics, pharmacokinetics, and pharmacodynamics, a fully fitted pharmacokinetics-viral kinetics model of 20 participants -- 10 in each study group -- showed a significantly slower loss rate of free virus in patients who relapsed versus those who had a sustained virologic response (clearance 3.57 daily versus 5.60 daily, P=0.009).
Treatment was well-tolerated, there were no deaths or discontinuation of treatment due to adverse events. Adverse events included headache, anemia, fatigue, and nausea, and were mostly mild to moderate in severity.
These findings show that patients -- including those in difficult-to-treat populations -- can achieve viral control through all-oral treatment regimens, according to Rolhit Talwani, MD, of the University of Maryland School of Medicine in Baltimore and study co-author.
"As we move forward and as these all-oral regimens for hepatitis C evolve, we'll hopefully find that we'll be able to treat certain populations with a shorter course, one to two agents, and perhaps a longer course for those at risk for relapse," he told MedPage Today.
The study was limited by its small sample size.
The study was funded by the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, the German Research Foundation, Pharmasset Pharmaceuticals, and Gilead Sciences.
The authors were supported by Roche Pharma, Novartis, Gilead, Merck, Vertex Pharmaceuticals, and Abbott.
- Reviewed by F. Perry Wilson, MD, MSCE Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Journal of the American Medical AssociationSource Reference: Kottilil S, et al "Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics" JAMA 2013; 310(8): 804-811; DOI: 10.1001/jama.2013.109309.