Background Direct acting anti-HCV drugs have demonstrated a high cure rate and favorable tolerability. The development of shorter courses of therapy may improve affordability and adherence. Sofosbuvir and ledipasvir together with ribavirin have yielded high efficacy when administered for 8, but not for 6 weeks. We hypothesized that addition of a third potent directly acting antiviral to sofosbuvir and ledipasvir would allow for shortened durations of therapy. Methods In this single center, open-label cohort, phase 2 atrial, sixty HCV GT-1 treatment naïve patients were sequentially enrolled onto three arms and treated with 12 weeks of sofosbuvir and ledipasvir (an NS5B nucleotide polymerase inhibitor and an NS5A inhibitor, respectively) (n=20); or 6 weeks with sofosbuvir, ledipasvir, and GS-9669 (a non-nucleoside NS5B inhibitor) (n=20) or 6 weeks with sofosbuvir, ledipasvir and GS-9451 (an NS3/4A protease inhibitor) (n=20). Patients and investigators were unmasked to treatment assignment. The primary efficacy analysis was SVR12 (HCV RNA less than the level of quantitation 12 weeks after treatment completion). Findings All subjects treated with sofosbuvir and ledipasvir for 12 weeks achieved SVR12 (95%CI: 83–100%). Nineteen of 20 patients (95% CI: 75–100%) treated with sofosbuvir, ledipasvir and GS-9669 achieved SVR12, with 1 patient relapsing 2 weeks after completion of therapy. Nineteen of 20 patients (95% CI: 75–100%) treated with sofosbuvir, ledipasvir, and GS-9451 for 6 weeks achieved SVR12, one patient was lost to follow up after achieving SVR4. There were no discontinuations of treatment due to adverse events. Interpretation In this small proof of concept study, two different three drug regimens administered for 6 weeks resulted in high cure rates for HCV infection with excellent tolerability. Funding NIAID, National Cancer Institute and Clinical Center Intramural Program. Clinical Trials.gov number NCT01805882. The study was also supported in part by the German Research Foundation (DFG) by the clinical research unit KFO 129 and a Collaborative Research and Development Agreement between NIH and Gilead Sciences.

Background The interferon (IFN)-free regimen of sofosbuvir and ribavirin for 24 weeks was recently approved to treat chronic hepatitis C virus (HCV), genotype-1 (GT-1) infection for interferon-ineligible patients . However, sofosbuvir/ribavirin therapy is associated with treatment relapse in 15-30% of HCV GT-1 study subjects. Neither the mechanism of relapse nor the optimal retreatment strategy for these subjects is defined. Objective To assess the safety and efficacy of sofosbuvir and ledipasvir in chronic HCV GT-1 infected subjects who relapsed following sofosbuvir/ribavirin therapy. Design Phase 2a, open-label study (ClinicalTrials.gov, number NCT01805882). Setting Single U.S site. Subjects Fourteen HCV, GT-1 subjects who relapsed following treatment with 24 weeks of sofosbuvir/ribavirin were treated with 12 weeks of sofosbuvir/ledipasvir. Measurments HCV RNA concentration and population sequencing to detect NS5B S282T mutations. Results All 14 subjects treated with sofosbuvir/ledipasvir for 12 weeks achieved a sustained virologic response, including seven with advanced liver disease (HAI-fibrosis 3-4) and one with a detectable NS5B S282T mutation post sofosbuvir/ribavirin therapy. Sofosbuvir/ledipasvir was well tolerated with few adverse events. Four grade 3 events (elevated serum creatinine in a subject with baseline renal insufficiency, hypercholesterolemia and hypophosphatemia (n=2)) occurred. There were no grade 4 events or treatment discontinuations. Limitations Small sample size. Conclusions The fixed-dose combination of sofosbuvir/ledipasvir was efficacious in a small cohort of subjects with HCV GT-1 infections who relapse following sofosbuvir/ribavirin therapy, even in the setting of advanced liver disease. Larger studies are needed to confirm these preliminary efficacy results. Primary Funding Source National Institute of Allergy and Infectious Diseases (NIAID), National Cancer Institute and Clinical Center Intramural Program and a Collaborative Research And Development Agreement between NIAID and Gilead Sciences, Inc.

Successful treatment of chronic hepatitis C virus infection can now be achieved using directly acting antiviral agents without interferon. We report a patient who achieved a sustained virologic response after 27 days of treatment with sofosbuvir and ribavirin. Identifying factors that allow for shorter treatment in some individuals is imperative.

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