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Retreatment of HCV Genotype-1 with Sofosbuvir and Ledipasvir after Relapse with Sofosbuvir and Ribavirin: A Pilot Study #MMPMID25364884
Osinusi A; Kohli A; Marti MM; Nelson A; Zhang X; Meissner EG; Silk R; Townsend K; Pang PS; Subramanian M; McHutchison JG; Fauci AS; Masur H; Kottilil S
Ann Intern Med 2014[Nov]; 161 (9): 634-8 PMID25364884show ga
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.