Outcomes of Treatment with Ledipasvir and Sofosbuvir Short Title : Ledipasvir / Sofosbuvir Baseline RASs and Treatment Outcomes

Background & Aims: We evaluated the effects of baseline hepatitis C virus (HCV) NS5A, NS5B, and NS3 resistance-associated substitutions ( RASs) on response to the combination of ledipasvir and sofosbuvir, with or without ribaviri n, in patients with HCV genotype 1 infection. Methods: We analyzed data from 2144 participants in phase 2 and 3 studies of patients with HCV genotype 1a or b infection received the combina tio of ledipasvir (90 mg) and sofosbuvir (400 mg) (ledipasvir/sofosbuvir) once daily, with o r without ribavirin twice daily. Population and/or deep sequence analyses of the HCV NS3, NS5A, and NS5B genes were performed on blood samples collected at baseline. Results: Overall, 16.0% of patients had detectable baselin e RASs in NS5A. Among patients with HCV genotype 1b infection, there was no significant effect of baseline RASs in NS5A on sustained viral response 12 weeks after the end of treatment (SVR12) with ledipasvir/sofosbuvir and only a small effect in patients with HCV genoty pe 1a infection. RASs in NS5A that increased the half maximal effective concentration 50 to ledipasvir by more than 100-fold (Q30H/R, L31M in genotype 1a HCV, and Y93H) reduced the rate of SVR12 in treatment-naïve patients given ledipasvir/sofosbuvir for 8 weeks, ( P=.011), but not 12 weeks. These same baseline NS5A RASs reduced the percentage of treatm ent-experienced patients who achieved an SVR12 to 12 weeks (but not 24 weeks) ledipasvir/sof o buvir (P<.001). These RASs had a small effect in patients given ledipasvir/sofosbuvir in c ombination with ribavirin for 12 weeks. Overall, 2.5% of patients had baseline NS5B nucleotide inhib tor RASs (L159F, N142T, S282G, or M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT 6 L320S) and all achieved an SVR12. Of patients previ ously treated with protease inhibitors, 53.7% had RASs in NS3 and 96.5% achieved an SVR12. Conclusions: Baseline RASs in NS5A have minimal effects on pat ients’ response to ledipasvir/sofosbuvir therapy. When these RASs do h ave effects, they could be largely overcome by extending treatment duration or through treatmen t intensification.