Real world effectiveness of 8 vs 12 weeks of ledipasvir/sofosbuvir (LDV/SOF) in blacks with HCV: A comparative analysis of clinical trials with real world cohorts.
Thompson A, Sarrazin C, Cooper CL, Manns MP, Reddy RK, Kowdley K, Dvory-Sobol H, Svarovskia E, Martin R, Doehle BP, Camus G, Stamm LM, Hyland RH, Brainard DM, Mo H, Gordon SC, Bourliere M, Zeuzem S, and Flamm SL. No impact of resistance-associated substitutions on the high efficacy of sofosbuvir-velpatasvir-voxilaprevir for 12 weeks in direct-acting antiviral-experienced patients: An integrated resistance analysis of the POLARIS-1 and POLARIS-4 studies. J Gastroenterol Hepatol 2017; 32:109-110.
Journal of Gastroenterology and Hepatology
Background and Aims: The pangenotypic combination of sofosbuvir (SOF), velpatasvir (VEL), and voxilaprevir (VOX) inhibits distinct hepatitis C virus targets: the NS5B polymerase, the NS5A protein, and NS3/4A protease, respectively. In phase 3 studies, SOF–VEL–VOX administered for 12 weeks demonstrated a 96% sustained virological response at 12 weeks (SVR12) rate in NS5A inhibitor‐experienced patients in POLARIS‐1, and a 98% SVR12 rate in direct‐acting antiviral (DAA)‐experienced patients who had not previously received an NS5A inhibitor in POLARIS‐4. Here, we evaluate the effect of baseline resistance‐associated substitutions (RASs) on treatment outcome and the emergence of RASs in patients who experienced virological failure.
Methods: NS3, NS5A, and NS5B deep sequencing was performed at baseline for all patients and at the time of virological failure. NS3 and NS5A class RASs, as well as VOX‐ or VEL‐specific RASs that confer > 2.5‐fold changes in EC50, were evaluated. Results are reported using a 15% cut‐off.
Results: In POLARIS‐1, 79% of NS5A inhibitor‐experienced patients (205/260) had baseline NS3 and/or NS5A class RASs. Of these, 75% (196/260) had baseline NS5A RASs, the most common RASs. The SVR12 rates were similar in patients with or without NS3 and/or NS5A class RASs and with or without VOX‐ or VEL‐specific RASs (Table 1). RASs at NS5A position Y93 were present in 39% of patients, of whom 63 (95%) achieved SVR12; all patients with ≥ 2 NS5A RASs achieved SVR12 (n = 77). Of patients with NS5B nucleoside inhibitor (NI) RASs, 95% (18/19) achieved SVR12; two patients had S282T at baseline and both achieved SVR12. In POLARIS‐4, the overall prevalence of baseline NS3 and/or NS5A class RASs was 47% (83/178), and all achieved SVR12. All patients with NS5B NI RASs (n = 14) achieved SVR12. Only one patient (GT4) who relapsed had a treatment‐emergent RAS.