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Background and Aim: Approved hepatitis C virus (HCV) treatments for patients on dialysis are associated with complexities, including drug-drug interactions, baseline resistance testing, use of ribavirin, and risk of hepatotoxicity. Despite higher concentrations of the primary circulating sofosbuvir (SOF) metabolite, GS-331007, in severe renal impairment, real-world case series showed substantial use of SOF-based regimens in this population, with no safety concerns identified. This study evaluated the safety, efficacy, and pharmacokinetics of sofosbuvir-velpatasvir (SOF/VEL) for 12 weeks in patients with HCV infection on dialysis. Method(s): Treatment-naive or -experienced patients, of any genotype, with or without compensated cirrhosis and undergoing hemodialysis or peritoneal dialysis, were enrolled to receive an open-label SOF/VEL (400 mg/100 mg daily) fixed-dose combination once daily for 12 weeks. The primary efficacy end-point was comparison of the sustained virological response 12 weeks after treatment (SVR12) to a prespecified historic control rate of 83%. The primary safety end-point was the proportion of patients who discontinued therapy due to adverse events (AEs). Secondary endpoints included safety, viral resistance, and pharmacokinetics. Result(s): A total of 59 patients were enrolled at 21 sites in Canada, the United Kingdom, Spain, Israel, Australia, and New Zealand. The median age was 60 years (range, 33-91), 59% were male, 53% white, 22% treatment-experienced, and 29% had cirrhosis. Most patients had HCV genotype 1 (42%), 2 (12%), or 3 (27%). Most (92%) were on hemodialysis, with a mean dialysis duration of 7.3 years (range, 0-40). Treatment was well tolerated; no one discontinued therapy due to AEs. One patient was discontinued from therapy on day 74 for non-compliance, with 48% study medication adherence by pill count. Overall, 56/59 patients (95%) achieved SVR12. Two (3%) had virological relapse (one with non-adherence). One patient did not achie

Background and Aims: Limited data on the long-term persistence of NS5A and NS3 HCV resistance associated substitutions (RASs) are available after treatment with clinically relevant HCV regimens. The aim of this study was to evaluate the persistence of NS3, NS5A and NS5B nucleotide inhibitor (NI) RASs in patients not achieving SVR in Gilead-sponsored treatment studies who were enrolled in a followup Sequence Registry. Method(s): Patients who did not achieve SVR following treatment with a DAA-containing regimen in a Gilead treatment protocol were eligible for enrollment into the Sequence Registry where they were followed for up to an additional 144 weeks. Patients had NS5A, NS3 and/or NS5B regions sequenced if they were exposed to an NSS5A inhibitor (ledipasvir [LDV] or velpatasvir [VEL]), an NS3 inhibitor (vedroprevir [VDV] or voxilaprevir [VOX]), and/or an NS5B NI (sofosbuvir [SOF]), respectively. Patients were discontinued if they received HCV treatment or once RASs were no longer detectable. Results are reported using a 15% cutoff. Result(s): Treatment-emergent NS5A and NS3 RASs were observed at the time of virologic failure (VF) in 95% and 93% of registry enrolled patients treated with non-SOF based regimens, respectively. NS5A and NS3 RASs were present at Week 144 in 63% and 25% of non-SOF treated patients, respectively. Treatment-emergent NS5A resistance was observed in 48% of registry enrolled patients at the time of VF with a SOF-based regimen. No treatment-emergent NS3 RASs were detected among the SOF/VEL/VOX failures enrolled in the study (Table). More than 1 NS5A RAS was detected in 47% and 7% of patients treated with non-SOF and SOF-based regimens, respectively. Treatment-emergent NS5B NI RASs were observed in 13/227 (6%) patients treated with a SOF-based regimens at the time of VF. No S282T was observed in any patient. Conclusion(s): Among patients enrolled in this follow up registry, treatment-emergent RASs at the time of VF as well as long-term persist

Background & Aims The efficacy of NS5A inhibitors for the treatment of patients chronically infected with hepatitis C virus (HCV) can be affected by the presence of NS5A resistance-associated substitutions (RASs). We analyzed data from 35 phase I, II, and III studies in 22 countries to determine the pretreatment prevalence of various NS5A RASs, and their effect on outcomes of treatment with ledipasvir-sofosbuvir in patients with genotype 1 HCV. Methods NS5A gene deep sequencing analysis was performed on samples from 5397 patients in Gilead clinical trials. The effect of baseline RASs on sustained virologic response (SVR) rates was assessed in the 1765 patients treated with regimens containing ledipasvir-sofosbuvir. Results Using a 15% cut-off, pretreatment NS5A and ledipasvir-specific RASs were detected in 13% and 8% of genotype 1a patients, respectively, and in 18% and 16% of patients with genotype 1b. Among genotype 1a treatment-naive patients, SVR rates were 91% (42/46) vs. 99% (539/546) for those with and without ledipasvir-specific RASs, respectively. Among treatment-experienced genotype 1a patients, SVR rates were 76% (22/29) vs. 97% (409/420) for those with and without ledipasvir-specific RASs, respectively. Among treatment-naive genotype 1b patients, SVR rates were 99% for both those with and without ledipasvir-specific RASs (71/72 vs. 331/334), and among treatment-experienced genotype 1b patients, SVR rates were 89% (41/46) vs. 98% (267/272) for those with and without ledipasvir-specific RASs, respectively. Conclusions Pretreatment ledipasvir-specific RASs that were present in 8-16% of patients have an impact on treatment outcome in some patient groups, particularly treatment-experienced patients with genotype 1a HCV. Lay summary The efficacy of treatments using NS5A inhibitors for patients with chronic hepatitis C virus (HCV) infection can be affected by the presence of NS5A resistance-associated substitutions (RASs). We reviewed results from 35 clinical t

Background & Aims The efficacy of NS5A inhibitors for the treatment of patients chronically infected with hepatitis C virus (HCV) can be affected by the presence of NS5A resistance-associated substitutions (RASs). We analyzed data from 35 phase I, II, and III studies in 22 countries to determine the pretreatment prevalence of various NS5A RASs, and their effect on outcomes of treatment with ledipasvir-sofosbuvir in patients with genotype 1 HCV. Methods NS5A gene deep sequencing analysis was performed on samples from 5397 patients in Gilead clinical trials. The effect of baseline RASs on sustained virologic response (SVR) rates was assessed in the 1765 patients treated with regimens containing ledipasvir-sofosbuvir. Results Using a 15% cut-off, pretreatment NS5A and ledipasvir-specific RASs were detected in 13% and 8% of genotype 1a patients, respectively, and in 18% and 16% of patients with genotype 1b. Among genotype 1a treatment-naïve patients, SVR rates were 91% (42/46) vs. 99% (539/546) for those with and without ledipasvir-specific RASs, respectively. Among treatment-experienced genotype 1a patients, SVR rates were 76% (22/29) vs. 97% (409/420) for those with and without ledipasvir-specific RASs, respectively. Among treatment-naïve genotype 1b patients, SVR rates were 99% for both those with and without ledipasvir-specific RASs (71/72 vs. 331/334), and among treatment-experienced genotype 1b patients, SVR rates were 89% (41/46) vs. 98% (267/272) for those with and without ledipasvir-specific RASs, respectively. Conclusions Pretreatment ledipasvir-specific RASs that were present in 8–16% of patients have an impact on treatment outcome in some patient groups, particularly treatment-experienced patients with genotype 1a HCV. Lay summary The efficacy of treatments using NS5A inhibitors for patients with chronic hepatitis C virus (HCV) infection can be affected by the presence of NS5A resistance-associated substitutions (RASs). We reviewed results from 35 clinical t

Background & Aims Patients with chronic hepatitis C virus (HCV) infection have high rates of sustained virologic response (SVR) after 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor velpatasvir. We assessed the efficacy of 8 weeks of treatment with sofosbuvir and velpatasvir plus the pangenotypic NS3/4A protease inhibitor voxilaprevir (sofosbuvir-velpatasvir-voxilaprevir). Methods In 2 phase 3, open-label trials, patients with HCV infection who had not been treated previously with a direct-acting antiviral agent were assigned randomly to groups given sofosbuvir-velpatasvir-voxilaprevir for 8 weeks or sofosbuvir-velpatasvir for 12 weeks. POLARIS-2, which enrolled patients infected with all HCV genotypes with or without cirrhosis, except patients with genotype 3 and cirrhosis, was designed to test the noninferiority of 8 weeks of sofosbuvir-velpatasvir-voxilaprevir to 12 weeks of sofosbuvir-velpatasvir using a noninferiority margin of 5%. POLARIS-3, which enrolled patients infected with HCV genotype 3 who had cirrhosis, compared rates of SVR in both groups with a performance goal of 83%. Results In POLARIS-2, 95% (95% confidence interval [CI], 93%–97%) of patients had an SVR to 8 weeks of sofosbuvir-velpatasvir-voxilaprevir; this did not meet the criterion to establish noninferiority to 12 weeks of sofosbuvir-velpatasvir, which produced an SVR in 98% of patients (95% CI, 96%–99%; difference in the stratum-adjusted Mantel–Haenszel proportions of -3.2%; 95% CI, -6.0% to -0.4%). The difference in the efficacy was owing primarily to a lower rate of SVR (92%) among patients with HCV genotype 1a infection receiving 8 weeks of sofosbuvir-velpatasvir-voxilaprevir. In POLARIS-3, 96% of patients (95% CI, 91%–99%) achieved an SVR in both treatment groups, which was significantly superior to the performance goal. Overall, the most common adverse events were headache, fatigue, diarrhea, and nausea; diarrhea and nausea were

Background: Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options. Method(s): We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. In POLARIS-4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir-voxilaprevir (163 patients) or sofosbuvir-velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. Result(s): In the three active-treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir-velpatasvir-voxilaprevir, as compared with 0% with placebo. In POLARIS-4, the rate of response was 98% with sofosbuvir-velpatasvir-voxilaprevir and 90% with sofosbuvir-velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower. Conclusion(s): Sofosbuvir-velpatasvir-voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV

UNLABELLED: The optimal retreatment strategy for patients chronically infected with hepatitis C virus who experience virologic failure after treatment with direct-acting antiviral-based therapies remains unclear. In this multicenter, open-label, phase 2 study, we evaluated the efficacy and safety of a fixed-dose combination of sofosbuvir-velpatasvir (400 mg/100 mg) plus weight-adjusted ribavirin administered for 24 weeks in patients who did not achieve sustained virologic response after prior treatment with direct-acting antiviral regimens that included the nucleotide analogue nonstructural protein 5B inhibitor sofosbuvir plus the nonstructural protein 5A inhibitor velpatasvir with or without the nonstructural protein 3/4A protease inhibitor voxilaprevir. The primary efficacy endpoint was the proportion of patients achieving sustained virologic response at 12 weeks after the cessation of treatment. In total, 63 of 69 (91%; 95% confidence interval, 82%-97%) patients achieved sustained virologic response at 12 weeks, including 36 of 37 (97%; 95% confidence interval, 86%-100%) patients with hepatitis C virus genotype 1 infection, 13 of 14 (93%; 95% confidence interval, 66%-100%) patients with genotype 2 infection, and 14 of 18 (78%; 95% confidence interval, 52%-94%) patients with genotype 3 infection. Most adverse events were of mild or moderate severity. The most frequently reported adverse events were fatigue, nausea, headache, insomnia, and rash. One patient (1%) with genotype 1a infection discontinued all study drugs due to an adverse event (irritability). CONCLUSION: Retreatment of patients who previously failed direct-acting antiviral-based therapies with sofosbuvir-velpatasvir plus ribavirin for 24 weeks was well tolerated and effective, particularly those with hepatitis C virus genotype 1 or 2 infection. (Hepatology 2017;66:1083-1089).

Background: The efficacy of some HCV regimens is influenced by the presence of certain NS5A resistance associated variants (RAVs). To investigate if the pretreatment prevalence of NS5A RAVs in genotypes (GT) 1a and 1b varied by country, race or ethnicity, comprehensive analyses were performed using deep sequencing of NS5A from more than 5000 patients from 17 countries. Method(s): NS5A deep sequencing analysis with a 1% cut-off was performed. GT1a RAVs were defined as K24G/N/R, M28A/G/T/V, Q30H/G/R/E/K, L31any, P32L, S38F, H58D, A92K/T, Y93any, and GT1b RAVs were L31any, P32L, P58D, A92K, Y93any. Result(s): Pretreatment samples from 5046 patients were analyzed. Prevalence of NS5A RAVs was similar between the different regions for both GT1a and GT1b HCV infected patients (Table). In addition, no significant differences were observed in NS5A RAV prevalence between patients with different race or ethnicity. In the subset of patients who were treated with LDV/SOF for 12 weeks, SVR12 rates were similar in GT1b patients with and without pretreatment NS5A RAVs across all regions. In GT1a patients with pretreatment RAVs, SVR12 rates in North America were 91% (75/82) compared to 98% without NS5A RAVs. All seven GT1a patients who relapsed had pretreatment NS5A RAVs conferring >1000-fold reduced susceptibility to LDV (H58D, Y93H/N/F or multiple RAV combinations). However, 18 GT1a patients with similar RAVs conferring >1000-fold reduced susceptibility achieved SVR12 after LDV/SOF for 12 weeks. Conclusion(s): No significant difference in prevalence of NS5A pretreatment RAVs was observed between different regions, races or ethnicities. Overall, high SVR12 rates (91-100%) were observed in patients with or without NS5A RAVs with LDV/ SOF. In GT1a patients, lower SVR rate (72%) was observed in patients with pretreatment NS5A RAVs conferring high level (>1000-fold) resistance to NS5A inhibitors. (Table Presented).