Deferred treatment with a fixed-dose combination of sofosbuvir-velpatasvir for chronic hepatitis C virus genotype 1, 2, 4 and 6 infection.

Sofosbuvir-velpatasvir is approved for the treatment of chronic hepatitis C virus (HCV) infection. In this single-arm, open-label, phase 3, deferred treatment study, we investigated the efficacy and safety of sofosbuvir-velpatasvir among patients randomized to the placebo group in the ASTRAL-1 study. Patients received sofosbuvir-velpatasvir (400/100 mg) once daily for 12 weeks. The primary efficacy endpoint was the proportion of patients with sustained virologic response 12 weeks after the end of therapy (SVR12). The primary safety endpoint was any adverse events (AEs) leading to the permanent discontinuation of study drug. Overall, 108/111 (97%, 95% confidence interval [CI], 92%-99%) achieved SVR12, and only one patient had virological failure. SVR12 was achieved by 61/63 (97%, 95%CI, 89%-100%) genotype 1 patients, 20/20 (100%; 95%CI, 83%-100%) with genotype 2, 19/19 (100%; 95%CI, 82%-100%) with genotype 4 and 8/9 (89%; 95% CI, 52%-100%) with genotype 6. All (19/19; 95%CI, 82-100) patients with cirrhosis and all (31/31, 95%CI, 89-100) with prior treatment experience achieved SVR12. The safety profile during treatment was similar to that observed in patients receiving placebo treatment. The most common AEs were headache, fatigue and nausea. One patient (1%) discontinued treatment due to an AE of gallbladder carcinoma, which was not considered related to treatment. Of five reported serious AEs, none were considered related to study drug. Sofosbuvir-velpatasvir for 12 weeks was effective and well tolerated among untreated and previously treated patients with HCV genotype 1, 2, 4 or 6 infection, including those with compensated cirrhosis (ClinicalTrials.gov NCT02346721).

Sofosbuvir-velpatasvir with ribavirin for 24 weeks in hepatitis C virus patients previously treated with a direct-acting antiviral regimen.

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).

Sofosbuvir With Velpatasvir in Treatment-Naive Noncirrhotic Patients With Genotype 1 to 6 Hepatitis C Virus Infection: A Randomized Trial.

BACKGROUND: Effective, pangenotypic treatments for hepatitis C virus (HCV) infection are needed. OBJECTIVE: To assess the safety and efficacy of sofosbuvir with velpatasvir in patients infected with HCV genotypes 1 to 6. DESIGN: Randomized, phase 2, open-label study. (ClinicalTrials.gov: NCT01858766). SETTING: 48 U.S. sites. PATIENTS: 377 treatment-naive noncirrhotic patients. In part A, patients infected with HCV genotypes 1 to 6 were randomly assigned to sofosbuvir, 400 mg, with velpatasvir, 25 or 100 mg, for 12 weeks. In part B, patients with genotype 1 or 2 HCV infection were randomly assigned to sofosbuvir, 400 mg, and velpatasvir, 25 or 100 mg, with or without ribavirin for 8 weeks. MEASUREMENTS: Sustained virologic response at 12 weeks (SVR12). RESULTS: In part A, SVR12 rates were 96% (26 of 27) with velpatasvir, 25 mg, and 100% (28 of 28) with velpatasvir, 100 mg, for genotype 1; 93% (25 of 27) in both groups for genotype 3; and 96% (22 of 23) with velpatasvir, 25 mg, and 95% (21 of 22) with velpatasvir, 100 mg, for genotypes 2, 4, 5, and 6. In part B, for genotype 1, SVR12 rates were 87% (26 of 30) with velpatasvir, 25 mg; 83% (25 of 30) with velpatasvir, 25 mg, plus ribavirin; 90% (26 of 29) with velpatasvir, 100 mg; and 81% (25 of 31) with velpatasvir, 100 mg, plus ribavirin. For genotype 2, SVR12 rates were 77% (20 of 26) with velpatasvir, 25 mg; 88% (22 of 25) with velpatasvir, 25 mg, plus ribavirin; 88% (23 of 26) with velpatasvir, 100 mg; and 88% (23 of 26) with velpatasvir, 100 mg, plus ribavirin. Adverse events included fatigue (21%), headache (20%), and nausea (12%). One patient committed suicide. LIMITATION: The study was open-label, no inferential statistics were planned, and sample sizes were small. CONCLUSION: Twelve weeks of sofosbuvir, 400 mg, and velpatasvir, 100 mg, was well-tolerated and resulted in high SVR in patients infected with HCV genotypes 1 to 6. PRIMARY FUNDING SOURCE: Gilead Sciences.

Overall safety profile of boceprevir plus peginterferon alfa-2b and ribavirin in patients with chronic hepatitis C genotype 1: a combined analysis of 3 phase 2/3 clinical trials.

BACKGROUND & AIMS: Triple therapy with peginterferon/ribavirin (PR) plus an NS3 protease inhibitor has emerged as the standard-of-care for patients with chronic hepatitis C genotype-1. We provide a detailed safety analysis comparing PR to boceprevir plus PR (BOC/PR) across three phase 2/3 studies. METHODS: SPRINT-1 was an open-label phase 2 study in 595 treatment-naive patients. In the two phase 3 studies, 1500 patients (1097 treatment-naive, SPRINT-2; 403 treatment-failure, RESPOND-2) were randomized to receive PR alone, or one of two regimens where BOC was added to PR after a 4-wk PR lead-in. In this analysis, the respective BOC/PR and PR arms were combined for all three trials. The benefit of shortened duration of treatment using response-guided therapy (RGT) was also explored in the SPRINT-2 trial. RESULTS: Only two adverse events, anaemia and dysgeusia, occurred 20% more often with the BOC-containing regimens compared with PR. Nausea, diarrhoea and neutropenia were the only other common events with an incidence of at least 5% greater when BOC was added to the PR backbone. The proportions of patients reporting serious adverse events (AE), life-threatening AEs, and study drug discontinuation because of an AE were similar in the PR and BOC/PR arms. In treatment-naive patients, RGT generally did not result in a lower frequency of common AEs; however, RGT led to decreased exposure to all 3 study drugs and to a decrease in the mean duration of several clinically relevant AEs such as anaemia, neutropenia, fatigue and depression, as well as earlier normalization of haemoglobin and neutrophil counts. CONCLUSIONS: The safety profile of BOC combination therapy largely reflects the known profile of peginterferon and ribavirin, with incremental haematolgical effects and dysgeusia. Shorter treatment duration with RGT significantly reduced the duration of AEs.

Sofosbuvir for previously untreated chronic hepatitis C infection.

BACKGROUND: In phase 2 trials, the nucleotide polymerase inhibitor sofosbuvir was effective in previously untreated patients with chronic hepatitis C virus (HCV) genotype 1, 2, or 3 infection. METHODS: We conducted two phase 3 studies in previously untreated patients with HCV infection. In a single-group, open-label study, we administered a 12-week regimen of sofosbuvir plus peginterferon alfa-2a and ribavirin in 327 patients with HCV genotype 1, 4, 5, or 6 (of whom 98% had genotype 1 or 4). In a noninferiority trial, 499 patients with HCV genotype 2 or 3 infection were randomly assigned to receive sofosbuvir plus ribavirin for 12 weeks or peginterferon alfa-2a plus ribavirin for 24 weeks. In the two studies, the primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: In the single-group study, a sustained virologic response was reported in 90% of patients (95% confidence interval, 87 to 93). In the noninferiority trial, a sustained response was reported in 67% of patients in both the sofosbuvir-ribavirin group and the peginterferon-ribavirin group. Response rates in the sofosbuvir-ribavirin group were lower among patients with genotype 3 infection than among those with genotype 2 infection (56% vs. 97%). Adverse events (including fatigue, headache, nausea, and neutropenia) were less common with sofosbuvir than with peginterferon. CONCLUSIONS: In a single-group study of sofosbuvir combined with peginterferon-ribavirin, patients with predominantly genotype 1 or 4 HCV infection had a rate of sustained virologic response of 90% at 12 weeks. In a noninferiority trial, patients with genotype 2 or 3 infection who received either sofosbuvir or peginterferon with ribavirin had nearly identical rates of response (67%). Adverse events were less frequent with sofosbuvir than with peginterferon. (Funded by Gilead Sciences; FISSION and NEUTRINO ClinicalTrials.gov numbers, NCT01497366 and NCT01641640, respectively.).

Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial.

BACKGROUND: The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV. METHODS: For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800,000 IU/mL vs ≥800,000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01329978. RESULTS: We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5). In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77-96) in cohort A, 97 patients (89%, 82-94) in cohort B, and by 135 (87%, 81-92) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0·94), or in cohort C (p=0·78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug--anaemia and neutropenia--were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event. INTERPRETATION: Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis. FUNDING: Gilead Sciences.

Resistance-associated amino acid variants associated with boceprevir plus pegylated interferon-α2b and ribavirin in patients with chronic hepatitis C in the SPRINT-1 trial.

BACKGROUND: Resistance to direct-acting antivirals represents a new challenge in the treatment of chronic hepatitis C. METHODS: SPRINT-1 was a randomized study of treatment-naive patients with genotype (G) 1 hepatitis C infection (n=595) that evaluated the safety and efficacy of boceprevir (BOC) when added to pegylated interferon-α2b plus ribavirin (PR). Plasma samples collected at protocol-specified visits were analysed by population sequencing for detection of BOC-associated resistance-associated variants (RAVs). RESULTS: A total of 17/24 (71%) patients randomized to BOC with baseline RAVs achieved sustained virological response (SVR). V55A/I (n=14), Q41H (n=11) and T54S (n=9) were the most frequently detected polymorphisms at baseline. Seven non-SVR patients with baseline RAVs had V55A (relapse, n=3; breakthrough, n=1; and non-response, n=1) and/or R155K (non-response, n=2). In total, 63/144 (44%) patients with sequenced post-baseline samples (2 SVR, 61 non-SVR) had detectable RAVs after BOC treatment (G1a: R155K [39/49; 80%], V36M [37/49; 76%] and T54S [24/49; 49%]; G1b: T54S [3/11; 27%], T54A [4/11; 35%], A156S [2/11; 18%] and V170A [2/11; 18%]). RAV frequency varied according to the virological response: 90%, 67%, 27% and 37% of breakthrough, incomplete virological response, relapse and non-responder patients, respectively, had post-baseline RAVs present. Similar RAVs were identified in both the PR lead-in and no-lead-in arms and the frequency of post-baseline RAVs was highest in the low-dose ribavirin arm. CONCLUSIONS: SVR rates were not compromised among patients with RAVs at baseline; however, a lower starting mg/kg dose of ribavirin was associated with a higher frequency of post-baseline RAVs.

Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial.

BACKGROUND: Peginterferon plus ribavirin achieves sustained virological response (SVR) in fewer than half of patients with genotype 1 chronic hepatitis C virus infection treated for 48 weeks. We tested the efficacy of boceprevir, an NS3 hepatitis C virus oral protease inhibitor, when added to peginterferon alfa-2b and ribavirin. METHODS: In part 1 of this trial, undertaken in 67 sites in the USA, Canada, and Europe, 520 treatment-naive patients with genotype 1 hepatitis C virus infection were randomly assigned to receive peginterferon alfa-2b 1.5 mug/kg plus ribavirin 800-1400 mg daily for 48 weeks (PR48; n=104); peginterferon alfa-2b and ribavirin daily for 4 weeks, followed by peginterferon alfa-2b, ribavirin, and boceprevir 800 mg three times a day for 24 weeks (PR4/PRB24; n=103) or 44 weeks (PR4/PRB44; n=103); or peginterferon alfa-2b, ribavirin, and boceprevir three times a day for 28 weeks (PRB28; n=107) or 48 weeks (PRB48; n=103). In part 2, 75 patients were randomly assigned to receive either PRB48 (n=16) or low-dose ribavirin (400-1000 mg) plus peginterferon alfa-2b and boceprevir three times a day for 48 weeks (low-dose PRB48; n=59). Randomisation was by computer-generated code, and study personnel and patients were not masked to group assignment. The primary endpoint was SVR 24 weeks after treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00423670. FINDINGS: Patients in all four boceprevir groups had higher rates of SVR than did the control group (58/107 [54%, 95% CI 44-64], p=0.013 for PRB28; 58/103 [56%, 44-66], p=0.005 for PR4/PRB24; 69/103 [67%, 57-76], p<0.0001 for PRB48; and 77/103 [75%, 65-83], p<0.0001 for PR4/PRB44; vs 39/104 [38%, 28-48] for PR48 control). Low-dose ribavirin was associated with a high rate of viral breakthrough (16/59 [27%]), and a rate of relapse (six of 27 [22%]) similar to control (12/51 [24%]). Boceprevir-based groups had higher rates of anaemia (227/416 [55%] vs 35/104 [34%]) and dysgeusia (111/416 [27%] vs nine of 104 [9%]) than did the control group. INTERPRETATION: In patients with untreated genotype 1 chronic hepatitis C infection, the addition of the direct-acting antiviral agent boceprevir to standard treatment with peginterferon and ribavirin after a 4-week lead-in seems to have the potential to double the sustained response rate compared with that recorded with standard treatment alone. FUNDING: Merck.

Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection.

BACKGROUND: Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for chronic hepatitis C virus (HCV) infection. However, these regimens have not been adequately compared. METHODS: At 118 sites, patients who had HCV genotype 1 infection and who had not previously been treated were randomly assigned to undergo 48 weeks of treatment with one of three regimens: peginterferon alfa-2b at a standard dose of 1.5 microg per kilogram of body weight per week or a low dose of 1.0 microg per kilogram per week, plus ribavirin at a dose of 800 to 1400 mg per day, or peginterferon alfa-2a at a dose of 180 microg per week plus ribavirin at a dose of 1000 to 1200 mg per day. We compared the rate of sustained virologic response and the safety and adverse-event profiles between the peginterferon alfa-2b regimens and between the standard-dose peginterferon alfa-2b regimen and the peginterferon alfa-2a regimen. RESULTS: Among 3070 patients, rates of sustained virologic response were similar among the regimens: 39.8% with standard-dose peginterferon alfa-2b, 38.0% with low-dose peginterferon alfa-2b, and 40.9% with peginterferon alfa-2a (P=0.20 for standard-dose vs. low-dose peginterferon alfa-2b; P=0.57 for standard-dose peginterferon alfa-2b vs. peginterferon alfa-2a). Estimated differences in response rates were 1.8% (95% confidence interval [CI], -2.3 to 6.0) between standard-dose and low-dose peginterferon alfa-2b and -1.1% (95% CI, -5.3 to 3.0) between standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Relapse rates were 23.5% (95% CI, 19.9 to 27.2) for standard-dose peginterferon alfa-2b, 20.0% (95% CI, 16.4 to 23.6) for low-dose peginterferon alfa-2b, and 31.5% (95% CI, 27.9 to 35.2) for peginterferon alfa-2a. The safety profile was similar among the three groups; serious adverse events were observed in 8.6 to 11.7% of patients. Among the patients with undetectable HCV RNA levels at treatment weeks 4 and 12, a sustained virologic response was achieved in 86.2% and 78.7%, respectively. CONCLUSIONS: In patients infected with HCV genotype 1, the rates of sustained virologic response and tolerability did not differ significantly between the two available peginterferon-ribavirin regimens or between the two doses of peginterferon alfa-2b. (ClinicalTrials.gov number, NCT00081770.)