Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection.

BACKGROUND: Patients with multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection have limited treatment options. Lenacapavir is a first-in-class capsid inhibitor that showed substantial antiviral activity in a phase 1b study. METHODS: In this phase 3 trial, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to the change in the plasma HIV-1 RNA level between the screening and cohort-selection visits. In cohort 1, patients were first randomly assigned in a 2:1 ratio to receive oral lenacapavir or placebo in addition to their failing therapy for 14 days; during the maintenance period, starting on day 15, patients in the lenacapavir group received subcutaneous lenacapavir once every 6 months, and those in the placebo group received oral lenacapavir, followed by subcutaneous lenacapavir; both groups also received optimized background therapy. In cohort 2, all the patients received open-label oral lenacapavir with optimized background therapy on days 1 through 14; subcutaneous lenacapavir was then administered once every 6 months starting on day 15. The primary end point was the percentage of patients in cohort 1 who had a decrease of at least 0.5 log10 copies per milliliter in the viral load by day 15; a key secondary end point was a viral load of less than 50 copies per milliliter at week 26. RESULTS: A total of 72 patients were enrolled, with 36 in each cohort. In cohort 1, a decrease of at least 0.5 log10 copies per milliliter in the viral load by day 15 was observed in 21 of 24 patients (88%) in the lenacapavir group and in 2 of 12 patients (17%) in the placebo group (absolute difference, 71 percentage points; 95% confidence interval, 35 to 90). At week 26, a viral load of less than 50 copies per milliliter was reported in 81% of the patients in cohort 1 and in 83% in cohort 2, with a least-squares mean increase in the CD4+ count of 75 and 104 cells per cubic millimeter, respectively. No serious adverse events related to lenacapavir were identified. In both cohorts, lenacapavir-related capsid substitutions that were associated with decreased susceptibility developed in 8 patients during the maintenance period (6 with M66I substitutions). CONCLUSIONS: In patients with multidrug-resistant HIV-1 infection, those who received lenacapavir had a greater reduction from baseline in viral load than those who received placebo. (Funded by Gilead Sciences; CAPELLA ClinicalTrials.gov number, NCT04150068.).

Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients.

BACKGROUND: Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe coronavirus disease 2019 (Covid-19). Whether the use of remdesivir in symptomatic, nonhospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalization is uncertain. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. The primary efficacy end point was a composite of Covid-19-related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a Covid-19-related medically attended visit or death from any cause by day 28. RESULTS: A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19-related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P = 0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19-related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group. CONCLUSIONS: Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo. (Funded by Gilead Sciences; PINETREE ClinicalTrials.gov number, NCT04501952; EudraCT number, 2020-003510-12.).

Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial.

Importance: Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with moderate disease is unknown. Objective: To determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on clinical status on day 11 after initiation of treatment. Design, Setting, and Participants: Randomized, open-label trial of hospitalized patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation >94%) enrolled from March 15 through April 18, 2020, at 105 hospitals in the United States, Europe, and Asia. The date of final follow-up was May 20, 2020. Interventions: Patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d. Main Outcomes and Measures: The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group. Results: Among 596 patients who were randomized, 584 began the study and received remdesivir or continued standard care (median age, 57 [interquartile range, 46-66] years; 227 [39%] women; 56% had cardiovascular disease, 42% hypertension, and 40% diabetes), and 533 (91%) completed the trial. Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group. On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; 95% CI, 1.09-2.48; P = .02). The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (P = .18 by Wilcoxon rank sum test). By day 28, 9 patients had died: 2 (1%) in the 5-day remdesivir group, 3 (2%) in the 10-day remdesivir group, and 4 (2%) in the standard care group. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients compared with standard care. Conclusions and Relevance: Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance. Trial Registration: ClinicalTrials.gov Identifier: NCT04292730.

Sofosbuvir plus ribavirin and sofosbuvir plus ledipasvir in patients with genotype 1 or 3 hepatitis C virus and severe renal impairment: a multicentre, phase 2b, non-randomised, open-label study.

BACKGROUND: There is a medical need for highly effective, safe, and well tolerated treatments for patients infected with hepatitis C virus (HCV) with severe renal impairment. We investigated the safety and efficacy of sofosbuvir with ribavirin or ledipasvir combined with sofosbuvir in a prospective study of patients with genotype 1 or 3 HCV infection and stage 4-5 chronic kidney disease (creatinine clearance by Cockcroft-Gault ≤30 mL/min) who were not on dialysis. METHODS: This phase 2b, open-label, non-randomised, multicentre study in the USA and New Zealand investigated three sequentially enrolled cohorts of patients. Patients were recruited from ten hospitals and clinical research centres and were included if they had genotype 1 or 3 HCV infection, a creatinine clearance less than or equal to 30 mL/min, and were not on dialysis. In cohorts 1 and 2, patients received sofosbuvir (200 mg in cohort 1 and 400 mg in cohort 2) plus ribavirin 200 mg once per day for 24 weeks. In cohort 3, 18 patients received ledipasvir combined with sofosbuvir (90 mg ledipasvir and 400 mg sofosbuvir) once per day for 12 weeks. The primary efficacy endpoint was the proportion of patients achieving sustained virological response 12 weeks after the end of treatment (SVR12). Safety and pharmacokinetic data were also collected. The trial is registered with ClinicalTrials.gov, number NCT01958281, and is completed. FINDINGS: This study was done between Oct 7, 2013, and Oct 29, 2017. In the sofosbuvir plus ribavirin cohorts, 32 patients were screened, of whom 20 were enrolled and assessed for efficacy and safety (ten patients in each cohort). In the ledipasvir plus sofosbuvir cohort, 33 patients were screened, of whom 18 were enrolled and assessed for treatment efficacy and safety. Four (40%, 95% CI 12-74) of ten patients in cohort 1 and six (60%, 26-88) of ten patients in cohort 2 achieved SVR12. All 18 (100%, 82-100) patients in cohort 3 achieved SVR12. Adverse events were mostly mild or moderate in severity. The most commonly reported adverse events overall were headache (eight [21%] of 38 patients), anaemia (seven [18%] of 38 patients), and fatigue (six [16%] of 38 patients). Eight patients had serious adverse events, none of which were treatment related. There were no treatment-related cardiac events or clinically significant changes in echocardiographic parameters or creatinine clearance by Cockcroft-Gault. INTERPRETATION: In this phase 2b study, ledipasvir combined with sofosbuvir for 12 weeks was safe and effective in patients with genotype 1 HCV infection and stage 4-5 chronic kidney disease who were not on dialysis. FUNDING: Gilead Sciences.

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19.

BACKGROUND: Remdesivir is an RNA polymerase inhibitor with potent antiviral activity in vitro and efficacy in animal models of coronavirus disease 2019 (Covid-19). METHODS: We conducted a randomized, open-label, phase 3 trial involving hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation of 94% or less while they were breathing ambient air, and radiologic evidence of pneumonia. Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir for either 5 days or 10 days. All patients received 200 mg of remdesivir on day 1 and 100 mg once daily on subsequent days. The primary end point was clinical status on day 14, assessed on a 7-point ordinal scale. RESULTS: In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). The median duration of treatment was 5 days (interquartile range, 5 to 5) in the 5-day group and 9 days (interquartile range, 5 to 10) in the 10-day group. At baseline, patients randomly assigned to the 10-day group had significantly worse clinical status than those assigned to the 5-day group (P = 0.02). By day 14, a clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group. After adjustment for baseline clinical status, patients in the 10-day group had a distribution in clinical status at day 14 that was similar to that among patients in the 5-day group (P = 0.14). The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%). CONCLUSIONS: In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined. (Funded by Gilead Sciences; GS-US-540-5773 ClinicalTrials.gov number, NCT04292899.).

Identification of 19 Novel Hepatitis C Virus Subtypes-Further Expanding HCV Classification.

BACKGROUND: Hepatitis C virus (HCV) is currently classified into 8 genotypes and 86 subtypes. The objective of this study was to characterize novel HCV subtypes and to investigate the impact of subtypes on treatment outcome. METHODS: Full-genome sequencing was performed on HCV plasma samples with <85% sequence homology of NS3, NS5A, and/or NS5B to HCV genotype (GT) 1-8 reference strains. RESULTS: A total of 14 653 patients with GT1-6 HCV infection were enrolled in clinical studies of sofosbuvir-based regimens. For the majority of the patients, a specific subtype could be assigned based on a close genetic relationship to previously described subtypes. However, for 19 patients, novel subtypes were identified with <85% homology compared with previously described subtypes. These novel subtypes had the following genotypes: 9 in GT2, 5 in GT4, 2 in GT6, and 1 each in GT1, GT3, and GT5. Despite the presence of polymorphisms at resistance-associated substitution positions, 18 of the 19 patients treated with sofosbuvir-containing therapy achieved SVR12. CONCLUSIONS: Nineteen novel HCV subtypes were identified, suggesting an even greater genetic diversity of HCV subtypes than previously recognized.

Sofosbuvir-velpatasvir single-tablet regimen administered for 12 weeks in a phase 3 study with minimal monitoring in India.

BACKGROUND AND AIMS: In clinical studies, sofosbuvir-velpatasvir has demonstrated high cure rates and favorable tolerability in patients chronically infected with chronic hepatitis C virus (HCV) of any genotype. We evaluated the effectiveness and safety of sofosbuvir-velpatasvir administered with minimal medical monitoring to patients in India. METHODS: At 16 sites in India, 129 adult patients with chronic HCV infection of any genotype initiated 12 weeks of once-daily sofosbuvir-velpatasvir (400-100 mg). Patients with compensated cirrhosis or prior treatment experience could be included in the study. Study drug was dispensed monthly, but there were no on-treatment study assessments. The primary efficacy endpoint was rate of sustained virologic response (HCV RNA < 15 IU/mL) 12 weeks after treatment (SVR12), which was compared to a pre-specified performance goal of 85%. RESULTS: The majority of patients had HCV genotype 3 infection (70%), followed by HCV genotype 1 (22%). The SVR12 rate was 93% (120/129; 95% CI, 87% to 97%) (p = 0.009 compared with the 85% performance goal). Of the nine patients who did not achieve SVR12, 1 experienced virologic failure, 2 relapsed after treatment, 1 withdrew consent after treatment, and 5 were lost to follow-up (1 during and 4 after treatment). Sofosbuvir-velpatasvir was well-tolerated, and no patients discontinued treatment because of an adverse event. The most frequently reported adverse events were headache (3% of patients), upper abdominal pain (2%), and pyrexia (2%). CONCLUSIONS: In this study conducted at multiple sites in India, sofosbuvir-velpatasvir administered without genotype restriction or on-treatment safety assessments was well-tolerated and highly effective.

Sofosbuvir/Velpatasvir/Voxilaprevir for patients with HCV who previously received a Sofosbuvir/Velpatasvir-containing regimen: Results from a retreatment study.

This study evaluated 12-week retreatment with sofosbuvir/velpatasvir/voxilaprevir in patients with chronic hepatitis C virus (HCV) infection who did not achieve sustained virologic response after previous treatment with a sofosbuvir- and velpatasvir-containing regimen. All 31 patients maintained a sustained virologic response 12 weeks after the last sofosbuvir/velpatasvir/voxilaprevir dose.

Sofosbuvir/velpatasvir for the treatment of HCV: excellent results from a phase-3, open-label study in Russia and Sweden.

BACKGROUND: In both Russia and Sweden, the dominant hepatitis C virus (HCV) is genotype 1, but around one-third of patients have genotype 3 infection. For such countries, HCV genotype testing is recommended prior to therapy. An effective pangenotypic therapy may potentially eliminate the need for genotyping. In this study, we evaluated the efficacy and safety of sofosbuvir/velpatasvir for 12 weeks in patients from Russia and Sweden. METHODS: In an open-label, single-arm phase-3 study, patients could have HCV genotype 1-6 infection and were treatment-naïve or interferon treatment-experienced. All patients received sofosbuvir/velpatasvir, once daily for 12 weeks. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). RESULTS: Of 122 patients screened, 119 were enrolled and treated. Overall, half (50%) were male, 18% had cirrhosis, and 24% had failed prior interferon-based therapy. In total, 66% of patients were infected with HCV genotype 1 (59% 1b and 7% 1a), 6% with genotype 2, and 29% with genotype 3. The overall SVR12 rate was 99% (118/119, 95% confidence interval 95-100%). One treatment-experienced patient infected with HCV genotype 3 experienced virologic relapse after completing treatment. The most common adverse events were headache (16%) and fatigue (7%). Serious adverse events were observed in four patients, but none were related to treatment. No patients discontinued treatment due to adverse events. CONCLUSION: Sofosbuvir/velpatasvir as a pangenotypic treatment for 12 weeks was highly effective in patients from Russia and Sweden infected with HCV genotypes 1, 2, or 3. Sofosbuvir/velpatasvir was safe and well-tolerated. Clinical trial number: ClinicalTrials.gov NCT02722837.

No impact of resistance-associated substitutions on the efficacy of sofosbuvir, velpatasvir, and voxilaprevir for 12 weeks in HCV DAA-experienced patients.

BACKGROUND & AIMS: In phase III studies, the fixed dose combination of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) administered for 12 weeks led to a sustained virologic response at 12 weeks (SVR12) in 96% of NS5A inhibitor-experienced patients, and an SVR12 rate of 98% in DAA-experienced patients who had not previously received an NS5A inhibitor. Herein, we evaluate the relationship between the presence of detectable resistance-associated substitutions (RASs) at baseline and treatment outcome, and whether RASs were selected for in cases of virologic failure. METHODS: NS3, NS5A, and NS5B deep sequencing analyses were performed at baseline for all patients and at the time of virologic failure. Results are reported using a 15% cut-off. RESULTS: A total of 82.7% of NS5A inhibitor-experienced patients (205/248) had baseline NS3 and/or NS5A RASs; 79% had baseline NS5A RASs. SVR12 rates were similar in patients with or without NS3 and/or NS5A RASs, and with or without VOX- or VEL-specific RASs. RASs at NS5A position Y93 were present in 37.3% of patients and 95% achieved SVR12. All patients with ≥2 NS5A RASs achieved SVR12. Baseline NS3 and/or NS5A RASs were present in 46.6% (83/178) of non-NS5A inhibitor DAA-experienced patients, all of whom achieved SVR12. All patients with baseline NS5B nucleoside inhibitor RASs, including two patients with S282T, achieved SVR12. Treatment-selected resistance was seen in one of seven patients who relapsed. CONCLUSIONS: Baseline RASs had no impact on virologic response in DAA-experienced patients following treatment with SOF/VEL/VOX for 12 weeks. Selection of viral resistance with virologic relapse was uncommon. LAY SUMMARY: In phase III studies, 12 weeks of treatment with the combination of sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) cured 97% of patients with hepatitis C virus who failed prior treatment with direct-acting antiviral drugs. Herein, we show that the presence of pretreatment drug resistance did not affect treatment outcome in these patients who had previously received direct-acting antivirals. We also showed that new drug resistance was rare in patients who failed treatment with SOF/VEL/VOX for 12 weeks. This has important implications for the selection of best retreatment strategies for these patients.

Identification of a Novel Hepatitis C Virus Genotype From Punjab, India: Expanding Classification of Hepatitis C Virus Into 8 Genotypes.

Background: Hepatitis C virus (HCV) exhibits great genetic diversity and is classified into 7 genotypes (GTs), with varied geographic prevalence. Until the recent development of pangenotypic direct-acting antiviral regimens, the determination of HCV GT was necessary to inform optimal treatment. Methods: Plasma samples with unresolved GT using standard commercial genotyping methods were subjected to HCV full-genome sequencing, and phylogenetic analysis was performed to assign GT. Results: Four patients, previously classified as GT5 by LiPA or Abbott RealTime polymerase chain reaction assays, were identified as infected with a novel HCV GT. This novel HCV GT, GT8, is genetically distinct from previously identified HCV GT1-7 with >30% nucleotide sequence divergence to the established HCV subtypes. All 4 patients were originally from Punjab, India, but now reside in Canada and are epidemiologically unlinked. Despite presence of baseline resistance-associated substitutions within the GT8 virus of all 4 patients (NS3: V36L, Q80K/R; NS5A: Q30S, Y93S), all patients achieved a sustained virologic response; 2 treated with sofosbuvir/velpatasvir/voxilaprevir for 8 weeks, 1 with sofosbuvir/ledipasvir plus ribavirin for 24 weeks and 1 with sofosbuvir plus daclatasvir for 12 weeks. Conclusions: The discovery of a novel HCV GT8 confirms the circulation of this newly identified lineage in the human population.

Deferred treatment with sofosbuvir-velpatasvir-voxilaprevir for patients with chronic hepatitis C virus who were previously treated with an NS5A inhibitor: an open-label substudy of POLARIS-1.

BACKGROUND: Direct-acting antiviral regimens containing NS5A inhibitors are highly effective treatments for chronic hepatitis C virus (HCV) infection, but are not always successful. In the POLARIS-1 phase 3 study, sofosbuvir-velpatasvir-voxilaprevir for 12 weeks was highly effective in the treatment of chronic HCV infection in patients previously treated with a direct-acting antiviral regimen containing an NS5A inhibitor. We aimed to assess the efficacy and safety of sofosbuvir-velpatasvir-voxilaprevir in patients from the deferred treatment group of POLARIS-1, who were initially assigned to masked placebo treatment. METHODS: This open-label, deferred treatment substudy was done at 73 clinical sites (hospitals and clinics) in the USA, France, Canada, the UK, Germany, Australia, and New Zealand. Patients who received placebo in the primary study and who did not have a new clinically significant illness at the post-treatment week 4 assessment were eligible to enter this substudy. Participants received a combination tablet of sofosbuvir (400 mg), velpatasvir (100 mg), and voxilaprevir (100 mg) once daily for 12 weeks. The primary efficacy outcome was achievement of sustained virological response (defined as HCV RNA concentration below the lower limit of quantification) 12 weeks after the end of treatment (SVR12). The primary safety outcome was the proportion of patients who discontinued treatment due to adverse events. This study is registered with ClinicalTrials.gov, number NCT02607735, and the EU Clinical Trials Register, number 2015-003455-21. FINDINGS: 152 patients received placebo in the primary study and were potentially eligible for participation in the open-label substudy, of whom 147 were enrolled from March 30, 2016, to Oct 12, 2016. All 147 patients completed treatment, and 143 (97%; 95% CI 93-99) achieved SVR12. Four (3%) patients had virological relapse; all had HCV genotype 1a infection and one also had compensated cirrhosis. The most common adverse events were fatigue (31 [21%]), headache (29 [20%]), diarrhoea (28 [19%]), and nausea (21 [14%]). No deaths, treatment discontinuations, or treatment-related serious adverse events occurred. INTERPRETATION: Supporting the results from the blinded portion of the phase 3 primary study, the single-tablet regimen of sofosbuvir-velpatasvir-voxilaprevir for 12 weeks was safe, well tolerated, and highly effective in patients with chronic HCV infection who had previous treatment failure with NS5A inhibitor-containing regimens. A salvage regimen for this population represents an important advance for patients with limited retreatment options. FUNDING: Gilead Sciences.

Sofosbuvir-Based Direct-Acting Antiviral Therapies for HCV in People Receiving Opioid Substitution Therapy: An Analysis of Phase 3 Studies.

BACKGROUND: Hepatitis C virus (HCV) direct-acting antiviral therapy is effective among people receiving opioid substitution therapy (OST), but studies are limited by small numbers of nongenotype 1 (GT1) patients. The aim of this study was to evaluate the treatment completion, adherence, SVR12, and safety of sofosbuvir-based therapies in HCV patients receiving and not receiving OST. METHODS: Ten phase 3 studies of sofosbuvir-based regimens included ION (ledipasvir/sofosbuvir ± ribavirin for 8, 12, or 24 weeks in GT1), ASTRAL (sofosbuvir/velpatasvir for 12 weeks in GT1-6), and POLARIS (sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir in GT1-6). Patients with clinically significant drug use (last 12 months) or noncannabinoids detected at screening were ineligible. RESULTS: Among 4743 patients, 4% (n = 194) were receiving OST (methadone; n = 113; buprenorphine, n = 75; other, n = 6). Compared with those not receiving OST (n = 4549), those receiving OST (n = 194) were younger (mean age, 48 vs 54), more often male (73% vs 61%), GT3 (38% vs 17%), treatment-naïve (78% vs 65%), and cirrhotic (36% vs 23%). Among those receiving and not receiving OST, there was no significant difference in treatment completion (97% vs 99%, P = .06), SVR12 (94% vs 97%, P = .06), relapse (0.5% vs 2.1%, P = .19), adverse events (78% vs 77%, P = .79), or serious adverse events (3.6% vs 2.4%, P = .24). There was no difference in SVR12 in patients with cirrhosis (99% vs 95%, P = .25) or those with G3 (95% vs 95%, P = .77) in those receiving OST. Among patients receiving OST, SVR12 was high among those receiving methadone (95%) and buprenorphine (96%). CONCLUSION: Sofosbuvir-based therapies are effective and safe in patients receiving OST.

Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection.

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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Sofosbuvir-velpatasvir-voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed. (Funded by Gilead Sciences; POLARIS-1 and POLARIS-4 ClinicalTrials.gov numbers, NCT02607735 and NCT02639247 .).

Efficacy and Safety of Ledipasvir/Sofosbuvir for the Treatment of Chronic Hepatitis C in Persons With Sickle Cell Disease.

Patients with sickle cell disease are at high risk for chronic hepatitis C infection. Prior treatment has been limited due to the use of ribavirin causing hemolytic anemia and interferon causing cytopenias. We demonstrate the safety and efficacy of fixed-dose combination ledipasvir and sofosbuvir for 12 weeks in this population.

Ledipasvir-Sofosbuvir Plus Ribavirin in Treatment-Naive Patients With Hepatitis C Virus Genotype 3 Infection: An Open-Label Study.

BACKGROUND: Patients chronically infected with genotype 3 hepatitis C virus (HCV) have faster disease progression and are less responsive to current direct-acting antiviral regimens than patients infected with other genotypes. We conducted an open-label trial to evaluate the safety, tolerability, and efficacy of ledipasvir and sofosbuvir plus ribavirin in patients with genotype 3 HCV infection. METHODS: We enrolled treatment-naive patients with and without compensated cirrhosis at 15 sites in Canada. All patients were treated with ledipasvir-sofosbuvir (90 mg and 400 mg) plus weight-based ribavirin for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). Secondary endpoints included evaluation of baseline and treatment-emergent drug resistance. RESULTS: Of the 111 patients enrolled, 105 (95%) had subtype 3a HCV and 39 (35%) had compensated cirrhosis. SVR12 was achieved by 99 of 111 patients (89%; 95% confidence interval, 82%-94%). Of the 39 patients with cirrhosis, 31 (79%) achieved SVR12, compared with 68 of 72 (94%) patients without cirrhosis. No treatment-emergent resistance mutations occurred in those who failed treatment. One patient discontinued treatment due to liver cancer and died 22 days after treatment discontinuation. The most common adverse events were fatigue (51%), headache (36%), and nausea (23%). CONCLUSIONS: In this multicenter trial involving treatment-naive patients with genotype 3 HCV, 12 weeks of ledipasvir-sofosbuvir provided a high level of SVR in those without cirrhosis. CLINICAL TRIALS REGISTRATION: NCT02413593.

Ledipasvir-sofosbuvir for 6 weeks to treat acute hepatitis C virus genotype 1 or 4 infection in patients with HIV coinfection: an open-label, single-arm trial.

BACKGROUND: The latest European Association for the Study of the Liver (EASL) guidelines now recommend that patients with acute hepatitis C virus (HCV) infection should be treated with a combination of sofosbuvir and an NS5A inhibitor for 8 weeks. However, the ideal duration of treatment with interferon-free regimens, particularly in HIV-coinfected individuals, remains unknown. We assessed the efficacy and safety of 6 weeks of ledipasvir-sofosbuvir for acute genotype 1 or 4 HCV in HIV-1-coinfected patients. METHODS: This open-label, single-arm trial, done in Germany and the UK, included patients with acute HCV genotype 1 or 4 and HIV-1. At screening, patients were either receiving HIV antiretrovirals and had HIV RNA less than 200 copies per mL, or not receiving antiretrovirals and had a CD4 T-cell count of greater than 500 cells per µL. All patients received ledipasvir-sofosbuvir once daily for 6 weeks. The primary efficacy endpoint was the proportion of patients with sustained virological response 12 weeks after the end of treatment (SVR12). This study is registered with ClinicalTrials.gov, number NCT02457611. FINDINGS: Between June 11, 2015, and Jan 8, 2016, we enrolled and treated 26 patients. All (100%) were men, 24 (92%) were white, and 25 (96%) were receiving antiretroviral treatment. 19 (73%) had genotype 1a and seven (27%) had genotype 4 HCV. Overall, 20 (77%; 95% CI 56-91) of 26 patients achieved SVR12: 15 (79%) of 19 with genotype 1a, and five (71%) of seven with genotype 4. Of six patients not achieving SVR12, three relapsed, two achieved sustained virological response 4 weeks after the end of treatment but were lost to follow-up, and one was reinfected. The most common adverse events were fatigue (seven participants [27%]), nasopharyngitis (seven [27%]), and headache (six [23%]). No patient discontinued or interrupted therapy due to adverse events. No HIV rebound occurred during the study. INTERPRETATION: The rate of cure with a fixed-dose combination of ledipasvir-sofosbuvir for patients with acute genotype 1 or 4 HCV infection and HIV-1 coinfection is similar to historic rates with interferon-based treatment, but with shorter treatment duration and more favourable safety outcomes. FUNDING: Gilead Sciences.

Efficacy of 8 Weeks of Sofosbuvir, Velpatasvir, and Voxilaprevir in Patients With Chronic HCV Infection: 2 Phase 3 Randomized Trials.

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 reported more frequently by patients receiving voxilaprevir. In both trials, the proportion of patients who discontinued treatment because of adverse events was low (range, 0%-1%). CONCLUSIONS: In phase 3 trials of patients with HCV infection, we did not establish that sofosbuvir-velpatasvir-voxilaprevir for 8 weeks was noninferior to sofosbuvir-velpatasvir for 12 weeks, but the 2 regimens had similar rates of SVR in patients with HCV genotype 3 and cirrhosis. Mild gastrointestinal adverse events were associated with treatment regimens that included voxilaprevir. ClinicalTrials.gov numbers: POLARIS-2, NCT02607800; and POLARIS-3, NCT02639338.

Comparison of on-treatment HCV RNA during direct antiviral therapy using two different COBAS TaqMan HCV assays.

BACKGROUND: Repeated measurements of hepatitis C virus (HCV) RNA levels during antiviral therapy are recommended to monitor treatment efficacy and adherence. Throughout most direct antiviral agent (DAA) approval studies, HCV RNA cutoffs and endpoints were established with the COBAS TaqMan assay for use with the High Pure System (HPS/CTM). Different assays used in clinical practice may yield different quantitative results and possibly impact treatment decisions. OBJECTIVES: The concordance of the fully-automated COBAS AmpliPrep/COBAS TaqMan assay (CAP/CTM) with HPS/CTM and its ability to predict response to DAA-treatment with ledipasvir/sofosbuvir was assessed in cirrhotic patients with HCV genotype-1-infection who had failed prior treatment with protease inhibitor-based regimens. STUDY DESIGN: Serum samples from patients (n=154) treated in the phase-2 SIRIUS-study were collected at baseline and during antiviral therapy (weeks 1-8), and were tested in parallel by both assays. RESULTS: The mean difference between HPS/CTM and CAP/CTM at baseline (n=153) was 0.32 log10 IU/mL HCV RNA. Discordant results were observed in 12% of samples collected at treatment weeks 1-8, with the greatest differences observed at weeks 2 and 4 (14% and 29%, respectively, for undetectable HCV RNA). SVR rates were 96%-97% in the study and were not significantly different between patients with detectable vs. undetectable HCV RNA according to both assays at weeks 1-4 of antiviral therapy. CONCLUSIONS: CAP/CTM and HPS/CTM showed significantly different response rates during the early stages of ledipasvir/sofosbuvir treatment. However, on-treatment response was not predictive of SVR with either assay, indicating that determination of on-treatment HCV RNA levels may not be useful to guide treatment decisions.