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.

Efficacy and safety of sofosbuvir-velpatasvir with or without ribavirin in HCV-infected Japanese patients with decompensated cirrhosis: an open-label phase 3 trial.

BACKGROUND: In Japan, hepatitis C virus (HCV)-infected patients with decompensated cirrhosis currently have no treatment options. In this Phase 3 study, we evaluated sofosbuvir-velpatasvir with or without ribavirin for 12 weeks in patients with any HCV genotype and decompensated cirrhosis [Child-Pugh-Turcotte (CPT) class B or C] in Japan. METHODS: Patients were randomized 1:1 to receive sofosbuvir-velpatasvir with or without ribavirin for 12 weeks. Randomization was stratified by CPT class and genotype. Sustained virologic response 12 weeks following completion of treatment (SVR12) was the primary efficacy endpoint. RESULTS: Of the 102 patients enrolled, 57% were treatment naive, 78% and 20% had genotype 1 and 2 HCV infection, respectively, and 77% and 20% had CPT class B and C cirrhosis, respectively, at baseline. Overall, 61% of patients were female and the mean age was 66 years (range 41-83). SVR12 rates were 92% (47/51) in each group. Among patients who achieved SVR12, 26% had improved CPT class from baseline to posttreatment week 12. Most adverse events (AEs) were consistent with clinical sequelae of advanced liver disease or known toxicities of ribavirin. Four patients (8%) who received sofosbuvir-velpatasvir and seven (14%) who received sofosbuvir-velpatasvir plus ribavirin experienced a serious AE. The 3 deaths (bacterial sepsis, gastric varices hemorrhage, hepatocellular carcinoma) were attributed to liver disease progression. CONCLUSION: Sofosbuvir-velpatasvir for 12 weeks provides a highly effective and well-tolerated therapy for Japanese patients with HCV and decompensated cirrhosis. Ribavirin did not improve efficacy but increased toxicity.

HCV phylogenetic signature and prevalence of pretreatment NS5A and NS5B NI-Resistance associated substitutions in HCV-Infected patients in Mainland China.

BACKGROUND & AIMS: Resistance associated substitutions (RAS) can reduce the efficacy of some direct-acting antiviral HCV regimens. Here, prevalence of RAS in genotype (GT) 1b, 2, 3, and 6 HCV-infected patients from Asian counties, North America and Europe are described and compared. METHODS: Pretreatment HCV RAS were assessed with 15% cutoff from patients enrolled in clinical trials of sofosbuvir-containing regimens in Mainland China, Japan, Korea, and India. Phylogenetic analyses were performed to investigating subtype diversity. RESULTS: In GT1b patients, the prevalence of NS5A RAS, including Y93H, was similar across Asian countries (18-21%), and North America (15%) or Europe (19%). The prevalence of NS5B NI RAS, including L159F, was lower in Asian countries (1-5%) compared to North America (4%) or Europe (20%). The prevalence of NS3 RAS in patients from China (22%) and North America (28%) were lower than in Europe (40%). For GT2 patients in China, 100% had GT2a subtype with high prevalence of NS5A L31M. For GT3, the prevalence of GT3b was substantially higher in China (54%) than in North America or Europe (<1%); 99% of GT3b patients in China had NS5A RAS A30K+L31M, which confers high levels of resistance to NS5A inhibitors. In GT3a patients in China, the prevalence of NS5A RAS was lower (5%) than in North America and Europe (14-16%). Prevalence of NS5B NI RAS in GT2 and GT3 patients was rare across regions (<2%). CONCLUSIONS: Differences in the prevalence of GT2 and GT3 subtypes and NS5A RAS were observed between Asian and Western countries.

Sofosbuvir-velpatasvir plus ribavirin in Japanese patients with genotype 1 or 2 hepatitis C who failed direct-acting antivirals.

BACKGROUND/PURPOSE: In Japan, there is a growing population of patients with chronic hepatitis C virus (HCV) infection who failed a direct-acting antiviral (DAA)-based regimen. In this Phase 3 study, we evaluated sofosbuvir-velpatasvir plus ribavirin in Japanese patients with genotype 1 or 2 HCV infection who previously received DAAs. METHODS: Patients were randomized 1:1 to receive sofosbuvir-velpatasvir plus ribavirin for 12 or 24 weeks. Randomization was stratified by HCV genotype and presence of cirrhosis. The primary endpoint was sustained virologic response 12-week post-treatment (SVR12). RESULTS: Of 117 participants, 81% had HCV genotype 1 infection, 33% had cirrhosis, and 95% had NS5A resistance-associated substitutions (RAS) at baseline. Overall, SVR12 rates were 97% (58/60; 95% CI 88-100%) with 24 weeks of treatment and 82% (47/57; 95% CI 70-91%) with 12 weeks. For HCV genotype 1 and 2 infected patients, the SVR12 rates with 24 weeks of treatment were 98% and 92%, respectively. In both treatment groups, SVR12 rates in HCV genotype 1 patients were statistically superior to a historical control rate of 50% (p < 0.001). For patients with NS5A RASs at baseline, 85% (46/54) in the 12-week group and 96% (54/56) in the 24-week group achieved SVR12. The most common adverse events were upper respiratory tract viral infection, anemia, and headache. Three (2.6%) patients discontinued treatment because of adverse events. CONCLUSION: Sofosbuvir-velpatasvir plus ribavirin was highly effective and well tolerated in Japanese patients who previously failed a DAA-based regimen. Baseline NS5A RASs did not affect treatment outcomes.

Persistence of Virologic Response after Liver Transplant in Hepatitis C Patients Treated with Ledipasvir / Sofosbuvir Plus Ribavirin Pretransplant.

INTRODUCTION: Recurrence of HCV infection in patients with chronic hepatitis C virus (HCV) at the time of liver transplantation is nearly universal and reduces the likelihood of graft and patient survival. MATERIALS AND METHODS: We evaluated outcomes of 17 patients (16 with HCV genotype 1 and 1 with genotype 4) who received up to 12 or 24 weeks of ledipasvir/sofosbuvir plus ribavirin prior to or up to the time of liver transplant in the SOLAR-1 and SOLAR-2 trials. In all patients, HCV RNA was < 15 IU/mL prior to transplant. At screening, 6 patients were Child-Pugh-Turcotte (CPT) class B and 11 were CPT class C. Seven patients underwent transplant prior to completing assigned treatment, with 4 treated for < 12 weeks. The primary endpoint was posttransplant virologic response 12 weeks after transplant (pTVR12) in patients with HCV RNA < 15 IU/mL at their last measurement prior to transplant. RESULTS: Overall, 94% (16/17) achieved pTVR12. All who achieved pTVR12 received at least 11 weeks of treatment. The single patient who did not achieve pTVR12 discontinued study drug on day 21 and underwent liver transplant the following day. The patient had HCV RNA < 15 IU/mL at post-transplant week 2 but died 15 days post-transplant because of multi-organ failure and septic shock. CONCLUSION: Among a small population of HCV patients with decompensated cirrhosis, virologic response to ledipasvir / sofosbuvir plus ribavirin prior to liver transplantation was maintained after transplantation, even if treatment was stopped early. Administration of ledipasvir / sofosbuvir plus ribavirin before liver transplant can prevent post-transplant HCV recurrence.

Rilpivirine vs. efavirenz-based single-tablet regimens in treatment-naive adults: week 96 efficacy and safety from a randomized phase 3b study.

OBJECTIVES: To compare efficacy, safety, tolerability, and patient-reported outcomes between two single-tablet regimens, rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) and efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF), in HIV-1-infected, treatment-naive adults. DESIGN: This was a phase 3b, 96-week, randomized, open-label, international, noninferiority trial. METHODS: A total of 799 participants were randomized (1 : 1) to receive RPV/FTC/TDF or EFV/FTC/TDF. The primary efficacy endpoint evaluated proportions of participants with HIV-1 RNA less than 50 copies/ml using the Snapshot algorithm. Additional assessments included CD4 cell counts, genotypic/phenotypic resistance, adverse events, patient-reported outcomes, and quality of life questionnaires. RESULTS: At week 96, trial completion rates were 80.2% (316/394; RPV/FTC/TDF) and 74.0% (290/392; EFV/FTC/TDF). Overall, RPV/FTC/TDF was noninferior to EFV/FTC/TDF [HIV-1 RNA <50 copies/ml: 77.9 vs. 72.4%, respectively; difference -5.5; 95%CI (-0.6, 11.5); P = 0.076]. RPV/FTC/TDF was significantly more efficacious compared with EFV/FTC/TDF in participants with baseline HIV-1 RNA equal to or less than 100 000 copies/ml (78.8 vs. 71.2%; P = 0.046) and in those with CD4 cell count greater than 200 cells/µl (80.6 vs. 73.0%; P = 0.018). There was no significant between-group difference in the CD4 cell count increase (278 ±â€Š189 vs. 259 ±â€Š191 cells/µl; P = 0.17). Few participants developed resistance after week 48 (1.0% RPV/FTC/TDF; 0.3% EFV/FTC/TDF). Compared with EFV/FTC/TDF, RPV/FTC/TDF was associated with fewer adverse event-related discontinuations (3.0 vs. 11.0%; P<0.001), significantly fewer adverse events due to central nervous system issues and rash, greater improvements in patient-reported symptoms, and significant improvements in the SF-12v2 quality of life questionnaire mental health composite score (P = 0.014). CONCLUSION: In treatment-naive, HIV-1-infected participants, 96-week RPV/FTC/TDF treatment demonstrated noninferior efficacy and better tolerability than EFV/FTC/TDF.

Patient-reported outcomes in the single-tablet regimen (STaR) trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate in antiretroviral treatment-naive adults infected with HIV-1 through 48 weeks of treatment.

This 96-week, randomized, open-label study was designed to assess the efficacy and safety of two single-tablet regimens in treatment naïve HIV-1-infected adults: rilpivirine (RPV) + emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and efavirenz (EFV) + FTC/TDF. Assessments included patient-reported Medication Adherence Self-Report Inventory, SF-12v2 Quality of Life assessment, HIV Treatment Satisfaction Questionnaire, and HIV Symptom Index Questionnaire through Week 48. Additional evaluations included study drug discontinuations due to treatment-emergent adverse events (TEAEs). A total of 786 participants (n=394 RPV/FTC/TDF, n=392 EFV/FTC/TDF) were included. Fewer RPV/FTC/TDF-treated than EFV/FTC/TDF-treated participants discontinued study drug due to TEAEs (2.5% vs. 8.7%), with 41% (14/34) TEAE-related discontinuations in the EFV/FTC/TDF group occurring within the first four weeks of treatment. Treatment adherence and satisfaction remained high through Week 48 and quality of life improved from baseline in both groups. There were no significant between-group differences in virologic success (HIV-1 RNA <50 copies/mL) regardless of adherence (<95% or ≥95%). Significant between-group differences favouring RPV/FTC/TDF were observed for the HIV SIQ symptoms of difficulty falling or staying asleep (p = .022) and diarrhea or loose bowel movements (p = .002). In conclusion, 48-week treatment with RPV/FTC/TDF or EFV/FTC/TDF was associated with high adherence, high treatment satisfaction, and improved quality of life. TEAE-related discontinuations and patient-reported symptoms indicate that RPV/FTC/TDF may be somewhat better tolerated than EFV/FTC/TDF.

Patient-Reported Outcomes After a Switch to a Single-Tablet Regimen of Rilpivirine, Emtricitabine, and Tenofovir DF in HIV-1-Positive, Virologically Suppressed Individuals: Additional Findings From a Randomized, Open-Label, 48-Week Trial.

BACKGROUND: Patient-reported outcomes (PROs) can provide important information about treatment tolerability in HIV-1-infected patients. OBJECTIVE: The aim of this study was to evaluate PROs following switching from a boosted protease inhibitor-based regimen to the single-tablet regimen (STR) of rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) in the 48-week open-label Switching Boosted PI to Rilpivirine in Combination with Truvada as a Single-Tablet Regimen (SPIRIT) trial. METHODS: In the open-label SPIRIT trial, patients were randomized to receive an STR of RPV/FTC/TDF (n = 317) for 48 weeks or stay on their baseline regimen of a ritonavir-boosted protease inhibitor and two nucleoside/nucleotide analog reverse transcriptase inhibitors (PI + RTV + 2NRTIs, n = 159) for 24 weeks before switching to RPV/FTC/TDF for another 24 weeks. PRO assessments included the HIV Treatment Satisfaction Questionnaire (TSQ) and the HIV Symptom Index Questionnaire (SIQ). RESULTS: At week 24, the mean HIV TSQ improvement from baseline was significantly greater in the RPV/FTC/TDF group than the PI + RTV + 2NRTIs group (p < 0.001). On the HIV SIQ, the percentage of patients reporting a shift from 'symptom' to 'no symptom' was significantly greater with RPV/FTC/TDF treatment compared with PI + RTV + 2NRTIs for all items (all p ≤ 0.01), with total within-group occurrence of 13/20 symptoms significantly decreasing from baseline for RPV/FTC/TDF patients. In the delayed switch group, significantly fewer patients reported diarrhea and sleep problems at week 48 vs. week 24. CONCLUSIONS: These data suggest that switching to the STR RPV/FTC/TDF from a PI-based multi-pill regimen is associated with greater patient-reported treatment satisfaction and improved tolerability in HIV-1-infected, virologically suppressed individuals.

Simplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants.

OBJECTIVE: To evaluate the efficacy and safety of antiretroviral simplification from a ritonavir-boosted protease inhibitor-based regimen [protease inhibitor+RTV+two nucleos(t)ide reverse transcriptase inhibitors (NRTIs); ≥6 months of exposure prior to study entry with no prior treatment failure] to the single-tablet regimen (STR) rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) in virologically suppressed, HIV-1-infected participants. DESIGN: Phase 3b, randomized, open-label, international, 48-week switch study. METHODS: Participants were randomized 2 : 1 to switch to RPV/FTC/TDF immediately or stay on their baseline protease inhibitor+RTV+2NRTIs regimen with a delayed switch to RPV/FTC/TDF at week 24. The primary endpoint was noninferiority (12% margin) of RPV/FTC/TDF compared with protease inhibitor+RTV+ two NRTIs in maintaining plasma HIV-1 RNA less than 50 copies/ml at week 24 by Snapshot analysis. RESULTS: A total of 476 participants were randomized and received at least one dose of study drug. Demographics and baseline characteristics were similar between arms. The primary objective of noninferiority at week 24 was met: HIV-1 RNA less than 50 copies/ml by Snapshot analysis, 93.7% of RPV/FTC/TDF versus 89.9% of protease inhibitor+RTV+ two NRTIs (difference 3.8%, 95% confidence interval -1.6 to 9.1%). Through week 48, 89.3% of participants in the immediate switch group maintained virologic suppression. High rates of suppression were maintained with RPV/FTC/TDF regardless of participant's pre-antiretroviral HIV-1 RNA level. Overall development of resistance mutations after switching to RPV/FTC/TDF was low. Decreases in total cholesterol, low-density lipoprotein (LDL), and triglycerides were significantly greater among RPV/FTC/TDF recipients than those in the protease inhibitor+RTV+ two NRTIs group. CONCLUSION: Switching to the STR RPV/FTC/TDF from an RTV-boosted protease inhibitor regimen in virologically suppressed, HIV-1-infected participants maintained virologic suppression with a low risk of virologic failure, while improving total cholesterol, LDL, and triglycerides.

Week 48 results from a randomized clinical trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate vs. efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1-infected adults.

OBJECTIVES: To compare the safety and efficacy of the two single-tablet regimens (STRs), rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) and efavirenz/emtricitabine/tenofovir DF (EFV/FTC/TDF), in HIV-1-infected, treatment-naive adults. DESIGN: This is a phase 3b, randomized, open-label, multicenter, international, 96-week study. METHODS: Participants were randomized 1:1 to receive either RPV/FTC/TDF or EFV/FTC/TDF. The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies/ml at week 48 by the Snapshot algorithm. RESULTS: A total of 786 participants were randomized. RPV/FTC/TDF was noninferior to EFV/FTC/TDF (85.8 vs. 81.6%) at week 48 for HIV-1 RNA less than 50 copies/ml [difference 4.1%, 95% confidence interval (CI) -1.1 to 9.2%]. A statistically significant difference in efficacy favoring RPV/FTC/TDF was demonstrated for participants with baseline HIV-1 RNA 100000  copies/ml or less [(n=510) 88.8% RPV/FTC/TDF vs. 81.6% EFV/FTC/TDF (difference 7.2%, 95% CI 1.1-13.4%)]. In participants with baseline HIV-1 RNA more than 100000 copies/ml (n=276), RPV/FTC/TDF demonstrated noninferior efficacy compared with EFV/FTC/TDF (79.9 vs. 81.7%, respectively, difference -1.8%, 95% CI -11.1 to 7.5%). In the RPV/FTC/TDF arm, more virologic failure was observed as baseline HIV-1 RNA levels increased. There were more participants with emergent resistance in the RPV/FTC/TDF arm than in the EFV/FTC/TDF arm (4 vs. 1%, respectively). There were fewer discontinuations because of adverse events with RPV/FTC/TDF (2.5%) than with EFV/FTC/TDF (8.7%). CONCLUSION: In treatment-naive participants, RPV/FTC/TDF demonstrated noninferior efficacy and improved tolerability compared with EFV/FTC/TDF, as well as a statistically significant difference in efficacy for participants with baseline HIV-1 RNA 100000  copies/ml or less at week 48.