Effectiveness of elbasvir/grazoprevir plus ribavirin for hepatitis C virus genotype 1a infection and baseline NS5A resistance.

INTRODUCTION AND OBJECTIVES: In clinical trials, patients with hepatitis C virus (HCV) genotype (GT)1a infection and baseline resistance-associated substitutions (RASs) at amino acid positions 28, 30, 31, or 93 receiving elbasvir/grazoprevir for 12 weeks achieved lower rates of sustained virologic response (SVR) than those without baseline RASs. SVR rates in patients with RASs were improved when elbasvir/grazoprevir treatment duration was extended from 12 to 16 weeks and administered concomitantly with ribavirin. MATERIALS AND METHODS: This was a retrospective, observational analysis using electronic health record abstraction. Patients with HCV GT1a infection and RASs at positions 28, 30, 31, or 93 who were prescribed 16 weeks of elbasvir/grazoprevir and ≥ 1 prescription for ribavirin were included. SVR was defined as HCV RNA below the lower limit of quantification ≥ 70 days after end of treatment. RESULTS: The primary analysis included patients with baseline RASs at positions 30, 31, or 93 (n = 76); a secondary analysis included patients with RASs at positions 28, 30, 31, or 93 (n = 93). SVR was achieved by 77.6% (59/76) of patients in the primary analysis and 80.6% (75/93) of those in the secondary analysis. Of the 18 (19.4%) patients in the secondary cohort who failed to achieve SVR, 8 relapsed (4 with treatment-emergent NS5A substitutions) and 10 did not have viral sequencing to distinguish relapse from reinfection. CONCLUSIONS: This analysis highlights the opportunities in leveraging real-world data to further understand treatment outcomes in smaller, discrete subgroups of patients with HCV infection who cannot be thoroughly evaluated in clinical trials.

Facilitating Next-Generation Pre-Exposure Prophylaxis Clinical Trials Using HIV Recent Infection Assays: A Consensus Statement from the Forum HIV Prevention Trial Design Project.

Standard-of-care HIV pre-exposure prophylaxis (PrEP) is highly efficacious, but uptake of and persistence on a daily oral pill is low in many settings. Evaluation of alternate PrEP products will require innovation to avoid the unpractically large sample sizes in noninferiority trials. We propose estimating HIV incidence in people not on PrEP as an external counterfactual to which on-PrEP incidence in trial subjects can be compared. HIV recent infection testing algorithms (RITAs), such as the limiting antigen avidity assay plus viral load used on specimens from untreated HIV positive people identified during screening, is one possible approach. Its feasibility is partly dependent on the sample size needed to ensure adequate power, which is impacted by RITA performance, the number of recent infections identified, the expected efficacy of the intervention, and other factors. Screening sample sizes to support detection of an 80% reduction in incidence for 3 key populations are more modest, and comparable to the number of participants in recent phase III PrEP trials. Sample sizes would be significantly larger in populations with lower incidence, where the false recency rate is higher or if PrEP efficacy is expected to be lower. Our proposed counterfactual approach appears to be feasible, offers high statistical power, and is nearly contemporaneous with the on-PrEP population. It will be important to monitor the performance of this approach during new product development for HIV prevention. If successful, it could be a model for preventive HIV vaccines and prevention of other infectious diseases.

A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Trial of Radiopaque Islatravir-Eluting Subdermal Implants for Pre-exposure Prophylaxis Against HIV-1 Infection.

BACKGROUND: Islatravir (MK-8591) is a deoxyadenosine analog in development for the treatment and prevention of HIV-1 infection. An islatravir-eluting implant could provide an additional option for pre-exposure prophylaxis (PrEP). SETTING: Previous data support a threshold islatravir triphosphate concentration for PrEP of 0.05 pmol/10 6 cells in peripheral blood mononuclear cells. Prototype islatravir-eluting implants were previously studied to establish general tolerability and pharmacokinetics (PKs) of islatravir relative to the threshold level. METHODS: In this randomized, double-blind, placebo-controlled, phase 1 trial, a next-generation radiopaque islatravir-eluting implant (48 mg, 52 mg, or 56 mg) or placebo implant was placed for a duration of 12 weeks in participants at low risk of HIV infection. Safety and tolerability, as well as PK for islatravir parent and islatravir triphosphate from plasma and peripheral blood mononuclear cells, were assessed throughout placement and 8 weeks after removal. RESULTS: In total, 36 participants (8 active and 4 placebo per dose arm) were enrolled and completed this study. Implants were generally well tolerated, with no discontinuations due to an adverse event, and no clear dose-dependence in implant-related adverse events. No clinically meaningful relationships were observed for changes in laboratory values, vital signs, or electrocardiogram assessments. Mean islatravir triphosphate levels at day 85 (0.101-0.561 pmol/10 6  cells) were above the PK threshold for all dose levels. CONCLUSION: Islatravir administered using a subdermal implant has the potential to be an effective and well-tolerated method for administering PrEP to individuals at risk of acquiring HIV-1.

Brief Report: Efficacy and Safety of Oral Islatravir Once Daily in Combination With Doravirine Through 96 Weeks for Treatment-Naive Adults With HIV-1 Infection Receiving Initial Treatment With Islatravir, Doravirine, and Lamivudine.

BACKGROUND: Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for treatment and prevention of HIV-1. We present efficacy and safety data for islatravir and doravirine (DOR) through 96 weeks of the phase 2b trial (NCT03272347). METHODS: In this randomized, double-blind, dose-ranging trial, participants initially received islatravir (0.25, 0.75, or 2.25 mg) with doravirine (100 mg) and lamivudine (3TC, 300 mg) or a fixed-dose combination of doravirine, 3TC, and tenofovir disoproxil fumarate (DOR/3TC/TDF) daily. Beginning at week 24, participants receiving islatravir stopped 3TC if HIV-1 RNA from the prior visit was <50 copies per milliliter and continued taking the assigned islatravir dose (still blinded) with doravirine. All islatravir groups transitioned to open-label use of 0.75 mg between weeks 60 and 84. Efficacy end points at week 96 included the proportion of participants maintaining HIV-1 RNA of <50 copies per milliliter (FDA Snapshot). Safety was assessed by adverse event (AE) reporting. RESULTS: One hundred twenty-one treatment-naive participants received the study drugs and were included in the analyses. Through week 96, HIV-1 RNA<50 copies per milliliter was maintained in 86.2% (25/29), 90.0% (27/30), and 67.7% (21/31) of participants in the 0.25-, 0.75-, and 2.25-mg islatravir groups, respectively, 81.1% (73/90) of the combined islatravir group, and 80.6% (25/31) of the DOR/3TC/TDF group. One participant in the 2.25-mg islatravir group had Protocol-Defined Virologic Failure after week 48. Drug-related AE rates were higher for DOR/3TC/TDF participants (22.6%) compared with islatravir (combined 7.8%). Two participants (2.2%) receiving islatravir with doravirine and one (3.2%) receiving DOR/3TC/TDF discontinued because of an AE. CONCLUSIONS: Treatment regimens containing islatravir and doravirine maintained viral suppression through week 96 and were well tolerated regardless of dose.

Reinfection and Risk Behaviors After Treatment of Hepatitis C Virus Infection in Persons Receiving Opioid Agonist Therapy : A Cohort Study.

BACKGROUND: Hepatitis C virus (HCV) reinfection after successful treatment may reduce the benefits of cure among people who inject drugs. OBJECTIVE: To evaluate the rate of HCV reinfection for 3 years after successful treatment among people receiving opioid agonist therapy (OAT). DESIGN: A 3-year, long-term, extension study of persons enrolled in the CO-STAR (Hepatitis C Patients on Opioid Substitution Therapy Antiviral Response) study (ClinicalTrials.gov: NCT02105688). SETTING: 55 clinical trial sites in 13 countries. PATIENTS: Aged 18 years and older with chronic HCV infection with genotypes 1, 4, or 6 receiving stable OAT. INTERVENTION: No treatments were administered. MEASUREMENTS: Serum samples were assessed for HCV reinfection. Urine drug screening was performed. RESULTS: Among 296 participants who received treatment, 286 were evaluable for reinfection and 199 were enrolled in the long-term extension study. The rate of HCV reinfection was 1.7 [95% CI, 0.8 to 3.0] per 100 person-years; 604 person-years of follow-up). A higher rate of reinfection was seen among people with recent injecting drug use (1.9 [95% CI, 0.5 to 4.8] per 100 person-years; 212 person-years). Ongoing drug use and injecting drug use were reported by 59% and 21% of participants, respectively, at the 6-month follow-up visit and remained stable during 3 years of follow-up. LIMITATIONS: Participants were required to be 80% adherent to OAT at baseline and may represent a population with higher stability and lower risk for HCV reinfection. Rate of reinfection may be underestimated because all participants did not continue in the long-term extension study; whether participants who discontinued were at higher risk for reinfection is unknown. CONCLUSION: Reinfection with HCV was low but was highest in the first 24 weeks after treatment completion and among people with ongoing injecting drug use and needle-syringe sharing. PRIMARY FUNDING SOURCE: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Islatravir in combination with doravirine for treatment-naive adults with HIV-1 infection receiving initial treatment with islatravir, doravirine, and lamivudine: a phase 2b, randomised, double-blind, dose-ranging trial.

BACKGROUND: Islatravir is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1 infection. We aimed to assess the efficacy and safety of islatravir-based regimens for the treatment of HIV-1. METHODS: We did a phase 2b, randomised, double-blind, comparator-controlled, dose-ranging trial at 24 clinics or hospitals in four countries (Chile, France, the UK, and the USA). Treatment-naive adults (≥18 years) with plasma HIV-1 RNA concentrations of at least 1000 copies per mL, CD4 T-cell counts of at least 200 cells per mL, and a calculated creatinine clearance of at least 50 mL/min (all within 60 days before study treatment) were eligible for inclusion. Participants were randomly assigned (1:1:1:1) with a block size of four via an interactive voice and web response system to receive oral treatment with one of three doses of islatravir (0·25 mg, 0·75 mg, or 2·25 mg) plus doravirine (100 mg) and lamivudine (300 mg) or to doravirine (100 mg) plus lamivudine (300 mg) plus tenofovir disoproxil fumarate (TDF; 300 mg) once daily with placebo (part 1). Treatment groups were stratified according to screening HIV-1 RNA concentration (≤100 000 copies per mL or >100 000 copies per mL). After at least 24 weeks of treatment, participants taking islatravir who achieved an HIV-1 RNA concentration lower than 50 copies per mL switched to a two-drug regimen of islatravir and doravirine (part 2). All participants and study investigators were masked to treatment in part 1; in part 2, the islatravir dose was masked to all participants and investigators, but the other drugs were given open label. The primary efficacy outcomes were the proportions of participants with an HIV-1 RNA concentration lower than 50 copies per mL at weeks 24 and 48 (US Food and Drug Administration snapshot approach). The primary safety outcomes were the number of participants experiencing adverse events and the number of participants discontinuing study drug owing to adverse events. All participants who received at least one dose of any study drug were included in the analyses. This trial is ongoing, but closed to enrolment of new participants; herein, we report study findings through 48 weeks of treatment. This trial is registered with ClinicalTrials.gov, NCT03272347. FINDINGS: Between Nov 27, 2017, and April 25, 2019, 121 participants (mean age 31 years [SD 10·9], 112 [93%] male, 92 [76%] white, 27 [22%] with HIV-1 RNA concentration >100 000 copies per mL) were randomly assigned: 29 to the 0·25 mg, 30 to the 0·75 mg, and 31 to the 2·25 mg islatravir groups, and 31 to the doravirine, lamivudine, and TDF group. At week 24, 26 (90%) of 29 participants in the 0·25 mg islatravir group, 30 (100%) of 30 in the 0·75 mg islatravir group, and 27 (87%) of 31 in the 2·25 mg islatravir group achieved HIV-1 RNA concentrations lower than 50 copies per mL compared with 27 (87%) of 31 in the doravirine plus lamivudine plus TDF group (difference 2·8%, 95% CI -14·9 to 20·4, for the 0·25 mg islatravir group; 12·9%, -1·6 to 27·5, for the 0·75 mg islatravir group; and 0·3%, -17·9 to 18·5, for the 2·25 mg islatravir group). At week 48, these data were 26 (90%) of 29 in the 0·25 mg islatravir group, 27 (90%) of 30 in the 0·75 mg islatravir group, and 24 (77%) of 31 in the 2·25 mg islatravir group compared with 26 (84%) of 31 in the doravirine plus lamivudine plus TDF group (difference 6·1%, 95% CI -12·4 to 24·4, for the 0·25 mg islatravir group; 6·2%, -12·2 to 24·6, for the 0·75 mg islatravir group; and -6·1%, -27·1 to 14·8, for the 2·75 mg islatravir group). 66 (73%) of participants in the islatravir groups combined and 24 (77%) of those in the doravirine plus lamivudine plus TDF group reported at least one adverse event. Two participants in the 2·25 mg islatravir group and one participant in the doravirine plus lamivudine plus TDF group discontinued owing to an adverse event. No deaths were reported up to week 48. INTERPRETATION: Treatment regimens containing islatravir and doravirine showed antiviral efficacy and were well tolerated regardless of dose. Doravirine in combination with islatravir has the potential to be a potent two-drug regimen that warrants further clinical development. FUNDING: Merck, Sharp, & Dohme Corp, a subsidiary of Merck & Co., Inc.

Efficacy and safety of elbasvir/grazoprevir in treatment-naive Chinese adults with hepatitis C virus infection: A randomized trial.

BACKGROUND AND AIM: In China, clinical experience with direct-acting antiviral treatments for hepatitis C virus (HCV) infection is still emerging. C-CORAL is a phase 3, multinational, placebo-controlled, double-blind trial of elbasvir/grazoprevir (EBR/GZR) in participants with HCV infection from the Asia-Pacific region and Russia. Here, we report the data from participants enrolled in China. METHODS: Treatment-naive participants with chronic HCV genotype (GT) 1, GT4, or GT6 infection were randomly assigned to receive 50 mg EBR/100 mg GZR for 12 weeks (immediate-treatment group, ITG) or placebo followed by deferred treatment with EBR/GZR (deferred-treatment group, DTG). The primary efficacy end-point was sustained virologic response at 12 weeks after completing treatment (SVR12), and the primary safety end-point was a comparison of safety between participants receiving EBR/GZR and placebo (NCT02251990; Protocol PN-5172-067). RESULTS: A total of 152 participants in China were randomly assigned (ITG, n = 115; DTG, n = 37). SVR12 was achieved in 96.7% (146/151) participants overall and in 97.3% (142/146) of those with GT1b infection. Four participants relapsed (GT1b, n = 3; GT6a, n = 1). Drug-related AEs were reported in 25 (21.7%) and 9 (24.3%) participants receiving EBR/GZR and placebo, respectively; no drug-related serious adverse events (AEs) occurred. Two (1.7%) participants receiving EBR/GZR had late hepatic transaminase elevations. Patient-reported outcomes indicate improved quality of life at follow-up week 4 in participants receiving EBR/GZR compared to placebo. CONCLUSION: EBR/GZR administered for 12 weeks represents a highly effective and safe treatment option for Chinese individuals with HCV GT1 infection.

Safety and tolerability of elbasvir/grazoprevir in chronic hepatitis C virus therapy: Integrated analysis from clinical trials.

Direct-acting antiviral treatments for chronic hepatitis C virus (HCV) infection are generally safe; however, understanding the safety profile of each regimen is essential for their continued use. Safety data were pooled from 12 clinical trials of elbasvir/grazoprevir (EBR/GZR) that enrolled adult participants with HCV infection. Pooled analyses are presented for participants receiving EBR/GZR for 12 weeks and those receiving EBR/GZR plus ribavirin (RBV) for 16-18 weeks. Safety data are also presented for participants with comorbidities receiving EBR/GZR for 12 weeks in individual clinical trials (chronic kidney disease [CKD] stage 4/5, inherited blood disorders [IBLD] or receiving opioid agonist therapy [OAT]). Among 1743 participants receiving EBR/GZR for 12 weeks, 1068 (61.3%) reported ≥1 adverse event (AE) and 491 had AEs (28.2%) considered drug-related. The most frequent AEs were headache (10.6%), fatigue (8.7%), nasopharyngitis (5.8%), nausea (5.1%) and diarrhoea (5.0%). Serious AEs were reported by 37 participants (2.1%), and 12 (0.7%) discontinued treatment due to an AE. In populations with CKD 4/5 or IBLD or receiving OAT, safety was similar in participants receiving EBR/GZR for 12 weeks and those receiving placebo. Some AEs occurred at higher frequencies in participants receiving RBV compared with those receiving EBR/GZR alone: fatigue (32.7% vs 8.7%); headache (21.6% vs 10.6%); and nausea (15.8% vs 5.1%). Safety was similar in participants with and those without cirrhosis. Grade 3/4 alanine aminotransferase elevations were reported in 0.7% participants. EBR/GZR is a safe treatment option for individuals with HCV genotype (GT) 1 or GT4 infections, even those with challenging comorbidities such as CKD or IBLD and those receiving OAT.

Elbasvir/Grazoprevir for HCV Infection in Russia: A Randomized Trial.

PURPOSE: Hepatitis C virus (HCV) infection is a major healthcare concern in Russia, where almost 5 million individuals are viremic. Elbasvir/grazoprevir is a fixed-dose combination therapy for the treatment of HCV genotype 1 and genotype 4 infection. The present analysis aimed to assess the safety and efficacy of elbasvir/grazoprevir in individuals with HCV infection enrolled at Russian study sites in the C-CORAL study. PATIENTS AND METHODS: C-CORAL (Protocol PN-5172-067; NCT02251990) was a Phase 3, placebo-controlled, double-blind study conducted throughout Asia and Russia. Treatment-naive participants with chronic HCV infection were randomly assigned to receive immediate or deferred treatment with elbasvir 50 mg/grazoprevir 100 mg once daily for 12 weeks. Participants in the immediate-treatment group received elbasvir/grazoprevir for 12 weeks, and those in the deferred-treatment group received placebo for 12 weeks, followed by open-label elbasvir/grazoprevir for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after completion of therapy (SVR12). RESULTS: One hundred and nineteen Russian participants were randomized (immediate-treatment group, n=88; deferred-treatment group, n=31). Most participants were white (99%) with HCV genotype 1b infection (97%) and mild-to-moderate (F0-F2) fibrosis (70%). SVR12 was achieved by 98.9% participants in the immediate-treatment group and by 100% of those receiving deferred elbasvir/grazoprevir in the deferred-treatment group. One participant relapsed with nonstructural protein 5A (NS5A) L28M and Y93H resistance-associated substitutions at baseline and at time of failure. Drug-related adverse events were reported by 19% of participants receiving elbasvir/grazoprevir in the immediate-treatment group and by 16% of those receiving placebo in the deferred-treatment group. No serious adverse event or deaths occurred, and no participant discontinued treatment owing to an adverse event. CONCLUSION: Elbasvir/grazoprevir for 12 weeks was highly effective in treatment-naive Russian individuals with HCV genotype 1b infection.

Efficacy and safety of elbasvir/grazoprevir for 12 weeks in people with hepatitis C virus infection aged 35 years or younger compared with older people: a retrospective integrated analysis.

Background: In the United States, the number of new cases of hepatitis C virus infection has risen in recent years, driven largely by transmission among young white adults in their 20s and 30s. Herein, we report an integrated analysis of participants with hepatitis C virus infection aged ≤35 years from 12 phase II/III clinical trials of elbasvir/grazoprevir.Methods: Treatment-naive and -experienced adults with hepatitis C virus genotype 1 or 4 infection received elbasvir (50 mg/day)/grazoprevir (100 mg/day) for 12 weeks without ribavirin. Analyses were stratified according to participant age (≤35 years vs >35 years). The primary endpoint was sustained virologic response (hepatitis C virus RNA < lower limit of quantitation at 12 weeks after completion of therapy).Results: Sustained virologic response was achieved by 98.9% (271/274) of participants aged ≤35 years and by 96.9% (2093/2160) aged >35 years. Three participants aged ≤35 years with genotype 1b infection relapsed. Eight participants with genotype 1a infection and baseline non-structural protein 5 A resistance-associated substitutions achieved sustained virologic response. Similarly, all 85 participants aged ≤35 years with genotype 1a infection and no baseline non-structural protein 5 A resistance-associated substitutions achieved sustained virologic response. Safety was favorable, with the incidence of drug-related adverse events similar in younger and older participants (30.1% vs 30.6%). One participant (0.4%) aged ≤35 years and 15 participants (0.7%) aged >35 years discontinued treatment owing to adverse events.Conclusions: Elbasvir/grazoprevir for 12 weeks was safe and highly effective in participants aged ≤35 years with hepatitis C virus genotype 1 or 4 infection.

Efficacy and safety of elbasvir/grazoprevir for 8 or 12 weeks for hepatitis C virus genotype 4 infection: A randomized study.

BACKGROUND & AIMS: Hepatitis C virus (HCV) genotype (GT) 4 infection is prevalent in sub-Saharan Africa and the Middle East, particularly in Egypt. This study evaluated the safety and efficacy of elbasvir/grazoprevir administered for 8 and 12 weeks in participants with HCV GT4 infection. METHODS: In this partially randomized, open-label multicentre study conducted in France (NCT03111108; Protocol MK5172-096), treatment-naive participants with GT4 infection and F0-F2 fibrosis were randomized 2:1 to elbasvir (50 mg)/grazoprevir (100 mg) for 8 or 12 weeks. Treatment-naive participants with F3-F4 fibrosis and all treatment-experienced participants (F0-F4) were assigned to elbasvir/grazoprevir for 12 weeks. The primary endpoint was sustained virologic response (SVR) 12 weeks after the end of therapy. RESULTS: One hundred and seventeen participants were enrolled. Among treatment-naive participants with F0-F2 fibrosis, SVR was achieved by 94% (50/53) and 96% (26/27) of those receiving elbasvir/grazoprevir for 8 or 12 weeks, respectively, and four participants relapsed. In the 12-week arm, 95% (35/37) achieved SVR and two participants relapsed. NS5A resistance-associated substitutions were present at baseline and virologic failure in five of the participants with relapse. Drug-related adverse events occurred in 42% (n = 22) and 50% (n = 32) of participants receiving 8 and 12 weeks of treatment, respectively. No participant discontinued treatment owing to an adverse event. CONCLUSION: These data confirm the efficacy of elbasvir/grazoprevir administered for 12 weeks in treatment-experienced individuals with HCV GT4 infection and those with advanced fibrosis. Treatment-naive individuals with mild fibrosis can be treated effectively with an 8-week regimen.

Elbasvir/grazoprevir in women with hepatitis C virus infection taking oral contraceptives or hormone replacement therapy.

INTRODUCTION: Some direct-acting antiviral regimens for hepatitis C virus (HCV) infection pose safety or efficacy concerns if coadministered with drugs containing ethinyl estradiol. The present analysis was conducted to examine the impact of concomitant oral contraceptive pills (OCP) or hormone replacement therapy (HRT) during treatment with elbasvir (EBR)/grazoprevir (GZR) in women with HCV genotype (GT)1 or GT4 infection. METHODS: This is a post hoc, integrated retrospective analysis of female participants with HCV GT1 or GT4 infection who received EBR 50 mg/GZR 100 mg once daily for 12 weeks in phase 2/3 clinical trials. The primary end point was sustained virologic response at 12 weeks after therapy completion (SVR12). For this analysis, participants were stratified according to whether they received OCP or HRT during the original treatment study. RESULTS: A total of 1,022 women with HCV GT1 or GT4 infection were included (receiving OCP/HRT, n=81; not receiving OCP/HRT, n=941). Most participants receiving OCP/HRT were treatment-naive (79%), noncirrhotic (91.4%), and aged >35 years (71.6%). SVR12 rates were similar in women receiving OCP/HRT and those not receiving OCP/HRT (95.1% vs 96.3%). SVR12 rates remained high across all subgroups within the population receiving OCP/HRT: SVR12 rates were 94.6%, 100%, and 100% in participants with GT1a, GT1b, and GT4 infection, and all women aged 18-35 years achieved SVR (21/21). Treatment-related adverse events occurred in 40.7% (33/81) and 30.1% (283/941) of women receiving and those not receiving OCP/HRT, respectively. CONCLUSION: The efficacy and safety of EBR/GZR administered for 12 weeks was similar in women receiving OCP/HRT and those not on OCP/HRT. These data indicate that EBR/GZR can be safely used for the treatment of HCV GT1 or GT4 infection in women receiving concomitant OCP/HRT.

The pharmacogenetics of OATP1B1 variants and their impact on the pharmacokinetics and efficacy of elbasvir/grazoprevir.

Aim: To evaluate the effect of SLCO1B1 genetic variants on grazoprevir pharmacokinetics and efficacy. Methods: A retrospective analysis of 1578 hepatitis C virus-infected participants from ten Phase II/III clinical trials. Results: Relative to noncarriers of the risk allele, geometric mean ratios (95% CI) of grazoprevir area under curve (AUC)0-24 were: rs4149056 (risk allele C), one copy, 1.13 (1.06-1.21), two copies, 1.43 (1.16-1.77); and rs11045819 (risk allele A), one copy, 0.93 (0.87-1.00); two copies, 0.78 (0.61-1.00). The rs2306283 variant was not associated with grazoprevir exposure. None of the SLCO1B1 variants were associated with sustained virologic response. Conclusion: Genetic variants in SLCO1B1 were associated with modest changes in grazoprevir pharmacokinetics, but not with meaningful differences in efficacy.

Efficacy and safety of a two-drug direct-acting antiviral agent regimen ruzasvir 180 mg and uprifosbuvir 450 mg for 12 weeks in adults with chronic hepatitis C virus genotype 1, 2, 3, 4, 5 or 6.

Ruzasvir (MK-8408, an NS5A inhibitor) and uprifosbuvir (MK-3682, a nonstructural protein 5B nucleotide inhibitor) are highly potent direct-acting antiviral agents for the treatment of hepatitis C virus (HCV) infection. A phase III clinical trial evaluating the two-drug combination of ruzasvir 60 mg plus uprifosbuvir 450 mg suggested suboptimal efficacy in certain HCV genotypes (C-BREEZE 1; NCT02759315). The aim of the present study was to evaluate the efficacy and safety of ruzasvir in combination with uprifosbuvir administered at a higher dose than that assessed in the earlier study (C-BREEZE 2: NCT02956629/Merck protocol PN041). Treatment-naïve or interferon (with or without ribavirin)-experienced participants with or without compensated cirrhosis were enrolled. All participants received ruzasvir 180 mg plus uprifosbuvir 450 mg once daily for 12 weeks. The primary objectives were the proportion of participants with HCV RNA <15 lU/mL at 12 weeks after the end of study therapy (SVR12), and safety and tolerability of the study drug. Overall, 282 participants were enrolled. SVR12 (n/N) was 91.3% (42/46) in participants infected with HCV genotype (GT) 1a; GT1b, 96.7% (29/30); GT2, 91.5% (43/47); GT3, 73.8% (45/61); GT4, 98.2% (55/56); GT5, 100.0% (18/18); and GT6, 90.9% (20/22). Adverse events (AEs) were reported by 61.3% of participants; drug-related AEs were reported by 33.3%. The most frequent (≥5% of participants) drug-related AEs in all participants were fatigue (7.8%) and headache (7.4%). In conclusion, the two-drug combination of ruzasvir 180 mg plus uprifosbuvir 450 mg for 12 weeks was highly effective and well tolerated in participants infected with HCV GT1, GT2, GT4, GT5 and GT6, with a lower efficacy in GT3-infected persons.

Efficacy and Safety of Elbasvir/Grazoprevir in Hepatitis C Virus GT1- and GT4-Infected People Aged 65 Years or Older.

Background: In elderly individuals aged ≥65 years with hepatitis C virus (HCV) infection, efficacious and safe HCV therapy is complicated by frequent comorbidities and concomitant medications. The aim of this analysis was to evaluate the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) in people aged ≥65 years. Methods: This is an integrated retrospective analysis of EBR/GZR administered for 12 weeks in participants with HCV genotype 1 or 4 infection enrolled in 12 Phase 2/3 clinical trials. The primary end point was sustained virologic response 12 weeks after completing therapy (SVR12; HCV RNA below the lower limit of quantification). Results: Most participants aged ≥65 years were receiving ≥1 concomitant medication (322/339; 95.0%) and had ≥1 comorbidity (334/339; 99%). SVR12 rates were 95.3% (323/339) in participants aged ≥65 years and 95.4% (2,041/2,139) in those aged <65 years. Rates of adverse events, drug-related adverse events, serious adverse events, and discontinuations were similar in participants aged ≥65 years and those aged <65 years. In participants aged ≥65 years, median estimated glomerular filtration rate was similar at baseline and at the end of treatment. Conclusion: The efficacy and safety of EBR/GZR were similar in participants with HCV infection aged ≥65 years and those aged <65 years.

Efficacy and safety of ruzasvir 60 mg and uprifosbuvir 450 mg for 12 weeks in adults with chronic hepatitis C virus genotype 1, 2, 3, 4 or 6 infection.

In clinical trials, the three-drug regimen of ruzasvir (RZR) 60 mg, uprifosbuvir (UPR) 450 mg and grazoprevir 100 mg, with or without ribavirin, has demonstrated promising efficacy and excellent tolerability across a wide range of hepatitis C virus (HCV)-infected individuals. The present study assessed the efficacy and safety of the two-drug combination of RZR 60 mg plus UPR 450 mg administered for 12 weeks in participants with HCV genotype (GT) 1-6 infection. In this open-label clinical trial, treatment-naive or -experienced and cirrhotic or noncirrhotic participants with chronic HCV GT1-6 infection received RZR 60 mg plus UPR 450 mg orally once daily for 12 weeks (NCT02759315/protocol PN035). The primary efficacy endpoint was sustained virologic response at 12 weeks after the end of therapy (SVR12). One hundred and sixty participants were enrolled. SVR12 rates were 96% (52 of 54) in participants with GT1a infection; 100% (15 of 15) in those with GT1b infection; 97% (28 of 29) in those with GT2 infection; 77% (30 of 39) in those with GT3 infection; 90% (18 of 20) in those with GT4 infection; and 67% (2 of 3) in those with GT6 infection. Drug-related adverse events (AEs) reported by >5% of participants were fatigue (n = 10, 6.3%) and diarrhoea (n = 9, 5.6%). Five participants reported a total of 11 serious AEs, none considered drug-related. One participant experienced on-treatment alanine aminotransferase/aspartate aminotransferase elevations that resolved without intervention. Data from the present study indicate that the combination of RZR 60 mg plus UPR 450 mg once daily for 12 weeks was well tolerated overall but was effective only for certain genotypes.

Safety and efficacy of elbasvir/grazoprevir in Asian participants with hepatitis C virus genotypes 1 and 4 infection.

BACKGROUND AND AIM: Estimates suggest that in Asia, more than 31 million individuals have hepatitis C virus infection. The present analysis was conducted to assess the efficacy and safety of elbasvir/grazoprevir in Asian participants enrolled in the elbasvir/grazoprevir phase 2/3 clinical trials. METHODS: This is an integrated analysis of data from 12 international phase 2/3 clinical trials. Asian participants with chronic hepatitis C virus genotype 1 or 4 infection who received elbasvir 50 mg/grazoprevir 100 mg once daily for 12 weeks or elbasvir/grazoprevir plus ribavirin for 16 weeks were included in this analysis. The primary end point was sustained virologic response at 12 weeks after completion of therapy (SVR12). RESULTS: Seven hundred eighty Asian participants from 15 countries were included in this analysis. SVR12 was achieved by 756/780 (96.9%) of all participants, including 748/772 (96.9%) of those who received elbasvir/grazoprevir for 12 weeks and 8/8 (100%) of those who received elbasvir/grazoprevir plus ribavirin for 16 weeks. In the genotype 1b-infected population, the SVR12 rate was 691/709 (97.5%), and there was no impact of age, high baseline viral load, or presence of cirrhosis. The most frequently reported adverse events were nasopharyngitis (8.0%), upper respiratory tract infection (5.4%), and diarrhea (5.2%). Twenty participants receiving elbasvir/grazoprevir for 12 weeks reported a total of 25 serious adverse events, and 7 (0.9%) discontinued treatment because of an adverse event. CONCLUSION: Elbasvir/grazoprevir administered for 12 weeks is an effective and generally well-tolerated treatment option for Asian individuals with hepatitis C virus genotype 1b infection.

Efficacy and safety of elbasvir/grazoprevir in participants with hepatitis C virus genotype 1, 4, or 6 infection from the Asia-Pacific region and Russia: Final results from the randomized C-CORAL study.

BACKGROUND AND AIM: Although treatment with direct-acting antivirals has dramatically improved morbidity and mortality attributable to chronic hepatitis C virus infection, universal access to these medicines has been slow in the Asia-Pacific region and Russia. This study evaluated efficacy and safety of elbasvir/grazoprevir in participants with hepatitis C virus infection from Asia-Pacific countries and Russia (C-CORAL). METHODS: C-CORAL was a phase 3, randomized, placebo-controlled study (NCT02251990). Treatment-naive, HIV-negative, cirrhotic and non-cirrhotic participants with chronic hepatitis C genotype 1, 4, or 6 infection were randomized to elbasvir 50 mg/grazoprevir 100 mg once daily for 12 weeks (immediate-treatment group) or placebo followed by deferred treatment with elbasvir/grazoprevir (deferred-treatment group). The primary efficacy outcome was sustained virologic response at 12 weeks, and the primary safety outcome was a comparison between the immediate-treatment group and placebo phase of the deferred-treatment group. RESULTS: A total of 489 participants were randomized (immediate-treatment group, n = 366; deferred-treatment group, n = 123). Sustained virologic response at 12 weeks in the combined immediate/deferred-treatment groups was 94.4% (459/486; 95% confidence interval = 92.4-96.5%). Sustained virologic response at 12 weeks was 98.2% in participants with genotype 1b, 91.9% with genotype 1a, and 66.7% with genotype 6 infection. Similar rates of adverse events and drug-related adverse events were seen in the immediate-treatment group versus placebo phase of the deferred-treatment group (51.0% vs 50.4% and 21.4% vs 21.1%). CONCLUSIONS: Elbasvir/grazoprevir for 12 weeks represents an effective and well-tolerated treatment option for treatment-naive people with genotype 1 infection from Asia-Pacific countries and Russia.

Elbasvir/grazoprevir and sofosbuvir for hepatitis C virus genotype 3 infection with compensated cirrhosis: A randomized trial.

Many direct-acting antiviral regimens have reduced activity in people with hepatitis C virus (HCV) genotype (GT) 3 infection and cirrhosis. The C-ISLE study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) plus sofosbuvir (SOF) with and without ribavirin (RBV) in compensated cirrhotic participants with GT3 infection. This was a phase 2, randomized, open-label study. Treatment-naive participants received EBR/GZR + SOF + RBV for 8 weeks or EBR/GZR + SOF for 12 weeks, and peginterferon/RBV treatment-experienced participants received EBR/GZR + SOF ± RBV for 12 weeks or EBR/GZR + SOF for 16 weeks. The primary endpoint was HCV RNA <15 IU/mL 12 weeks after the end of treatment (sustained virologic response at 12 weeks [SVR12]). Among treatment-naive participants, SVR12 was 91% (21/23) in those treated with RBV for 8 weeks and 96% (23/24) in those treated for 12 weeks. Among treatment-experienced participants, SVR12 was 94% (17/18) and 100% (17/17) in the 12-week arm, with and without RBV, respectively, and 94% (17/18) in the 16-week arm. Five participants failed to achieve SVR: 2 relapsed (both in the 8-week arm), 1 discontinued due to vomiting/cellulitis (16-week arm), and 2 discontinued (consent withdrawn/lost to follow-up). SVR12 was not affected by the presence of resistance-associated substitutions (RASs). There was no consistent change in insulin resistance, and 5 participants reported serious adverse events (pneumonia, chest pain, opiate overdose, cellulitis, decreased creatinine). High efficacy was demonstrated in participants with HCV GT3 infection and cirrhosis. Treatment beyond 12 weeks was not required, and efficacy was maintained regardless of baseline RASs. CONCLUSION: Data from this study support the use of EBR/GZR plus SOF for 12 weeks without RBV for treatment-naive and peginterferon/RBV-experienced people with GT3 infection and cirrhosis (ClinicalTrials.gov NCT02601573). (Hepatology 2018;67:2113-2126).