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.

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.

The accuracy of baseline viral load for predicting the efficacy of elbasvir/grazoprevir in participants with hepatitis C virus genotype 1a infection: An integrated analysis.

European treatment guidelines for hepatitis C virus (HCV) infection recommend that people with genotype (GT) 1a infection and baseline viral load ≤800 000 IU/mL receive elbasvir/grazoprevir (EBR/GZR) for 12 weeks, and those with baseline viral load >800 000 IU/mL receive EBR/GZR plus ribavirin for 16 weeks. This analysis was conducted to clarify whether baseline viral load can serve as an accurate, sensitive or specific stratification factor for defining EBR/GZR regimens. In this post hoc, integrated analysis, participants with GT1a infection who received EBR 50 mg/GZR 100 mg for 12 weeks were stratified according to baseline viral load. Sustained virologic response at 12 weeks post-treatment was achieved by 95.2% (911/957) of participants and was higher among participants with baseline viral load ≤800 000 IU/mL vs >800 000 IU/mL (98.5% vs 93.9%). The 800 000 IU/mL threshold had a positive predictive value of 98.5%, a negative predictive value of 6.1%, a specificity of 91.3%, a sensitivity of 28.4% and an overall accuracy of 31.5%. A baseline viral load cutpoint of 800 000 IU/mL had high positive predictive value and specificity but poor negative predictive value, sensitivity and accuracy in predicting treatment outcomes in this population. Baseline NS5A resistance-associated substitutions (RASs) were detected in 25% (1/4) of virologic failures with baseline viral load ≤800 000 IU/mL and 59.5% (25/42) of those with baseline viral load >800 000 IU/mL. Overall, these data suggest that, compared with the use of a baseline viral load cutpoint, baseline testing for NS5A RASs enables more individuals to receive the 12-week EBR/GZR regimen without compromising the opportunity for SVR.

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.

KEYNOTE-585: Phase III study of perioperative chemotherapy with or without pembrolizumab for gastric cancer.

BACKGROUND: Surgical resection is the only curative treatment option for gastric cancer. Despite widespread adoption of multimodality perioperative treatment strategies, 5-year overall survival rates remain low. In patients with advanced gastric or gastroesophageal junction adenocarcinoma, pembrolizumab has demonstrated promising efficacy and manageable safety as monotherapy in previously treated patients and as first-line therapy in combination with cisplatin and 5-fluorouracil. Combining chemotherapy with pembrolizumab in the neoadjuvant/adjuvant setting may benefit patients with locally advanced, resectable disease. AIM: To describe the design and rationale for the global, multicenter, randomized, double-blind, Phase III KEYNOTE-585 study to evaluate the efficacy and safety of pembrolizumab plus chemotherapy compared with placebo plus chemotherapy as neoadjuvant/adjuvant treatment for localized gastric or gastroesophageal junction adenocarcinoma. ClinicalTrials.gov : NCT03221426.

Safety and Efficacy of Elbasvir/Grazoprevir in Patients With Hepatitis C Virus Infection and Compensated Cirrhosis: An Integrated Analysis.

BACKGROUND & AIMS: Persons with hepatitis C virus (HCV) infection are at risk of progressive liver disease, cirrhosis, and decompensation. We analyzed the effects of the direct-acting antiviral agents elbasvir and grazoprevir in patients with HCV infection and compensated cirrhosis, combining data from 6 clinical trials. METHODS: We performed an integrated analysis of 402 patients with HCV genotype 1, 4, or 6 infection and Child-Pugh A compensated cirrhosis enrolled in 6 clinical trials. All patients received elbasvir/grazoprevir 50 mg/100 mg once daily, with or without ribavirin, for 12-18 weeks. The primary end point was sustained virologic response 12 weeks after completion of therapy (SVR12), defined as a level of HCV RNA <15 IU/mL. RESULTS: Among treatment-naïve and treatment-experienced patients receiving elbasvir/grazoprevir for 12 weeks, 97.8% (135 of 138) and 88.9% (48 of 54) achieved SVR12, respectively. Among patients receiving elbasvir/grazoprevir for 12 weeks, addition of ribavirin did not increase the proportion of treatment-naïve patients (90.3%, 28 of 31) or treatment-experienced patients who achieved an SVR12 (91.4%, 74 of 81). All (49 of 49) treatment-experienced patients receiving elbasvir/grazoprevir with ribavirin for 16 or 18 weeks, and 93.9% (46 of 49) of patients receiving elbasvir/grazoprevir without ribavirin for 16 or 18 weeks achieved SVR12. Virologic failure was higher among patients with HCV genotype 1a infections compared with patients with genotype 1b or 4 infections, particularly in patients who had not responded to previous interferon therapy. Baseline tests for resistance-associated substitutions (RASs) led to an individualized approach for selecting treatment duration and established a need for ribavirin for patients with HCV genotype 1a infection and RASs, regardless of treatment history. Among patients with HCV genotype 1a infection with and without baseline RASs in HCV nonstructural protein 5A who received elbasvir/grazoprevir for 12 weeks, 73% (8 of 11) and 98% (96 of 98) achieved SVR12, respectively. Both patients with HCV genotype 1a infection with baseline RASs who received 16 or 18 weeks of elbasvir/grazoprevir and ribavirin achieved SVR12. Grade 3 or 4 increases in levels of alanine aminotransferase and aspartate aminotransferase, which did not cause symptoms, were reported in 2.3% (6 of 264) of patients receiving elbasvir/grazoprevir. Serious adverse events were reported in 3% (8 of 264) patients and no patient had a decompensation-related event. CONCLUSIONS: In an analysis of data from 6 clinical trials, rates of SVR12 ranged from 89% to 100% in patients with HCV genotype 1, 4, or 6 infections and compensated cirrhosis treated with elbasvir/grazoprevir, with or without ribavirin. Addition of ribavirin to a 12-week regimen of elbasvir/grazoprevir had little effect on the proportion of treatment-naïve or treatment-experienced patients who achieved an SVR12. However, virologic failure did not occur in any treatment-experienced patients when the duration of elbasvir/grazoprevir and ribavirin therapy was extended to 16 or 18 weeks. Baseline analysis of RASs (or in the absence of this test, a history of nonresponse to interferon) can be used to determine treatment duration and the need for ribavirin in patients with HCV genotype 1a infection. Clinicaltrials.gov ID: NCT02092350, NCT02105662, NCT02105467, NCT02105701, NCT01717326, and NCT02105454.

Elbasvir/grazoprevir in black adults with hepatitis C virus infection: a pooled analysis of phase 2/3 clinical trials.

OBJECTIVES: Although direct-acting antiviral regimens have dramatically improved the treatment of hepatitis C virus (HCV) infection, there is some evidence that black race may be an independent predictor of treatment failure. We report a retrospective analysis of black participants receiving elbasvir/grazoprevir (EBR/GZR) in nine phase 2/3 clinical trials. METHODS: Black participants with chronic HCV genotype 1 or 4 (GT1 or GT4) infection who received EBR 50 mg/GZR 100 mg once daily for 12 weeks, or in combination with ribavirin for 16 weeks, were included. The primary end point was sustained virologic response 12 weeks after completion of therapy (SVR12, HCV RNA < 15 IU/mL). RESULTS: Compared with nonblack participants (n = 1310), black participants (n = 332) were more likely to have chronic kidney disease stage 4/5 (9.2% vs. 31.0%, respectively), while other comorbidities were similar between the groups. In black and nonblack participants receiving EBR/GZR for 12 weeks, SVR12 rates were 93.7% (282/301) and 94.2% (1072/1138) in those with GT1 infection, and 93.8% (15/16) and 94.6% (88/93) in those with GT4 infection. SVR12 was 100.0% (15/15) in black participants and 97.5% (77/79) in nonblack participants with GT1 infection receiving EBR/GZR plus ribavirin for 16 weeks. Rates of drug-related adverse events (AEs) were 30% vs. 36.6%, and serious AEs were 7.6% vs. 3.4% in black and nonblack participants, respectively. CONCLUSION: EBR/GZR showed high efficacy in black participants with HCV GT1 or GT4 infection and was generally well tolerated, with a safety profile similar to that reported overall in phase 2/3 clinical trials.

Elbasvir/Grazoprevir for Patients With Hepatitis C Virus Infection and Inherited Blood Disorders: A Phase III Study.

Direct-acting antiviral agents have not been studied exclusively in patients with inherited blood disorders and hepatitis C virus (HCV) infection. The objective of the randomized, placebo-controlled, phase III C-EDGE IBLD study was to assess the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) in patients with inherited bleeding disorders and HCV infection. One hundred fifty-nine adults with HCV infection and sickle cell anemia, thalassemia, or hemophilia A/B or von Willebrand disease were enrolled at 31 study sites in the United States, Europe, Australia, Canada, Israel, and Thailand. Patients were given an oral, once-daily, fixed-dose combination of EBR/GZR 50 mg/100 mg for 12 weeks and randomized to the immediate-treatment group (ITG) or deferred-treatment group (DTG; placebo followed by active treatment). The primary endpoints were the proportion of patients in the ITG with unquantifiable HCV RNA 12 weeks posttreatment (sustained virological response 12 weeks after completion of study treatment; SVR12) and the comparison of safety in the ITG and DTG. In the ITG, 100 of 107 patients (93.5%) achieved SVR12, 6 relapsed, and 1 was lost to follow-up. SVR12 was achieved in 94.7% (18 of 19), 97.6% (40 of 41), and 89.4% (42 of 47) of patients with sickle cell disease, ß-thalassemia, and hemophilia A/B or von Willebrand disease, respectively. Serious adverse events were reported by 2.8% (n = 3) and 11.5% (n = 6) of patients in the ITG and DTG, respectively. Hemoglobin levels and international normalized ratio values were similar in patients receiving EBR/GZR and placebo; among patients with hemoglobinopathies, change in mean hemoglobin levels was similar in those receiving EBR/GZR compared to those receiving placebo. CONCLUSION: These results add to the expanding pool of data available for EBR/GZR, indicating a high level of efficacy and favorable tolerability in patients with HCV infection. (Hepatology 2017;66:736-745).

Short-duration treatment with elbasvir/grazoprevir and sofosbuvir for hepatitis C: A randomized trial.

Direct-acting antiviral agents (DAAs) represent the standard of care for patients with hepatitis C virus (HCV) infection. Combining DAAs with different mechanisms may allow for shorter treatment durations that are effective across multiple genotypes. The aim of the C-SWIFT study was to identify the minimum effective treatment duration across multiple genotypes. C-SWIFT was an open-label, single-center trial in treatment-naïve patients with chronic HCV genotype (GT)1 or 3 infection. All patients received elbasvir (EBR) 50 mg/grazoprevir (GZR) 100 mg with sofosbuvir (SOF) 400 mg for 4-12 weeks. Patients with GT1 infection who failed therapy were eligible for retreatment with EBR/GZR+SOF and ribavirin for 12 weeks. The primary efficacy endpoint was sustained virological response [SVR]12 (SVR of HCV RNA <15 IU/mL 12 weeks after the end of therapy). Rates of SVR12 were 32% (10 of 31) and 87% (26 of 30) in patients without cirrhosis with GT1 infection treated for 4 and 6 weeks and 80% (16 of 20) and 81% (17 of 21) in GT1-infected patients with cirrhosis treated for 6 and 8 weeks. Among GT3-infected patients without cirrhosis, SVR12 was 93% (14 of 15) and 100% (14 of 14) after 8 and 12 weeks. SVR12 in GT3-infected patients with cirrhosis was 83% (10 of 12) after 12 weeks of treatment. Twenty-three GT1-infected patients who relapsed following initial treatment completed retreatment; all achieved SVR12. In the initial treatment phase, there was one serious adverse event of pneumonia, which led to treatment discontinuation, and during retreatment, 1 patient discontinued ribavirin because of pruritus. CONCLUSION: Data from this study support the use of 8-week treatment regimens that maintain high efficacy, even for patients with HCV GT3 infection. Retreatment of patients who failed short-duration therapy was achieved through extended treatment duration and addition of ribavirin. (Hepatology 2017;65:439-450).

Efficacy of elbasvir and grazoprevir in participants with hepatitis C virus genotype 4 infection: A pooled analysis.

BACKGROUND & AIMS: The aim of this integrated analysis was to assess the efficacy of the once-daily combination of elbasvir 50 mg and grazoprevir 100 mg, with and without ribavirin in HCV genotype 4 (GT4)-infected participants enrolled in the Phase 2/3 clinical programme with elbasvir/grazoprevir. METHODS: Treatment-naïve and treatment-experienced participants 18 years of age or older with chronic HCV GT4 infection and baseline HCV RNA ≥10 000 IU/mL were included in the analysis. The analysis population was the full analysis set (FAS; all participants who received at least 1 dose of study medication) and a total of 155 HCV GT4 participants were evaluated. The primary endpoint was sustained virologic response at week 12 (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the completion of study therapy). RESULTS: Overall, among GT4-infected participants treated with 12 or 16 weeks of elbasvir/grazoprevir ± ribavirin, the SVR12 efficacy rates were 96.4% (107/111) in treatment-naïve participants and 88.6% (39/44) in treatment-experienced participants. The SVR12 rates were 96.0% (97/101) in treatment-naïve participants treated with 12 weeks of elbasvir/grazoprevir and 100% (8/8) in treatment-experienced participants treated with 16 weeks of elbasvir/grazoprevir plus ribavirin. Efficacy was not impacted by GT4 subtype. CONCLUSIONS: The regimens of 12 weeks of elbasvir/grazoprevir without ribavirin, and 16 weeks of elbasvir/grazoprevir plus ribavirin, were efficacious in HCV GT4-infected treatment-naïve and treatment-experienced participants respectively. Baseline NS5A resistance-associated substitutions did not impact the efficacy of elbasvir/grazoprevir in GT4-infected participants.

Elbasvir/grazoprevir does not worsen renal function in patients with hepatitis C virus infection and pre-existing renal disease.

AIM: Treatment options have been limited for patients with hepatitis C virus (HCV) infection and chronic kidney disease stage 4/5 (CKD 4/5). The aim of this analysis was to evaluate the impact of elbasvir/grazoprevir (EBR/GZR) on estimated glomerular filtration rate (eGFR) in patients with CKD stage 3 enrolled in phase II/III clinical trials. METHODS: We undertook a retrospective integrated analysis of patients with CKD 3 enrolled in the EBR/GZR phase II/III clinical trials. All patients were required to have chronic HCV infection and have received EBR 50 mg/GZR 100 mg, with or without ribavirin, for 8-18 weeks. Patients with CKD 3 (eGFR <60 to ≥30 mL/min/1.73 m2 ) at baseline plus ≥1 eGFR assessment postbaseline were included. In all studies, the primary endpoint was sustained virologic response 12 weeks after completion of therapy. RESULTS: Thirty-two patients with CKD 3 were identified from a pooled dataset of 1689 patients enrolled in the EBR/GZR clinical trial program. Thirty-one (97%) patients achieved SVR12 and one patient relapsed. In these 32 patients, there was no decline in median eGFR at the end of treatment or at follow-up week 12 compared with baseline. Median eGFR values were 56 mL/min/1.73 m2 (range, 45-59) at baseline, 58 mL/min/1.73 m2 (range, 41-78) at the end of treatment and 59 mL/min/1.73 m2 (range, 38-78) 12 weeks after completing treatment. DISCUSSION: Elbasvir/grazoprevir is a safe and effective treatment option for patients with compromised renal function, irrespective of baseline eGFR.

Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial.

BACKGROUND: Both hepatitis C virus (HCV) mono-infected and HIV/HCV co-infected patients are in need of safe, effective, all-oral HCV regimens. In a phase 2 study we aimed to assess the efficacy and safety of grazoprevir (MK-5172; HCV NS3/4A protease inhibitor) and two doses of elbasvir (MK-8742; HCV NS5A inhibitor) in patients with HCV mono-infection and HIV/HCV co-infection. METHODS: The C-WORTHY study is a phase 2, multicentre, randomised controlled trial of grazoprevir plus elbasvir with or without ribavirin in patients with HCV; here, we report findings for previously untreated (genotype 1) patients without cirrhosis who were HCV mono-infected or HIV/HCV co-infected. Eligible patients were previously untreated adults aged 18 years or older with chronic HCV genoype 1 infection and HCV RNA at least 10 000 IU/mL in peripheral blood without evidence of cirrhosis, hepatocellular carcinoma, or decompensated liver disease. In part A of the study we randomly assigned HCV-mono-infected patients to receive 12 weeks of grazoprevir (100 mg) plus elbasvir (20 mg or 50 mg) with or without ribavirin (arms A1-3); in part B we assigned HCV-mono-infected patients to 8 or 12 weeks of grazoprevir (100 mg) plus elbasvir (50 mg) with or without ribavirin (arms B1-3) and HIV/HCV co-infected patients to 12 weeks of therapy with or without ribavirin. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL 12 weeks after end of treatment (SVR12). Randomisation was by presence or absence of ribavirin, 8 or 12 weeks of treatment, and dosage of elbasvir. Patients were stratified by gentoype 1a versus 1b. The patients, investigators, and study site personnel were masked to treatment group assignements but the funder was not. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01717326. FINDINGS: 218 patients with HCV mono-infection (n=159) and HIV/HCV co-infection (n=59) were enrolled. SVR12 for patients treated for 12 weeks with or without ribavirin ranged from 93-98% in mono-infected and 87-97% in co-infected patients. SVR12 rates in mono-infected and co-infected patients treated for 12 weeks without ribavirin were 98% (95% CI 88-100; 43/44) and 87% (95% CI 69-96; 26/30), respectively, and with ribavirin were 93% (95% CI 85-97; 79/85) and 97% (95% CI 82-100; 28/29), respectively. Among mono-infected patients with genotype 1a infection treated for 8 weeks, SVR12 was 80% (95% CI 61-92; 24/30). Five of six patients who discontinued early for reasons other than virological failure had HCV RNA less than 25 IU/mL at their last study visit. Virological failure among patients treated for 12 weeks occurred in seven patients (7/188, 4%) and was associated with emergence of resistance-associated variants to one or both drugs. The safety profile of grazoprevir plus elbasvir with or without ribavirin was similar in mono-infected and co-infected patients. No patient discontinued due to an adverse event or laboratory abnormality. The most common adverse events were fatigue (51 patients, 23%), headache (44, 20%), nausea (32, 15%), and diarrhoea (21, 10%). INTERPRETATION: Once-daily grazoprevir plus elbasvir with or without ribavirin for 12 weeks in previously untreated HCV-mono-infected and HIV/HCV-co-infected patients without cirrhosis achieved SVR12 rates of 87-98%. These results support the ongoing phase 3 development of grazoprevir plus elbasvir. FUNDING: Merck & Co, Inc.

Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial.

BACKGROUND: There is a high medical need for an interferon-free, all-oral, short-duration therapy for hepatitis C virus (HCV) that is highly effective across diverse patient populations, including patients with cirrhosis or previous null response to pegylated interferon (peginterferon) plus ribavirin (PR-null responders). We aimed to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response. METHODS: The C-WORTHY trial is a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without ribavirin; here we report findings for two cohorts of previously untreated patients with cirrhosis (cohort 1) and those with previous PR-null response with or without cirrhosis (cohort 2) enrolled in part B of the study. Eligible patients were adults aged 18 years or older with chronic HCV genotype 1 infection and HCV RNA concentrations of 10 000 IU/mL or higher in peripheral blood. We randomly assigned patients to receive grazoprevir (100 mg daily) and elbasvir (50 mg daily) with or without ribavirin for 12 or 18 weeks. Randomisation was done centrally with an interactive voice response system; patients and study investigators were masked to treatment duration up to week 12 but not to treatment allocation. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL at 12 weeks after end of treatment (SVR12), assessed by COBAS TaqMan version 2.0. This study is registered with ClinicalTrials.gov, number NCT01717326. FINDINGS: We describe findings for 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with ribavirin and 29 with no ribavirin) and 63 to the 18-week regimen (32 with ribavirin and 31 with no ribavirin); in cohort 2, we randomly assigned 65 patients to the 12-week regimen (32 with ribavirin and 33 with no ribavirin) and 65 to the 18-week regimen (33 with ribavirin and 32 with no ribavirin. High SVR12 rates were achieved irrespective of the use of ribavirin or extension of the treatment duration from 12 to 18 weeks; SVR12 rates ranged from 90% (95% CI 74-98; 28/31; cohort 1, 12 weeks, ribavirin-containing) to 100% (95% CI 89-100; 33/33; cohort 2, 18 weeks, ribavirin-containing). Among patients treated for 12 weeks with grazoprevir plus elbasvir without ribavirin, 97% (95% CI 82-100, 28/29) of patients in cohort 1 and 91% (76-98, 30/33) of patients in cohort 2 achieved SVR12. Adverse events reported in more than 10% of patients were fatigue (66 patients, 26% [95% CI 21-32]), headache (58 patients, 23% [95% CI 18-29]), and asthenia (35 patients, 14% [95% CI 10-19]). INTERPRETATION: Treatment with grazoprevir plus elbasvir, both with and without ribavirin and for both 12 and 18 weeks' treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis. These results support the phase 3 development of grazoprevir plus elbasvir. FUNDING: Merck & Co, Inc.

The combination of MK-5172, peginterferon, and ribavirin is effective in treatment-naive patients with hepatitis C virus genotype 1 infection without cirrhosis.

BACKGROUND & AIMS: MK-5172 is an inhibitor of the hepatitis C virus (HCV) nonstructural protein 3/4A protease; MK-5172 is taken once daily and has a higher potency and barrier to resistance than licensed protease inhibitors. We investigated the efficacy and tolerability of MK-5172 with peginterferon and ribavirin (PR) in treatment-naive patients with chronic HCV genotype 1 infection without cirrhosis. METHODS: We performed a multicenter, double-blind, randomized, active-controlled, dose-ranging, response-guided therapy study. A total of 332 patients received MK-5172 (100, 200, 400, or 800 mg) once daily for 12 weeks in combination with PR. Patients in the MK-5172 groups received PR for an additional 12 or 36 weeks, based on response at week 4. Patients in the control group (n = 66) received a combination of boceprevir and PR, dosed in accordance with boceprevir's US product circular. RESULTS: At 24 weeks after the end of therapy, sustained virologic responses were achieved in 89%, 93%, 91%, and 86% of the patients in the groups given the combination of PR and MK-5172 (100, 200, 400, or 800 mg), respectively, vs 61% of controls. In the MK-5172 group receiving 100 mg, 91% of patients had undetectable levels of HCV RNA at week 4 and qualified for the short duration of therapy. The combination of MK-5172 and PR generally was well tolerated. Transient increases in transaminase levels were noted in the MK-5172 groups given 400 and 800 mg, at higher frequencies than in the MK-5172 groups given 100 or 200 mg, or control groups. CONCLUSIONS: Once-daily MK-5172 (100 mg) with PR for 24 or 48 weeks was highly effective and well tolerated among treatment-naive patients with HCV genotype 1 infection without cirrhosis. Studies are underway to evaluate interferon-free MK-5172-based regimens. ClinicalTrials.gov number: NCT01353911.

Virologic resistance analysis from a phase 2 study of MK-5172 combined with pegylated interferon/ribavirin in treatment-naive patients with hepatitis C virus genotype 1 infection.

BACKGROUND: Virologic failure following treatment of hepatitis C virus (HCV) genotype 1 with direct-acting antiviral agents is often accompanied by the emergence of resistant variants. MK-5172 is an investigational once-daily protease inhibitor. We analyzed variants in treatment-naive noncirrhotic patients with virologic failure on MK-5172 (100-800 mg/day) plus pegylated interferon alfa/ribavirin (peg-IFN/RBV) during a phase 2 trial. METHODS: Population and selective clonal sequencing were performed at baseline and at virologic failure in the 4 MK-5172 dosing arms. MK-5172 activity was determined using a mutant replicon assay. RESULTS: Six of 266 (2.3%) MK-5172 recipients satisfied prespecified criteria for virologic failure, all with genotype 1a infection. Five patients with virologic failure were in the MK-5172 100-mg arm, including 4 patients with low plasma MK-5172 levels documented during triple therapy. Variants associated with >4-fold loss of potency were detected in 3 of the 4 patients with genotype 1a breakthrough while on MK-5172. The fifth patient had undetectable HCV-RNA levels at the end of triple therapy but subsequently broke through during the peg-IFN/RBV tail 16 weeks after completion of MK-5172. Three patients had D168 variants at virologic failure, including 2 with the D168A variant associated with a 95-fold loss of potency. The sole apparent relapse was actually a genotype 3a reinfection in the MK-5172 200-mg group. CONCLUSIONS: Virologic failure occurred uncommonly (6/266 [2.3%]) in MK-5172/peg-IFN/RBV recipients. The most prevalent treatment-emergent variants were detected at the D168 locus. D168A variants conferring approximately 2-log reduction in MK-5172 susceptibility emerged in 2 of the 4 evaluable patients with genotype 1a breakthrough. Clinical Trials Registration. NCT01353911.

Combination of vaniprevir with peginterferon and ribavirin significantly increases the rate of SVR in treatment-experienced patients with chronic HCV genotype 1 infection and cirrhosis.

BACKGROUND & AIMS: The combination of vaniprevir (a NS3/4A protease inhibitor) with peginterferon and ribavirin was shown to increase rates of sustained virologic response (SVR) significantly, compared with peginterferon and ribavirin alone, in treatment-experienced patients with chronic hepatitis C virus (HCV) genotype 1 infection without cirrhosis. We performed a blinded, randomized, controlled trial of the effects of vaniprevir with peginterferon and ribavirin in patients with cirrhosis who did not respond to prior therapy with peginterferon and ribavirin. METHODS: Treatment-experienced patients (88% white and 35% prior null responders) with HCV genotype 1 infection and compensated cirrhosis were assigned randomly to groups given vaniprevir (600 mg twice daily) with peginterferon and ribavirin for 24 weeks (n = 16), vaniprevir (600 mg twice daily) for 24 weeks with peginterferon and ribavirin for 48 weeks (n = 14), vaniprevir (300 mg twice daily) with peginterferon and ribavirin for 48 weeks (n = 15), vaniprevir (600 mg twice daily) with peginterferon and ribavirin for 48 weeks (n = 15), or placebo with peginterferon and ribavirin for 48 weeks (n = 14, control). Cirrhosis was documented by liver biopsy (84%) or noninvasive methods (16%). Before randomization, participants were stratified based on their historical response to peginterferon and ribavirin. RESULTS: In the primary analysis, SVR rates among patients in the respective vaniprevir groups were 9 of 15 (60.0%), 9 of 13 (69.2%), 8 of 15 (53.3%), and 10 of 13 (76.9%), compared with 2 of 14 (14.3%) in the control group (pairwise P values ≤ .016). Cirrhotic patients with null or partial responses to prior therapy achieved SVR less often than patients with prior breakthrough or relapse, although 42.1% of prior null responders in the vaniprevir groups achieved SVRs. Patients in the vaniprevir groups more frequently experienced mild-moderate nausea, vomiting, and diarrhea than controls; 5% developed grade 2 anemia compared with none in the control group (no patient developed grade 3 or 4 anemia). Among patients in the vaniprevir groups who experienced virologic failure, resistance-associated variants were detected predominantly at positions 155, 156, and 168 in the HCV protease gene. CONCLUSIONS: In a controlled phase 2B trial, vaniprevir with peginterferon and ribavirin significantly increased rates of SVR among treatment-experienced patients with chronic HCV genotype 1 infection, compared with re-treatment with peginterferon and ribavirin alone. Vaniprevir generally was well tolerated for up to 48 weeks in patients with compensated cirrhosis. ClinicalTrials.gov number, NCT00704405.

A phase 2B study of MK-7009 (vaniprevir) in patients with genotype 1 HCV infection who have failed previous pegylated interferon and ribavirin treatment.

BACKGROUND & AIMS: MK-7009 (vaniprevir) is a non-covalent competitive inhibitor of the hepatitis C virus (HCV) NS3/4A protease. This report presents the primary analysis results (safety and sustained viral response) of a phase 2b study of MK-7009 given in combination with peginterferon (PegIFN) alfa2a 180 µg weekly and ribavirin (RBV) 1000-1200 mg/day, for 24-48 weeks to non-cirrhotic patients who have failed previous PegIFN and RBV treatment. METHODS: We present results of a randomized, placebo-controlled, double-blind study of MK-7009 administered for 24-48 weeks in combination with PegIFN and RBV in 4 regimens to at least 40 patients per arm. Stratification by prior response to PegIFN and RBV was as follows: null response, partial response, breakthrough and relapse. HCV RNA was determined by Roche Cobas Taqman with a lower limit of detection (LLoD) of 10 IU/ml and a lower limit of quantification (LLoQ) of 25 IU/ml. RESULTS: SVR24 in patients on MK-7009+PegIFN and ribavirin (P/R) was statistically superior to placebo+P/R in all treatment groups (p<0.001). MK-7009 at 300 mg b.i.d. and 600 mg b.i.d. is generally well tolerated for use for up to 48 weeks of therapy. Patients in MK-7009 regimens had higher rates of gastrointestinal adverse events as compared to control (mostly mild to moderate). There were no significant differences in rates of anemia and rash between the MK-7009 regimens and control. CONCLUSIONS: In conclusion, patients treated with MK-7009 plus P/R experienced significant improvement in SVR compared to P/R control in a population of GT 1 experienced patients.

Vaniprevir with pegylated interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C: a randomized phase II study.

UNLABELLED: Vaniprevir (MK-7009) is a macrocyclic hepatitis C virus (HCV) nonstructural protein 3/4A protease inhibitor. The aim of the present phase II study was to examine virologic response rates with vaniprevir in combination with pegylated interferon alpha-2a (Peg-IFN-α-2a) plus ribavirin (RBV). In this double-blind, placebo-controlled, dose-ranging study, treatment-naïve patients with HCV genotype 1 infection (n = 94) were randomized to receive open-label Peg-IFN-α-2a (180 µg/week) and RBV (1,000-1,200 mg/day) in combination with blinded placebo or vaniprevir (300 mg twice-daily [BID], 600 mg BID, 600 mg once-daily [QD], or 800 mg QD) for 28 days, then open-label Peg-IFN-α-2a and RBV for an additional 44 weeks. The primary efficacy endpoint was rapid viral response (RVR), defined as undetectable plasma HCV RNA at week 4. Across all doses, vaniprevir was associated with a rapid two-phase decline in viral load, with HCV RNA levels approximately 3 log(10) IU/mL lower in vaniprevir-treated patients, compared to placebo recipients. Rates of RVR were significantly higher in each of the vaniprevir dose groups, compared to the control regimen (68.8%-83.3% versus 5.6%; P < 0.001 for all comparisons). There were numerically higher, but not statistically significant, early and sustained virologic response rates with vaniprevir, as compared to placebo. Resistance profile was predictable, with variants at R155 and D168 detected in a small number of patients. No relationship between interleukin-28B genotype and treatment outcomes was demonstrated in this study. The incidence of adverse events was generally comparable between vaniprevir and placebo recipients; however, vomiting appeared to be more common at higher vaniprevir doses. CONCLUSION: Vaniprevir is a potent HCV protease inhibitor with a predictable resistance profile and favorable safety profile that is suitable for QD or BID administration.

Molnupiravir for intra-household prevention of COVID-19: The MOVe-AHEAD randomized, placebo-controlled trial.

OBJECTIVES: To evaluate the efficacy and safety of molnupiravir for intra-household post-exposure prophylaxis (PEP) of COVID-19. METHODS: MOVe-AHEAD was a randomized, controlled, double-blind, phase 3 trial comparing molnupiravir (800 mg twice daily for 5 days) with placebo. Eligible participants were adult, unvaccinated, asymptomatic household contacts of patients with laboratory-confirmed COVID-19. The primary efficacy endpoint was the incidence of COVID-19 through day 14 in modified intention-to-treat (MITT) participants (those who received ≥1 dose of study intervention) without detectable SARS-CoV-2 at baseline, termed the MITT-VN population. Superiority of molnupiravir was prespecified as a stratified one-sided p-value of <0.0249 for the treatment difference in this endpoint. RESULTS: The MITT population comprised 763 participants randomized to molnupiravir and 764 to placebo; 83.6% had anti-SARS-CoV-2 antibodies at baseline. In the MITT-VN population, COVID-19 rates through day 14 were 6.5% with molnupiravir and 8.5% with placebo (one-sided p-value: 0.0848). In the molnupiravir arm, 25/35 of confirmed COVID-19 events (71.4%) occurred after completion of treatment (versus 17/49 [34.7%] for placebo). Adverse event rates were low and similar between molnupiravir and placebo. CONCLUSIONS: Molnupiravir was well-tolerated but did not meet the prespecified superiority criterion, possibly influenced in part by the high pre-existing immunity in the trial population.