mk-8742 and Liver-Cirrhosis

The therapeutic landscape for the treatment of chronic hepatitis C virus infection has been rapidly evolving, and by 2016 there will be six approved, all-oral regimens for use in patients in the USA and most of Western Europe. However, as many as patient populations will have limited access to new direct acting antiviral regimens, patients and physicians are often faced with the challenge of selecting the best regimen available, as opposed to the optimal treatment. In this paper, the challenges and opportunities in developing a high cure regimen for different patient populations will be discussed and highlighted through case-based scenarios.

Topics: Adult; Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Interferon-alpha; Liver Cirrhosis; Male; Middle Aged; Protease Inhibitors; Quinoxalines; Ribavirin; Simeprevir; Sofosbuvir; Sulfonamides; Young Adult

Treatment options are limited for people infected with hepatitis C virus (HCV) with decompensated liver disease. The C-SALT study assessed elbasvir (EBR) plus grazoprevir (GZR) in individuals with HCV genotype 1 infection and Child-Pugh class B (CP-B) cirrhosis.. In this 12-week, phase 2, nonrandomized, open-label study (NCT02115321; Protocol MK-5172-059), participants with CP-B cirrhosis received EBR 50 mg plus GZR 50 mg once daily, and a control group of noncirrhotic participants received EBR 50 mg plus GZR 100 mg once daily. The primary endpoint was sustained virologic response 12 weeks after the end of therapy.. Sustained virologic response at 12 weeks after the end of therapy was achieved by 27/30 (90.0%) CP-B participants and 10/10 (100.0%) noncirrhotic participants. Two participants relapsed, and one died during follow-up after having undetectable HCV RNA at the end of treatment. Most CP-B participants had stable or improved model for end-stage liver disease and Child-Pugh scores at follow-up week 12 compared with baseline. There was no significant difference in drug exposure between groups, despite the differing GZR dose. Adverse events occurring in >10% of participants were fatigue (CP-B: 30.0%; noncirrhotic: 30.0%), arthralgia (16.7%; 20.0%), nausea (10.0%; 20.0%), and headache (10.0%; 50.0%). No serious treatment-related adverse events or hepatic events of clinical interest occurred.. EBR 50 mg plus GZR 50 mg once daily for 12 weeks was highly effective and well tolerated in a traditionally hard-to-treat population.. Although EBR plus reduced-dose GZR is not available for people with CP-B cirrhosis, these results complement phase 2/3 trial data and real-world experience with EBR/GZR.

Topics: Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Liver Cirrhosis; Male; Middle Aged; Quinoxalines; RNA, Viral; Severity of Illness Index; Sulfonamides; Sustained Virologic Response

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.. 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).. 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.. 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.

Topics: Adult; Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Internationality; Liver Cirrhosis; Male; Middle Aged; Quinoxalines; Ribavirin; Sulfonamides; Sustained Virologic Response; Young Adult

Elbasvir (EBR) in combination with grazoprevir (GZR) has demonstrated efficacy in patients with hepatitis C virus (HCV) infections in trials primarily conducted in the USA and Europe. We investigated the safety and efficacy of EBR in combination with GZR in Japanese patients with chronic HCV infection, with or without cirrhosis.. The study was conducted in two parts. In part 1, noncirrhotic patients were randomized 1:1 to receive EBR (50 mg) in combination with GZR (50 or 100 mg) once daily for 12 weeks. In part 2, noncirrhotic patients were randomized 3:1 to receive immediate or deferred treatment with EBR (50 mg) and GZR (100 mg, determined in part 1) for 12 weeks; cirrhotic patients received open-label immediate treatment. The primary efficacy end point was the rate of sustained virologic response 12 weeks after completion of the study treatment.. In part 1, 63 patients were randomized to receive EBR in combination with GZR at a dose of 50 mg (n = 31) or 100 mg (n = 32). The SVR12 rates were 100% with GZR at a dose of 50 mg and 96.8% with GZR at a dose of 100 mg. Tolerability was similar in both arms. In part 2, 301 noncirrhotic patients were randomized to receive immediate treatment (n = 227) or deferred treatment (n = 74), and 35 cirrhotic patients were enrolled. The SVR12 rates were 96.5% and 97.1% after immediate treatment in noncirrhotic and cirrhotic patients respectively. Safety was generally similar between immediate and deferred treatment.. Treatment with EBR in combination with GZR for 12 weeks is effective and well tolerated in Japanese patients with chronic HCV infection. CLINICALTRIALS.. NCT02203149.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Double-Blind Method; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Liver Cirrhosis; Male; Middle Aged; Quinoxalines; RNA, Viral; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Young Adult

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.. 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.. 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]).. 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.. Merck & Co, Inc.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Interferons; Liver Cirrhosis; Male; Middle Aged; Polyethylene Glycols; Quinoxalines; Ribavirin; RNA, Viral; Sulfonamides; Treatment Failure; Treatment Outcome; Viral Load; Young Adult

Novel interferon- and ribavirin-free regimens are needed to treat hepatitis C virus (HCV) infection.. To evaluate the safety and efficacy of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A inhibitor) in treatment-naive patients.. Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02105467).. 60 centers in the United States, Europe, Australia, Scandinavia, and Asia.. Cirrhotic and noncirrhotic treatment-naive adults with genotype 1, 4, or 6 infection.. Oral, once-daily, fixed-dose grazoprevir 100 mg/elbasvir 50 mg for 12 weeks, stratified by fibrosis and genotype. Patients were randomly assigned 3:1 to immediate or deferred therapy.. Proportion of patients in the immediate-treatment group achieving unquantifiable HCV RNA 12 weeks after treatment (SVR12); adverse events in both groups.. Among 421 participants, 194 (46%) were women, 157 (37%) were nonwhite, 382 (91%) had genotype 1 infection, and 92 (22%) had cirrhosis. Of 316 patients receiving immediate treatment, 299 of 316 (95% [95% CI, 92% to 97%]) achieved SVR12, including 144 of 157 (92% [CI, 86% to 96%]) with genotype 1a, 129 of 131 (99% [CI, 95% to 100%]) with genotype 1b, 18 of 18 (100% [CI, 82% to 100%]) with genotype 4, 8 of 10 (80% [CI, 44% to 98%]) with genotype 6, 68 of 70 (97% [CI, 90% to 100%]) with cirrhosis, and 231 of 246 (94% [CI, 90% to 97%]) without cirrhosis. Virologic failure occurred in 13 patients (4%), including 1 case of breakthrough infection and 12 relapses, and was associated with baseline NS5A polymorphisms and emergent NS3 or NS5A variants or both. Serious adverse events occurred in 9 (2.8%) and 3 (2.9%) patients in the active and placebo groups, respectively (difference <0.05 percentage point [CI, -5.4 to 3.1 percentage points]); none were considered drug related. The most common adverse events in the active group were headache (17%), fatigue (16%), and nausea (9%).. The study lacked an active-comparator control group and included relatively few genotype 4 and 6 infections.. Grazoprevir-elbasvir achieved high SVR12 rates in treatment-naive cirrhotic and noncirrhotic patients with genotype 1, 4, or 6 infection. This once-daily, all-oral, fixed-combination regimen represents a potent new therapeutic option for chronic HCV infection.. Merck & Co.

Topics: Administration, Oral; Adult; Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; Fatigue; Female; Genotype; Headache; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Liver Cirrhosis; Male; Middle Aged; Nausea; Quinoxalines; Sulfonamides; Treatment Outcome; Viral Load; Young Adult

Hepatitis C virus (HCV) infection is a leading cause of morbidity and mortality in patients with HIV-1. The C-EDGE CO-INFECTION study assessed the efficacy, safety, and tolerability of grazoprevir (MK-5172) plus elbasvir (MK-8742) in patients with HCV and HIV co-infection.. In this uncontrolled, non-randomised, phase 3, open-label, single-arm study, treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection and HIV co-infection, with or without cirrhosis, were enrolled from 37 centres in nine countries across Europe, the USA, and Australia. Patients were either naive to treatment with any antiretroviral therapy (ART) or stable on ART for at least 8 weeks. All patients received grazoprevir 100 mg plus elbasvir 50 mg in a fixed-dose combination tablet once daily for 12 weeks. The primary endpoint was sustained virological response (HCV RNA <15 IU/mL) 12 weeks after the end of therapy (SVR12). The primary population for efficacy analyses was all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT02105662.. Between June 11, 2014, and Aug 29, 2014, 218 patients were enrolled and received grazoprevir plus elbasvir for 12 weeks, all of whom completed follow-up at week 12. SVR12 was achieved by 210 (96%) of 218 patients (95% CI 92·9-98·4). One patient did not achieve SVR12 because of a non-virological reason, and seven patients without cirrhosis relapsed (two subsequently confirmed as reinfections). All 35 patients with cirrhosis achieved SVR12. The most common adverse events were fatigue (29; 13%), headache (27; 12%), and nausea (20; 9%). No patient discontinued treatment because of an adverse event. Two patients receiving ART had transient HIV viraemia.. This HCV treatment regimen seems to be effective and well tolerated for patients co-infected with HIV with or without cirrhosis. These data are consistent with previous trials of this regimen in the monoinfected population. This regimen continues to be studied in phase 3 trials.. Merck Sharp & Dohme Corp.

Topics: Adult; Amides; Antiviral Agents; Australia; Benzofurans; Carbamates; Coinfection; Cyclopropanes; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Europe; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; HIV Infections; HIV-1; Humans; Imidazoles; Liver Cirrhosis; Male; Middle Aged; Quinoxalines; RNA, Viral; Sulfonamides; Treatment Outcome; United States; Viral Load

Second generation direct acting antivirals (DAAs) drastically changed the landscape of chronic HCV (CHCV). Aim of this paper was to assess the effectiveness of DAAs, also looking at the demographic characteristics of subjects enrolled.. Ambispective multi-center real-life study conducted among patients with CHCV treated with DAAs in Campania Region (Southern Italy). Patient were enrolled in two cohorts according to time of enrolment.. 1,479 patients were enrolled. Patients aged ≥60 years were 74.7% in the historic cohort (953 patients) and 70.2% in the prospective cohort (526 patients. Patients aged ≥ 60 years showed a higher prevalence of genotype 1b (p<0.001) and 2 (p<0.001), while patients aged < 60 years showed a higher prevalence of genotype 1a (p<0.001), 3 (p<0.001) and 4 (p<0.05). SVR12 was 98.5% in both cohorts. SVR12 was similar among patients of the prospective cohort aged < and ≥ 60 years (99.4% vs 98.1%). SVR12 among patients with and without cirrhosis was 96.0% and 98.9%, respectively.. DAAs provide high efficacy also in harder to treat patients. The effectiveness of DAAs is leading to a shift in patients characteristics with a greater prevalence of younger subjects and persons with mild liver disease.

Topics: Adult; Age Distribution; Aged; Amides; Aminoisobutyric Acids; Antiviral Agents; Benzimidazoles; Benzofurans; Carbamates; Cyclopropanes; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Italy; Lactams, Macrocyclic; Leucine; Liver Cirrhosis; Male; Middle Aged; Proline; Prospective Studies; Pyrrolidines; Quinoxalines; Retrospective Studies; Sulfonamides; Sustained Virologic Response

Grazoprevir/elbasvir (GZR/EBR) was approved for the treatment of chronic hepatitis C virus (HCV) genotype 1 and 4 infected patients with or without compensated liver cirrhosis. The aim of this study was to assess GZR/EBR regimen in the real-world experience, particularly in previously "difficult-to-treat" patients with chronic kidney diseases, human immunodeficiency virus-coinfected, cirrhotics, and treatment-experienced.. The analysis included patients treated with GZR/EBR selected from 10 152 individuals from the EpiTer-2 database, large national real-world study evaluating antiviral treatment in 22 Polish hepatology centers between 2015 and 2018. Data were completed retrospectively and submitted online.. A total of 1615 patients who started GZR/EBR therapy in 2017 and 2018 with a female predominance (54%) and median age of 54 years were analyzed. The majority were infected with GT1b (89%) and treatment naïve (81%). Liver cirrhosis was diagnosed in 19%, and 70% of patients had comorbidities, of which chronic renal disease was present in 7% and HIV-coinfection in 4%. Overall, a sustained virologic response (SVR) was achieved by 95% according to intent-to-treat (ITT) and 98% after exclusion of lost to follow up (modified ITT). No differences were found in cure rate between all included patients and subpopulations previously considered as difficult-to-treat. Majority of patients completed the treatment course as scheduled, adverse events were mostly mild and did not lead to therapy discontinuation.. GZR/EBR treatment carried-out in patients infected with HCV genotype 1 and 4 demonstrated good tolerability and an excellent SVR rate with no effectiveness reduction in so called difficult-to-treat populations.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amides; Antiviral Agents; Benzofurans; Carbamates; Comorbidity; Cyclopropanes; Data Analysis; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; HIV Infections; Humans; Imidazoles; Liver Cirrhosis; Male; Middle Aged; Quinoxalines; Renal Insufficiency, Chronic; Retrospective Studies; Sex Factors; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Young Adult

Genotype 1b (GT1b) is the most common subtype of the hepatitis C virus (HCV). We present an integrated analysis of 1070 participants with HCV GT1b infection from 30 countries who received elbasvir/grazoprevir for 12 weeks.. This is a retrospective analysis of data from participants with chronic HCV GT1b infection enrolled in 11 phase II/III clinical trials. All participants received elbasvir 50 mg plus grazoprevir 100 mg once daily for 12 weeks. The primary end point of all studies was sustained virologic response 12 weeks after completion of therapy (SVR12, HCV RNA < 15 IU/ml).. SVR12 was 97.2% (1040/1070). Of the 30 participants who failed to attain SVR12, 15 relapsed and 15 had nonvirologic failure. Among participant subgroups, SVR12 was high in those with compensated cirrhosis (188/189, 99.5%), HIV co-infection (51/54, 94.4%), and baseline viral load > 800,000 IU/ml (705/728, 96.8%). Resistance-associated substitutions (RASs) at NS5A positions 28, 30, 31, or 93 were present in 21.6% of participants at baseline. SVR12 was 99.6% (820/823) in participants without baseline NS5A RASs and 94.7% (215/227) in those with baseline NS5A RASs. Serious adverse events occurred in 3.2% (34/1070) of participants, nine of which occurred after study medication was completed.. Elbasvir/grazoprevir for 12 weeks represents an effective treatment option for participants with HCV GT1b infection. SVR12 was high in all participant subgroups, including those with compensated cirrhosis, HIV co-infection, and high baseline viral load. CLINICALTRIALS.. The trials discussed in this paper were registered with Clinicaltrial.gov as the following: NCT02092350 (C-SURFER), NCT02105662 (C-EDGE Co-Infection), NCT02105467 (C-EDGE treatment-naive), NCT02105701 (C-EDGE treatment-experienced), NCT01717326 (C-WORTHy), NCT02251990 (C-CORAL), NCT02105688 (C-EDGE COSTAR), NCT02252016 (C-EDGE IBLD), NCT02115321 (C-SALT), NCT02203149 (Japan phase 2/3 study), NCT02358044 (C-EDGE Head-2-Head).

Topics: Adolescent; Adult; Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Coinfection; Cyclopropanes; Drug Resistance, Viral; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; HIV Infections; Humans; Imidazoles; Liver Cirrhosis; Male; Middle Aged; Quinoxalines; Retrospective Studies; Sulfonamides; Sustained Virologic Response; Viral Load; Viral Nonstructural Proteins; Young Adult

To assess the cost-effectiveness of the elbasvir/grazoprevir (EBR/GZR) regimen in patients with genotype 1 chronic hepatitis C virus (HCV) infection with severe and end-stage renal disease compared to no treatment.. This study uses a health economic model to estimate the cost-effectiveness of treating previously untreated and treatment experienced chronic hepatitis C patients who have severe and end stage renal disease with the elbasvir-grazoprevir regimen versus no treatment in the French context. The lifetime homogeneous markovian model comprises of forty combined health states including hepatitis C virus and chronic kidney disease. The model parameters were from a multicentre randomized controlled trial, ANRS CO22 HEPATHER French cohort and literature. 1000 Monte Carlo simulations of patient health states for each treatment strategy are used for probabilistic sensitivity analysis and 95% confidence intervals calculations. The results were expressed in cost per quality-adjusted life year (QALY) gained.. The mean age of patients in the HEPATHER French cohort was 59.6 years and 56% of them were men. 22.3% of patients had a F0 fibrosis stage (no fibrosis), 24.1% a F1 stage (portal fibrosis without septa), 7.1% a F2 stage (portal fibrosis with few septa), 21.4% a F3 stage (numerous septa without fibrosis) and 25% a F4 fibrosis stage (compensated cirrhosis). Among these HCV genotype 1 patients, 30% had severe renal impairment stage 4, 33% had a severe renal insufficiency stage 5 and 37% had terminal severe renal impairment stage 5 treated by dialysis.. Fixed-dose combination of direct-acting antiviral agents elbasvir and grazoprevir compared to no-treatment.. EBR/GZR increased the number of life years (6.3 years) compared to no treatment (5.1 years) on a lifetime horizon. The total number of QALYs was higher for the new treatment because of better utility on health conditions (6.2 versus 3.7 QALYs). The incremental cost-utility ratio (ICUR) was of €15,212 per QALY gained for the base case analysis.. This cost-utility model is an innovative approach that simultaneously looks at the disease evolution of chronic hepatitis C and chronic kidney disease. EBR/GZR without interferon and ribavirin, produced the greatest benefit in terms of life expectancy and quality-adjusted life years (QALY) in treatment-naïve or experienced patients with chronic hepatitis C genotype 1 and stage 4-5 chronic kidney disease including dialysis patients. Based on shape of the acceptability curve, EBR/GZR can be considered cost-effective at a willingness to pay of €20,000 /QALY for patients with renal insufficiency with severe and end-stage renal disease compared to no treatment.

Topics: Amides; Antiviral Agents; Benzofurans; Carbamates; Cost-Benefit Analysis; Cyclopropanes; Drug Therapy, Combination; Female; France; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Kidney Failure, Chronic; Liver Cirrhosis; Male; Middle Aged; Models, Economic; Quality-Adjusted Life Years; Quinoxalines; Randomized Controlled Trials as Topic; Renal Dialysis; RNA, Viral; Sulfonamides

The real-world effectiveness and safety of all-oral direct-acting antivirals (DAAs) for chronic hepatitis C (HCV) infection and chronic kidney disease (CKD) have not been fully elucidated. This study assesses elbasvir (EBR) plus grazoprevir (GZR) for patients with HCV genotype 1 infection in the clinical setting, focusing on CKD stage 3-5D. This multicenter, real-world cohort study consisted of 282 Japanese patients who were treated with EBR (50 mg) plus GZR (100 mg) for a fixed 12-week duration. We evaluated the sustained viral response rate 12 weeks after the end of treatment (SVR12), longitudinal liver and renal parameters, and adverse effects according to the cirrhosis and CKD status. Of those enrolled, 89 (31.6%) were CKD stage 3-5 and 21 (7.4%) were CKD stage 5D (hemodialysis-dependent). The overall and CKD stage 3-5D SVR12 rates in the per protocol populations were 98.6% (272/276) and 98.1% (101/103). High SVR12 rates were observed in almost all groups, except for prior all-oral DAA failure with NS5A resistance-associated substitutions. There was no significant change during treatment or follow-up period in estimated glomerular filtration rate, irrespective of CKD status. In contrast, the serum complement level (C3 and C4) increased, with significance for C3. Serious adverse effects were very rare, both in the groups with normal eGFR and CKD, and discontinuation was required for only six (2.1%) patients. EBR plus GZR for HCV genotype 1 was highly effective with a low rate of adverse effects, regardless of CKD status. In addition, liver parameters and complement levels improved longitudinally.

Topics: Adult; Aged; Aged, 80 and over; Amides; Antiviral Agents; Benzofurans; Carbamates; Cohort Studies; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Liver Cirrhosis; Male; Middle Aged; Quinoxalines; Renal Insufficiency, Chronic; RNA, Viral; Sulfonamides; Sustained Virologic Response; Young Adult

The presence of baseline NS5A resistance-associated variants (RAVs) impacted treatment response in HCV genotype 1a (GT1a)-infected patients treated with elbasvir/grazoprevir (EBR/GZR) for 12 weeks, but not patients treated with EBR/GZR and ribavirin (RBV) for 16 weeks.. To assess the cost-effectiveness of baseline testing for NS5A RAVs in EBR/GZR-treated patients compared without testing, and with current treatments for GT1a patients.. We simulated the course of treatment with EBR/GZR, ledipasvir/sofosbuvir (LDV/SOF) and ombitasvir/paritaprevir/ritonavir+dasabuvir (3D) with or without RBV and natural history of disease of GT1a patients. Treatment-related data from clinical trials were used in a state-transition model of the natural history of chronic HCV GT1a infection and liver disease to project lifetime costs (US$2015) and quality-adjusted life years (QALY). Other clinical and economic inputs were estimated from published sources. We conducted base case and sensitivity analyses.. RAVs testing-guided treatment with EBR/GZR resulted in more QALYs than EBR/GZR without testing, 3D+RBV, or LDV/SOF8. This strategy was cost-saving relative to 3D+RBV or LDV/SOF8 and was cost-effective compared with EBR/GZR without testing. LDV/SOF12 was not cost-effective compared with the EBR/GZR RAVs testing-based strategy. Treatment with EBR/GZR guided by RAVs testing is the most effective regimen among treatment-experienced patients without cirrhosis and cirrhotic patients. In sensitivity analysis, RAVs testing was cost-effective in 48-55% and 63-85% among noncirrhotic and cirrhotic patients respectively.. RAVs testing before treatment with EBR/GZR is likely to be a cost-effective alternative to the use of EBR/GZR without testing, LDV/SOF, or 3D among GT1a treatment-naïve or treatment-experienced patients.

Topics: Administration, Oral; Amides; Antiviral Agents; Benzofurans; Carbamates; Cost-Benefit Analysis; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Liver Cirrhosis; Polymorphism, Genetic; Predictive Value of Tests; Quinoxalines; Sulfonamides; United States; Viral Nonstructural Proteins; Virology

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.. 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.. 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.. 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.

Topics: Adult; Aged; Aged, 80 and over; Amides; Antiviral Agents; Benzofurans; Carbamates; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cyclopropanes; Drug Combinations; Drug Resistance, Viral; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Liver Cirrhosis; Male; Middle Aged; Quinoxalines; Randomized Controlled Trials as Topic; Retreatment; Retrospective Studies; Ribavirin; RNA, Viral; Sulfonamides; Sustained Virologic Response; Viral Nonstructural Proteins; Young Adult

Topics: Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Female; Hepatitis C, Chronic; HIV Infections; Humans; Imidazoles; Liver Cirrhosis; Male; Quinoxalines; Ribavirin; RNA, Viral; Sulfonamides