Ledipasvir/Sofosbuvir for 12 Weeks Is Safe and Effective in CHC and CHB Coinfection Patients: A Phase 3 Study in Taiwan

( Chun-Jen Liu ),( Wan-Long Chuang ),( I-Shyan Sheen ),( Horng-Yuan Wang ),( Chi-Yi Chen ),( Kuo-Chih Tseng ),( Ting-Tsung Chang ),( Benede tta Massetto ),( Jenny Yang ),( Gregory Camus ),( Fangqiu Zh 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Patients co-infected with HCV and HBV have more rapid progression and worse outcomes than mono-infected patients. Taiwan has among the highest prevalence of chronic HCV/HBV coinfection in Southeast Asia. This study evaluated the safety and efficacy of an all-oral treatment with ledipasvir(LDV)/sofosbuvir(SOF) for 12 weeks in chronic HCV and HBV coinfection. Methods: Patients with or without compensated cirrhosis chronic HCV GT1/GT2 and HBV (HBsAg+) treatment naïve were enrolled into open-label, receiving LDV 90 mg/SOF 400 mg(QD) for 12 weeks. The primary efficacy endpoint is SVR12. HBV DNA was monitored at all study visits and it will be monitored for 2 years post-treatment. Results: A total of 111 patients (68[61%] with GT1 and 43[39%] with GT2) were enrolled and treated. The majority were female(62%), treatment naive(67%), and non-cirrhotic(85%), with a mean age of 55 years and mean BMI of 24.5kg/m2. All but one was HBeAg negative. Mean baseline HBV DNA was 2.1 log10IU/mL. SVR4 was 100%(111/111). The mean change in HBV DNA ranged from -0.06 log10IU/mL at week 1 to +0.49 log10IU/mL at follow-up visit 4; HBV DNA kinetics are shown in Fig 1. 60(54%) patients had an increase in HBV DNA> 10 x BL or became HBV DNA > LLOQ. No patients had ALT ≥ 2 X baseline. No patients discontinued treatment due to adverse events (AEs). Three patients had serious AEs(optic neuritis, post procedural bleeding and duodenal ulcer bleeding; none was considered drug related). Conclusions: In chronic HCV/HBV infection patients, LDV/SOF for 12 weeks resulted in an SVR4 rate of 100%. Although most patients had an increase in HBV DNA during treatment, this was not associated with ALT elevations ≥2 X baseline, and no patients started HBV therapy to date. This all-oral, interferon-free regimen was well tolerated, supporting its potential as a treatment option for HCV/HBV co-infected patients.

Efficacy and Safety of Elbasvir/Grazoprevir in Treatment- Naive Subjects with Chronic HCV GT 1, GT 4 and GT 6 Infection (C-CORAL): A Phase III Randomized Multinational Clinical Trial

( Do Young Kim ),( Lai Wei ),( Konstantin Zhdanov ),( Eduard Burnevich ),( I-Shyan Sheen ),( Jeong Heo ),( Van Kinh Nguyen ),( Tawesak Tanwandee ),( Pin-Nan Cheng ),( Won Young Tak ),( Svetlana Kizhlo 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Hepatitis C virus (HCV) contributes significantly to the overall liver disease burden in the Asia Pacific region and Russia where the seroprevalence rates vary from 1-5% and genotype (GT) 1b accounts for about half of infections. The efficacy and safety of the fixed-dose combination of elbasvir (EBR) 50 mg and grazoprevir (GZR) 100 mg has been demonstrated in a broad population of HCV-infected subjects and supports evaluation in this region where clinical experience with direct-acting antivirals is limited. EBR/GZR is approved in the United States for treatment of HCV GT1 and 4 infection. Methods: C-CORAL is a double-blind placebo-controlled, Phase 3 trial that randomized treatment-naive HCV GT1, 4 or 6 infected subjects in a 3:1 ratio to an immediate treatment group (ITG; 12 wks of EBR/GZR) or deferred treatment group (DTG; 12 wks of placebo, followed by 12 wks of EBR/GZR). Subjects were enrolled in an ex-China cohort that included subjects from Korea, Taiwan, Vietnam, Thailand, Australia, and Russia; and a second cohort enrolled subjects from China. The primary endpoints include the % of patients in the ITG who achieved SVR12 and a comparison of the safety and tolerability of EBR/GZR in the ITG vs placebo in the DTG. We will present the efficacy results of the ITG and safety results of the ITG and DTG in both cohorts. Results: To date, data from the ex-China cohort are available. In this cohort, a total of 250 subjects were enrolled in the ITG and 86 in the DTG. Mean age (±SD) was 50 ±12 years, 57% were females, 59% were Asian, 74% were GT1b, and 19% were cirrhotic. SVR12 in the ITG was 92.8% (table). Eighteen subjects in the ITG did not achieve SVR12: 11 were relapses, 6 were on-treatment failures (all GT6) and 1 GT1b subject withdrew consent. The incidence of adverse events (AEs) was generally comparable between the ITG vs the DTG including drug-related AEs (21.2% vs 19.8%) and serious AEs (0.8% vs 1.2%; none considered drug-related). During treatment with EBR/GZR or placebo 2/250 (0.8%) subjects in the ITG and 11/86 (12.8%) subjects in the DTG had an ALT value >5x ULN and greater than baseline. One subject in the ITG withdrew after meeting a trial specific discontinuation criterion for elevated ALT, which was not considered drug related. Updated safety and efficacy data will be presented for the ITG for both the ex-China and China study cohorts. Conclusions: A 12-week regimen of EBR/GZR is effective and well-tolerated in GT1 and GT4-infected, treatment-naive patients in the Asia Pacific/Russia region.

Efficacy and Safety of Elbasvir/Grazoprevir in Treatment- Naive Subjects with Chronic HCV GT 1, GT 4 and GT 6 Infection (C-CORAL): A Phase III Randomized Multinational Clinical Trial

( Jeong Heo ),( Lai Wei ),( Konstantin Zhdanov ),( Eduard Burnevich ),( I-Shyan Sheen ),( Van Kinh Nguyen ),( Tawesak Tanwandee ),( Pin-Nan Cheng ),( Do Young Kim ),( Won Young Tak ),( Svetlana Kizhlo 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Hepatitis C virus (HCV) contributes significantly to the overall liver disease burden in the Asia Pacific region and Russia where the seroprevalence rates vary from 1-5% and genotype (GT) 1b accounts for about half of infections. The efficacy and safety of the fixed-dose combination of elbasvir (EBR) 50 mg and grazoprevir (GZR) 100 mg has been demonstrated in a broad population of HCV-infected subjects and supports evaluation in this region where clinical experience with direct-acting antivirals is limited. EBR/GZR is approved in the United States for treatment of HCV GT1 and 4 infection. Methods: C-CORAL is a double-blind placebo-controlled, Phase 3 trial that randomized treatment-naïve HCV GT1, 4 or 6 infected subjects in a 3:1 ratio to an immediate treatment group (ITG; 12 wks of EBR/GZR) or deferred treatment group (DTG; 12 wks of placebo, followed by 12 wks of EBR/GZR). Subjects were enrolled in an ex-China cohort that included subjects from Korea, Taiwan, Vietnam, Thailand, Australia, and Russia; and a second cohort enrolled subjects from China. The primary endpoints include the % of patients in the ITG who achieved SVR12 and a comparison of the safety and tolerability of EBR/GZR in the ITG vs placebo in the DTG. We will present the efficacy results of the ITG and safety results of the ITG and DTG in both cohorts. Results: To date, data from the ex-China cohort are available. In this cohort, a total of 250 subjects were enrolled in the ITG and 86 in the DTG. Mean age (±SD) was 50 ±12 years, 57% were females, 59% were Asian, 74% were GT1b, and 19% were cirrhotic. SVR12 in the ITG was 92.8% (table). Eighteen subjects in the ITG did not achieve SVR12: 11 were relapses, 6 were on-treatment failures (all GT6) and 1 GT1b subject withdrew consent. The incidence of adverse events (AEs) was generally comparable between the ITG vs the DTG including drug-related AEs (21.2% vs 19.8%) and serious AEs (0.8% vs 1.2%; none considered drug-related). During treatment with EBR/GZR or placebo 2/250 (0.8%) subjects in the ITG and 11/86 (12.8%) subjects in the DTG had an ALT value >5x ULN and greater than baseline. One subject in the ITG withdrew after meeting a trial specific discontinuation criterion for elevated ALT, which was not considered drug related. Updated safety and efficacy data will be presented for the ITG for both the ex-China and China study cohorts. Conclusions: A 12-week regimen of EBR/GZR is effective and well-tolerated in GT1 and GT4-infected, treatment-naïve patients in the Asia Pacific/Russia region.