Between June 2018 and April 2019, chronic HCV patients receiving hemodialysis were prospectively recruited at 6 academic centers in Taiwan. Patients were screened for eligibility if they were aged ≥20 years, had body mass index (BMI) between 18.5–35.0 kg/m2, had documented the presence of detectale HCV antibody (anti-HCV; Abbott HCV EIA 2.0, Abbott Laboratories, Abbott Park, Illinois, USA) for ≥6 months, had estimated glomerular filtration (eGFR) rate <15 mL/min/1.73m2 and received maintenance hemodialysis. Patients were excluded from screening if they had documented past or current presence of decompensated cirrhosis (Child-Pugh B or C), had a history of hepatocellular carcinoma (HCC), had a history of non-HCC malignancies (except for cutaneous melanoma) within 5 years of screening, had received organ transplantation (except for prior renal transplantation with graft failure), had prior exposure to DAAs, host-targeting agents or therapeutic vaccines for HCV, were pregnant, were unwilling to have contraception during the study period, or refused to provide written informed consent. Patients were not eligible for the study if they had serum HCV RNA level ≤1000 IU/mL (Cobas TaqMan HCV Test v2.0, Roche Diagnostics GmbH, Mannheim, Germany, lower limit of quantification [LLOQ]: 15 IU/mL), were infected with HCV non-GT1b genotypes (Abbott RealTime HCV Genotype II, Abbott Laboratories, Abbott Park, Illinois, USA), were seropositive for hepatitis B virus (HBV) surface antigen (HBsAg, Abbott Architect HBsAg qualitative assay, Abbott Laboratories, Abbott Park, Illinois, USA) or human immunodeficiency virus (HIV) antibody (anti-HIV, Abbott Architect HIV Ag/Ab Combo, Abbott Laboratories, Abbott Park, Illinois, USA), were present with decompensated cirrhosis, malignancies or pregnancy18. Patients were also excluded if the hemoglobin level <10.0 g/dL, platelet count <70 × 109 cells/L, international normalized ratio (INR) > 2.0, serum albumin level <3.0 g/dL, serum total bilirubin level >2.0 mg/dL, serum alanine aminotransferase (ALT) quotient >10 (upper limit of normal: 30 IU/L for males and 17 IU/L for females), or serum alfa-fetoprotein level (AFP) > 100 ng/mL19. The study was approved by the Ethics Committee of each participating center (National Taiwan University Hospital Ethics Committee, China Medical University & Hospital Research Ethics Center, Taipei Medical University Joint Institutional Review Board, Taichung Veterans General Hospital Institutional Review Board, and Far Eastern Memorial Hospital Research Ethics Review Committee), conducted in accordance with the principles of Declaration of Helsinki and the International Conference on Harmonization for Good Clinical Practice, and registered in ClinicalTrials.gov (NCT03420300). All patients provided written informed consent before enrollment.
This was a one-arm, open-label, multicenter study. Data for demographics, hemogram, INR, serum albumin, total bilirubin, ALT, creatinine, AFP, anti-HCV, anti-HIV, HBsAg, HCV RNA, HCV genotype, interleukin-28B (IL28B) rs12979860 genotype (Applied Biosystems, Life Technologies Corporation, Grand Island, NY, USA), abdominal ultrasonography, and liver stiffness measurement (LSM, FibroScan®, Echosens, Paris, France) were collected for all screened patients20. The stage of hepatic fibrosis by METAVIR score was determined by LSM (F0–1: <7.0 kPa; F2: 7.0–9.4 kPa; F3: 9.5–12.4 kPa; F4: ≥ 12.5 kPa). Baseline HCV resistance-associated substitutions (RASs) for elbasvir and grazoprevir at the NS5A and NS3 regions for HCV GT1b were analyzed by population sequencing with a cut-off level of 15%21. If patients had on-treatment or off-therapy virologic failure, including non-response, viral breakthrough or relapse, the RAS testing was performed at the time of treatment failure. The potential drug-drug interaction (DDI) between EBR/GZR and concomitant medications was checked by HEP Drug Interaction Checker as proposed by the University of Liverpool (Liverpool, UK)22. If patients had comedications that were contraindicated for concomitant use, a switch to non-contraindicated comedications was performed before EBR/GZR treatment.
Patients who were eligible for the study received EBR/GZR (Zepatier®, 50 mg/100 mg fixed dose combination (FDC) table, Merck Sharp & Dohme (MSD) International GmbH, Ballydine, Clonmel, Ireland) 1 table daily with or without food for 12 weeks. Treatment was permanently discontinued if the patient had on-treatment viral breakthrough which was defined as patients with on-treatment undetectable viremia, but the viral load rebounded to detectable levels by continuous treatment, or had non-response which was defined as patients with persistently detectable HCV RNA beyond week 8 of treatment.
Patients received outpatient visits at treatment weeks 1, 2, 4, 6, 8, and 12, and at off-therapy weeks 4, 8, 12 to assess efficacy and tolerability. Hemoglobin, platelet count, serum total bilirubin, ALT and HCV RNA were checked at each visit. Furthermore, INR, serum albumin, eGFR, AFP, and abdominal ultrasonography were checked at on-treatment week 12 (end-of-treatment, EOT) and at off-therapy week 12.
The primary efficacy endpoint was SVR12 by intention-to-treat (ITT) analysis, which was defined as HCV RNA level <LLOQ at off-therapy week 12, for patients who received at least one dose of EBR/GZR. The secondary efficacy endpoint was SVR12 by modified ITT (mITT) analysis, which excluded patients who failed to achieve SVR12 due to non-virologic reasons. In patients who permanently discontinued treatment, the serum HCV RNA level at the last on-treatment visit was taken as EOT viral response. Patients were considered failure to achieve SVR12 if they had on-treatment viral breakthrough/non-response or off-therapy viral relapse, or had missing SVR12.
All patients received tolerability assessment for the severity and the causality of constitutional adverse events (AEs), serious AEs and laboratory abnormalities at each outpatient visit by pre-specified checklists. The severity of AEs was graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The investigators can temporarily or permanently discontinue EBR/GZR based on patients’ safety concerns. If the patient had ALT quotient ≥2.5, the alternative etiology for ALT elevation (including drug-induced hepatitis, HBV reactivation, biliary obstruction, etc.) can be assessed at investigators’ discretion. If the patient had ALT quotient ≥5, the investigators must evaluate the alternative etiology for ALT elevation. When patients presented with on-treatment ALT quotient ≥20, ALT quotient ≥10 combined with total bilirubin >3.0 mg/dL, or clinical symptoms or signs of hepatic decompensation, the EBR/GZR permanently discontinued. Dose titration for EBR/GZR was not permitted. For patients who permanently discontinued treatment, the safety summary was assessed from the beginning of treatment to the last visit. Furthermore, the common AE rates of ≥5% were also assessed. Oral nucleot(s)ides agents, such as entecavir or tenofovir, were initiated if patients were diagnosed HBV-associated hepatitis flare, defined as the combined presence of HBV reactivation (HBsAg seropositivity or HBV DNA level ≥100 IU/mL) and ALT quotient ≥523.
The adherence of EBR/GZR was assessed by self-reporting diaries and pill counts, which were calculated as the number of pills taken (the number of pills dispensed minus the number of pills counted) at each outpatient visit. The compliance was presented as the total pills consumed during the study period divided by the scheduled 84 pills.
Statistical Program for Social Sciences (SPSS Statistics Version 23.0, IBM Corp., Armonk, New York, USA) was used for statistical analyses. We assumed a total of 40 patients would provide an SVR rate in HCV GT1b patients who receive EBR/GZR for 12 weeks to be 95% with a 95% lower confidence bound to be 83%, and with a 10% of response rate higher than the 95% upper confidence bound to be 73% in the historical SVR rate of 64% in East-Asian HCV GT1b patients treated by pegylated IFN plus ribavirin (RBV)24. The baseline patient characteristics were shown in median (range) and percentages when appropriate. The on-treatment and off-therapy viral response rates were shown in number and percentages with 95% confidence interval (CI). Patients’ baseline characteristics, early viral kinetics and HCV RASs potentially affecting SVR12 were analyzed. The safety summaries were shown in number and percentages when appropriate.