EBR/GZR for HCV-1b Patients Receiving Hemodialysis
EBR/GZR for HCV-1b Patients Receiving Hemodialysis
Hepatitis C virus (HCV) infection is common in patients receiving hemodialysis. The uptake of
 antiviral therapy for these patients is limited in the era of interferon (IFN) plus ribavirin
 (RBV), probably because the sustained virologic response (SVR) rates are low and the risk of
 treatment-related adverse events (AEs) are high. In the era of IFN-free direct acting
 antiviral agents (DAAs), several studies have indicated high rates of SVR and excellent
 safety profiles to treat patients with severe renal impairment. With regard to
 elbasvir/grazoprevir (EBR/GZR) treatment, a phase 3 study (C-SURFER) study has shown 99% of
 SVR in HCV-1 patients with chronic kidney disease (CKD) stage 4 or 5. Furthermore, most
 patients tolerated the treatment well. Although the data confirmed the excellent safety and
 efficacy in HCV-1 patients with severe renal impairment, data regarding the safety and
 efficacy for Asian HCV-1b patients receiving hemodialysis is lacking. Therefore, we aim to
 evaluated the safety and efficacy of EBR/GZR for 12 weeks in treatment-naive and
 treatment-experienced HCV-1b patients receiving hemodialysis.
Hepatitis C virus (HCV) infection remains a major co-morbidity in hemodialysis patients. The
 incidence and prevalence rates of HCV infection in hemodialysis patients are much higher than
 those in the general population, and are attributed to high rates of nosocomial HCV
 transmission. With regard to HCV genotype distribution, HCV genotype 1 (GT-1) infection is
 the most prevalent type of infection worldwide and the genotype distribution in HCV-infected
 individuals receiving hemodialysis (HD) is similar to that observed in HCV-infected
 individuals with normal renal function. Compared to non-HCV infected hemodialysis patients,
 HCV-infected patients have increased risks of liver-related morbidity and mortality. Although
 HCV-infected hemodialysis patients who receive renal transplantation have survival advantages
 over those who remain on maintenance dialysis, these patients still have poor patient and
 graft survival, as well as have poor responses to interferon (IFN)-based therapy.In contrast,
 hemodialysis patients who eradicate HCV infection have improved biochemical, virologic and
 histologic responses, whether on maintenance dialysis or after renal transplantation.

 Approximately one third of hemodialysis patients with chronic HCV infection achieve sustained
 virological response (SVR) by conventional IFN or peginterferon monotherapy.In addition
 18-30% of patients receiving IFN-based monotherapy prematurely discontinued treatment due to
 adverse events (AEs). Although the addition of ribavirin to IFN further improves the SVR rate
 in HCV-infected patients with normal renal function, ribavirin has been considered
 contraindicated to treat HCV-infected hemodialysis patients because of concern for
 life-threatening hemolytic anemia. Recently, pilot studies have indicated the feasibility of
 adding low-dose ribavirin (200 mg three times per week to daily 400 mg, adjusted to achieve a
 target concentration of 10-15 μmol/L), to IFN for treatment of HCV-infected hemodialysis
 patients. Generally, the SVR rate and the premature discontinuation rate due to
 null-response, severe anemia, and/or heart failure for combination therapy are 56% and 22%,
 respectively. Based on these small-scale studies, low-dose ribavirin (daily 200 mg) was
 approved in August 2011 by the U.S. Food and Drug Administration to treat HCV-infected
 hemodialysis patients.30 Two recent well-conducted randomized control studies to compare the
 efficacy and safety of combination therapy with peginterferon alfa-2a (135 μg/week) plus
 low-dose ribavirin (RBV) (200 mg/day) or monotherapy with peginterferon (135 μg/week) for 48
 and 24 weeks in treatment-naïve HCV GT-1 and GT-2 infected individuals receiving hemodialysis
 showed that the SVR rates of combination therapy groups were greater than those of
 monotherapy groups (64% versus 34%, p < 0.001 for HCV GT-1; 74% versus 44%, p < 0.001 for HCV
 GT-2), respectively. Although the SVR rate of combination therapy with peginterferon plus
 low-dose ribavirin is higher than that of peginterferon monotherapy. About 70-75% of these
 patients experienced clinically significant anemia which needed high dose of erythropoiesis
 stimulating agents (ESAs) to keep the hemoglobin level within the safety range. Although
 telaprevir (TVR)-based triple therapy has been used to treat 4 HCV-1 patients receiving
 hemodialysis who were not responsive to prior peginterferon plus RBV with good efficacy, the
 added on-treatment adverse events (AEs) and the pill burden precluded the widespread use of
 this agent.

 The recent introduction of IFN-free direct acting antiviral agents (DAAs) has made a paradigm
 shift with regard to the medical treatment for HCV-infected individuals, based on the
 excellent efficacy and safety in ordinary patients. Among the various IFN-free DAA regimens,
 treatment with elbasvir/grazoprevir (EBR/GZR) has been approved in 2016 to treat patients
 with chronic HCV GT-1 and GT-4 infection. Treatment with EBR/GZR with/without weight-based
 ribavirin for 12-16 weeks achieved an SVR12 rate of 94-100% in treatment-naïve and PR or
 protease-inhibitor based treatment-experienced HCV GT-1a, GT-1b or GT-4 patients,
 respectively (C-EDGE TN, TE, SALVAGE). Furthermore, the SVR12 rates in HIV-coinfected
 patients with HCV GT-1a, GT-1b and GT-4 were 95.3% and 98.0% by using EBR/GZR for 12 weeks
 (C-EDGE Coinfection). In addition to high SVR rates by 12-16 weeks of EBR/GZR treatment, the
 overall safety profiles are excellent, with only 1% of the patients who discontinue treatment
 due to drug-related adverse event. With regard to constitutional symptoms, treatment with
 EBR/GZR had comparable rates to the placebo arms. With regard to laboratory abnormalities,
 about 1% and less than 1% of the treatment patients experience AST/ALT elevation and
 hyperbilirubinemia. Clinically significant anemia is more commonly encountered in patients
 receiving EBR/GZR with weight-based ribavirin. Taking together, treatment with EBR/GZR is
 efficacious and safe for HCV-infected subjects with HCV GT-1 or 4 infection. The post-hoc
 analyses for potential factors affecting the SVR rates showed that among GT-1a infected
 patients with baseline NS5A resistant associated variants (RAVs) at position of 28, 30, 31
 and 93, the SVR rates will be compromised for those receiving 12 weeks of treatment or
 without adding RBV. In addition, treatment-experienced HCV GT-4 patients should also receive
 16 weeks of EBR/GZR plus RBV to secure the SVR rates. In GT-1a or GT-1b patients who fail
 prior protease inhibitor-based triple therapy, 12 weeks of GZR/EBR plus RBV are recommended
 to secure the high SVR rates. For GT-1a treatment-naïve or PR-experienced patients without
 the presence of baseline NS5A RAVs, GT-1b treatment-naïve or PR-experienced patients or GT-4
 treatment-naïve patients, EBR/GZR for 12 weeks offer satisfactory safety and efficacy
 profiles. Gender, ethnicity, age, interleukin-28B (IL28B) genotype, cirrhosis status and
 baseline HCV RNA levels do not affect the overall SVR rates in EBR/GZR treatment patients.

 The pharmacokinetic (PK) study of elbasvir and grazoprevir was evaluated 16 subjects with
 severe renal impairment and end-stage renal disease (ESRD) on maintenance hemodialysis and
 matched healthy controls. Compared to subjects with matched healthy controls, the area under
 the curves (AUCs) of elbasvir in subjects with severe renal impairment and ESRD were 99% and
 86%; the AUCs of grazoprevir in subjects with severe renal impairment and ESRD were 85% and
 83%, respectively. The pharmacokinetic study indicated that dose dosage adjustments of
 EBR/GZR are not needed for patients with severe renal impairment or those who are on
 maintenance hemodialysis.

 The phase 3 C-SUFER study evaluated the safety and efficacy of EBR/GZR BV for 12 weeks in a
 total of 235 treatment-naïve and treatment-experienced HCV GT-1 patients with severe renal
 impairment or ESRD.42 About 82% of the patients had chronic kidney disease (CKD) stage 5, and
 the remaining 18% of the patients had CKD stage 4. The full set and the modified full set
 analyses for SVR12 in patients receiving 12 weeks of treatment were 94% and 99% respectively.
 On-treatment undetectable HCV RNA levels at weeks 4 and 12 were 90% and 100%, respectively.
 In patients with ESRD, the overall SVR12 was 98.9%. No patients discontinued the study drugs
 due to adverse events. Furthermore, the constitutional and the laboratory abnormalities were
 mild in grades and were lower in frequency, compared to the control arm. This large-scale
 study shows that treatment with EBR/GZR is efficacious and safe for HCV-1 patients with
 severe renal impairment and those with end-stage renal disease.

 Although peginterferon monotherapy and combination therapy with peginterferon plus low-dose
 RBV for 24-48 weeks have been evaluated in many studies, the efficacy for the treatment
 regimens were only modest (SVR rate about 60%). In addition, the on-treatment AEs and SAEs by
 IFN-based therapies were frequently encountered in HCV-infected patients receiving
 hemodialysis. Of note was the pronounced on-treatment hemoglobin level decrease in patients
 receiving combination therapy by peginterferon plus low-dose RBV, necessitating significant
 RBV dose reduction and high-dose erythrocyte stimulating agent (ESA) support.

 By receiving IFN-free DAA therapies, HCV-infected patients have excellent SVR rates, low
 on-treatment SAE and AE rates, shorter treatment duration, and low pill burdens. The PK study
 of EBR/GZR proves the excellent safety profiles and dose adjustment are not needed for
 EBR/GZR regimen in subjects with various degrees of renal impairment. The C-SURFER study
 showed the excellent on-treatment and off-therapy antiviral effects in HCV GT-1a and GT-1b
 infected patients receiving EBR/GZR, respectively. However, the C-SURFER study enrolled only
 limited patients of Asian ancestry, making the safety and efficacy in this group of patients
 still to be confirmed. Based on the excellent safety and efficacy profiles of EBR/GZR
 treatment for HCV GT-1b infected patients with normal renal function, we aim to evaluate the
 safety and efficacy of EBR/GZR for 12 weeks in treatment-naïve and treatment-experienced HCV
 GT-1b patients receiving hemodialysis in Asian population, taking HCV GT-1b patients treated
 by peginterferon plus ribavirin for 48 weeks as the historical control.
Inclusion Criteria:

 -  20 yeas or more

 -  Male or female

 -  Body mass index (BMI) 18.5-35.0 kg/m2

 -  Chronic HCV infection, defined as patients who meet as least one of the two following
 criteria:

 1. Anti-HCV antibody (Abbott HCV EIA 2.0, Abbott Laboratories, Abbott Park,
 Illinois, USA) or HCV RNA > 1,000 IU/mL for at least 6 months before screening

 2. Positive HCV RNA > 1,0000 IU/mL (Cobas TaqMan HCV Test v2.0, Roche Diagnostics
 GmbH, Mannheim, Germany, low limit of quantification (LLOQ): 25 IU/mL) at the
 time of screening with a liver biopsy consistent with chronic HCV infection

 -  HCV genotype 1 (HCV GT-1b) infection (Abbott RealTime HCV genotype II, Abbott
 Molecular Inc. Illinois, USA)

 -  Treatment-naïve or treatment-experienced (including patients who relapsed, who had
 virological breakthrough, or who were null-responsive to IFN-based therapies)

 -  HCV RNA > 10,000 IU/mL at screening

 -  Estimated glomerular filtration (eGFR) rate < 15 mL/min/1.73m2 as assessed by modified
 of diet in renal disease (MDRD) equation, and receiving regular hemodialysis

 Exclusion Criteria:

 -  HCV infection other than HCV GT-1b

 -  HBV or HIV coinfection

 -  Presence of decompensated cirrhosis (Child-Pugh class B or C)

 -  Any primary cause of liver disease other than chronic HCV infection, including but not
 limited to the following

 1. Hemochromatosis

 2. Alfa-1 antitrypsin deficiency

 3. Wilson's disease

 4. Autoimmune hepatitis

 5. Alcoholic liver disease

 6. Drug-induced hepatitis

 7. Screening laboratory analyses showing any of the following results

 -  Hemoglobin (Hb) level < 10 g/dL

 -  Absolute neutrophil count (ANC) < 1,500 cells/μL

 -  Platelet count < 70,000 cells/mm3

 -  International normalized ratio (INR) > 2.0

 -  Albumin (Alb)< 3.0 g/dL

 -  Bilirubin (Bil) > 2.0 mg/dL

 -  Alanine aminotransferase (ALT) > 10X upper limit of normal (ULN)

 -  Aspartate aminotransferase (AST) > 10X upper limit of normal (ULN)

 -  Serum alfa-fetoprotein (AFP) > 100 ng/mL

 -  Presence of hepatocellular carcinoma (HCC) on imaging studies such as computed
 tomography (CT) scan or magnetic resonance imaging (MRI)

 -  History of malignancy (except cutaneous melanoma) within 5 years at the screening

 -  Organ transplantation other than cornea and hair (prior renal transplantation with
 graft failure not included)

 -  Prior exposure to investigational agents for HCV (direct acting antiviral agents,
 host-targeting agents, or therapeutic vaccines)

 -  Pregnancy

 -  Unwilling to have contraception during the study period

 -  Unwilling to provide informed consent