PrOD for Non-Cirrhotic Patients With HCV-1b Receiving Hemodialysis
PrOD for Non-Cirrhotic Patients With HCV-1b 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
 ombitasvir/paritaprevir/ritonavir plus dasabuvir (PrOD) treatment, a phase 2 study (RUBY-1)
 study has shown 90% of SVR in treatment-naive HCV-1 patients with chronic kidney disease
 (CKD) stage 4 or 5. Among the HCV-1b patients, who received PrOD for 12 weeks, all 7 patients
 achieved SVR. Although the data confirmed the excellent safety and efficacy in HCV-1b
 patients with severe renal impairment, the patient number was small and the data with regard
 to treatment-experienced patients was lacking. Therefore, we aimed to evaluated the safety
 and efficacy of ProD for 12 weeks in treatment-naive and treatment-experienced HCV-1b
 patients receiving hemodialysis.
Overview 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.10 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.

 Clinical experience of IFN-based Therapy 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.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.

 Clinical experience of IFN-free therapy by ombitasvir/paritaprevir/ritonavir plus dasabuvir
 in HCV GT-1 patients 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 ombitasvir/paritaprevir/ritonavir plus
 dasabuvir (PrOD) has been approved in 2014 to treat patients with chronic HCV GT-1 infection.
 Treatment with PrOD plus weight-based ribavirin for 12 weeks achieved an SVR12 rate of 96.2%
 and 96.3% in treatment-naïve and treatment-experienced non-cirrhotic HCV GT-1 patients,
 respectively (SAPPHIRE-I and SAPPHIRE-II). Furthermore, the SVR12 rates in those with GT-1a
 and GT-1b were 95.3% and 98.0% in treatment-naïve patents, and 96.0% and 96.7% in
 treatment-experienced patients, respectively. Among treatment-experienced HCV-1 patients, the
 SVR rates of PrOD plus RBV were comparable in those with various prior treatment responses by
 peginterferon plus RBV (relapse: 95.3%; partial response: 100%, null response: 95.2%).36
 Among treatment-naïve and treatment-experienced compensated cirrhotic HCV GT-1 patients,
 treatment with PrOD plus RBV for 12 or 24 weeks achieved and SVR rate of 91.8% and 95.%,
 respectively (TURQUOISE-II).37 The SVR12 rates in HCV GT-1b cirrhotic patients were similar
 in those receiving 12 and 24 weeks of treatment (98.5% versus 100%); the SVR12 rate in HCV
 GT-1a cirrhotic patients receiving 24 week of treatment was greater than those receiving 12
 weeks of treatment (94.2% versus 88.6%), particularly for prior non-responders to
 peginterferon plus RBV (92.9% versus 80%). The PEARL-III and PEARL-IV studies compared the
 SVR12 rates in treatment-naïve non-cirrhotic HCV GT-1b and HCV GT-1a patients receiving PrOD
 with/without RBV for 12 weeks.37 The SVR12 rate of PrOD without RBV was similar to that of
 PrOD with RBV in HCV GT-1b patients (99.0% versus 99.5%). However, the SVR12 rate in HCV
 GT-1a patients receiving PrOD with RBV was marginally higher than those receiving PrOD
 without RBV (97.0% versus 90.2%). The PEARL-II study further confirmed that in
 treatment-experienced non-cirrhotic HCV GT-1b patients, treatment with PrOD without RBV for
 12 weeks had comparable SVR12 rate to PrOD with RBV therapy (100% versus 96.6%). In
 TURQUOISE-III study, PrOD without RBV for 12 weeks achieved an SVR12 rate of 100% in
 treatment-naïve and treatment-experienced compensated cirrhotic HCV GT-1b patients. With
 regard to safety, PrOD with/without RBV showed excellent safety profiles with few patients
 experiencing serious adverse events (SAEs) and prematurely treatment discontinuation. The
 constitutional AEs in patients receiving PrOD based treatment showed were slightly higher
 than those receiving placebo. Furthermore, most of these symptoms were mild in grades. About
 5% of the non-cirrhotic patients and about 8% of the cirrhotic patients receiving PrOD plus
 RBV had an on-treatment hemoglobin level of < 10 g/dL; and none of the non-cirrhotic patients
 and about 2% of the compensated cirrhotic patients receiving PrOD had an on-treatment
 hemoglobin level of < 10 g/dL, respectively.35-40 In addition, the on-treatment AST/ALT
 elevation of more than 5 times the upper limit of normal (ULN) were 0.6%-1.7% and 0.5% in
 non-cirrhotic patients receiving PrOD with and without RBV; and were 2.9% and 2.0% in
 compensated cirrhotic patients receiving PrOD with and without RBV, respectively. The
 on-treatment total bilirubin elevation of more than 3 times ULN were 2.4%-5.7% and 0.5% in
 non-cirrhotic patients receiving PrOD with and without RBV; 13.5% and 0% in compensated
 cirrhotic patients receiving PrOD with and without RBV, respectively.35-40 Based on the above
 evidence, treatment with PrOD for 12 weeks is recommended for treatment-naïve and
 treatment-experienced HCV GT-1b patients, regardless of cirrhosis or not. Treatment with PrOD
 plus RBV for 12 weeks is recommended for HCV GT-1a patients, except for compensated cirrhotic
 HCV GT-1a null responders to prior therapy where treatment with PrOD plus RBV for 24 weeks is
 recommended.

 Clinical experience of IFN-free therapy by ombitasvir/paritaprevir/ritonavir plus dasabuvir
 in HCV GT-1 patients with severe renal impairment or end-stage renal disease (ESRD) The
 pharmacokinetic (PK) study of ombitasvir, paritaprevir, ritonavir, and dasabuvir was
 evaluated in 24 subjects with normal renal function, and with mild, moderate or severe renal
 impairment (each arm 6 patients). Compared to subjects with normal renal function, the area
 under the curves (AUCs) in subjects with mild renal impairment were comparable for
 ombitasvir, 20% higher for paritaprevir and dasabuvir, and 42% higher for ritonavir; the AUCs
 in subjects with moderate renal impairment were comparable for ombitasvir, 37% higher for
 paritaprevir and dasabuvir, and 80% higher for ritonavir; the AUCs in subjects with severe
 renal impairment were comparable for ombitasvir, 50% higher for paritaprevir and dasabuvir,
 and 114% higher for ritonavir. All patients were well tolerated for PrOD treatment except for
 mild AEs, including nausea, myalgia, and catheter-site erythema, encountered in 1 subject
 with moderate renal impairment. Based on the PK study, the changes of the drug exposure were
 not clinically relevant and the doses of PrOD do not require adjustment.

 The phase 3b RUBY-I study evaluated the safety and efficacy of PrOD with RBV and PrOD without
 RBV for 12 weeks in 13 and 7 HCV GT-1a and HCV GT-1b treatment-naïve non-cirrhotic patients
 with severe renal impairment or ESRD. The interim safety analysis showed that no patients had
 study drug discontinuation, no treatment-related serious adverse events (SAEs) and no
 clinically significant changes in markers of liver or kidney function. With regard to
 efficacy, 14 of the 20 patients completed 12 weeks of treatment and all of them achieved
 end-of-treatment virologic response (EOTVR). Ten patients (8 in GT-1a and 2 in GT-1b)
 completed post-treatment follow-up for 4 weeks and all achieved SVR4. Furthermore, 2 HCV
 GT-1a patients completed post-treatment follow-up for 12 weeks and all achieved SVR12.

 Rationale of the study design 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 ombitasvir, paritaprevir, ritonavir and dasabuvir proves the excellent safety profiles and
 dose adjustment are not needed for PrOD regimen in subjects with various degrees of renal
 impairment. The interim analysis of RUBY-I study showed the excellent on-treatment and
 off-therapy antiviral effects in HCV GT-1a and GT-1b infected patients receiving PrOD plus
 low-dose RBV and PrOD, respectively. However, all the patients enrolled in the RUBY-I study
 were treatment-naïve and were non-cirrhotic. Furthermore, only 7 patients in the RUBY-I study
 were HCV GT-1b patients. Based on the excellent safety and efficacy profiles of PrOD
 treatment for HCV GT-1b infected patients with normal renal function, we aim to evaluate the
 safety and efficacy of PrOD for 12 weeks in treatment-naïve and treatment-experienced HCV
 GT-1b non-cirrhotic patients receiving hemodialysis.
Inclusion Criteria:

 -  Ages of 20 to 70 yeas

 -  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 enzyme-linked immunosorbent assay [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
 Gesellschaft mit beschränkter Haftung [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 GT-1b infection (Abbott RealTime HCV genotyping 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

 -  Absence of cirrhosis with documented results of one of the following criteria:

 1. Liver biopsy within 24 months prior to or during screening demonstration the
 absence of cirrhosis, e.g. METAVIR score ≤ 3 or Ishak score ≤ 4.

 2. A screening transient elastography (Fibroscan) result of < 12.5 kilopascal (kPa)

 3. A screening Fibrosis Index Based on 4 markers (FIB-4) of ≤ 1.45 and Aspartate
 Aminotransferase to Platelet Ratio Index (APRI) of ≤ 2

 4. Subjects with non-qualifying FIB-4/APRI or Fibroscan result may only be enrolled
 if they have a qualifying liver biopsy within 24 months prior to or during
 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

 -  Hepatitis B virus (HBV) or HIV co-infection

 -  Presence of cirrhosis (Child-Puge class A, 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

 -  Screening laboratory analyses showing any of the following results

 1. Hemoglobin (Hb) level < 10 g/dL

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

 3. Platelet count < 60,000 cells/mm3

 4. International normalized ratio (INR) > 2.0

 5. Albumin (Alb) < 2.8 g/dL

 6. Bilirubin (Bil) > 3.0 mg/dL

 7. Alanine aminotransferase (ALT) > 5X upper limit of normal (ULN)

 8. Aspartate aminotransferase (AST) > 5X upper limit of normal (ULN)

 9. 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 [12] Unwilling to provide
 informed consent