PrOD for Non-Cirrhotic Patients With HCV-1b Receiving Hemodialysis
Condition: Hepatitis Viruses
MeSH terms: Hepatitis A; Hepatitis
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): PTV/r/OBV/DSV
Intervention type(s): Drug
Intervention description(s): Viekirax/Exviera for 12 weeks
Other intervention name(s): Viekirax/Exviera
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hepatitis C virus; Hemodialysis; Direct acting antiviral agents