Pegylated Interferon Alfa-2a Plus Low Dose Ribavirin for Treatment-Naïve Hemodialysis Patients With Chronic Hepatitis C

Study Overview
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Brief Summary
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Chronic hepatitis C virus (HCV) infection is common in dialysis patients. Interferon (IFN)-based treatment for chronic hepatitis C has been the mainstay therapy in immunocompetent patients. In dialysis patients, treatment with conventional or pegylated interferon has also received much attention recently. Two meta-analyses evaluating the efficacy and safety of conventional IFN alfa monotherapy showed that the sustained virologic response (SVR) rates were 37% and 33%, respectively; and the corresponding dropout rates were 17% and 29.6%, respectively.The efficacy and safety of pegylated IFN alfa-2a and 2b in treating dialysis patients showed conflicting results, with a more favorable outcome of patients treated with pegylated IFN alfa-2a (135-180 μg/week: SVR 33-75%, well tolerated) than those treated with pegylated IFN alfa-2b (0.5-1.0 μg/week: SVR 12.5%, poorly tolerated. Currently, IFN-based therapy to treatment HCV infection should be initiated in dialysis stages, because the use of IFN in RT patients harbors high risks of acute graft rejection,and have low response rates under the concomitant use of immunosuppressive agents. Ribavirin, which has been used in combination with IFN to treat chronic hepatitis C in the general patients and achieve a higher SVR rate than IFN monotherapy, is considered contraindicated in dialysis patients with chronic hepatitis C due to the risk of severe hemolytic anemia. However, some pilot studies evaluating combined conventional IFN alfa plus low dose ribavirin (170-300 mg/day) showed SVR rates of 17%-66% after 24-48 weeks of treatment. In addition, a recent study including 6 patients with combination of pegylated IFN alfa plus low dose ribavirin also showed a SVR rate of 50%. In this study, treatment with pegylated IFN alfa-2a plus low dose ribavirin achieved a higher SVR rate that that with pegylated IFN alfa-2b plus low dose ribavirin (100% vs. 25%). Based on the long-term favorable outcome in dialysis patients who eradicate HCV, and the superior response of pegylated IFN alfa-2a plus low dose ribavirin to pegylated IFN alfa-2b plus low dose ribavirin in treating dialysis patients with chronic hepatitis C, the aim of the study is to evaluate the efficacy and safety of pegylated IFN alfa-2a plus low dose ribavirin versus pegylated interferon alfa-2a alone in treatment naïve dialysis patients with chronic hepatitis C.

Detailed Description
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Chronic hepatitis C virus (HCV) infection is common in dialysis patients, with the reported prevalence varying from 3% to 80% worldwide. (1-3) Although these patients usually have mild symptoms and moderate elevation of alanine transaminase levels, recent international collaborative survey and prospective studies found that anti-HCV seropositivity and positive HCV RNA were risk factors for mortality and hepatocellular carcinoma (HCC). (4-7) Furthermore, progressive hepatic fibrosis, poor patient and graft survival were observer in dialysis patients with HCV infection who undergo renal transplantation (RT), suggesting immunosuppression following RT may worsen the course of hepatic fibrosis and renal graft function. (8-13) These lines of evidence indicate that HCV infection in the dialysis population is an important issue to be tackled. Interferon (IFN)-based treatment for chronic hepatitis C has been the mainstay therapy in immunocompetent patients. In dialysis patients, treatment with conventional or pegylated interferon has also received much attention recently. Two meta-analyses evaluating the efficacy and safety of conventional IFN alfa monotherapy showed that the sustained virologic response (SVR) rates were 37% and 33%, respectively; and the corresponding dropout rates were 17% and 29.6%, respectively.(14,15) The efficacy and safety of pegylated IFN alfa-2a and 2b in treating dialysis patients showed conflicting results, with a more favorable outcome of patients treated with pegylated IFN alfa-2a (135-180 μg/week: SVR 33-75%, well tolerated) than those treated with pegylated IFN alfa-2b (0.5-1.0 μg/week: SVR 12.5%, poorly tolerated), (16-21) which may result from different pharmacokinetic profiles between these two pegylated IFNs. Currently, IFN-based therapy to treatment HCV infection should be initiated in dialysis stages, because the use of IFN in RT patients harbors high risks of acute graft rejection,(22,23) and have low response rates under the concomitant use of immunosuppressive agents. (24,25) Ribavirin, which has been used in combination with IFN to treat chronic hepatitis C in the general patients and achieve a higher SVR rate than IFN monotherapy, is considered contraindicated in dialysis patients with chronic hepatitis C due to the risk of severe hemolytic anemia. However, some pilot studies evaluating combined conventional IFN alfa plus low dose ribavirin (170-300 mg/day) showed SVR rates of 17%-66% after 24-48 weeks of treatment. (26-28) In addition, a recent study including 6 patients with combination of pegylated IFN alfa plus low dose ribavirin also showed a SVR rate of 50%. (29) In this study, treatment with pegylated IFN alfa-2a plus low dose ribavirin achieved a higher SVR rate that that with pegylated IFN alfa-2b plus low dose ribavirin (100% vs. 25%) Based on the long-term favorable outcome in dialysis patients who eradicate HCV, and the superior response of pegylated IFN alfa-2a plus low dose ribavirin to pegylated IFN alfa-2b plus low dose ribavirin in treating dialysis patients with chronic hepatitis C, the aim of the study is to evaluate the efficacy and safety of pegylated IFN alfa-2a plus low dose ribavirin versus pegylated interferon alfa-2a in treatment naïve dialysis patients with chronic hepatitis C.

Official Title
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Pegylated Interferon Alfa-2a Plus Low Dose Ribavirin Versus Pegylated Interferon Alfa-2a Alone for Treatment-naïve Hemodialysis Patients With Chronic Hepatitis C

Conditions
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Chronic Hepatitis C

Intervention / Treatment
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* Drug: Peginterferon alfa-2a and ribavirin
* Drug: Peginterferon alfa-2a


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-65 years old Creatinine clearance (Ccr) < 15 ml/min/1.73 m2 Anti-HCV (Abbott HCV EIA 3.0, Abbott Diagnostic, Chicago, IL) positive > 6 months Detectable serum quantitative HCV-RNA (Cobas Taqman HCV test, version 2, Roche Diagnostics) with a dynamic range of 25-391000000 IU/ml Exclusion Criteria: Receiving interferon-based therapy for chronic hepatitis C Severe anemia (hemoglobin < 10 g/dL) or hemoglobinopathy Neutropenia (neutrophil count, <1,500/mm3) Thrombocytopenia (platelet <90,000/ mm3) Co-infection with HBV or HIV Chronic alcohol abuse (daily consumption > 20 g/day) Autoimmune liver disease Decompensated liver disease (Child classification B or C) Neoplastic disease An organ transplant Immunosuppressive therapy Poorly controlled autoimmune diseases, pulmonary diseases, cardiac diseases, psychiatric diseases, neurological diseases, diabetes mellitus Evidence of drug abuse Unwilling to have contraception

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Peginterferon alfa-2a and ribavirin<br>Pegylated interferon alfa-2a (Pegasys, F. Hoffman-LaRoche) 135 ug/week plus ribavirin (Copegus, F. Hoffman-LaRoche) 200 mg/day for 24 to 48 weeks (genotype 1: 48 weeks, genotype 2: 24 weeks) | Drug: Peginterferon alfa-2a and ribavirin<br>* Pegylated interferon alfa-2a (Pegasys, F. Hoffman-LaRoche) 135 ug/week plus ribavirin (Copegus, F. Hoffman-LaRoche) 200 mg/day for 24 to 48 weeks (genotype 1: 48 weeks, genotype 2: 24 weeks)<br>* Other names: Ribavirin (Copegus, F. Hoffman-LaRoche);|
| Experimental: Peginterferon alfa-2a<br>Pegylated interferon alfa-2a (Pegasys, F. Hoffman-LaRoche) 135 ug/week for 24 to 48 weeks (genotype 1: 48 weeks, genotype 2: 24 weeks) | Drug: Peginterferon alfa-2a<br>* Pegylated interferon alfa-2a (Pegasys, F. Hoffman-LaRoche) 135 ug/week for 24 to 48 weeks (genotype 1: 48 weeks, genotype 2: 24 weeks)<br>* Other names: Pegylated interferon alfa-2a (Pegasys, F. Hoffman-LaRoche);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained Virologic Response (SVR)Rate |  | 1.5 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Event (AE)-Related Withdrawal Rate |  | 1.5 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic hepatitis C, Hemodialysis, Interferon, Ribavirin