Chronic Hepatitis C, Hemodialysis
Conditions
Keywords
Chronic hepatitis C, hemodialysis, interferon, ribavirin
Brief summary
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. 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%. Although dialysis patients have a higher SVR rate to conventional IFN or pegylated IFN monotherapy than patients with normal renal function for HCV therapy. More than half of these patients are relapsers or non-responders to IFN monotherapy. Retreatment of HCV-patients with normal renal function by combined pegylated IFN alfa plus ribavirin who fail to response to IFN monotherapy has achieved a SVR rate of 28%. Based on the long-term favorable outcome in dialysis patients who eradicate HCV, the aim of the study is to evaluate the efficacy and safety of retreatment by pegylated IFN alfa-2a plus low dose ribavirin in dialysis patients who fail to achieve HCV eradication by conventional or pegylated IFN alfa.
Detailed description
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) Although dialysis patients have a higher SVR rate to conventional IFN or pegylated IFN monotherapy than patients with normal renal function for HCV therapy. More than half of these patients are relapsers or non-responders to IFN monotherapy. Retreatment of HCV-patients with normal renal function by combined pegylated IFN alfa plus ribavirin who fail to response to IFN monotherapy has achieved a SVR rate of 28%.(30) Based on the long-term favorable outcome in dialysis patients who eradicate HCV, the aim of the study is to evaluate the efficacy and safety of retreatment by pegylated IFN alfa-2a plus low dose ribavirin in dialysis patients who fail to achieve HCV eradication by conventional or pegylated IFN alfa.
Interventions
Pegylated interferon alfa-2a (Pegasys, F. Hoffman-LaRoche) 135 ug/week plus ribavirin (Copegus, F. Hoffman-LaRoche) 200 mg/day for 48 weeks
Sponsors
National Science and Technology Council, Taiwan
Department of Health, Executive Yuan, R.O.C. (Taiwan)
National Taiwan University Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Non-responders or relapsers of dialysis patients to conventional interferon or pegylated interferon monotherapy * Age 18\ 65 years old * Creatinine clearance (Ccr) \< 10 ml/min/1.73 m2 * Anti-HCV (Abbott HCV EIA 2.0, Abbott Diagnostic, Chicago, IL) positive \> 6 months * Detectable serum quantitative HCV-RNA (Cobas Taqman HCV Monitor v2.0, Roche Diagnostics) with dynamic range 25- 391000000 IU/ml
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 1.Number of Participants With Sustained Virologic Response (SVR) 2.Number of Participants Who Droppoed Out of the Study Prematurely Due to Adverse Events (AEs) | 1.5 year | 1. Number of participants with sustained virologic response (SVR): number of patients with undetectable HCV RNA 6 months off therapy by real-time PCR test (Cobas TaqMan HCV Test v2.0, Roche Diagnostics GmbH, Mannheim, Germany, limit of detection \< 25 IU/mL) 2. Number of participants who droppoed out of the study prematurely due to adverse events (AEs): number of patients who prematurely withdrew from the study due to any adverse events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Histologic Response(HR) | 1.5 year | Number of participants with histologic response (HR): number of patients who had improvement of as least 2 scores at the end of follow-up liver biopsy compared to baseline liver biopsy by Ishak scoring system (the sum of Ishak necroinflammation score (0-18) and Ishak fibrosis score (0-6); the higher the total scores, the severer the histologic changes) |
Countries
Taiwan
Participant flow
Recruitment details
Recruitment period: June 2006- June 2007 Location: 5 academic centers
Pre-assignment details
Wash out period: 6 months after last interferon intervention
Participants by arm
| Arm | Count |
|---|---|
| Pegylated Interferon and Ribavirin for 48 Weeks (Genotype 1) Pegylated interferon alfa-2a (Pegasys, F. Hoffman-LaRoche) 135 ug/week plus ribavirin (Copegus, F. Hoffman-LaRoche) 200 mg/day for 48 weeks | 25 |
| Pegylated Interferon and Ribavirin for 24 Weeks (Genotype 2) Pegylated interferon alfa-2a (Pegasys, F. Hoffman-LaRoche) 135 ug/week plus ribavirin (Copegus, F. Hoffman-LaRoche) 200 mg/day for 24 weeks | 10 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Pegylated Interferon and Ribavirin for 24 Weeks (Genotype 2) | Pegylated Interferon and Ribavirin for 48 Weeks (Genotype 1) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 25 Participants | 35 Participants |
| Age Continuous | 44 years STANDARD_DEVIATION 12 | 48 years STANDARD_DEVIATION 8 | 47 years STANDARD_DEVIATION 10 |
| Region of Enrollment Taiwan | 10 participants | 25 participants | 35 participants |
| Sex: Female, Male Female | 4 Participants | 8 Participants | 12 Participants |
| Sex: Female, Male Male | 6 Participants | 17 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 22 / 25 | 8 / 10 |
| serious Total, serious adverse events | 2 / 25 | 1 / 10 |
Outcome results
Primary
1.Number of Participants With Sustained Virologic Response (SVR) 2.Number of Participants Who Droppoed Out of the Study Prematurely Due to Adverse Events (AEs)
1. Number of participants with sustained virologic response (SVR): number of patients with undetectable HCV RNA 6 months off therapy by real-time PCR test (Cobas TaqMan HCV Test v2.0, Roche Diagnostics GmbH, Mannheim, Germany, limit of detection \< 25 IU/mL) 2. Number of participants who droppoed out of the study prematurely due to adverse events (AEs): number of patients who prematurely withdrew from the study due to any adverse events
Time frame: 1.5 year
Population: Outcome measures:intention-to-treat (ITT) analysis Imputation technique: last observation carried forward
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pegylated Interferon and Ribavirin for 48 Weeks (Genotype 1) | 1.Number of Participants With Sustained Virologic Response (SVR) 2.Number of Participants Who Droppoed Out of the Study Prematurely Due to Adverse Events (AEs) | Sustained virologic response (SVR) | 13 Participants |
| Pegylated Interferon and Ribavirin for 48 Weeks (Genotype 1) | 1.Number of Participants With Sustained Virologic Response (SVR) 2.Number of Participants Who Droppoed Out of the Study Prematurely Due to Adverse Events (AEs) | Drop-out | 7 Participants |
| Pegylated Interferon and Ribavirin for 24 Weeks (Genotype 2) | 1.Number of Participants With Sustained Virologic Response (SVR) 2.Number of Participants Who Droppoed Out of the Study Prematurely Due to Adverse Events (AEs) | Sustained virologic response (SVR) | 8 Participants |
| Pegylated Interferon and Ribavirin for 24 Weeks (Genotype 2) | 1.Number of Participants With Sustained Virologic Response (SVR) 2.Number of Participants Who Droppoed Out of the Study Prematurely Due to Adverse Events (AEs) | Drop-out | 2 Participants |
Secondary
Number of Participants With Histologic Response(HR)
Number of participants with histologic response (HR): number of patients who had improvement of as least 2 scores at the end of follow-up liver biopsy compared to baseline liver biopsy by Ishak scoring system (the sum of Ishak necroinflammation score (0-18) and Ishak fibrosis score (0-6); the higher the total scores, the severer the histologic changes)
Time frame: 1.5 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pegylated Interferon and Ribavirin for 48 Weeks (Genotype 1) | Number of Participants With Histologic Response(HR) | 11 Participants |
| Pegylated Interferon and Ribavirin for 24 Weeks (Genotype 2) | Number of Participants With Histologic Response(HR) | 6 Participants |