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NDT Advance Access originally published online on October 18, 2005
Nephrology Dialysis Transplantation 2006 21(2):437-443; doi:10.1093/ndt/gfi231
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Dialysis and Transplantation

Randomized trial of pegylated interferon {alpha}-2b monotherapy in haemodialysis patients with chronic hepatitis C

Mark W. Russo1, Reem Ghalib2, Samuel Sigal3 and Viren Joshi4

1 University of North Carolina, Chapel Hill, NC, 2 The Liver Institute at Methodist Dallas, Dallas, TX, 3 Mount Sinai School of Medicine, New York, NY and 4 Tulane University School of Medicine, New Orleans, LA, USA

Correspondence and offprint requests to: Mark W. Russo, MD MPH, University of North Carolina, Division of Gastroenterology and Hepatology, Bioinformatics Bldg Rm 1104, 130 Mason Farm Road, Chapel Hill, NC 27599-7080, USA. Email: Mark_Russo{at}med.unc.edu



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Chronic hepatitis C infection is prevalent among haemodialysis patients. The goal of our study was to determine the efficacy and safety of pegylated interferon {alpha}-2b in haemodialysis patients with chronic hepatitis C.

Methods. We conducted a trial which randomized haemodialysis patients with chronic hepatitis C to 1.0 or 0.5 µg/kg of pegylated interferon {alpha}-2b subcutaneously, weekly for up to 48 weeks. End-points were sustained viral response and adverse events. Data were analysed as intention to treat and as intended per protocol.

Results. After 16 patients were enrolled, the study was terminated because of adverse events and modifications needed in the study design. Nine subjects were randomized to the 1.0 µg/kg group and seven subjects were randomized to the 0.5 µg/kg group. Serious adverse events requiring discontinuation of therapy occurred in five (56%) subjects in the 1.0 µg/kg group and in two (28%) subjects in the 0.5 µg/kg group (P = 0.36). The most common adverse events were hypertension and infection unrelated to neutropenia. Two (22%) subjects in the 1.0 µg/kg group, both genotype 1, had a sustained viral response, and none of the subjects in the 0.5 µg/kg group had a sustained viral response (P = 0.47). Five subjects in the 1.0 µg/kg group were able to complete 24 weeks or longer of therapy as per protocol and two (40%) were sustained responders.

Conclusions. In our study group, pegylated interferon {alpha}-2b was poorly tolerated and was associated with substantial side effects. Sustained response rates seen with pegylated interferon in our study do not appear to be better than rates reported for standard interferon {alpha}-2b.

Keywords: kidney; renal; treatment; viral



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Hepatitis C is prevalent in haemodialysis patients and is a cause of substantial morbidity in patients with end-stage renal disease. The prevalence of chronic hepatitis C infection in haemodialysis patients is estimated at 8%, which is ~4-fold higher than the prevalence of chronic hepatitis C infection in the general population in the USA [1]. Ten to 15% of haemodialysis patients with chronic hepatitis C infection may have bridging fibrosis or cirrhosis on liver biopsy [2,3]. Hepatitis C with advanced liver fibrosis may be a contraindication to isolated kidney transplantation at some centres. Studies on the natural history of chronic hepatitis C in renal transplant recipients have reported that patient and graft survival are 10 and 25% lower, respectively, after 10 years compared with uninfected recipients; however, other studies, typically with shorter follow-up, have not found a difference in survival [4–6].

Treatment of chronic hepatitis C in patients with ESRD is controversial. Although antiviral therapy with {alpha}-interferons has been reported to have increased efficacy against hepatitis C in dialysis patients, therapy may be poorly tolerated and associated with greater side effects in this population. Sustained viral response rates as high as 60% have been demonstrated with interferon monotherapy in haemodialysis patients with chronic hepatitis C, with a pooled sustained response rate across studies of 30% [7–10]. Most studies have been small prospective, non-randomized studies using standard interferon. The largest prospective study enrolled 37 patients and was terminated early because of adverse events [10]. There have been two randomized trials of interferon monotherapy in dialysis patients with hepatitis C, which reported sustained response rates of 21 and 58% [8,11]. Few studies have used interferon in combination with ribavirin because of the concern of severe haemolysis with ribavirin in dialysis patients, although two studies suggest low dose ribavirin may be well tolerated [12,13].

The group that may derive the most benefit from successful eradication of hepatitis C are those with ESRD and bridging fibrosis or well compensated cirrhosis. With successful antiviral therapy, fibrosis may regress and this group could undergo isolated kidney transplantation. Other potential benefits of eradicating hepatitis C before kidney transplantation include decreasing de novo glomerulonephritis and diabetes after kidney transplantation [14]. However, experience with pegylated interferons in haemodialysis patients with chronic hepatitis C is limited. An interim report of 10 haemodialysis patients treated with pegylated interferon {alpha}-2a for chronic hepatitis C reported that 87.5% of patients had undetectable hepatitis C RNA by polymerase chain reaction (PCR) at treatment week 12 [15]. There may be greater exposure to pegylated interferon {alpha}-2b in haemodialysis patients because the area under the curve and half-life of pegylated interferon {alpha}-2b are increased in haemodialysis patients compared with patients with normal renal function [16].

Because there are few randomized trials of antiviral therapy in haemodialysis patients with chronic hepatitis C and no data on sustained response rates or optimal dosing with pegylated interferon, we conducted a trial to determine the efficacy, safety and optimal dose of pegylated interferon {alpha}-2b monotherapy in this group. The study was originally designed to include two treatment arms without an untreated arm because spontaneous clearance of hepatitis C is rare. We originally intended to enrol 50 subjects, but the trial was terminated early due to a relatively high number of adverse events.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
This randomized clinical trial of pegylated interferon {alpha}-2b was approved by the Institutional Review Boards at the participating institutions.

Protocol
Patients were eligible if they had chronic hepatitis C defined as hepatitis C virus (HCV) RNA positive by PCR and they were on haemodialysis. Subjects had to meet the following inclusion and exclusion criteria.

Inclusion criteria
Haemodialysis patients were eligible for the study if they met the following criteria: (i) age 18 years or older, (ii) serum positive for HCV RNA by PCR or other assay (bDNA); (iii) liver biopsy within 36 months of inclusion confirming a pathological diagnosis of chronic hepatitis C; (iv) compensated liver disease defined as absence of a history of ascites, variceal bleeding or encephalopathy and, platelets >90 000 mm3; (v) haemoglobin values of ≥8.0 g/dl; (vi) white blood cell count ≥2500/mm3 and neutrophil count ≥1500/mm3; (vii) thyroid-stimulating hormone within normal limits or thyroid disease under control; (viii) subjects were treatment naïve (never treated with interferon {alpha}2-b, interferon {alpha}2-a, consensus interferon or pegylated interferon); and (ix) subjects were required to use two elective methods of contraception. A urine pregnancy test was obtained at entry prior to the initiation of treatment. Female patients must not have been breast feeding at the time of screening or during the study.

Exclusion criteria
Exclusion criteria included: (i) hypersensitivity to {alpha}-interferons; (ii) any cause for chronic liver disease other than chronic hepatitis C; (iii) evidence of decompensated liver disease such as a history of or presence of ascites due to liver disease (subjects with non-portal hypertensive ascites, i.e. nephrotic syndrome or peritoneal dialysis, were not excluded), bleeding varices or spontaneous encephalopathy; (iv) any known history of active seizure disorders requiring medication, poorly controlled diabetes mellitus, serious pulmonary disease; systemic immunologically mediated diseases (subjects with membranoproliferative glomerulonephritis were not excluded) or any medical condition requiring, or likely to require during the course of the study, chronic systemic administration of steroids; (v) patients with evidence of ischaemia on stress testing, electrocardiographic evidence of ischaemia, a significant arrhythmia, cardiac failure, recent coronary surgery, hypertension poorly controlled with medication, angina or a myocardial infarction within the previous 12 months; (vi) ongoing substance abuse, such as alcohol (>80 g/day), intravenous drugs or inhaled drugs; (vii) patients with a history of organ transplantation on immunosuppression (subjects with retained non-functioning grafts not on immunosuppression were eligible); (viii) patients with untreated and uncontrolled depression, or a history of severe psychiatric disorder, such as major psychoses, suicidal ideation and/or suicidal attempt; and (ix) patients who were HIV positive.

Pegylated interferon {alpha}-2b was administered by the patient on a day when they were not on dialysis and when the day following the injection was also an off dialysis day (e.g. on a Saturday morning in patients on a Monday, Wednesday, Friday schedule). Based upon our experience and discussion with subjects, side effects were tolerated better if medication was administered on an off dialysis day, but data were not collected on side effects in relation to day of administration. Subjects were taught by the hepatologist or nurse how to administer the medication on the first week of therapy and observed for proper technique. Thereafter, patients self-administered medication. Blood work was obtained every week for the first 4 weeks for liver chemistries and complete blood count. After the first 4 weeks of treatment, blood work was obtained every 2 weeks. Subjects were seen by the treating hepatologist on weeks 1, 2 and 4 of treatment and then monthly or as clinically indicated. The dose of pegylated interferon was reduced by 50% if absolute neutrophil counts declined below 750 mm3 and discontinued if absolute neutrophil counts declined below 500 mm3. The dose of pegylated interferon was reduced by 50% if the platelet count decreased below 70 000 mm3 and was discontinued if the platelet count decreased below 50 000 mm3. Dose reduction for decreases in haemoglobin and changes in erythropoietin dose were left to the discretion of the treating physician.

Assignment
Subjects were randomized using concealed envelopes at a central site to 1.0 or 0.5 µg/kg of pegylated interferon {alpha}-2b monotherapy subcutaneously, weekly for up to 48 weeks. Therapy was discontinued if subjects were HCV RNA positive by PCR on treatment week 24. These two doses of peginterferon were chosen based upon existing literature of standard interferon {alpha}-2b suggesting that 5 x 106 units three times a week is poorly tolerated (the equivalent of 1.5 µg/week pegylated interferon {alpha}-2b) and 1.5 x 106 and 3 x 106 units have reasonable side effect profiles and efficacy. The duration of therapy was not stratified based on genotype because most haemodialysis patients are genotype 1 and it was anticipated that there would be too few non-genotype 1 subjects to conduct meaningful analyses stratified on genotype.

Masking
Subjects and investigators were not blinded to treatment arm.

Participant flow and follow-up
Quantitation for serum HCV RNA by PCR was determined at baseline, week 24, week 48 and week 72. If subjects were serum HCV RNA positive at treatment week 24, therapy was terminated. A sustained viral response was defined as undetectable serum HCV RNA by PCR at week 72, 24 weeks after therapy was terminated. Subjects were allowed to discontinue the study if they were called for a kidney transplant.

Quantitation of serum HCV RNA and genotyping
Quantitation of HCV RNA was determined by PCR at each centre. Four centres used Cobas Amplicor-HCV test version 2.0 with a lower limit of detection of 600 IU/ml (Roche Molecular Diagnostics, Sommerville, NJ) and one site used transcription-mediated amplification (Bayer Diagnostics, Tarrytown, NY). Genotyping was performed using a commercially available line probe assay (Bayer Diagnostics).

Histology
Liver biopsies were performed percutaneously with ultrasound marking on an out-patient basis by the hepatologist. Patients were monitored for 6–8 h after the liver biopsy. Factor replacement or desmopressin acetate (DDAVP) were not routinely administered. No complications from the liver biopsy were reported.

Liver biopsy was obtained within 36 months of enrolment and stained with Masson's trichrome. Liver biopsies were graded for hepatitis activity and staged for fibrosis according to standardized criteria [17]. Follow-up liver biopsies were not performed.

Primary outcomes
The primary outcomes were sustained viral response and serious adverse events. Sustained viral response was defined as undetectable hepatitis C RNA by PCR in the serum 24 weeks after stopping therapy. Serious adverse events were defined as those resulting in hospitalization, death or any intervention not part of routine standard of care. Secondary outcomes were 24 week treatment response rate defined as undetectable serum HCV RNA by PCR and end of treatment response defined as undetectable serum HCV RNA by PCR.

Statistical analysis
The study was originally designed to enrol 50 subjects, 25 in each arm, to detect a 35% difference in sustained response rates between the two doses at an {alpha} of 0.05 and power of 80%. Proportions were compared using Fisher's exact test and means were compared with Student's t-test or Wilcoxon rank sum test, where appropriate. Analyses were performed as intention to treat where subjects who received at least one dose of study medication were included in the analysis. Per protocol (adherence) analysis was performed in subjects who received study medication as outlined in the protocol.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Figure 1 shows the study design and outcomes of subjects enrolled in the trial. Sixteen subjects were enrolled in the study and received at least one dose of pegylated interferon {alpha}-2b and were included in the analysis. The characteristics of the study group, by treatment group are shown in Table 1. Ten (62.5%) subjects had normal alanine aminotransferase (ALT) values before starting therapy. One subject was genotype 2. Liver biopsy demonstrated stage 0–2 fibrosis in eight (50%) subjects and stage 3 or 4 fibrosis in eight (50%) subjects. Fourteen subjects were listed for kidney transplantation. Five subjects from three different sites were randomized, but did not return for follow-up. They did not receive a dose of study medication and were not included in the analysis.


Figure 1
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  		Fig. 1. Flow chart of the study population.

 

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  		Table 1. Characteristics of the study population

 
Efficacy
Outcomes and serious events are shown in Table 2. Three subjects (33%) in the 1.0 µg/kg group and none of the subjects in the 0.5 µg/kg group had a 24 week treatment response, P = 0.21. Two of nine subjects (22%) in the 1.0 µg/kg group had a sustained viral response; both subjects were infected with genotype 1 and both were Caucasian. Two (25%) subjects with bridging fibrosis or cirrhosis and one (12.5%) subject with stage 0–2 fibrosis had a sustained response (P = 1.0). Aminotransferase levels did not increase with therapy.


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  		Table 2. Outcome of subjects

 
Adherence (per protocol analysis)
Five (56%) subjects in the 1.0 µg/kg group and two (29%) subjects in the 0.5 µg/kg group received 24 weeks or more of therapy as outlined in the protocol. The sustained response rate if subjects tolerated 24 weeks or more of therapy was 40% in the 1.0 µg/kg group. Six (66%) subjects in the 1.0 µg/kg group and three (43%) subjects in the 0.5 µg/kg arm received 12 or more weeks of therapy. The sustained response rate in the 1.0 µg/kg arm if subjects tolerated 12 or more weeks of therapy was 33%.

Safety
Mild adverse events included constitutional symptoms, including fatigue, myalgias and fevers reported in two subjects in the 1.0 µg/kg group and one subject in the 0.5 µg/kg arm. One subject in the 0.5 µg/kg arm reported an increase in anxiety and depression that responded to an antidepressant. None of these events required dose reduction. No subject required dose reduction or discontinuation due to neutropenia, anaemia, thrombocytopenia, neurological symptoms or pancreatitis. All subjects were on erythropoietin or an erythropoietin derivative.

Serious adverse events occurred in five (56%) subjects in the 1.0 µg/kg group and two (28.6%) subjects in the 0.5 µg/kg group, P = 0.36 (Table 2). Three adverse events were believed by the investigator to be probably due to pegylated interferon, two events were believed to be possibly due to therapy and two events were believed to be unrelated to therapy. One subject died, in the 1.0 µg/kg group, from hypoglycaemia-associated seizure and cardiac arrest. The subject was an insulin-dependent diabetic and had lost 34 lb over 2 months after a cholecystectomy. The subject was not on pegylated interferon at the time of death and it was believed that the seizure was due to hypoglycaemia induced by changing insulin requirements from the weight loss and unrelated to therapy. One subject in each group with a history of hypertension developed uncontrolled hypertension while on therapy, which responded to 50% dose reduction and therapy was continued. In one subject, the medication was increased to full dose and hypertension returned, and the dose was reduced by 50% again. The exacerbation in hypertension was believed to be related to therapy. This subject discontinued the study at week 12 to receive a kidney transplant. The subject was HCV RNA negative at week 12 but relapsed 12 weeks after the kidney transplant. One subject in the 1.0 µg/kg group with stage 0 fibrosis developed Staphylococcus aureus bacteraemia in week 5 of therapy thought to be secondary to a haemodialysis catheter, and he required hospitalization and intravenous antibiotics. The subject was not neutropenic at the time and it was believed that the event was unrelated to therapy, but therapy was discontinued because the subject had active infection. One subject with cirrhosis in the 1.0 µg/kg arm developed pneumonia in week 17 of therapy requiring intravenous antibiotics and hospitalization. The subject was not neutropenic, but therapy was discontinued and it was believed that the event was possibly related to therapy. A subject in the 1.0 µg/kg arm discontinued therapy due to severe constitutional symptoms and dehydration, and it was concluded that the event was probably due to therapy. One subject in the 0.5 µg/kg group developed left sided flank, back and leg pain on week 8 of therapy. The subject had a retained, non-functioning kidney graft, but she was not on prednisone or immunosuppression. Therapy was discontinued because of the concern of graft necrosis, but removal of the graft showed no pathological evidence of necrosis.

Three (37.5%) subjects with stage 0–2 fibrosis on liver biopsy stopped therapy for an adverse event, compared with four (50%) subjects with stage 3 or 4 fibrosis on liver biopsy, P = 1.0. The mean age in subjects who did and did not discontinue therapy for adverse events was 46 years in both groups. The most common aetiology of kidney disease in subjects who did and did not discontinue therapy was hypertension, 57 and 56%, respectively.



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
There have been many non-randomized trials of standard interferons for treatment of chronic hepa-titis C in haemodialysis patients reporting sustained response rates of 20–60%, which is higher than rates of interferon monotherapy in patients with normal kidney function [7–10,18]. There have been few randomized trials of standard interferon and no randomized trials of pegylated interferon reporting sustained response rates in haemodialysis patients with chronic hepatitis C. In the current study, subjects were randomized to one of two doses of pegylated interferon {alpha}-2b. Dosing was based on data from trials of standard interferon demonstrating that high dose interferon is poorly tolerated and low or moderate dose interferon is well tolerated with reasonable efficacy. The sustained viral response rate reported in our study was similar to that reported in trials of standard interferon. The associated side effects and additional cost of pegylated interferon without an increase in efficacy do not support its routine use in the dialysis population.

The risks of infection with HCV may include cirrhosis, hepatocellular carcinoma or liver failure. If patients do develop complications from chronic hepatitis C infection, they typically occur after 20 years of infection. Studies demonstrating increased morbidity from hepatitis C in kidney transplant recipients followed patients for at least 10 years after transplant [4,5]. Treatment for hepatitis C includes standard interferon {alpha}-2a or -2b three times a week with weekly ribavirin, or weekly peginterferon {alpha}-2a or -2b with daily ribavirin. The addition of ribavirin to interferon increases response rates almost 3-fold in patients with normal renal function. Peginterferon is associated with ~10–15% higher sustained response rates in genotype 1 patients compared with standard interferon. The goal of therapy is to eradicate HCV determined by measuring HCV RNA by PCR in the serum. Other benefits seen with antiviral therapy and viral eradication prior to kidney transplant include lower rates of hepatitis C-related glomerulonephritis and diabetes [14]. Kidney transplant patients with hepatitis C who are successfully treated may have the most to gain because post-transplant glomerulonephritis may be lower compared with untreated recipients.

The study was terminated before achieving target enrolment because modifications were needed in the study design and there were a large number of serious adverse events. It is unclear from the current study if this was due to therapy or underlying co-morbidity in patients with ESRD. For example, haemodialysis patients develop line infections or difficult to control hypertension, which were some of the reported serious adverse events. From this standpoint, it would have been useful to have designed the study to include a group that was randomized to no treatment or to include data on morbidity from a historical control group. Including a group randomized to no treatment or a historical control group would have allowed documentation of the number of ‘adverse events’ that occur over 48 weeks in patients with chronic hepatitis C on haemodialysis.

In the current study, the sustained response rate was 22% in genotype 1 patients and 40% if subjects were able to tolerate 24 weeks of 1.0 µg/kg weekly as planned in the protocol. There are several possible explanations why lower efficacy was seen in this study compared with other studies of standard interferon in dialysis patients with chronic hepatitis C. Lower response rates to antiviral therapy are reported in patients with hepatitis C and cirrhosis. Subjects in the current study had relatively advanced fibrosis, with 25% of subjects with cirrhosis, and 50% of subjects had bridging fibrosis or cirrhosis, although two sustained responders had advanced fibrosis. These rates are higher than rates of cirrhosis or bridging fibrosis reported in other interferon trials in haemodialysis patients [7,8,10]. In addition, all but one of the subjects were infected with hepatitis C genotype 1, which is the genotype most resistant to treatment. Two-thirds of our patients in the high dose group were African-Americans, and African-Americans have lower response rates for unclear reasons [19]. Other studies in dialysis patients consist of up to 20% genotype 2 or 3 patients and included fewer African-Americans. Finally, data were analysed as intention to treat, and intention to treat results have not been routinely reported in other trials.

Therapy was poorly tolerated and the number of adverse events reported in the current study seems high compared with other studies of interferon in dialysis patients. However, another study was also terminated early due to adverse events. A study that originally was designed to enrol 120 patients was terminated because of adverse events after 37 patients were enrolled [10]. The most common adverse events in their study were cardiac and neuropsychiatric side effects, compared with the current study where hypertension and infection were the most common indications for termination of therapy. Reasons why adverse events may have been higher in the current study compared wih other studies are greater exposure to drug with pegylated interferon compared with standard interferon or differences in aetiology of underlying kidney disease. A greater proportion of subjects with ESRD from hypertension were included in this study compared with other studies, which included a greater proportion of patients with membranoproliferative glomerulonephritis. From our experience, we would consider it difficult to treat hypertension and a history of severe recurrent infections, such as bacteraemia, as contraindications to therapy.

Although the current study enrolled only 16 subjects, only eight of which had advanced fibrosis, and was underpowered to draw any definitive conclusions, results from this study may be helpful for designing larger treatment trials in dialysis patients with chronic hepatitis C. Although results from this trial suggest that higher viral eradication rates are seen with 1.0 µg/kg compared with 0.5 µg/kg weekly, the rate of adverse events was higher than the sustained response rate in the 1.0 µg/kg arm. The numbers of adverse events were lower, but not significantly different, in the 0.5 µg/kg group, but there were no 24 week treatment responders or sustained responders in this arm and the dose may be too low to be effective. In addition to including an untreated arm or historical control group, perhaps 0.7 µg/kg weekly should be studied. A small study suggests that low dose ribavirin may be well tolerated and could potentially be studied in a larger trial [13], or ribavirin analogues with less toxicity could be studied. We did not collect pharmacokinetic data, and clearance of peginterferon {alpha}-2b may be reduced by 44% in haemodialysis patients, which may partly explain the high rate of adverse events (Schering-Plough, Product Information).

There were several important lessons derived from this trial. Although reasonable sustained response rates are seen with pegylated interferon monotherapy, adverse events are considerable in haemodialysis patients. The risk of developing cirrhosis from HCV is small in dialysis patients, and antiviral therapy may not be justified due to its side effects. Side effects included hypertension, and patients with difficult to control hypertension or who are taking multiple antihypertensive medications may develop elevations in their blood pressure that may respond to dose reduction. From our experience, the optimal time to administer peginterferon to minimize side effects seems to be on the off dialysis day. Subjects did not develop seizures, pancreatitis, anaemia or neutropenia as has been previously reported [9]. None of the subjects required dose reduction or discontinuation due to anaemia, neutropenia or thrombocytopenia, although data on erythropoietin dose were not collected, which should be included in future studies.

In conclusion, the sustained response rate with pegylated interferon {alpha}-2b monotherapy in haemodialysis patients with chronic hepatitis C is low, and also may be associated with a substantial number of adverse events. Based upon the study design, we could not determine if adverse events were due to peginterferon or morbidity from ESRD. A subset of haemodialysis patients with hepatitis C may have reasonable response rates and benefit from antiviral therapy. Future trials should include an untreated arm or historical control group to determine if adverse events are due to peginterferon or to general morbidity seen in the haemodialysis population. Combination therapy with ribavirin analogues that are associated with less haemolysis should be investigated given the low response rates seen with peginterferon monotherapy.



   Acknowledgments
 
This research was supported by an unrestricted grant from Schering-Plough Research Institute.

Conflict of interest statement. The authors received grant support from Schering-Plough.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Tokars JI, Miller ER, Alter MJ et al. National surveillance of dialysis associated disease in the U.S., 1995. ASAIO J 1998; 44: 98–107[Web of Science][Medline]
  2. Martin P, Carter D, Fabrizi F et al. Histopathological features of hepatitis C in renal transplant candidates. Transplantation 2000; 69: 1479–1484[CrossRef][Medline]
  3. Sterling RK, Sanyal AJ, Luketic VA et al. Chronic hepatitis C infection in patients with end stage renal disease: characterization of liver histology and viral load in patients awaiting renal transplantation. Am J Gastroenterol 1999; 94: 3576–3582[CrossRef][Web of Science][Medline]
  4. Legendre Ch, Garrigue V, Le Bihan C et al. Harmful long-term impact of hepatitis C virus infection in kidney transplant recipients. Transplantation 1998; 65: 667–670[Web of Science][Medline]
  5. Hanafusa T, Ichikawa Y, Kishikawa H et al. Retrospective study on the impact of hepatitis C virus infection on kidney transplant patients over 20 years. Transplantation 1998; 66: 471–476[CrossRef][Web of Science][Medline]
  6. Pereira BJG, Natov SN, Bothout BA et al. Effect of hepatitis C infection and renal transplantation on survival in end stage renal disease. Kidney Int 1998; 53: 1374–1381[CrossRef][Web of Science][Medline]
  7. Izopet J, Rostaing L, Moussion F et al. High rate of hepatitis C virus clearance in hemodialysis patients after interferon-alpha therapy. J Infect Dis 1997; 176: 1614[Medline]
  8. Campistol JM, Esforzado N, Martinez J et al. Efficacy and tolerance of interferon-alpha 2b in the treatment of chronic hepatitis C virus infection in haemodialysis patients. Pre- and post-renal transplantation assessment. Nephrol Dial Transplant 1999; 14: 2704–2709[Abstract/Free Full Text]
  9. Russo MW, Goldsweig C, Jacobson IM, Brown RS Jr. Interferon monotherapy for dialysis patients with chronic hepatitis C: an analysis of the literature on efficacy and safety. Am J Gastroenterol 2003; 98: 1610–1615[CrossRef][Medline]
  10. Degos F, Pol S, Chaix ML et al. The tolerance and efficacy of interferon-{alpha} in haemodialysis patients with HCV infection: a multicenter prospective study. Nephrol Dial Transplant 2001; 16: 1017–1023[Abstract/Free Full Text]
  11. Fernandez JL, Rendo P, del Pino N. A double-blind controlled trial of recombinant interferon-alpha 2b in haemodialysis patients with chronic hepatitis C virus infection and abnormal aminotransferase levels. J Viral Hepatitis 1997; 4: 113–119[Medline]
  12. Bruchfeld A, Stahle L, Andersson J et al. Ribavirin treatment in dialysis patients with chronic hepatitis C infection—a pilot study. J Viral Hepatitis 2001; 8: 287–292[CrossRef][Medline]
  13. Mousa DH, Abdalla AH, AL-Shoail G et al. Alpha-interferon with ribavirin in the treatment of hemodialysis patients with hepatitis C. Transplant Proc 2004; 36: 1831–1834[CrossRef][Medline]
  14. Cruzado JM, Casanovas-Taltavull T, Torras J et al. Pretransplant interferon prevents hepatitis C virus-associated glomerulonephritis in renal allografts by HCV-RNA clearance. Am J Transplant 2003; 3: 357–360[CrossRef][Web of Science][Medline]
  15. Sporea I, Sirli R, Golea O, Totolici C, Canila M, Popescu A. Peg-interferon alfa-2a (40kDa) in patients on chronic haemodialysis with chronic hepatitis C. Preliminary results. Rom J Gastroenterol 2004; 13: 99–102[Medline]
  16. Gupta SK, Pittenger AL, Swan SK et al. Single-dose pharmacokinetics and safety of pegylated interferon-alfa 2b in patients with chronic renal dysfunction. J Clin Pharmacol 2002; 42: 1109–1115[Abstract]
  17. Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol 1995; 19: 1409–1417[Web of Science][Medline]
  18. Pol S, Thiers V, Carnot F et al. Efficacy and tolerance of alpha-2b interferon therapy on HCV infection of hemodialyzed patients. Kidney Int 1995; 47: 1412–1418[Medline]
  19. Muir AJ, Bornstein JD, Killenberg PG; Atlantic Coast Hepatitis Treatment Group. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med 2004; 350: 2265–2271[Abstract/Free Full Text]
Received for publication: 6. 4.05
Accepted in revised form: 28. 9.05


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N. A. Terrault and D. B. Adey
The Kidney Transplant Recipient with Hepatitis C Infection: Pre- and Posttransplantation Treatment
Clin. J. Am. Soc. Nephrol., May 1, 2007; 2(3): 563 - 575.
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A. Bruchfeld, K. Lindahl, O. Reichard, T. Carlsson, and R. Schvarcz
Pegylated interferon and ribavirin in haemodialysis patients
Nephrol. Dial. Transplant., May 1, 2006; 21(5): 1444 - 1445.
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