NDT Advance Access originally published online on March 3, 2006
Nephrology Dialysis Transplantation 2006 21(5):1444-1445; doi:10.1093/ndt/gfl072
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Pegylated interferon and ribavirin in haemodialysis patients
Email: Annette.Bruchfeld{at}ki.seSir,
Recently Russo et al. [1] reported a randomized study of sixteen haemodialysis patients with chronic hepatitis C virus infection (HCV), treated with pegylated interferon-alpha-2b. They concluded that its use was poorly tolerated and associated with substantial side-effects in their study. Two study-arms randomized patients to pegylated interferon-alpha-2b 1.0 µg/kg or 0.5 µg/kg per week. Only three subjects had a 24-week treatment response and two of these had a sustained viral response after the termination of therapy, all in the 1.0 µg/kg group.
Standard therapy today for patients with HCV is long-acting pegylated interferon and ribavirin. Until recently, there has been little experience with either drug in end-stage renal disease (ESRD). Sustained viral responses with the use of interferon-alpha has been reported, in a number of both controlled and uncontrolled studies, to vary between 16 and 64% with the lowest response rate in the difficult to treat HCV genotypes i.e genotype 1. However, tolerance issues are common with at least 30% never completing therapy [2,3]. Pegylated interferons are currently available as peg-alpha-2a (Pegasys® 40 kDa; Roche Diagnostics) or peg-alpha-2b (PegIntron® 12 kDa; Schering–Plough), the former reported to have a large metabolic clearance compared with a higher degree of renal clearance for the latter.
We have previously published treatment studies in both dialysis patients as well as in patients with reduced renal function with HCV infection [4,5]. A high performance liquid chromatography (HPLC) method was developed to measure ribavirin in plasma based on patients with normal renal function, which enabled the use of ribavirin together with interferon in renal insufficiency.
In a more recent article, we used pegylated interferons with ribavirin in dialysis patients [6]. Six haemodialysis patients were treated with peg-alpha-2b (n = 4) and peg-alpha-2a (n = 2) for 24–48 weeks according to HCV genotype, with a dose of 50 or 135 µg/week, respectively. All but one patient had difficult to treat HCV genotypes. The dose selected for peg-alpha-2b was reduced by 25–30% from the dose of 1 µg/kg/week, because of its larger renal elimination, which in most patients was equivalent to 0.7 µg/kg. Peg-alpha-2a was reduced to 135 µg according to the recommendation from the manufacturer for patients with a creatinine clearance of <20 ml/min. As in previous studies, patients were given reduced ribavirin doses and were subsequently monitored with ribavirin plasma concentration aiming at a target concentration of 10–15 µmol/l. Average ribavirin dose was 170–300 mg/day.
All patients became HCV-RNA-PCR negative during treatment, which was completed or nearly completed in four patients.
Ribavirin-induced anaemia was treated with high doses of erythropoietin and low doses of iron. Blood transfusions were not needed. Interferon related side-effects such as initial flu-like syndrome, myalgia and fatigue were common. In one patient peg-alfa-2b was permanently reduced to 50 µg every 9–10 days with improvement in tolerance. In spite of this reduction, this patient attained a sustained viral response. One patient terminated therapy prematurely due to pronounced interferon related side-effects and another died of myocardial infarction, probably not related to therapy. Three patients have remained HCV-RNA negative with extended follow-up, two of whom have subsequently had a successful kidney transplant.
As mentioned by Russo et al. [1], the dosing of peginterferon might have been inadequate in their study; possibly the lower dose was too low for any effect and the higher dose associated with more side-effects. The poor outcome could in addition be due to difficult to treat HCV genotypes and the fact that a substantial number of patients in the study were African-Americans who have lower response rates. The degree of liver damage was also fairly advanced in many patients, which is generally a negative predictor for treatment outcome. Finally, interferon monotherapy, both the pegylated and unpegylated forms, clearly has limitations. Combination therapy with ribavirin as in our experience, and possibly future ribavirin analogues associated with less anaemia or protease inhibitors currently undergoing clinical trials, are likely to contribute to better efficacy, also in ESRD.
The authors also recommend administrating peginterferon on the off-dialysis day. The reasons for this are somewhat unclear. For practical reasons, we have given the patient the injection at the end of the dialysis session without any side-effects other than those to be expected with interferon therapy in general.
Pegylated interferons are, in our opinion, likely to become a valuable addition for HCV therapy in ESRD and are possible to combine with ribavirin. However, we would favour prospective pharmacokinetic and tolerability studies of both peg-alfa-2a and 2b before definite dosing recommendations can be made.
Conflict of interest statement. The authors have conducted research sponsored by Schering–Plough and Roche.
1 The Feinstein Institute for Medical Research North Shore-LIJ Health System 350 Community Drive Manhasset NY 11030, USA2 Department of Renal Medicine3 Department of Infectious Diseases Karolinska University Hospital Karolinska Institutet S-141 86 Stockholm Sweden
References
- Russo MW, Ghalib R, Sigal S, Joshi V. Randomized trial of pegylated interferon {alpha}-2b monotherapy in haemodialysis patients with chronic hepatitis C. Nephrol Dial Transplant 2006; 21: 437–443
[Abstract/Free Full Text] - Fabrizi F, Dulai G, Dixit V, Bunnapradist S, Martin P. Meta-analysis: interferon for the treatment of chronic hepatitis C in dialysis patients. Aliment Pharmacol Ther 2003; 18: 1071–1081[CrossRef][Medline]
- Russo MW, Goldsweig CD, 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]
- Bruchfeld A, Ståhle L, Andersson J, Schvarcz R. Ribavirin treatment in dialysis patients with chronic hepatitis C virus infection – a pilot study. J Viral Hepat 2001; 8: 287–292[CrossRef][Medline]
- Bruchfeld A, Lindahl K, Ståhle L, Söderberg M, Schvarcz R. Interferon and ribavirin treatment in patients with hepatitis C-associated renal disease and renal insufficiency. Nephrol Dial Transplant 2003; 18: 1573–1580
[Abstract/Free Full Text] - Bruchfeld A, Lindahl K, Reichard O, Carlsson T, Schvarcz R. Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients. J Viral Hepat 2005; doi: 10.1111/j.1365-2893.2005.00680.x
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