Burnier, Michel

Francioli, Patrick

Gonvers, Jean-Jacques

Lüscher, Brigitte Landtwing

Phan, Olivier

Teta, Daniel

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Nephrol Dial Transplant (2005) 20: 991–993doi:10.1093/ndt/gfh747Advance Access publication 1 March 2005Case ReportPegylated interferon for the treatment of hepatitis C virusin haemodialysis patientsDaniel Teta1,*, Brigitte Landtwing Lu¨scher1,*, Jean-Jacques Gonvers2,Patrick Francioli3, Olivier Phan1 and Michel Burnier11Division of Nephrology, 2Division of Gastroenterology and Hepatology, and 3Division of Hospital Hygiene,University Hospital, Lausanne, Switzerland*These authors contributed equally to this workKeywords: HCV; interferon-2a; polyethylene glycolIntroductionIn patients undergoing maintenance haemodialysis,hepatitis C virus (HCV) infection is common and maylead to severe complications such as chronic hepatitis,cirrhosis and hepatocellular carcinoma. It is recom-mended to eradicate HCV infection in dialysispatients awaiting renal transplantation and those withacute hepatitis C or signiﬁcant chronic liver disease.Interferon-a-2a in monotherapy thrice weekly, whichis the standard treatment for HCV infection in thissetting, has many drawbacks such as poor toleranceand marginal response [1]. The addition of ribavirinis generally contra-indicated in these patients due to arisk of haemolytic anaemia. Pegylated interferon wasdeveloped by attaching a large polyethylene glycol(PEG) moiety (40 kDa) to interferon in order toconfer greater stability and prolonged systemic expo-sure to allow once-weekly administration [2]. In tworandomized controlled trials, PEG–interferon-a-2ain monotherapy was more efﬁcient than conventionalinterferon for the treatment of HCV infection asso-ciated with chronic liver disease [3,4]. Currently, thereis no published experience concerning the use of thiscompound in patients with end-stage renal disease(ESRD).CasesBetween January 2002 and April 2003, two HCVpatients with biopsy-proven chronic liver diseaseand one patient with acute hepatitis C were treatedwith PEG–interferon-a-2a in our institution. Clinicalcharacteristics were as follows.Case 1Patient 1 was a 37-year-old male patient known forESRD due to chronic interstitial nephritis and dialysedsince 1992. HCV infection was diagnosed in 1996,following routine screening. A renal transplantationwas performed in 1997 but dialysis was resumed in 2000because of chronic allograft rejection. He was thenconsidered for a second renal transplantation. A pre-transplant evaluation revealed persistent elevation ofliver enzymes and positivity for antibodies to HCV.The HCV genotype was 1b. The HCV RNA level was290 kIU/ml. A liver biopsy showed moderately activehepatitis and ﬁbrosis (Metavir score A2F2).Case 2Patient 2 was a 61-year-old man on dialysis for ESRDsecondary to vascular and hypertensive nephropathy.He received a cadaveric renal allograft in 1987 and wasfound to be positive for anti-HCV antibodies in 1991,presumably consecutive to graft transmission. Chronichepatitis C progressively developed, and liver cirrhosisChild A was diagnosed in 2000. Dialysis consequentlywas resumed and the transplant removed in 2002. Adouble kidney–liver transplantation was considered. Aliver biopsy conﬁrmed moderate micronodular cirrho-sis (Metavir score F4). Liver enzymes were normal andHCV RNA level was 253 kIU/ml. Typing revealedHCV genotype 3a.Case 3Patient 3 was a 56-year-old man who had beenundergoing haemodialysis since 2001 because ofESRD due to autosomal dominant polycystic kidneyCorrespondence and offprint requests to: Professor M. Burnier,Division of Nephrology, CHUV, Rue du Bugnon 17, 1011Lausanne, Switzerland. Email: michel.burnier@hospvd.ch The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.For Permissions, please email: journals.permissions@oupjournals.orgdisease. In January 2002, he suddenly developednausea, vomiting, diarrhoea, fatigue and frank eleva-tion of liver enzymes. Acute hepatitis C was diagnosed.Although the cause of HCV infection was not clearlyidentiﬁed, exposure to infected material from thehaemodialysis setting was thought to be the mostlikely source. The HCV RNA level in serum was594 kIU/ml and HCV genotype was 1b.TreatmentEach patient was scheduled to receive subcutaneoustreatment with PEG–interferon-a-2a (Pegasys,Roche, Basle, Switzerland) over 48 weeks, starting at180 mg once weekly, immediately following the dialysissession. Patients were monitored by weekly bloodformulae and a precise dose-adjustment scheduleaccording to blood cell count; patient clinical tolerancewas applied according to the manufacturer’s recom-mendations (Table 1). During the treatment period, thepatients underwent three dialysis sessions of 3 h 30minper week through high-ﬂux polysulfone dialysers.The HCV RNA level was determined in serumby polymerase chain reaction (PCR) assay (CobasAmplicor HCV Monitor assay, Roche DiagnosticsSystems) immediately before the haemodialysis session.Samples were collected at the following time points:1–4 weeks before the treatment was started, during thetreatment at weeks 12, 24 and 48, and 6 months afterthe end of the treatment, i.e. at week 72. The absenceof detectable levels of HCV RNA was deﬁned as<50 IU/ml. Sustained virological response (SVR) wasdeﬁned as the absence of detectable levels of HCVRNA in serum at 72 weeks, i.e. 6 months after the endof treatment. Genotype analysis was carried out byreverse transcriptase–PCR followed by hybridizationof ampliﬁed products on an array of genotype-speciﬁcprobes [Versant HCV genotype assay (LiPA), Bayer].The applied treatment and clinical follow-up of thepatients are summarized in Table 2. HCV RNA wasundetectable in all three patients after 12 weeks oftherapy. In patients 1 and 3 (genotype 1b), HCV RNAremained undetectable during the entire 48 week treat-ment course and these patients reached SVR. Incontrast, the viraemia reappeared under treatment at24 weeks in patient 2 (genotype 3a) without elevation ofliver enzymes. This situation was considered as a failureof therapy and Pegasys treatment was stopped.Most of the observed side effects such as anorexia,weight loss, insomnia, depression and ﬂu-like symp-toms were predictable and manageable. Myelotoxicitywas mitigated by strict adherence to the dose-reduction schedule, so that neutropoenia and throm-bopoenia remained moderate and not associated withclinically related events. Anaemia needed an increaseof recombinant epoetin doses, enabling haemoglobinlevels to be maintained without blood transfusions.Two adverse events were peculiar and deserve a specialdescription. Patient 2 complained of chronic dry coughassociated with bilateral interstitial inﬁltrates on chestX-ray. Both cough and lung inﬁltrates disappearedwhen dry weight was decreased and recurred 4 monthsafter Pegasys therapy was stopped. Extensive inves-tigations revealed mixed interstitial and obstructivebronchopneumopathy. Oral steroids allowed resolu-tion of symptoms, but minimal lung inﬁltrates per-sisted. A side effect of Pegasys treatment could notbe ruled out. Patient 3 presented cutaneous bullouslesions on both hands, diagnosed as pseudoporphyriacutanea, after 8 months of Pegasys treatment.Furosemide, a frequent cause of dialysis-relatedpseudoporphyria cutanea, was stopped and the lesionsprogressively disappeared within 3–4 months. Thus,whether this side effect was attributable to Pegasys ornot remains unclear.DiscussionConventional interferon in monotherapy leads to SVRrates of 30–40% in patients on dialysis [1]. However,a high percentage of adverse events and early dis-continuations makes this treatment difﬁcult to apply inthese patients. PEG–interferon-a-2a and 2b havesigniﬁcantly improved antiviral therapy for HCV inpatients without renal insufﬁciency [3,4]. Furthermore,PEG–interferon-a-2a is more efﬁcient than standardinterferon-a-2a in HCV patients with genotype 1 [3].This report is the ﬁrst to describe the use of pegylatedinterferon in haemodialysed patients. PEG-interferon-a-2a was chosen since this compound is mostly clearedvia hepatic metabolism, in contrast to PEG-inter-feron-a-2b, which essentially shows renal clearance.Table 1. Treatment schedule and monitoring of side effectsParameter Downward dose adjustment of PEG–interferonNeutrophil count (cell/mm3)>1000 None750–999 Weeks 1–2: immediate one level adjustmentWeeks 3–48: no adjustment500–749 Weeks 1–2: delay or hold dose until >750,then resume dose with one level adjustmentWeeks 3–48: Immediate one level adjustment250–499 Weeks 1–2: Delay or hold dose until >750,then resume dose with two level adjustmentWeek 3–48: Delay or hold dose until >750,then resume dose with one level adjustment<250 Stop drugPlatelet count (cell/mm3)>50 000 None35 000–49 000 Delay or hold dose until >50 000,then resume dose with one level adjustment25 000–34 000 Delay or hold dose until >50 000,then resume dose with two level adjustment<25 000 Stop drugPegasys (40 kDa branched PEG–interferon-a-2a) dose adjustmentsfor low absolute neutrophil and platelet counts: assigned dose,Pegasys 180mg; one level adjustment, Pegasys 135mg; two leveladjustment, Pegasys 90mg; three level adjustment, Pegasys 45 mg.992 D. Teta et al.Furthermore, its pharmacokinetics following a singledose subcutaneous administration are already knownin patients with ESRD [5]. In the latter study, differentpharmacokinetic parameters were assessed usingascending doses of Pegasys. The dose of 180 mg ledto the highest area under the curve, but serum half-lifeand maximal concentrations of the drug were similar tothose seen in healthy subjects [5]. Thus, we elected toinitiate the treatment at this dose, being prepared toreduce it according to weekly clinical and haematolo-gical observations.In patients without renal insufﬁciency, acutehepatitis C can be treated successfully in 24 weeks [6].However, the natural history of HCV acute infectionin dialysed patients is less predictable and usually lessfavourable [7,8]. In the absence of guidelines in thisparticular setting, we felt that a treatment of 48 weeksin patient 3 might have given the best chance toeradicate the virus in order to make the patient eligibleto receive a renal transplant.SVR was observed in both HCV patients withgenotype 1b, which is a remarkable ﬁnding since thisgenotype is typically associated with lower successrates. There was no serious adverse event and thereported side effects were manageable by appropriatedose reductions.ConclusionIn this cumulative experience of 30 months, PEG–interferon-a-2a appears to be an interesting treatmentoption in HCV patients undergoing maintenancehaemodialysis. Large controlled studies are nowneeded to conﬁrm these encouraging preliminary data.Conﬂict of interest statement. None declared.References1. Russo MW, Goldsweig CD, Jacobson IM, Brown RS.Interferon monotherapy for dialysis patients with chronichepatitis C: an analysis of the literature on efﬁcacy and safety.Am J Gastroenterol 2003; 98: 1610–16152. Xu Z-X, Hoffmann J, Patel I, Joubert P. Single-dosesafety/tolerability and pharmacokinetics/pharmacodynamics(PK/PD) following administration of ascending subcutaneousdoses of pegylated-interferon (PEG–IFN) and interferon a-2a(IFN a-2a) to healthy subjects [abstract]. Hepatology 1998; 28:[Suppl] 7023. Zeuzem S, Feinman SV, Rasenack J et al. Peginterferonalpha-2a in patients with chronic hepatitis C. N Engl J Med2000; 343: 1666–16724. Heathcote EJ, Shiffman ML, Cooksley WG et al. Peginterferonalpha-2a in patients with chronic hepatitis C and cirrhosis.N Engl J Med 2000; 343: 1673–16805. Lamb MW, Marks IM, Modi MW, Preston RA, Rappas SC.Peginterferon alpha-2a (40 KD) (PEGASYS) can be adminis-tered safely in patients with end-stage renal disease [abstract].Hepatology 2001; 34: 3266. Jaeckel E, Cornberg M, Wedemeyer H et al. Treatment of acutehepatitis C with interferon alfa-2b. N Engl J Med 2001; 345:1452–14577. Espinosa M, Martin-Malo A, Alvarez de Lara MA, Aljama P.Risk of death and liver cirrhosis in anti-HCV positive longterm haemodialysis patients. Nephrol Dial Transplant 2001; 16:1669–16748. Martin P, Carter D, Fabrizi F et al. Histopathological featuresof hepatitis C in renal transplant candidates. Transplantation2000; 69: 1479–1484Received for publication: 26.10.04Accepted in revised form: 25.1.05Table 2. Treatment, responses and side-effectsPatient 1 Patient 2 Patient 3Liver disease Chronic hepatitis Cirrhosis Child A Acute hepatitisHCV genotype 1b 3a 1bEffective treatment duration 48 weeks 24 weeks 48 weeksWeekly dose and causes ofdose adjustments180mg for 48 weeks 180mg for 4 weeksDecrease to 90 mg for 2 weeks(thrombopoenia, insomnia)180mg for 7 weeksDecrease to 135mg for 4 weeks(neutropoenia)Increase to 135mg for 10 weeks Decrease to 90mg for 37 weeks(neutropoenia and depression)Decrease to 90 mg for 8 weeks(thrombopoenia)HCV RNA level at 72 weeks (SVR) Not detectable 189 kIU/ml at 24 weeks Not detectableALAT Normalized at 12 weeks Normal (entire follow-up) Normalized at 4 weeksMinimal Hb level (g/l) 103 92 125Minimal leukocyte count (G/L) 2.8 2.8 1.3Minimal neutrophil count (G/L) 1.0 1.4 0.5Minimal platelet count (G/L) 107 49 107Side effects None Weight loss, insomnia (oxazepamprescription), cough and X-rayinﬁltratesWeight loss, fatigue, depression(citalopram prescription)ﬂu-like symptoms,cutaneous bullous lesionsG/L=giga/literPegylated interferon for the treatment of HCV in HD patients 993

Pegylated interferon for the treatment of hepatitis C virus in haemodialysis patients

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