Michael W. Fried, MDUniversity of North Carolina at Chapel HillUNC Liver CenterChapel Hill, NC 27599Email: mfried@med.unc.eduTreatment of HCV in Patients with Chronic Kidney DiseaseEpidemiology of HCV in Renal DiseaseHepatitis C testing is routinely recommended for patients with chronic kidney disease onhemodialysis , who have a higher prevalence of hepatitis C infection compared with the generalpopulation 1 . Serologic studies in the United States have estimated the prevalence of HCVinfection among patients on hemodialysis ranges between 10% to 36% 1 . While many of thesepatients have independent risk factors for HCV infection, de novo infections during hemodialysismay occur. Common source outbreaks from a breakdown of universal precautions, such as useof multidose vials have been reported 2 . In a study that examined procedures at 53 dialysiscenters in the U.S., the prevalence of anti-HCV was 9.9% among over 2900 patients tested 3 .After adjusting for non-dialysis related HCV risk factors, several patient care practices duringdialysis were associated with a higher risk of HCV infection (reusing priming receptacles withoutdisinfection, handling blood specimens adjacent to medications and clean supplies, and usingmobile carts to deliver injectable medications) 3 . A higher patient to staff ratio and longerduration of hemodialysis were also associated with a higher prevalence of HCV infection 3 .Neither hemodialysis machines nor dialysis membranes have been considered sources of HCVinfection and anti-HCV positive patients are not required to be dialyzed in isolation, unlike forchronic hepatitis B infection 1 .Increased morbidity and mortalityThe presence of hepatitis C infection in patients with chronic kidney disease does have animpact on morbidity and mortality. As may be expected, hepatocellular carcinoma and cirrhosisas causes of death were more frequent among anti-HCV positive than anti-HCV negativehemodialysis patients 4 . Interestingly, it has generally been noted that HCV liver diseaseappears to be less aggressive, as evidenced by lower levels of aminotransferases anddiminished necroinflammatory activity, in those on hemodialysis than in non-hemodialyzed HCVcontrols 5,6 . However, several observational studies have demonstrated that all-cause mortalityis also significantly higher among hemodialysis patients with hepatitis C, a finding which couldbe linked to increased HCV-associated cardiovascular mortality reported in this population 7 .Patient and graft survival after kidney transplantation is also lower for anti-HCV positiverecipients compared to non-infected individuals, although patient survival curves diverge onlyafter 10 years post-kidney transplantation with some of the excess mortality attributed tocomplications of chronic liver disease 8,9 .Treatment of HCV in hemodialysis and kidney transplant patientsTreatment for hepatitis C in patients with chronic kidney disease may be extremely challengingand is associated with higher rates of adverse events, although sustained virological responsecan be achieved in some patients 10,11 . Treatment must be modified for patients onhemodialysis. Peginterferon at reduced doses (Peginterferon alfa-2a = 135 µg /week orpeginterferon alfa-2b = 1.0 µg/kg/week) and ribavirin at 200 mg/day can be administered topatients on hemodialysis. Extreme caution and close monitoring is required with the use ofribavirin in the setting of hemodialysis since this medication is not dialyzed and hemolyticanemia will worsen. Several small studies have utilized low dose, weekly dosing, or dosing

titrated to blood ribavirin levels in an attempt to improve sustained virological response andminimize adverse events. Regardless of the regimen, HCV therapy in the hemodialysispopulation has consistently demonstrated a high rate of adverse events and frequent prematurediscontinuation due to side effects 12 .The absence of well-designed controlled clinical trials using peginterferon and ribavirin withsufficient statistical power to identify the regimen that optimizes safety and efficacy hashampered the treatment of hemodialysis patients. Similarly, the roles of HCV proteaseinhibitors, boceprevir and telaprevir, remain under investigation. The pharmacokinetics of thesedrugs is not substantially altered by severe renal impairment and dosage modification wouldappear not to be necessary. However, a search of clinicaltrials.gov yielded only a pilot study ofboceprevir combined with peginterferon and ribavirin in the hemodialysis population.Treatment of chronic hepatitis C in patients following kidney transplantation has generally notbeen routinely recommended due to concerns of renal allograft dysfunction and rejection whichhave been reported in numerous case series of interferon-based treatment 13 14 . Serial liverbiopsies after kidney transplantation to identify patients with progressive liver disease may helpin assessing the benefits/risk of antiviral therapy. Fibrosing cholestatic hepatitis (FCH), is aunique rapidly progressive, frequently fatal liver injury reported in several types of solid organtransplantation, for whom interferon-based therapy may be effective 13,15 .References1. Recommendations for preventing transmission of infections among chronic hemodialysispatients. MMWR Recomm Rep 2001;50:1-43.2. Lanini S, Abbate I, Puro V, et al. Molecular epidemiology of a hepatitis C virus epidemic in ahaemodialysis unit: outbreak investigation and infection outcome. BMC Infect Dis2010;10:257.3. Shimokura G, Chai F, Weber DJ, et al. Patient-care practices associated with an increasedprevalence of hepatitis C virus infection among chronic hemodialysis patients. Infect ControlHosp Epidemiol 2011;32:415-24.4. Fabrizi F, Takkouche B, Lunghi G, Dixit V, Messa P, Martin P. The impact of hepatitis Cvirus infection on survival in dialysis patients: meta-analysis of observational studies. J ViralHepat 2007;14:697-703.5. Cotler SJ, Diaz G, Gundlapalli S, et al. Characteristics of hepatitis C in renal transplantcandidates. J Clin Gastroenterol 2002;35:191-5.6. Aslinia FM, Wasan SK, Mindikoglu AL, et al. End-stage renal disease and African Americanrace are independent predictors of mild liver fibrosis in patients with chronic hepatitis Cinfection. J Viral Hepat 2012;19:371-6.7. Fabrizi F, Dixit V, Messa P, Martin P. Hepatitis C-related liver disease in dialysis patients.Contributions to nephrology 2012;176:42-53.8. Fabrizi F, Martin P, Dixit V, Bunnapradist S, Dulai G. Hepatitis C virus antibody status andsurvival after renal transplantation: meta-analysis of observational studies. Am J Transplant2005;5:1452-61.9. Morales JM, Bloom R, Roth D. Kidney transplantation in the patient with hepatitis C virusinfection. Contributions to nephrology 2012;176:77-86.10. Fabrizi F, Dixit V, Messa P, Martin P. Pegylated interferon monotherapy of chronic hepatitisC in dialysis patients: Meta-analysis of clinical trials. J Med Virol;82:768-75.

11. Berenguer M. Treatment of chronic hepatitis C in hemodialysis patients. Hepatology2008;48:1690-9.12. Esforzado N, Campistol JM. Treatment of hepatitis C in dialysis patients. Contributions tonephrology 2012;176:54-65.13. Rostaing L, Weclawiak H, Izopet J, Kamar N. Treatment of hepatitis C virus infection afterkidney transplantation. Contributions to nephrology 2012;176:87-96.14. Fabrizi F, Lunghi G, Dixit V, Martin P. Meta-analysis: anti-viral therapy of hepatitis C virusrelatedliver disease in renal transplant patients. Aliment Pharmacol Ther 2006;24:1413-22.15. Zylberberg H, Carnot F, Mamzer MF, Blancho G, Legendre C, Pol S. Hepatitis C virusrelatedfibrosing cholestatic hepatitis after renal transplantation. Transplantation1997;63:158-60.

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