mini review

http://www.kidney-international.org & 2013 International Society of Nephrology

Hepatitis C treatment in patients with kidney disease

Fabrizio Fabrizi1, Alessio Aghemo2 and Piergiorgio Messa1
1

Division of Nephrology, Maggiore Hospital and IRCCS Foundation, Milano, Italy and 2Division of Gastroenterology, Maggiore Hospital and IRCCS Foundation, University School of Medicine, Milano, Italy

Hepatitis C virus (HCV) remains the most common cause of liver damage in patients with kidney disease, including those on long-term dialysis. The natural history of HCV in patients on regular dialysis is not fully elucidated, but an adverse effect of HCV on survival has been noted; a novel metaanalysis of observational studies (14 studies including 145,608 unique patients) showed that the summary estimate for adjusted relative risk (all-cause mortality) was 1.35 with a 95% confidence interval of 1.251.47. The adjusted RR for liver diseaserelated death and cardiovascular mortality among maintenance dialysis patients was 3.82 (95% CI, 1.927.61) and 1.26 (95% CI, 1.101.45), respectively. It has been recommended that the decision to treat HCV in patients with chronic kidney disease be based on the potential benefits and risks of therapy, including life expectancy, candidacy for kidney transplant, and comorbidities. A pooled analysis including 494 dialysis patients on monotherapy with conventional interferon reported a summary estimate for sustained viral response and dropout rate of 39% (95% CI, 3246) and 19% (95% CI, 1326), respectively. All renal transplant candidates (dialysis dependent or not) with HCV should be assessed for antiviral treatment given the increased risk of progressive liver disease with immunosuppressive therapy, the increased life expectancy compared to other HCV-positive patients on dialysis, and the inability to receive interferon after transplant. Current guidelines support monotherapy with standard interferon in these patients, but modern antiviral approaches (that is, dual therapy with peg-IFN plus ribavirin) in a well-controlled setting may be an appropriate alternative.
Kidney International (2013) 84, 874879; doi:10.1038/ki.2013.264; published online 3 July 2013 KEYWORDS: dialysis; hepatitis C; interferon; ribavirin; survival

The hepatitis C virus (HCV) is a major public health problem and a leading cause of chronic liver disease worldwide. Despite the introduction of protective measures in dialysis units and universal screening of blood products, HCV infection remains prevalent in dialysis population and kidney transplant recipients.1,2 According to the DOPPS (Dialysis Outcomes and Practice Patterns Study) survey, which included 8615 patients on maintenance dialysis from the industrialized world, the mean prevalence of anti-HCVpositive patients was 13.5%.3 The aim of this review is to report on the antiviral therapy for HCV infection in kidney disease patients, as important advances have been made over the past decade in this field.
IMPACT OF HCV INFECTION ON SURVIVAL IN CHRONIC KIDNEY DISEASE POPULATION

Correspondence: Fabrizio Fabrizi, Divisione Nefrologica, Ospedale Maggiore, Padiglione Croff, Via Commenda 15, 20122, Milano, Italy. E-mail: fabrizi@policlinico.mi.it Received 15 January 2013; revised 19 March 2013; accepted 21 March 2013; published online 3 July 2013 874

The natural history of HCV in patients with chronic kidney disease (CKD) remains incompletely appreciated. Surveys conducted in individuals without kidney disease have reported that untreated HCV-infected patients with compensated cirrhosis have 3-, 5-, and 10-year survival of 96, 91, and 79%, respectively. Patients with decompensated cirrhosis have a 5-year survival of 50%. It has been assumed that survival in the majority of patients with CKD stage 1 and most patients with CKD stage 2 is not significantly different from that of the general population with normal kidney function.4 For patients with CKD stage 3, the 5-year survival in those without HCV infection has been reported to be 76%.4 This allows for extrapolation from the general population for many of these patients, although if other comorbidities are present (diabetes, coronary artery disease, and so on) then the anticipated survival must be considered on an individual basis. In patients with CKD stage 4, survival at 5 years has been reported to be B54%.4 In contrast to CKD stages 14, the stage 5 patients have a markedly reduced survival compared with the general population with normal kidney function. Some information on the relationship between anti-HCV-positive serologic status and survival in long-term dialysis patients has been recently accumulated. HCV infection in dialysis patients is usually asymptomatic with an apparently indolent course. HCV extends over decades rather than years even in patients with intact kidney function; thus, adverse consequences of chronic HCV infection may not be obvious in patients followed up for shorter periods of time. Patients with CKD
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have higher morbidity and mortality rates than the general population, because their average age is greater and because of their frequent comorbidities. The long-term consequences of HCV infection are therefore difficult to assess in this population. Mortality is an unequivocal end point in the natural history of HCV, but data concerning the relationship between HCV infection and risk for death among HCVinfected patients are not abundant. However, longitudinal studies with an appropriate size and follow-up have found an independent and significant relationship between anti-HCV antibody positivity and reduced patient survival in the dialysis population. A recent meta-analysis of 14 observational studies demonstrated an independent and significant impact of HCV on mortality among patients on long-term dialysis (n 145,608); the summary estimate for adjusted relative risk (RR; all-cause mortality) was 1.35 with a 95% confidence interval (CI) of 1.251.47 (Table 1).5 The negative impact of HCV on all-cause survival in dialysis population is in keeping with other sources. An independent and significant association between anti-HCV-positive serologic status and mortality (RR, 1.17; Po0.0159) was found in the DOPPS, a prospective observational study of representative samples of hemodialysis (HD) patients from western countries.6 The same meta-analysis gave information on disease specificrelated deaths among dialysis patients according to HCV status;5 a stratified analysis showed that the adjusted RR for liver diseaserelated death was 3.82 (95% CI, 1.927.61). In most studies included in this systematic review, the major complications of HCV-related chronic liver disease (cirrhosis and hepatocellular carcinoma) were significantly more frequent causes of death in anti-HCV antibodypositive patients on dialysis than in anti-HCV antibodynegative patients on dialysis. In addition, our stratified analysis showed that the adjusted RR for cardiovascular mortality was 1.26 (95% CI, 1.101.45) among HCV-positive versus HCV-negative dialysis patients.5 The relationship between anti-HCV serologic status and increased cardiovascular mortality persisted after adjustment for various covariates including age, dialysis vintage, and others; in addition, various lines of evidence are in keeping with this observation. The link between
Table 1 | Impact of HCV infection on survival in patients on maintenance dialysis: aRR of all-cause mortality
Authors Pereira et Stehman-Breen et al.32 Nakayama et al.33 Espinosa et al.34 Di Napoli et al.35 Kalantar-Zadeh et al.36 Wang et al.37 Johnson et al.38 Scott et al.39 Ohsawa et al.40 al.31 Patients, n 496 200 1470 175 6412 13,664 538 76,201 21,487 23,046 1077 aRR 1.41 1.97 1.57 1.62 1.29 1.28 2.19 1.37 1.29 1.25 1.48 Anti-HCV positive 44.9% 22% 18.8% 32% 30.6% 12% 13.9% NA 1.6% 10.1% Country USA USA Japan Spain Italy USA Taiwan Australia Australia Japan

cardiovascular mortality and HCV infection in patients on regular dialysis has been addressed by Oyake et al.7 using pulse-wave velocimeter measurements. They prospectively evaluated 95 dialysis patients (17 being HCV positive) by measurements of aortic stiffness (by carotidfemoral pulsewave velocity). Multiple logistic regression analysis found that, in addition to mean blood pressure, HCV viremia (odds ratio, 9.79, 95% CI, 1.1881.19, Po0.05) was independently associated with high pulse-wave velocimeter (410.0 m/s, mean). The authors suggested that HCV has an atherogenic role through aggravation of metabolic syndrome and dyslipidemia. In addition to conventional cardiovascular risk factors in dialysis population, such as arterial hypertension, hypercholesterolemia, and hyperhomocysteinemia, HCV infection may be an additional factor. This view is supported by the notion that traditional risk factors only partially explain the mortality excess among dialysis patients.

ANTIVIRAL TREATMENT OF HCV IN CKD POPULATION: BACKGROUND AND RATIONALE

Abbreviations: aRR, adjusted relative risk; HCV, hepatitis C virus; NA, not applicable.

Unfortunately, all major randomized controlled trials for the treatment of HCV infection have specifically excluded patients with abnormal kidney function. Accordingly, the available data that evaluate the indications for treatment and determine the most efficacious and safe treatment protocols in CKD patients are limited. The KDIGO (Kidney Disease: Improving Global Outcomes) work group suggested that all CKD patients with HCV infection be evaluated for antiviral treatment.4 The decision to treat HCV infection in the CKD patients should be based on the potential benefits and risks of therapy, including life expectancy, candidacy for kidney transplantation, and comorbidities. The patients should be appropriately informed of the risks and benefits of antiviral therapy and should also participate in the decision-making process. The quality of evidence on the efficacy and safety of antiviral therapy for hepatitis C in dialysis patients is rather low. The size of the study group was satisfactory in some trials only, and a few randomized controlled trials have been published on this topic. In addition, there is concern about the applicability of these results to all dialysis patients, as most of the individuals included in these studies were on the waiting list for kidney transplantation and were younger and probably healthier than the general dialysis population. Finally, a minority of studies was from North America, where many CKD patients are African American. This is of special relevance, because there are racial differences in the response to interferon (IFN) therapy in patients with intact kidney function. Life expectancy is a determining factor in advising therapy for HCV-infected patients with CKD. In the context of the lower life expectancy of maintenance HD patients and the slowly progressive course of chronic HCV infection, long observation periods are needed to observe the benefits of successful antiviral therapy in these patients. Thus, antiviral
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therapy is likely to be of less benefit in CKD patients with a life expectancy of o5 years. The KDIGO Work Group4 gave recommendation to treat HCV-infected patients accepted for kidney transplantation. The impetus to treat the HCV-infected kidney transplant candidate is different from that in the general population. Potential benefits of successful antiviral therapy in kidney transplant candidates include slowing the acceleration of liver disease8 and reducing the risk of post-transplant complications associated with HCV. The antiviral therapy of HCV-infected kidney transplant candidates is targeted to both treat the disease (slowing the progression of hepatitis C) and the infection (avoiding the extrahepatic complications of HCV after transplant). Positive anti-HCV serologic status after kidney transplantation is implicated in the pathogenesis of acute glomerulopathy,9 de novo glomerulonephritis,1012 new-onset diabetes after transplantation,13 excessive exposure to cyclosporine,14 a higher incidence of humoral rejection,15 and chronic allograft nephropathy.16 Information in support of antiviral therapy of kidney transplant candidates is mostly based on three controlled clinical trials. Overall, the quality of evidence on this point is low because patient allocation was not randomized. In the trial by Cruzado et al.,17 of the 15 HCV-positive recipients who received pretransplant IFN therapy, 10 (67%) had sustained virological response (SVR); only 1 (7%) of these 15 treated patients, who remained viremic, developed de novo glomerulonephritis. Among the 63 untreated HCV-positive allograft recipients, all of whom were RNA viremic at the time of transplantation, 12 (19%) developed de novo glomerulonephritis (Po0.001). Pretransplant antiviral therapy of HCV-infected transplant recipients appears to lower the incidence of NODAT (newonset post-transplant diabetes mellitus after transplantation). In their controlled trial, Gursoy et al.18 observed a higher proportion of NODAT in the group of HCV-positive recipients who had not received IFN compared with those who were treated with IFN before transplantation (25% (10/40) vs. 7% (1/14), P 0.009). In a cohort of 50 kidney transplant recipients, a higher frequency of nontreated controls developed chronic allograft nephropathy compared with IFN-treated patients (41% (13/ 32) vs. 6% (1/18), P 0.009). In the logistic regression analysis, the absence of IFN therapy before kidney transplantation was a risk factor for chronic allograft nephropathy with an odds ratio of 12 (P 0.02).19
ANTIVIRAL TREATMENT OF HCV IN CKD: ADJUSTED DOSING AND ADVERSE REACTIONS

Six HCV genotypes and a large number of subtypes (from a to f) are known. Although genotype does not predict the outcome of infection, it has been shown to both predict the probability of response to and determine the necessary duration of therapy. Infections with HCV genotypes 1 and 4 are less responsive to IFN-based therapy and require 48 weeks of treatment. In contrast, genotypes 2 and 3 are far more
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responsive to treatment and require only 24 weeks of therapy to achieve SVR. These results have been obtained in patients with HCV infection and normal kidney function.4 A systematic review of studies addressing antiviral therapy based on conventional IFN in patients on maintenance HD reported an overall summary estimate for SVR of 39% in the whole group and 33% in those patients with HCV genotype 1.20 In randomized controlled trials of HCV-infected patients with intact kidney function, the highest overall SVRs to date have been achieved with the combination of weekly subcutaneous injections of pegylated IFN (peg-IFN) and oral ribavirin (RBV). This represents the current standard of care for HCV infection, according to the current AASLD (American Association for the Study of Liver Diseases) guidelines.21 This recommendation is based on the results of three large randomized trials that were completed in IFN-naive patients with normal kidney function.2224 Combination therapy allows for SVR in B45% of genotype 1infected patients treated for 48 weeks; SVR rates for patients with genotypes 2 and 3 (and 5 or 6) are 7685% when treated for 24 weeks.2224 The level of kidney function in the CKD population has a crucial role in the pharmacokinetics of antiviral drugs targeted at HCV. Kidney filtration and catabolism have a significant contribution to the clearance of IFN and RBV; thus, there is the need to make appropriate dosing adjustment and caution. No data exist in the literature to guide therapy for HCV in patients with CKD stages 1 and 2. However, in patients with glomerular filtration rate 450 ml/min per 1.73 m2, kidney function does not have a major impact on the efficacy and safety of combined IFN and RBV therapy. As such, the results reported in patients with normal kidney function treated with conventional or pegIFN monotherapy or in combination with RBV should apply to CKD stages 1 and 2.4 Very limited data exist about dual antiviral therapy (conventional or peg-IFN plus RBV) in CKD stage 35 patients. Identical doses of conventional IFN have been recommended in nonuremic and dialysis patients.4 Recent evidence suggests that patients with creatinine clearance o30 ml/min should receive a reduced dose of peg-IFN, and those with creatinine clearance p50 ml/min should receive a reduced dose of RBV (http:// www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ ucm267594.htm). Patients with moderate renal impairment (creatinine clearance 3050 ml/min) should be given 200 mg of RBV daily, alternating with 400 mg the following day, whereas those with creatinine clearance o30 ml/min (including dialysis patients) should receive 200 mg of RBV ribavirin daily. A 2545% higher exposure to peg-IFN-a-2a is seen in subjects undergoing HD (http://www.fda.gov/ ForConsumers/ByAudience/ForPatientAdvocates/ucm267594. htm)a 135 mg (once weekly) dose of peg-IFN-a-2a by subcutaneous route in patients with creatinine clearance o30 ml/min has been recommended. The dose may be reduced to 90 mg once weekly as appropriate. Patients with
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CKD stages 35 should receive a lesser dose of peg-IFN-a-2b (1.0 mg/kg/weekly by subcutaneous route), as recommended by the KDIGO Study Group.4 The side effects associated with IFN use for hepatitis C have been categorized into early and late side effects. Early side effects occur during the first few days of treatment; they are common but do not usually present a problem in the IFN administration. Prominent among early side effects are a complex of symptoms termed influenza-like syndrome. In contrast to the early side effects, the late side effects appear after 1 to 2 weeks of treatment and may necessitate reducing IFN dosage or stopping IFN treatment altogether. They include systemic (such as weight and/or hair loss), hematologic (bone marrow suppression), autoimmune (that is, thyroid abnormalities), infectious, and psychiatric changes. Patients on RBV therapy should be carefully monitored for decreased hemoglobin, as RBV commonly causes hemolytic anemia. As reported below, IFN-based therapy gives a greater rate of side effects (particularly late side effects) in dialysis patients than among nonuremic patients.
ANTIVIRAL TREATMENT OF HCV IN DIALYSIS: CURRENT SCHEDULES

Table 2 | Efficacy of antiviral therapy (peg-IFN alone) for chronic HCV in patients on maintenance dialysis
Authors Peck-Radosavljevic et Basic-Jukic et al.42 Akhan et al.43 Ayaz et al.44 Sikole et al.45 Espinosa et al.46 Covic et al.47 Russo et al.48 Sporea et al.49 al.41 SVR ratea Treatment Reference year 2011 2011 2008 2008 2007 2007 2006 2006 2006 37% (30/81) Peg-IFN-a-2a 56% (9/16) Peg-IFN-a-2a 50% (6/12) Peg-IFN-a-2a 50% (11/22) Peg-IFN-a-2a 41.6% (5/14) Peg-IFN-a-2a 25% (4/16) Peg-IFN-a-2a (n 7) Peg-IFN-a-2b (n 9) 14.1% (11/78) Peg-IFN-a-2a 12.5% (2/14) Peg-IFN-a-2b 30% (3/30) PegIFN-a-2a

Abbreviations: HCV, hepatitis C virus; IFN, interferon; peg-IFN, pegylated IFN; SVR, sustained virological response. a Results have been calculated according to an intention-to-treat (ITT) analysis.

of patients with normal kidney function (936212 pgh/ml vs. 485184 pgh/ml; Po0.0001).25
ANTIVIRAL TREATMENT OF HCV IN DIALYSIS: DUAL THERAPY

New clinical guidelines4 suggest that monotherapy with standard IFN (24 or 48 weeks according to HCV genotype) is the therapy of choice for HCV-infected renal transplant candidates (dialysis dependent or not). The benefits and risks of antiviral therapy with IFN-based regimens in HCVinfected patients on maintenance HD have been evaluated in several studies, even if the quality of evidence in this area is low overall. Tolerance to IFN appears to be lower in dialysis patients than in non-CKD patients with chronic hepatitis C; the summary estimate of dropout rate was 19% in dialysis patients on monotherapy with conventional IFN,20 whereas the frequency of side effects requiring IFN discontinuation ranged between 5 and 9% in non-CKD patients with chronic hepatitis C who received a standard dose of conventional IFN monotherapy (3 MU three times weekly for 6 months). The profile of side effects to IFN-based therapy in dialysis patients seems different from normal controls. In addition to flu-like symptoms, other common side effects leading to interruption of IFN therapy in the CKD population are late side effects such as neurologic and cardiovascular disorders. Nevertheless, approximately one-third of HD patients with chronic hepatitis C have obtained SVR with standard IFN monotherapy.20 What we need now is to understand whether successful antiviral therapy translates into longer survival in this population. The altered pharmacokinetic parameters of IFN in the HD population, higher age, and high rate of comorbid conditions may, to some extent, explain the higher frequency of side effects leading to IFN discontinuation. In a prospective controlled trial, the half-life of IFN-a-2a was greater in dialysis patients than in normal controls (9.62.9 vs. 5.31.3 h; P 0.001), and the observed area under the plasma a-IFN concentration-time curve was about twice that
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The information on dual antiviral therapy (that is, conventional IFN plus RBV) in CKD population is preliminary in nature, and the data on peg-IFN with RBV are even more sparse.26 The quality of evidence on this issue is very low. The results provided in some trials have been encouraging in terms of efficacy and safety, but the limited size of the study groups and the small number of clinical studies do not allow definitive recommendations. Nephrologists have been reluctant so far to use dual therapy in dialysis patients with HCV, as RBV in this setting was not recommended.21 Impaired excretion of RBV occurs in patients with CKD, as RBV is mostly eliminated by the kidney. Very little RBV is removed via dialysis, and thus there is a propensity for the drug to accumulate, exacerbating hemolysis in the dialysis population already at significant risk for anemia. We feel that if a decision is made to use RBV in patients on maintenance HD, it should be used very cautiously and only after the implementation of several safety precautions, including the following: (1) very low doses of RBV (200400 mg three times weekly), (2) weekly monitoring of hemoglobin levels, (3) titration of erythropoietin to treat anemia, and (4) intravenous iron supplementation to boost erythropoietin activity.4 The efficacy and safety (Table 2) of dual antiviral therapy (conventional or peg-IFN plus RBV) in dialysis patients with chronic hepatitis C was evaluated by a systematic review of the literature with a pooled analysis of clinical studies.26 The primary outcome was SVR (as a measure of efficacy); the secondary outcome was dropout rate (as a measure of tolerability). A total of 10 clinical studies (151 unique patents) were identified, with 1 (10%) being a controlled clinical trial. Most of the patients (97.4%) were on long-term HD. The summary estimate for SVR and dropout rate was 56% (95% CI, 2884) and 25% (95% CI, 1040), respectively. The most common side effects requiring interruption of treatment were anemia (26%) and heart failure (9%). We found a large difference between studies with regard to
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Review: Antiviral therapy for HCV in HD Comparison: 01 peg-IFN plus ribavirin for HCV in HD Outcome: 01 peg-IFN+RBV for chronic HCV in HD Study or subcategory Rendina et al.50 Carriero et al.51 SVR rate (s.e.) 0.9700 (0.0288) 0.2800 (0.1200) 0.7100 (0.1700) 0.0500 (0.0487) 0.6000 (0.0820) 0.5000 (0.0880) 0.7600 (0.1000) SVR rate (random) 95% Cl Weight SVR rate (random) % 95% Cl 14.89 14.00 13.16 14.78 14.49 14.42 14.27 0.97 (0.91 to 1.03) 0.28 (0.04 to 0.52) 0.71 (0.38 to 1.04) 0.05 (0.05 to 0.15) 0.60 (0.44 to 0.76) 0.50 (0.33 to 0.67) 0.76 (0.56 to 0.96) Year 2007 2008 2008 2009 2009 2011 2011

Van Leusen et al.52 Hakim et al.53 Liu et al.54 Deltenre et al.55 Giguere et al.56

100.00 0.55 (0.20 to 0.90) 4 2 0 2 4 Total (95% Cl) Test for heterogeneity: 2 = 285.23, d.f. = 6 (P < 0.00001), I 2 = 97.9% Test for overall effect: Z = 3.09 (P = 0.002)

Figure 1 | Summary estimate for sustained viral response after combined antiviral therapy for HCV among dialysis patients. CI, confidence interval; HCV, hepatitis C virus; HD, hemodialysis; IFN, interferon; peg-IFN, pegylated IFN; RBV, ribavirin; SVR, sustained virological response.

dropout rate; studies from the United States showed the highest frequency of dropouts (6771%). Racial differences affecting the tolerability to the drug, higher rates of comorbidities, and socioeconomic differences could be a potential explanation. The summary estimate of SVR rate after dual antiviral therapy (peg-IFN RBV) for chronic HCV in patients on long-term HD is reported in Figure 1, with the most recent trials being identified. Thus, preliminary evidence suggests that dual antiviral therapy (peg-IFN RBV) is an advance, in terms of viral response, compared with monotherapy with IFN in patients on long-term dialysis. It remains unclear whether dual therapy based on peg-IFN use is superior to standard IFN plus RBV in dialysis patients with HCV.
ANTIVIRAL TREATMENT OF HCV AFTER KIDNEY TRANSPLANTATION

direct-acting antiviral drugs targeted against HCV. Telaprevir and boceprevir are two new potent protease inhibitors that have been recently licensed from the Food and Drug Administration (FDA). Both of these drugs inhibit the HCV nonstructural protein 3-4A serine protease, and recent studies have shown significantly higher SVR rates in patients with genotype 1.28,29 For the treatment of genotype 1 HCV infection, recent guidelines now recommend their use in combination with peg-IFN and RBV (triple antiviral therapy) in treatment-naive and treatment-experienced patients with genotype 1 chronic HCV infection.30 Some limitations of triple therapy have been already emphasized in the general population, including safety (cutaneous rash or anemia), drug interactions, cost, compliance, and viral resistance.30 Telaprevir and boceprevir apparently do not require dose adjustments to the renal function, but evidence concerning triple therapy in CKD population is not currently available safety issues need to be carefully addressed. Given that the HCV therapy field is moving very quickly toward IFN-free and RBV-free regimens, efficacy and safety of these approaches in patients with CKD will also be an important research area in the near future.
DISCLOSURE

All the authors declared no competing interests.

ACKNOWLEDGMENTS

This work has been supported in part by the grant Project Glomerulonephritis, in memory of Pippo Neglia.
REFERENCES
Pol S, Vallet-Pichard A, Corouge M et al. Hepatitis C: epidemiology, diagnosis, natural history and therapy. Contrib Nephrol 2012; 176: 19. 2. Jadoul M, Barril G. Hepatitis C in haemodialysis: epidemiology and prevention of hepatitis C virus transmission. Contrib Nephrol 2012; 176: 3541. 3. Fissell R, Bragg-Gresham J, Woods J et al. Patterns of hepatitis C prevalence and seroconversion in hemodialysis units from three continents: The DOPPS. Kidney Int 2004; 65: 23352342. 4. Kidney Disease: Improving Global Outcomes. KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int 2008; 73(Suppl 109): S1S99. 5. Fabrizi F, Dixit V, Messa P. Impact of hepatitis C on survival in dialysis patients: a link with cardiovascular mortality? J Viral Hepat 2012; 19: 601607. 6. Goodkin D, Bragg-Gresham J, Koenig G et al. Association of comorbid conditions and mortality in haemodialysis patients in Europe, Japan, and the United States: the dialysis outcomes, and practice patterns. J Am Soc Nephrol 2003; 14: 32703277. 7. Oyake N, Shimada T, Murakami Y et al. Hepatitis C virus infection as a risk factor for increased aortic stiffness and cardiovascular events in dialysis patients. J Nephrol 2008; 21: 345353. 8. Roth D, Gaynor J, Reddy K et al. Effect of kidney transplantation on outcomes among patients with hepatitis C. J Am Soc Nephrol 2011; 22: 11521160. 9. Cosio F, Sedmak D, Henry M et al. The high prevalence of severe early post-transplant renal allograft pathology in hepatitis C positive recipients. Transplantation 1996; 62: 10541059. 10. Cruzado J, Carrera M, Torras J et al. Hepatitis C virus infection and de novo glomerular lesions in renal allografts. Am J Transplant 2001; 1: 171178. 11. Morales J, Pascual-Capdevila J, Campistol J et al. Membranous glomerulonephritis associated with hepatitis C virus infection in renal transplant patients. Transplantation 1997; 63: 16341639.
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Graft dysfunction is a common side effect of IFN-based therapy administered after kidney transplant. Dropout rates of 35% have been observed in renal transplant patients with HCV who received a-IFN alone or a-IFN plus RBV.27 Dropouts on antiviral therapy after renal transplantation are mostly related to IFN-induced acute rejection, which is frequently steroid resistant and irreversible. The quality of evidence is very low on this point. It has been suggested that treatment of HCV after kidney transplantation should only be considered in patients with fibrosing cholestatic hepatitis or life-threatening vasculitis in whom the risk of not treating justifies the possible loss of the allograft.4 The patient needs to be informed of these complications before the initiation of anti-HCV therapy. Other options, such as RBV monotherapy or RBV plus amantadine therapy, are not able to induce SVR even if RBV may have an effect upon HCV-related proteinuria.27
ANTIVIRAL TREATMENT OF HCV IN CKD PATIENTS: FUTURE PERSPECTIVES

Novel improvements in the understanding of the viral cycle, and the characterization of viral enzymes that are potential targets, resulted in the development of new molecules,
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