Management of Hepatitis C Infection in Renal Transplant Recipients

Abstract

Infection with hepatitis C virus (HCV) in renal transplant recipients is associated with an increased risk of death and is the leading cause of post‐transplant liver disease. The prevalence of hepatitis C in this population is high. As ascertained by a positive anti‐HCV test, between 10 and 41% of the renal transplant recipients are infected with the virus, with a wide variation among different centers and countries (1Vosnides GG. Hepatitis C in renal transplantation.Kidney Int. 1997; 52: 843-861Abstract Full Text PDF PubMed Scopus (90) Google Scholar). Despite impressive advances in our knowledge about the epidemiology, clinical course and management of HCV infection, a number of important questions regarding the care of the HCV‐infected renal transplant recipient remain unanswered. In this review, we discuss a comprehensive approach to the management of HCV infection in renal transplant recipients. Early detection of HCV infection in patients with end‐stage renal disease (ESRD) is essential for their optimal care. The great majority of renal transplant recipients infected with HCV acquire the virus prior to transplantation, most frequently while on hemodialysis (HD), and only a small portion become infected perioperatively or in the post‐transplant period. Therefore, the emphasis is on the diagnosis of HCV infection in the pretransplant period. Serum ALT levels are a poor predictor of HCV‐induced liver disease among patients on renal replacement therapy, and when used alone have limited diagnostic value. Overall, serum ALT elevations in dialysis patients with HCV infection have been detected only in 4–67% of those who have antibodies directed against HCV, in 12–31% of those who are HCV RNA‐positive and in 33% of patients with biopsy‐proven hepatitis (2Natov SN Pereira BJG. Hepatitis C infection in patients on dialysis.Semin Dial. 1994; 7: 360-368Crossref Google Scholar, 3Pereira BJG Levey AS. Hepatitis C virus infection in dialysis and renal transplantation.Kidney Int. 1997; 51: 981-999Abstract Full Text PDF PubMed Scopus (360) Google Scholar). Biochemical evidence of liver disease is present in only 42–52% of the HCV RNA‐positive transplant recipients (4Aeder MI Shield CF Tegtmeier GE et al.The incidence and clinical impact of hepatitis C virus (HCV) positive donors in cadaveric transplantation.Transplant Proc. 1993; 25: 1469-1471PubMed Google Scholar, 5Pereira BJG Milford EL Kirkman RL et al.Prevalence of HCV RNA in hepatitis C antibody positive cadaver organ donors and their recipients.N Eng J Med. 1992; 327: 910-915Crossref PubMed Scopus (247) Google Scholar). Normal ALT levels do not exclude the presence of liver disease for the following reasons. First, the course of chronic HCV infection is characterized by ALT fluctuations with multiple peaks and troughs, which are usually within the normal range (6Farci P Alter HJ Wong D et al.A long‐term study of hepatitis C virus replication in non‐A, non‐B hepatitis.N Engl J Med. 1991; 325: 98-104Crossref PubMed Scopus (492) Google Scholar). Second, HCV infection is not always associated with chronic liver disease. In fact, there is clear evidence of the existence of HCV healthy carrier status following renal transplantation. For example, in one study, about 20% of the renal transplant recipients with chronic HCV infection were considered to be healthy HCV carriers because they had persistent active HCV infection (demonstrated by the presence of HCV RNA in successive serum samples), consistently normal serum ALT levels on consecutive tests and normal histology on liver biopsy performed after at least 2 years follow‐up (7Haem J Berthoux P Mosnier JF et al.Clear evidence of the existence of healthy carriers of hepatitis C virus among renal transplant recipients.Transplantation. 1996; 62: 699Crossref PubMed Scopus (23) Google Scholar). In these cases, viral replication probably occurs at extrahepatic sites in the absence of any apparent liver involvement. Third, anti‐HCV may be the remnant of past infection. Fourth, dialysis patients have depressed serum ALT levels at baseline (8Wolf PL Williams D Coplon N Coulson AS. Low aspartate transaminase activity in serum of patients undergoing chronic hemodialysis.Clin Chem. 1972; 18: 567-573Crossref PubMed Scopus (69) Google Scholar) and ALT elevations from baseline values might be unrecognized if they remain within the generally accepted normal range. In fact, some authors have suggested that the reference range for normal ALT values should be adjusted for dialysis patients (9Yuki N Ishida H Inoue T et al.Reappraisal of biochemical hepatitis C activity in hemodialysis patients.J Clin Gastroenterol. 2000; 30: 187-194Crossref PubMed Scopus (22) Google Scholar, 10Espinosa M Martin‐Malo A Alvarez de Lara MA Soriano S Aljama P. High ALT levels predict viremia in anti‐HCV‐positive HD patients if a modified normal range of ALT is applied.Clin Nephrol. 2000; 54: 151-156PubMed Google Scholar). The sensitivity, specificity and predictive values of an elevated ALT level for the diagnosis of HCV infection in dialysis patients are also an important consideration. A newly elevated ALT level was found to be sensitive (83% sensitivity) and specific (90% specificity) for the diagnosis of acute HCV infection, but had a low positive predictive value of only 4%. For chronic HCV infection, a newly elevated ALT level had a low sensitivity (21%), but a good specificity (91%) and again a low positive predictive value (16%). The negative predictive value of a newly elevated ALT level was 99% for acute HCV infection and 94% for chronic HCV infection (11Saab S Martin P Brezina M Gitnick G Yee HFJ. Serum alanine aminotransferase in hepatitis C screening of patients on hemodialysis.Am J Kidney Dis. 2001; 37: 91-97Abstract Full Text Full Text PDF Scopus (42) Google Scholar). These data provide additional evidence that an elevated ALT level is an ineffective method for screening for HCV infection in dialysis patients. Today, serologic tests are the mainstay for the diagnosis of HCV infection (3Pereira BJG Levey AS. Hepatitis C virus infection in dialysis and renal transplantation.Kidney Int. 1997; 51: 981-999Abstract Full Text PDF PubMed Scopus (360) Google Scholar). Both enzyme‐linked immunosorbent assays (ELISAs) and recombinant immunoblot assays (RIBAs) have been developed to detect non‐neutralizing antibodies to HCV (anti‐HCV). ELISAs are used as screening tests, while RIBAs usually serve as confirmatory tests due to their higher specificity. Currently, the third‐generation anti‐HCV tests are most widely used because of their better performance as compared with the previous two generations (12Soffredini R Rumi M Lampertico P et al.Increased detection of antibody to hepatitis C virus in renal transplant patients by third‐generation assays.Am J Kidney Dis. 1996; 28: 437-440Abstract Full Text PDF PubMed Scopus (26) Google Scholar, 13Fabrizi F Lunghi G Raffaele L et al.Serologic survey for control of hepatitis C in haemodialysis patients: third‐generation assays and analysis of cost.Nephrol Dial Transplant. 1997; 12: 298Crossref PubMed Scopus (34) Google Scholar). In most cases, serologic testing for anti‐HCV is first performed pretransplantation, while the patient is on dialysis or when undergoing pretransplant evaluation. For early detection of HCV infection, the CDC recommend routine serologic testing for HCV of all dialysis patients. This should include initial anti‐HCV testing at the time of initiation of dialysis, followed by semi‐annual testing for anti‐HCV of all anti‐HCV‐negative patients only (14Centers for Disease Control and PreventionRecommendations for preventing transmission of infections among chronic hemodialysis patients.MMWR. 2001; 50 (No. RR‐5): 1-46PubMed Google Scholar). Once the diagnosis of HCV infection is established by a positive serologic test, testing for HCV RNA (usually by PCR) is recommended to confirm the presence of viremia, i.e. active infection. Renal transplant recipients are in a state of iatrogenic immunosuppression and many of those who acquire HCV infection perioperatively or in the post‐transplant period experience profound impairment in the humoral immune response to HCV. Consequently, HCV‐infected renal transplant recipients may demonstrate markedly delayed or even absent antibody production. In this case, they remain anti‐HCV‐negative despite being viremic, i.e. positive for HCV RNA, and the diagnosis of HCV infection would have been missed if only anti‐HCV testing were performed (15Lok ASF Chien D Choo QL et al.Antibody response to core, envelope and nonstructural hepatitis C virus antigens: comparison of immunocompetent and immunosuppressed patients.Hepatology. 1993; 18: 497-502Crossref PubMed Scopus (147) Google Scholar, 16Lau JYN Davis GL Brunson ME et al.Hepatitis C virus infection in kidney transplant recipients.Hepatology. 1993; 18: 1027-1031Crossref PubMed Scopus (104) Google Scholar, 17Maple PA McKee T Desselberger U Wreghitt TG. Hepatitis C virus infections in transplant patients: serological and virological investigations.J Med Virol. 1994; 44: 43-48Crossref PubMed Scopus (25) Google Scholar, 18Preiksaitis JK Cockfield SM Fenton JM Burton NI Chui LW‐L. Serologic responses to hepatitis C virus in solid organ transplant recipients.Transplantation. 1997; 64: 1775-1780Crossref PubMed Scopus (38) Google Scholar). Indeed, HCV RNA can be detected in about 9–18% of the anti‐HCV‐negative renal transplant recipients (16Lau JYN Davis GL Brunson ME et al.Hepatitis C virus infection in kidney transplant recipients.Hepatology. 1993; 18: 1027-1031Crossref PubMed Scopus (104) Google Scholar, 19Roth D. Hepatitis C virus infection and the renal allograft recipient [editorial] [Review].Nephron. 1995; 71: 249-253Crossref PubMed Google Scholar). Obviously, serologic testing alone might be insufficient to establish the diagnosis of HCV infection in this population. If viral hepatitis is suspected, detecting the presence of HCV RNA is advisable, as it is a significantly more sensitive method and the only definitive way to diagnose HCV infection in renal transplant recipients (18Preiksaitis JK Cockfield SM Fenton JM Burton NI Chui LW‐L. Serologic responses to hepatitis C virus in solid organ transplant recipients.Transplantation. 1997; 64: 1775-1780Crossref PubMed Scopus (38) Google Scholar). Overall, these data suggest that all anti‐HCV‐negative renal transplant recipients with abnormal liver function tests or proteinuria should be screened for the presence of HCV RNA (18Preiksaitis JK Cockfield SM Fenton JM Burton NI Chui LW‐L. Serologic responses to hepatitis C virus in solid organ transplant recipients.Transplantation. 1997; 64: 1775-1780Crossref PubMed Scopus (38) Google Scholar). Conversely, HCV RNA screening of anti‐HCV‐negative renal transplant recipients with normal liver function is not advisable, as the cost will be high and the yield low (18Preiksaitis JK Cockfield SM Fenton JM Burton NI Chui LW‐L. Serologic responses to hepatitis C virus in solid organ transplant recipients.Transplantation. 1997; 64: 1775-1780Crossref PubMed Scopus (38) Google Scholar). As a next step in the diagnosis of HCV infection, quantitative determination of the viral load could be pursued. In some studies, determining viral load has been used as a predictor of patient response to interferon‐alfa (INFα) therapy. A low pretreatment viral load has been associated with a sustained response, while a relatively high load has been predictive of nonsustained response or lack of response to IFNα therapy. However, in the individual patient, the correlation of HCV RNA levels with response to IFNα therapy has proven to be poor. Today, determination of viral load has limited use in clinical practice (20Umlauft F Gruenewald K Weiss G et al.Patterns of hepatitis C viremia in patients receiving hemodialysis.Am J Gastroenterol. 1997; 92: 73-78PubMed Google Scholar, 21Chan TM Wu PC Lau JY Lok AS Lai CL Cheng IK. Interferon treatment for hepatitis C virus infection in patients on haemodialysis.Nephrol Dial Transplant. 1997; 12: 1414-1419Crossref PubMed Scopus (73) Google Scholar, 22Davis G Lau JYN. Factors predictive of a beneficial response to therapy of hepatitis C.Hepatology. 1997; 26: 122-127SCrossref PubMed Scopus (321) Google Scholar). Similarly, genotype testing to determine the type and the number of infecting HCV strains is of little practical use for the management of the individual ESRD patient. The HCV genotype and the type of HCV infection, single (infection with one HCV genotype) vs. mixed (infection with more than one HCV genotype), have not been found to affect patient survival among renal transplant candidates (23Natov SN Lau JYN Ruthazer R et al.HCV genotype does not affect patient survival among renal transplant candidates.Kidney Int. 1999; 56: 700-706Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). In fact, the prevalence and severity of chronic hepatitis were similar among patients on renal replacement therapy (renal transplantation or dialysis) who were infected with HCV genotype 1b and those infected with non‐1b genotypes (24Chan TM Lau JYN Wu PC Lai CL Lok ASF Cheng IKP. Hepatitis C virus genotypes in patients on renal replacement therapy.Nephrol Dial Transplant. 1998; 13: 731-734Crossref PubMed Scopus (14) Google Scholar). The value of HCV genotyping as a predictor of patient response to IFNα therapy is also debatable. In the general population, infections with HCV genotype 1 have been associated with a lower response rate to IFNα than infections with other HCV genotypes (22Davis G Lau JYN. Factors predictive of a beneficial response to therapy of hepatitis C.Hepatology. 1997; 26: 122-127SCrossref PubMed Scopus (321) Google Scholar). In HD patients, however, studies have failed to find any correlation between HCV genotype and response to IFNα therapy (20Umlauft F Gruenewald K Weiss G et al.Patterns of hepatitis C viremia in patients receiving hemodialysis.Am J Gastroenterol. 1997; 92: 73-78PubMed Google Scholar, 25Tokumoto T Tanabe K Ishikawa N et al.Effect of interferon‐alpha treatment in hemodialysis patients and renal transplant recipients with chronic hepatitis C.Transplant Proc. 1999; 31: 2887-2889Crossref PubMed Scopus (27) Google Scholar). Therefore, determination of HCV genotype is currently limited to research purposes or epidemiological investigations to trace the source of infection. Liver biopsy is the gold standard for confirming the diagnosis of HCV‐induced liver disease and the only means of precisely assessing the degree of liver involvement. The histological severity of liver damage is a strong predictor of liver failure and death after transplantation. Therefore, liver biopsy is recommended routinely in all renal transplant candidates as a part of their comprehensive pretransplant evaluation. The final decision, whether to proceed with renal transplantation, should be based largely on the severity of liver histology. HCV‐infected renal transplant candidates whose liver histology reveals chronic persistent hepatitis or mild active hepatitis may be accepted for renal transplantation without reservations. It is still debatable whether HCV‐infected patients with biopsy‐proven advanced chronic active hepatitis or early cirrhosis should be considered for renal transplantation or be advised to continue on dialysis. Because liver disease in immunosuppressed patients may often take a progressive course, many nephrologists are reluctant to offer renal transplantation to this group of patients. Patients with advanced cirrhosis may be considered for combined liver and kidney transplantation. However, current data are insufficient to determine precisely which is the best option for the ESRD patient with HCV infection and the recommendations discussed above are, to a large extent, opinion‐based rather than evidence‐based and adopted from studies in the general population. Therefore, we believe that any decision regarding transplantation should be made after considering the effect of immunosuppression on the natural course of HCV that may result in enhanced viral replication and possible exacerbation of liver disease, the life expectancy of the patient, the quality of life on dialysis, the expected quality of life after transplantation and the patient's informed choice between dialysis and transplantation. Finally, liver histology has been useful as a predictor of patient response to IFNα therapy and could serve for patient selection for antiviral treatment. General measures that could prevent additional hepatic injury can favorably affect the course of HCV‐induced liver disease. Since the great majority of HCV‐infected renal transplant recipients contract the virus in the pretransplant period and are diagnosed prior to transplantation, these general measures should be implemented as part of the pretransplant care and continued after transplantation. In all other cases, these measures should be initiated in the post‐transplant period as soon as the diagnosis is established. Hepatotoxic medications should be avoided in all HCV‐infected renal transplant recipients. The immunosuppressive regimen may need to be modified, as there have been significant concerns about azathioprine hepatotoxicity in renal transplant recipients with hepatotropic viral infections. In one study, azathioprine‐induced hepatitis among renal transplant recipients had a prevalence of 2% and was found only in patients who were positive for serologic or viral markers of hepatotropic infection (HBsAg, HBV RNA, or anti‐HCV) (26Pol S Cavalcanti R Carnot F et al.Azathioprine hepatitis in kidney transplant recipients. A predisposing role of chronic viral hepatitis.Transplantation. 1996; 61: 1774-1776Crossref PubMed Scopus (56) Google Scholar). Although this study did not address the mechanisms of azathioprine‐induced hepatotoxicity, the authors have speculated that active hepatotropic viral infection (HBV and/or HCV) causes liver disease and decreases catabolism of azathioprine toxic metabolites, which could possibly predispose to azathioprine toxicity or even induce it. Therefore, they recommended considering azathioprine dose reduction or withdrawal during diagnostic evaluation and treatment of viral liver disease in patients whose immunosuppressive regimens included azathioprine (26Pol S Cavalcanti R Carnot F et al.Azathioprine hepatitis in kidney transplant recipients. A predisposing role of chronic viral hepatitis.Transplantation. 1996; 61: 1774-1776Crossref PubMed Scopus (56) Google Scholar). Mycophenolate mofetil (MMF) therapy in long‐term HCV‐infected renal transplant recipients with chronic allograft dysfunction and cyclosporine‐based maintenance immunosuppressive regimen has also been shown to be associated with a significant increase in plasma HCV RNA levels. The rise in HCV viremia was not related to the HCV genotype and was not associated with significant changes in liver enzymes. The increase in HCV RNA levels occurred only in patients who had low viral load prior to introduction of MMF therapy. Patients with initially high HCV RNA titers did not experience any change in viremia after initiation of MMF. No information was available on the effect of the rising viremia on liver histology, as liver biopsy was not performed. Although this study could not provide data to explain the observed changes in HCV RNA levels following MMF therapy, the authors suggested that this drug should be used with caution in stable renal transplant recipients whose maintenance immunosuppressive therapy is based on cyclosporine, particularly in those with low HCV RNA levels (27Rostaing L Izopet J Sandres K Cisterne J‐M Puel J Durand D. Changes in hepatitis C virus RNA viremia consentrations in log‐term renal transplant patients after introduction of mycophenolate mofetil.Transplantation. 2000; 69: 991-994Crossref PubMed Scopus (83) Google Scholar). Prevention of other forms of viral hepatitis is very important. Coinfection of HCV with other hepatotropic viruses has been associated with poor clinical outcomes in the general population and among renal transplant recipients. Coinfection with hepatitis A in nonrenal patients with chronic hepatitis C has resulted in fulminant hepatitis (28Vento S Garofano T Renzini C et al.Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C.N Engl J Med. 1998; 338: 286-290Crossref PubMed Scopus (659) Google Scholar). Coinfection with HBV and HCV is quite frequent among renal transplant recipients – 30–40% of those who are HBsAg‐positive are coinfected with HCV (29Durlik M Gaciong Z Soluch L et al.Risk of chronic liver disease in HBsAg and/or anti‐HCV‐positive renal allograft recipients.Transplant Proc. 1996; 28: 50-51PubMed Google Scholar, 30Fornairon S Pol C Legendre C et al.The long‐term virologic and pathologic impact of renal transplantation on chronic hepatitis B virus infection.Transplantation. 1996; 62: 297-299Crossref PubMed Scopus (180) Google Scholar, 31Pouteil‐Noble C Tardy JC Chossegros P et al.Co‐infection by hepatitis B virus and hepatitis C virus in renal trasnplantation: morbidity and mortality in 1098 patients.Nephrol Dial Transplant. 1995; 10: 122-124Crossref PubMed Scopus (34) Google Scholar), and 20% of those who have HCV infection are coinfected with HBV (31Pouteil‐Noble C Tardy JC Chossegros P et al.Co‐infection by hepatitis B virus and hepatitis C virus in renal trasnplantation: morbidity and mortality in 1098 patients.Nephrol Dial Transplant. 1995; 10: 122-124Crossref PubMed Scopus (34) Google Scholar). Probably due to the synergistic effects of these two viruses (29Durlik M Gaciong Z Soluch L et al.Risk of chronic liver disease in HBsAg and/or anti‐HCV‐positive renal allograft recipients.Transplant Proc. 1996; 28: 50-51PubMed Google Scholar, 31Pouteil‐Noble C Tardy JC Chossegros P et al.Co‐infection by hepatitis B virus and hepatitis C virus in renal trasnplantation: morbidity and mortality in 1098 patients.Nephrol Dial Transplant. 1995; 10: 122-124Crossref PubMed Scopus (34) Google Scholar), coinfections with HBV and HCV in this population, as compared with infections with HCV or HBV alone, have been associated with an increased risk of post‐transplant chronic liver disease, a higher incidence of severe histological lesions, particularly cirrhosis, on liver biopsy (31Pouteil‐Noble C Tardy JC Chossegros P et al.Co‐infection by hepatitis B virus and hepatitis C virus in renal trasnplantation: morbidity and mortality in 1098 patients.Nephrol Dial Transplant. 1995; 10: 122-124Crossref PubMed Scopus (34) Google Scholar, 32Rostaing L Izopet J Cisterne J‐M et al.Impact of hepatitis C virus duration and hepatitis C virus genotypes on renal transplant patients: correlation with clinicopathological features.Transplantation. 1998; 65: 930-936Crossref PubMed Scopus (41) Google Scholar, 33Zylberberg H Landau A Carnot F et al.Impact of co‐infection by hepatitis B virus and hepatitis C virus in renal transplantation.Transplant Proc. 1998; 30: 2820-2822Crossref PubMed Scopus (8) Google Scholar) and significantly more frequent liver‐related deaths (33Zylberberg H Landau A Carnot F et al.Impact of co‐infection by hepatitis B virus and hepatitis C virus in renal transplantation.Transplant Proc. 1998; 30: 2820-2822Crossref PubMed Scopus (8) Google Scholar). To prevent the occurrence of other forms of viral hepatitis, hepatitis A and B vaccination of all susceptible HCV‐infected patients is strongly recommended (28Vento S Garofano T Renzini C et al.Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C.N Engl J Med. 1998; 338: 286-290Crossref PubMed Scopus (659) Google Scholar). However, in organ transplant recipients, the immunogenicity of most routine vaccinations is significantly lower than in healthy adults. There are only limited data on the immunologic response to hepatitis A vaccination among renal transplant recipients. In one study, renal transplant recipients required a full course of two doses of hepatitis A vaccine to be able to achieve protective HAV antibody titers with a seroconversion rate of 72%, in contrast to healthy individuals, whose response rate to a single vaccine dose usually exceeds 90% (34Stark K Gunther M Neuhaus R et al.Immunogenicity and safety of hepatitis A vaccine in liver and renal transplant recipients.J Infect Dis. 1999; 180: 2014-2017Crossref PubMed Scopus (87) Google Scholar). In addition, renal transplant recipients have demonstrated rapid decline of postvaccination antibody titers. Two years after hepatitis A vaccination, protective antibody titers were present in only 26% of renal transplant recipients as compared with 100% in healthy controls (35Gunther M Stark K Neuhaus R Reinke P Schroder K Bienzle U. Rapid decline of antibodies after hepatitis A immunization in liver and renal transplant recipients.Transplantation. 2001; 71: 477-490Crossref PubMed Scopus (92) Google Scholar). In some countries, routine hepatitis A vaccination of patients with chronic liver disease is already recommended. Renal transplant recipients with chronic HCV could certainly benefit from such a practice (34Stark K Gunther M Neuhaus R et al.Immunogenicity and safety of hepatitis A vaccine in liver and renal transplant recipients.J Infect Dis. 1999; 180: 2014-2017Crossref PubMed Scopus (87) Google Scholar). The rates of immunologic response to hepatitis B vaccine among renal transplant recipients have been even more disappointing. Hepatitis B vaccine is very weakly immunogenic in this population and even with enhanced vaccination schedules, the response rates (17.6–36%) are much lower than those observed in patients on chronic HD (36Jacobson IM Jaffers G Dienstag JL et al.Immunogenicity of hepatitis B vaccine in renal transplant recipients.Transplantation. 1985; 39: 393-395Crossref PubMed Scopus (48) Google Scholar, 37Lefebure AF Verpooten GA Couttenye MM De Broe ME. Immunogenicity of a recombinant DNA hepatitis B vaccine in renal transplant recipients.Vaccine. 1993; 11: 397-399Crossref PubMed Scopus (52) Google Scholar). However, in contrast to the primary immune responses that are strongly depressed, the secondary immune responses are relatively well maintained under immunosuppression and, in renal transplant recipients who were successfully vaccinated prior to transplantation, a booster with a double dose resulted in a rise in HBsAb titer above protective levels. These data strongly advocate hepatitis B vaccination of patients with chronic renal failure prior to transplantation, and possibly even before they reach ESRD, and then close monitoring of HBsAb titer in responders and giving a booster dose if these titers fall below protective levels (37Lefebure AF Verpooten GA Couttenye MM De Broe ME. Immunogenicity of a recombinant DNA hepatitis B vaccine in renal transplant recipients.Vaccine. 1993; 11: 397-399Crossref PubMed Scopus (52) Google Scholar). Finally, HCV‐infected patients should be advised against alcohol consumption because alcohol promotes the progression of chronic HCV‐induced liver disease. Patient counseling and patient education about the routes of HCV transmission, the risk of infecting household and sexual contacts and the impact of renal transplantation on the natural course of HCV infection should be a part of the comprehensive approach to the management of the HCV‐infected ESRD patient. It should be explained to the patient with HCV infection that renal transplantation has not been shown to adversely affect the course of HCV infection in patients with ESRD and that, in fact, current data suggest that transplantation has a beneficial rather than an adverse effect on long‐term survival in anti‐HCV‐positive patients on renal replacement therapy (38Pereira BJG Natov SN Bouthot BA et al.Effect of hepatitis C infection and renal transplantation on survival in end‐stage renal disease.Kidney Int. 1998; 53: 1374-1381Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar). Therefore, HCV infection should not be considered as a contraindication for renal transplantation and patients should not be discouraged from receiving a renal transplant. Interferon‐alfa is the mainstay of the therapeutic regimens for hepatitis C. The efficacy of IFNα has been demonstrated in a number of randomized controlled trials, and its use is currently recommended in anti‐HCV‐positive patients with abnormal serum aminotransferase and well‐compensated chronic hepatitis on liver biopsy (39Lindsay KL. Therapy of hepatitis C: overview.Hepatology. 1997; 26: 71S-77SCrossref PubMed Scopus (240) Google Scholar, 40Management of hepatitis C. NIH Consensus Statement. Online March 24–26 1997; 15: 1–41.Google Scholar). Four forms of IFNα have been evaluated for clinical use in large studies: IFNα‐2b (most commonly used), IFNα‐2a, IFNα‐n1, and IFN alfacon (or consensus interferon, CIFN) (39Lindsay KL. Therapy of hepatitis C: overview.Hepatology. 1997; 26: 71S-77SCrossref PubMed Scopus (240) Google Scholar). Although the approved dose and duration of therapy vary among the different preparations, they appear to be similarly effective. Recently, a new modified form of IFNα, pegylated IFNα, also called peginterferon‐alfa, was developed by attaching a 40‐kDa branched‐chain polyethylene glycol moiety to IFNα. Two formulations of pegylated interferon have been developed: pegylated IFNα‐2a (Pegasys, F. Hoffman‐LaRoche, Basel, Switzerland), and pegylated IFNα‐2b (Peg‐Intron, Schering Corporation, Kenilworth, NJ, USA), and are currently under clinical investigation (41Zeuzem S Feinman SV Rasenack J et al.Peginterferon alfa‐2a in patients with chronic hepatitis C.N Engl J Med. 2000; 343: 1666-1672Crossref PubMed Scopus (1183) Google Scholar, 42Heathcote EJ Shiffman ML Cooksley GE et al.Peginterferon alfa‐2a in patients with chronic h