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Treatment of Chronic Hepatitis C Infection in Patients With Renal Failure
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2005;3:S113–S117
Treatment of Chronic Hepatitis C Infection in Patients With Renal Failure PAUL MARTIN* and FABRIZIO FABRIZI‡ *Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York; and ‡Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS, Milano, Italy
Patients with end-stage renal disease continue to have a high prevalence of hepatitis C virus infection despite screening of blood products and efforts to prevent the transmission of viral hepatitis within dialysis units. Although biochemical dysfunction often is absent in infected patients, an increased rate of mortality from liver disease has been observed in patients on long-term dialysis. In addition, hepatitis C–infected renal transplant recipients have diminished patient and graft survival rates compared with uninfected controls. Antiviral therapy with interferon in renal transplantation candidates has resulted in sustained viral responses that have been durable even after subsequent renal transplantation. Graft dysfunction remains a major concern, limiting the use of interferon after renal transplant. Ribavirin, which accumulates and cannot be removed by dialysis, and may induce hemolysis, generally has been avoided in patients with end-stage renal disease. In pilot studies, cautious use of reduced doses of ribavirin has been possible in this population with close monitoring of hematocrit levels and additional measures to enhance compensatory erythropoiesis.
atients with end-stage renal disease (ESRD) on renal replacement therapy, especially hemodialysis (HD), continue to have a high prevalence of hepatitis C virus (HCV) infection despite screening of blood products and precautions to prevent the spread of viral hepatitis in dialysis units. HCV infection in this population is notable for the frequent absence of biochemical dysfunction despite viremia and histologic activity. HCV infection now has been implicated clearly in diminished patient survival on chronic hemodialysis and patient and graft survival after renal transplantation (RT). A small but growing body of literature has described successful antiviral therapy with interferon (IFN) in patients with ESRD with rates of sustained virologic response (SVR) comparable with patients with normal renal function. Importantly, SVR is durable even after subsequent renal transplant and therapeutic immunosuppression. Major concern persists about IFN-induced renal graft loss, effectively limiting its routine use to the pretransplant setting.
P
Hepatitis C Virus in Dialysis Patients The prevalence of anti-HCV among patients undergoing regular HD in the United States was 7.8% in 2002.1 However, many centers have reported a decrease in HCV prevalence in recent years, reflecting a number of factors including diminished blood product requirement in patients with ESRD because of erythropoietin use, highly successful efforts to exclude blood donors with HCV infection, and increased attention to preventing HCV spread within dialysis units. In a multinational cohort, the Dialysis Outcomes and Practice Patterns Study, which included centers in the United States, Japan, and western Europe, the presence of highly trained staff in dialysis units predicted lower HCV infection rates, reflecting the importance of adherence to precautions to prevent the spread of HCV in this setting.2 Jadoul et al3 reported a 50% decrease in anti-HCV seropositivity in Belgian dialysis units, comparing the early to late 1990s with a similar trend in most other western European countries surveyed, although its prevalence remained high in eastern Europe. Routine third-generation serologic testing for HCV now accurately identifies infected hemodialysis patients, most of whom also are viremic by polymerase chain reaction; false-negative serologic testing had been more frequent with earlier-generation tests.4 Polymerase chain reaction and branched DNA assays also are reliable in these patients and may be useful especially in early detection of HCV infection before seroconversion has taken place. The natural history of HCV infection in the hemodialysis population is not well defined for a number of Abbreviations used in this paper: ESRD, end-stage renal disease; ETR, end treatment response; GN, glomerulonephritis; HCV, hepatitis C virus; HD, hemodialysis; IFN, interferon; RT, renal transplantation; SVR, sustained virologic response. © 2005 by the American Gastroenterological Association 1542-3565/05/$30.00 PII: 10.1053/S1542-3565(05)00710-X
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reasons.4 Hemodialysis patients, by virtue of their comorbidities, have diminished long-term survival rates, and with the typically slow progression of HCV infection its most serious consequences, most notably decompensated cirrhosis and hepatocellular carcinoma, may not evolve during the shortened life span of an HCV-infected patient maintained on HD. Serial liver biopsy examination data on adequate numbers of ESRD patients with HCV infection generally are not available to assess disease progression. Although liver disease is recognized infrequently in this population, there is information about the development of at least some complications of cirrhosis in dialysis patients. Data from the Case Mix Severity Special Study of the US Renal Data System and the Lombardy Dialysis and Transplant Registry suggested that although cirrhosis is infrequent in the dialysis population (2% in the United States, 1.5% in Lombardy), the death rate for dialysis patients with cirrhosis was 35% higher in comparison with those without cirrhosis.5 In addition, a multicenter study from the United States, Europe, Australia, and New Zealand showed that there is an excess of liver cancer in ESRD patients, most likely reflecting an increased prevalence of chronic viral hepatitis.6 In other single-center, prospective studies, the mortality rate was higher in anti–HCVpositive chronic HD patients compared with seronegative controls.7,8 A recent meta-analysis has confirmed that HCV-infected dialysis patients have a lower survival rate than uninfected patients on dialysis with chronic liver disease implicated in the worse outcomes.9 Combining data from more than 2000 patients on chronic hemodialysis, HCV infection was associated with a relative risk of mortality of 1.57 compared with uninfected patients with hepatocellular carcinoma and cirrhosis, which are more frequent causes of death in HCV-seropositive patients.9 HCV infection also has been implicated in the development of diabetes mellitus, which in turn may increase waiting list mortality in candidates for renal transplantation.10 Treatment of Hepatitis C Virus Infection in Dialysis Patients Despite the high prevalence of HCV infection in the hemodialysis population, indications for therapy remain ill defined. Concern about the ability of this population to tolerate IFN and more recently ribavirin has been a factor.
Interferon Therapy There are no large-scale studies of antiviral therapy for HCV in ESRD patients and much of the available
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 10
Table 1. Treatment of Chronic Hepatitis C Virus Infection in ESRD SVR rate, % IFN alfa Combination IFN alfa/ribavirin Pegylated IFN
33,12 3711 12.513 33.315
literature consists predominantly of small uncontrolled clinical trials of interferon monotherapy with at least some treated patients achieving an SVR (see Table 1). In a recent meta-analysis, 14 clinical trials were included, only 2 of which were controlled studies.11 The mean overall estimated SVR was 37% (95% confidence interval, 28 – 48), with a drop-out rate of 17% (95% confidence interval, 10 –28). The overall weighted estimate for SVR in patients with HCV genotype 1 was 30.6% (95% confidence interval, 20.9 – 48.0). In the minority of these trials (n ⫽ 5) using a more standard IFN regimen (3 MU, 3 ⫻ weekly, subcutaneous route), the overall mean estimate of SVR was 39% (95% confidence interval, 25–56). A meta-analysis performed by Russo et al12 included 11 studies of HCV therapy in dialysis patients with an overall SVR of 33%, and for those with genotype 1 an SVR of 26%. Thus, the literature on monotherapy for HCV in the ESRD population indicates that therapy may be at least as effective as in the nonuremic population, albeit with a high rate of treatment discontinuation because of side effects, perhaps in part reflecting delayed IFN clearance. As described later, excellent SVR rates are possible in renal transplant candidates.
Interferon Plus Ribavirin Therapy Ribavirin therapy enhances SVR rates when used in combination with IFN in patients with normal renal function. However, there has been considerable reluctance to use ribavirin in patients with ESRD mainly because it causes hemolytic anemia in a population already prone to anemia. Furthermore, ribavirin and its metabolites accumulate in renal failure and are not removed by dialysis. However, Bruchfeld et al13 provided information about its safe use in ESRD. They described the use of low-dose ribavirin, monitoring of plasma concentrations, and administration of high-dose erythropoietin to replete iron stores to aid in erythropoiesis. In a pilot study they treated 5 HCV-infected patients on regular HD and 1 patient on peritoneal dialysis with IFN alfa-2b plus ribavirin.13 IFN alfa-2b was given initially as monotherapy at a dose of 3 MU 3 times weekly after dialysis for 4 weeks; thereafter low-dose ribavirin was added, starting at 200 – 400 mg/day for 6 months. Five
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(83.3%) of 6 patients became HCV RNA negative during treatment, but 4 patients relapsed after treatment. Average daily doses of ribavirin were 170 –300 mg. Tan et al14 reported another small experience in preliminary form with on-treatment virologic response in 4 of 5 patients treated with IFN and ribavirin, although 2 patients required permanent withdrawal of ribavirin owing to anemia.
Pegylated Interferons Even less data are available yet on the role of the pegylated IFNs in patients with ESRD. Annicchiarico et al15 reported an SVR in 2 of 6 chronic HD patients with pegylated IFN alfa-2b monotherapy (12-wk course), with therapy being discontinued in 2 of these 6 patients because of anemia. Sporea et al,16 in another preliminary report, described an on-treatment response in 7 of 10 HD patients with HCV patients receiving pegylated IFN alfa-2a monotherapy in a dose of 180 mcg/wk for 48 weeks, with dose reduction necessary in 2 cases. SVR data were not provided. Interferon-Based Therapy in Dialysis Patients Before Renal Transplantation Despite the frequency of HCV in patients with ESRD, there is no consensus about which patients should be offered antiviral therapy. Renal transplant candidates are a more robust group than the dialysis population as a whole and would seem better able to tolerate treatment side effects.17 IFN therapy also has been attempted after RT, but its use has been implicated in severe renal graft dysfunction. Importantly, SVR in successfully treated renal candidates can be durable despite subsequent transplant and therapeutic immunosuppression. In a prospective study, 29 RT candidates maintained on chronic HD received IFN (3 MU, 3 ⫻ weekly for 6 months followed by 1.5 MU for an additional 6 months) with an SVR of 64.2%.18 Seven of 9 of these responders remained HCV RNA negative with a mean follow-up time of 41 months after subsequent renal transplant.18 Other investigators also have described SVR in this population with an absence of HCV viremia despite subsequent RT and therapeutic immunosuppression.19 –21 Another potential benefit of successful antiviral therapy is decreasing the risk for graft glomerulonephritis after renal transplant. Cruzado et al22 reported their experience in HCV-seropositive RT recipients. Only 1 of 15 recipients previously treated with IFN developed graft glomerulonephritis (GN) and that patient had not achieved an SVR with IFN. In contrast, 12 of 27 (44%) untreated viremic recipients suffered graft GN. Importantly, GN only occurred in viremic patients.
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Hepatitis C Virus in Renal Transplant Patients HCV infection has been confirmed as a factor in reduced patient and graft survival rates after RT.23 Mathurin et al,24 in a series of 834 RT recipients including 216 with anti-HCV antibody present, identified HCV seropositivity as a predictor of diminished 10-year survival. Only 65% of the HCV group were alive at 10 years compared with 80% of uninfected controls. Graft survival also was significantly poorer in the HCV group, 49% at 10 years compared with 69% in recipients without viral hepatitis. Many deaths were related to liver disease in the HCV group. In a recent meta-analysis HCV seropositivity also was confirmed as a predictor of increased mortality and graft failure in RT recipients.25 Treatment of Hepatitis C Virus Infection After Renal Transplantation There had been understandable reluctance to use IFN in RT recipients because of older reports of precipitation of graft dysfunction during therapy of cytomegalovirus infection.26 However, with increasing concern about the adverse consequences of HCV infection in the ESRD population, a number of groups have explored antiviral therapy in RT recipients. Rostaing et al27 reported a placebo-controlled study in which 14 cadaveric renal transplant recipients with chronic HCV infection received recombinant IFN alfa-2b (3 MU 3 ⫻ weekly for 6 mo) with 14 untreated controls. Patients had stable renal allograft function for at least 1 year before therapy. No patient had an SVR, although 4 (28%) patients had had an end treatment response (ETR). A more significant concern in the IFN-treated group was the development of graft dysfunction in 5 (35.7%) patients, 4 of whom received intravenous steroid pulses in response; serum creatinine levels decreased significantly only in 2 patients. One patient returned to dialysis within 4 months of IFN alfa therapy. No predictors of IFN-induced graft injury could be identified. Shu et al28 treated 11 RT recipients with chronic HCV infection with ultra low-dose IFN alfa (1 ⫻ 10 U subcutaneously 3 ⫻ wk) plus ribavirin (600 mg/day) for 48 weeks. Despite the low dose of IFN used, acute graft failure developed in 1 patient. An SVR was obtained in 3 patients (27.3%). Tang et al29 treated 4 RT recipients with acute HCV infection with IFN plus ribavirin for 48 weeks, resulting in an SVR in 3 without inducing allograft dysfunction. Ribavirin monotherapy for HCV also has been explored in RT recipients. Fontaine et al30 treated 13 RT recipients with hepatic fibrosis with ribavirin alone for a
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mean monotherapy period of 22 months. Although transaminase levels decreased significantly there was no significant decrease in serum HCV RNA levels. Comparison of pretreatment and on-treatment biopsy specimens showed a significant decrease in necroinflammatory activity, with a trend toward a decrease in fibrosis. In contrast, Kamar et al31 evaluated ribavirin monotherapy prospectively in 16 RT recipients with 32 HCVpositive untreated controls. Although therapy resulted in a decrease in liver enzyme and serum creatinine levels and a lessening of proteinuria if present, no decrease in HCV viremia occurred. Hemoglobin levels decreased significantly despite recombinant erythropoietin therapy and in 3 cases ribavirin had to be stopped. No improvement in liver inflammation scores occurred and a significant progression of liver fibrosis was detected on repeat liver biopsy examination. The results of these various treatment regimens suggest that IFN therapy for HCV is effective in at least some RT recipients although at the risk of graft viability. As in other settings, ribavirin monotherapy for HCV has little or no role. IFN therapy at this time cannot be recommended for routine treatment of HCV after RT except in exceptional circumstances.
Hepatitis C Virus–Associated Glomerulonephritis An important indication for antiviral therapy in patients with HCV infection is to ameliorate extrahepatic manifestations including GN. A number of groups reported the use of IFN monotherapy in patients with cryoglobulinemia associated with HCV infection with features such as microscopic hematuria, hypertension, proteinuria, or mild-to-moderate renal failure.32,33 Antiviral response was accompanied typically by improvement in reduction in renal dysfunction but was limited to the duration of therapy. More recently, IFN plus ribavirin therapy has been described in HCV-associated cryoglobulinemic GN. In a series of 3 patients with HCV-related cryoglobulinemic GN who were treated with IFN-alfa and ribavirin for 12 months, all 3 patients achieved an SVR with improvement in clinical, biochemical, and histologic features. In contrast, some immunologic features, such as serum levels of C4 and rheumatoid factor activity, did not normalize.34 Early reports describing treatment with the pegylated IFNs for this form of GN indicated that SVR leads to long-term improvement of the glomerular disease.35,36
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Conclusions HCV is an important cause of decreased patient survival in patients with ESRD and limits recipient and graft survival after RT. IFN-based therapy is effective in patients on chronic HD with durable virologic responses even after subsequent RT and results in a reduction in graft GN. Ribavirin can be used cautiously in patients with ESRD in combination with IFN. The risk for graft rejection and possible loss remains a major deterrent to the use of IFN in RT recipients. At present, the identification and treatment of HCV in RT candidates is the most effective strategy to manage HCV in this population; longer-term strategies will involve further reducing the spread of HCV within dialysis units. Cryoglobulinemic GN associated with HCV improves with response to antiviral response and is an important albeit relatively uncommon indication for antiviral therapy.
References 1. Finelli L, Miller JT, Tokars JI, et al. National surveillance of dialysis-associated diseases in the United States, 2002. Semin Dial 2005;18:52– 61. 2. Fissell RB, Bragg-Gresham JL, Woods JD, et al. Patterns of HCV prevalence and seroconversion in hemodialysis units from three continents: the DOPPS Study. Kidney Int 2004;65:2335–2342. 3. Jadoul M, Poignet JL, Geddes C, et al. The changing epidemiology of hepatitis C virus (HCV) in hemodialysis: European multicenter study. Nephrol Dial Transplant 2004;19:904 –909. 4. Fabrizi F, Poordad FF, Martin P. Hepatitis C infection and the patient with end-stage renal disease. Hepatology 2002;36:3–10. 5. Marcelli D, Stannard D, Conte F, et al. ESRD patient mortality with adjustment for comorbid conditions in Lombardy (Italy) versus the United States. Kidney Int 1996;50:1013–1018. 6. Maisonneuve P, Agodoa L, Gellert R, et al. Cancer in patients on dialysis for end-stage renal disease: an international collaborative study. Lancet 1999;354:93–99. 7. Stehman-Breen CO, Emerson S, Gretch D, et al. Risk of death among chronic dialysis patients infected with hepatitis C virus. Am J Kidney Dis 1998;32:629 – 634. 8. Nakayama E, Akiba T, Marumo F, et al. Prognosis of anti-hepatitis C virus antibody-positive patients on regular hemodialysis therapy. J Am Soc Nephrol 2000;11:1896 –1902. 9. Fabrizi F, Martin P, Dixit V, et al. Meta-analysis: effect of hepatitis C virus infection on mortality in dialysis. Aliment Pharmacol Ther 2004;20:1271–1277. 10. Bloom RD, Sayer G, Fa K, et al. Outcome of hepatitis C virusinfected kidney transplant candidates who remain on the waiting list. Am J Transplant 2005;4:139 –144. 11. Fabrizi F, Dulai G, Dixit V, et al. Meta-analysis: interferon for the treatment of chronic hepatitis C in dialysis patients. Aliment Pharmacol Ther 2003;18:1071–1081. 12. Russo MW, Goldsweig CD, Jacobson IM, et al. 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. 13. Bruchfeld A, Stahle L, Andersson J, et al. Ribavirin treatment in dialysis patients with chronic hepatitis C virus infection—a pilot study. J Viral Hepat 2001;8:287–292. 14. Tan AC, Brouwer JT, Glue P, et al. Safety of interferon and ribavirin therapy in haemodialysis patients with chronic hepatitis C: results of a pilot study. Nephrol Dial Transplant 2001;16:193–195.
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15. Annicchiarico BE, Siciliano M. Pegylated interferon-alpha 2b monotherapy for haemodialysis patients with chronic hepatitis C. Aliment Pharmacol Ther 2004;20:123–124. 16. Sporea I, Sirli R, Golea O, et al. Peg-interferon alfa 2a (40kDa) in patients on chronic haemodialysis with chronic C hepatitis. Preliminary results. Rom J Gastroenterol 2004;13:99 –102. 17. Wolfe RA, Ashby VB, Milford E, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999;341:1725–1730. 18. Casanovas-Taltavull T, Baliellas C, Benasco C, et al. Efficacy of interferon for chronic hepatitis C virus-related hepatitis in kidney transplant candidates on hemodialysis: results after transplantation. Am J Gastroenterol 2001;96:1170 –1177. 19. Huraib S, Iqbal A, Tanimu D, et al. Sustained virological and histological response with pretransplant interferon therapy in renal transplant patients with chronic viral hepatitis C. Am J Nephrol 2001;21:435– 440. 20. Campistol JM, Esforzado N, Martinez J, et al. Efficacy and tolerance of interferon-alpha(2b) in the treatment of chronic hepatitis C virus infection in haemodialysis patients. Pre- and post-renal transplantation assessment. Nephrol Dial Transplant 1999;14: 2704 –2709. 21. Bunnapradist S, Fabrizi F, Vierling J, et al. Hepatitis C therapy with long term remission after renal transplantation. Int J Artif Organs 2002;25:1189 –1193. 22. Cruzado JM, Casanovas-Taltavull T, Torres J, et al. Pretransplant interferon prevents hepatitis C associated glomerulonephritis in renal allografts by HCV RNA clearance. Am J Transplant 2003;3: 357–360. 23. Legendre C, Garrigue V, Le Bihan C, et al. Harmful long term impact of hepatitis C virus infection in kidney transplant recipients. Transplantation 1998;65:667– 670. 24. Mathurin P, Mouquet C, Poynard T, et al. Impact of hepatitis B and C virus on kidney transplant outcome. Hepatology 1999;29: 257–263. 25. Fabrizi F, Martin P, Dixit V, et al. Hepatitis C virus antibody status and survival after renal transplant: meta-analysis of observational studies. Am J Transplant 2005;5:452– 461. 26. Kovarik J, Mayer G, Pokanta E, et al. Adverse effect of low dose
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27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
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prophylactic human recombinant leukocyte interferon-alpha in renal transplant recipients. Transplantation 1988;45:402– 405. Rostaing L, Izopet J, Baron E, et al. Treatment of chronic hepatitis C with recombinant interferon alpha in kidney transplant recipients. Transplantation 1995;59:1426 –1431. Shu KH, Lan JL, Wu MJ, et al. Ultralow-dose alpha-interferon plus ribavirin for the treatment of active hepatitis C in renal transplant recipients. Transplantation 2004;77:1894 –1896. Tang S, Cheng IK, Leung VK, et al. Successful treatment of hepatitis C after kidney transplantation with combined interferon alpha-2b and ribavirin. J Hepatol 2003;39:875– 878. Fontaine H, Vallet-Pichard A, Equi-Andrade C, et al. Histopathologic efficacy of ribavirin monotherapy in kidney allograft recipients with chronic hepatitis C. Transplantation 2004;78:853– 857. Kamar N, Sandres-Saune K, Selves J, et al. Long-term ribavirin therapy in hepatitis C virus-positive renal transplant patients: effects on renal function and liver histology. Am J Kidney Dis 2003;42:184 –192. Misiani R, Bellavita P, Fenili D, et al. Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 1994;330:751–756. Johnson RJ, Gretch DR, Couser WG, et al. Hepatitis C virusassociated glomerulonephritis. Effect of alpha-interferon therapy. Kidney Int 1994;46:1700 –1704. Rossi P, Bertani T, Baio P, et al. Hepatitis C virus-related cryoglobulinemic glomerulonephritis: long-term remission after antiviral therapy. Kidney Int 2003;63:2236 –2241. Alric L, Plaisier E, Thebault S, et al. Influence of antiviral therapy in HCV-associated cryoglobulinemia MPGN. Am J Kidney Dis 2004;43:617– 623. Mazzaro C, Zanel F, Caizzi M, et al. Treatment with pegylated interferon alpha 2b and ribavirin of HCV-associated mixed cryoglobulinemia: a pilot study. J Hepatol 2005;42:632– 636.
Address requests for reprints to: Paul Martin, MD, Box 1104, Mount Sinai School of Medicine, New York, New York 10029. e-mail: [email protected]; fax: (212) 996-9688. Dr Martin has been an Investigator and Consultant for Schering and Roche.
Treatment of Chronic Hepatitis C Infection in Patients With Renal Failure PAUL MARTIN* and FABRIZIO FABRIZI‡ *Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York; and ‡Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS, Milano, Italy
Patients with end-stage renal disease continue to have a high prevalence of hepatitis C virus infection despite screening of blood products and efforts to prevent the transmission of viral hepatitis within dialysis units. Although biochemical dysfunction often is absent in infected patients, an increased rate of mortality from liver disease has been observed in patients on long-term dialysis. In addition, hepatitis C–infected renal transplant recipients have diminished patient and graft survival rates compared with uninfected controls. Antiviral therapy with interferon in renal transplantation candidates has resulted in sustained viral responses that have been durable even after subsequent renal transplantation. Graft dysfunction remains a major concern, limiting the use of interferon after renal transplant. Ribavirin, which accumulates and cannot be removed by dialysis, and may induce hemolysis, generally has been avoided in patients with end-stage renal disease. In pilot studies, cautious use of reduced doses of ribavirin has been possible in this population with close monitoring of hematocrit levels and additional measures to enhance compensatory erythropoiesis.
atients with end-stage renal disease (ESRD) on renal replacement therapy, especially hemodialysis (HD), continue to have a high prevalence of hepatitis C virus (HCV) infection despite screening of blood products and precautions to prevent the spread of viral hepatitis in dialysis units. HCV infection in this population is notable for the frequent absence of biochemical dysfunction despite viremia and histologic activity. HCV infection now has been implicated clearly in diminished patient survival on chronic hemodialysis and patient and graft survival after renal transplantation (RT). A small but growing body of literature has described successful antiviral therapy with interferon (IFN) in patients with ESRD with rates of sustained virologic response (SVR) comparable with patients with normal renal function. Importantly, SVR is durable even after subsequent renal transplant and therapeutic immunosuppression. Major concern persists about IFN-induced renal graft loss, effectively limiting its routine use to the pretransplant setting.
P
Hepatitis C Virus in Dialysis Patients The prevalence of anti-HCV among patients undergoing regular HD in the United States was 7.8% in 2002.1 However, many centers have reported a decrease in HCV prevalence in recent years, reflecting a number of factors including diminished blood product requirement in patients with ESRD because of erythropoietin use, highly successful efforts to exclude blood donors with HCV infection, and increased attention to preventing HCV spread within dialysis units. In a multinational cohort, the Dialysis Outcomes and Practice Patterns Study, which included centers in the United States, Japan, and western Europe, the presence of highly trained staff in dialysis units predicted lower HCV infection rates, reflecting the importance of adherence to precautions to prevent the spread of HCV in this setting.2 Jadoul et al3 reported a 50% decrease in anti-HCV seropositivity in Belgian dialysis units, comparing the early to late 1990s with a similar trend in most other western European countries surveyed, although its prevalence remained high in eastern Europe. Routine third-generation serologic testing for HCV now accurately identifies infected hemodialysis patients, most of whom also are viremic by polymerase chain reaction; false-negative serologic testing had been more frequent with earlier-generation tests.4 Polymerase chain reaction and branched DNA assays also are reliable in these patients and may be useful especially in early detection of HCV infection before seroconversion has taken place. The natural history of HCV infection in the hemodialysis population is not well defined for a number of Abbreviations used in this paper: ESRD, end-stage renal disease; ETR, end treatment response; GN, glomerulonephritis; HCV, hepatitis C virus; HD, hemodialysis; IFN, interferon; RT, renal transplantation; SVR, sustained virologic response. © 2005 by the American Gastroenterological Association 1542-3565/05/$30.00 PII: 10.1053/S1542-3565(05)00710-X
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reasons.4 Hemodialysis patients, by virtue of their comorbidities, have diminished long-term survival rates, and with the typically slow progression of HCV infection its most serious consequences, most notably decompensated cirrhosis and hepatocellular carcinoma, may not evolve during the shortened life span of an HCV-infected patient maintained on HD. Serial liver biopsy examination data on adequate numbers of ESRD patients with HCV infection generally are not available to assess disease progression. Although liver disease is recognized infrequently in this population, there is information about the development of at least some complications of cirrhosis in dialysis patients. Data from the Case Mix Severity Special Study of the US Renal Data System and the Lombardy Dialysis and Transplant Registry suggested that although cirrhosis is infrequent in the dialysis population (2% in the United States, 1.5% in Lombardy), the death rate for dialysis patients with cirrhosis was 35% higher in comparison with those without cirrhosis.5 In addition, a multicenter study from the United States, Europe, Australia, and New Zealand showed that there is an excess of liver cancer in ESRD patients, most likely reflecting an increased prevalence of chronic viral hepatitis.6 In other single-center, prospective studies, the mortality rate was higher in anti–HCVpositive chronic HD patients compared with seronegative controls.7,8 A recent meta-analysis has confirmed that HCV-infected dialysis patients have a lower survival rate than uninfected patients on dialysis with chronic liver disease implicated in the worse outcomes.9 Combining data from more than 2000 patients on chronic hemodialysis, HCV infection was associated with a relative risk of mortality of 1.57 compared with uninfected patients with hepatocellular carcinoma and cirrhosis, which are more frequent causes of death in HCV-seropositive patients.9 HCV infection also has been implicated in the development of diabetes mellitus, which in turn may increase waiting list mortality in candidates for renal transplantation.10 Treatment of Hepatitis C Virus Infection in Dialysis Patients Despite the high prevalence of HCV infection in the hemodialysis population, indications for therapy remain ill defined. Concern about the ability of this population to tolerate IFN and more recently ribavirin has been a factor.
Interferon Therapy There are no large-scale studies of antiviral therapy for HCV in ESRD patients and much of the available
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 10
Table 1. Treatment of Chronic Hepatitis C Virus Infection in ESRD SVR rate, % IFN alfa Combination IFN alfa/ribavirin Pegylated IFN
33,12 3711 12.513 33.315
literature consists predominantly of small uncontrolled clinical trials of interferon monotherapy with at least some treated patients achieving an SVR (see Table 1). In a recent meta-analysis, 14 clinical trials were included, only 2 of which were controlled studies.11 The mean overall estimated SVR was 37% (95% confidence interval, 28 – 48), with a drop-out rate of 17% (95% confidence interval, 10 –28). The overall weighted estimate for SVR in patients with HCV genotype 1 was 30.6% (95% confidence interval, 20.9 – 48.0). In the minority of these trials (n ⫽ 5) using a more standard IFN regimen (3 MU, 3 ⫻ weekly, subcutaneous route), the overall mean estimate of SVR was 39% (95% confidence interval, 25–56). A meta-analysis performed by Russo et al12 included 11 studies of HCV therapy in dialysis patients with an overall SVR of 33%, and for those with genotype 1 an SVR of 26%. Thus, the literature on monotherapy for HCV in the ESRD population indicates that therapy may be at least as effective as in the nonuremic population, albeit with a high rate of treatment discontinuation because of side effects, perhaps in part reflecting delayed IFN clearance. As described later, excellent SVR rates are possible in renal transplant candidates.
Interferon Plus Ribavirin Therapy Ribavirin therapy enhances SVR rates when used in combination with IFN in patients with normal renal function. However, there has been considerable reluctance to use ribavirin in patients with ESRD mainly because it causes hemolytic anemia in a population already prone to anemia. Furthermore, ribavirin and its metabolites accumulate in renal failure and are not removed by dialysis. However, Bruchfeld et al13 provided information about its safe use in ESRD. They described the use of low-dose ribavirin, monitoring of plasma concentrations, and administration of high-dose erythropoietin to replete iron stores to aid in erythropoiesis. In a pilot study they treated 5 HCV-infected patients on regular HD and 1 patient on peritoneal dialysis with IFN alfa-2b plus ribavirin.13 IFN alfa-2b was given initially as monotherapy at a dose of 3 MU 3 times weekly after dialysis for 4 weeks; thereafter low-dose ribavirin was added, starting at 200 – 400 mg/day for 6 months. Five
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(83.3%) of 6 patients became HCV RNA negative during treatment, but 4 patients relapsed after treatment. Average daily doses of ribavirin were 170 –300 mg. Tan et al14 reported another small experience in preliminary form with on-treatment virologic response in 4 of 5 patients treated with IFN and ribavirin, although 2 patients required permanent withdrawal of ribavirin owing to anemia.
Pegylated Interferons Even less data are available yet on the role of the pegylated IFNs in patients with ESRD. Annicchiarico et al15 reported an SVR in 2 of 6 chronic HD patients with pegylated IFN alfa-2b monotherapy (12-wk course), with therapy being discontinued in 2 of these 6 patients because of anemia. Sporea et al,16 in another preliminary report, described an on-treatment response in 7 of 10 HD patients with HCV patients receiving pegylated IFN alfa-2a monotherapy in a dose of 180 mcg/wk for 48 weeks, with dose reduction necessary in 2 cases. SVR data were not provided. Interferon-Based Therapy in Dialysis Patients Before Renal Transplantation Despite the frequency of HCV in patients with ESRD, there is no consensus about which patients should be offered antiviral therapy. Renal transplant candidates are a more robust group than the dialysis population as a whole and would seem better able to tolerate treatment side effects.17 IFN therapy also has been attempted after RT, but its use has been implicated in severe renal graft dysfunction. Importantly, SVR in successfully treated renal candidates can be durable despite subsequent transplant and therapeutic immunosuppression. In a prospective study, 29 RT candidates maintained on chronic HD received IFN (3 MU, 3 ⫻ weekly for 6 months followed by 1.5 MU for an additional 6 months) with an SVR of 64.2%.18 Seven of 9 of these responders remained HCV RNA negative with a mean follow-up time of 41 months after subsequent renal transplant.18 Other investigators also have described SVR in this population with an absence of HCV viremia despite subsequent RT and therapeutic immunosuppression.19 –21 Another potential benefit of successful antiviral therapy is decreasing the risk for graft glomerulonephritis after renal transplant. Cruzado et al22 reported their experience in HCV-seropositive RT recipients. Only 1 of 15 recipients previously treated with IFN developed graft glomerulonephritis (GN) and that patient had not achieved an SVR with IFN. In contrast, 12 of 27 (44%) untreated viremic recipients suffered graft GN. Importantly, GN only occurred in viremic patients.
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Hepatitis C Virus in Renal Transplant Patients HCV infection has been confirmed as a factor in reduced patient and graft survival rates after RT.23 Mathurin et al,24 in a series of 834 RT recipients including 216 with anti-HCV antibody present, identified HCV seropositivity as a predictor of diminished 10-year survival. Only 65% of the HCV group were alive at 10 years compared with 80% of uninfected controls. Graft survival also was significantly poorer in the HCV group, 49% at 10 years compared with 69% in recipients without viral hepatitis. Many deaths were related to liver disease in the HCV group. In a recent meta-analysis HCV seropositivity also was confirmed as a predictor of increased mortality and graft failure in RT recipients.25 Treatment of Hepatitis C Virus Infection After Renal Transplantation There had been understandable reluctance to use IFN in RT recipients because of older reports of precipitation of graft dysfunction during therapy of cytomegalovirus infection.26 However, with increasing concern about the adverse consequences of HCV infection in the ESRD population, a number of groups have explored antiviral therapy in RT recipients. Rostaing et al27 reported a placebo-controlled study in which 14 cadaveric renal transplant recipients with chronic HCV infection received recombinant IFN alfa-2b (3 MU 3 ⫻ weekly for 6 mo) with 14 untreated controls. Patients had stable renal allograft function for at least 1 year before therapy. No patient had an SVR, although 4 (28%) patients had had an end treatment response (ETR). A more significant concern in the IFN-treated group was the development of graft dysfunction in 5 (35.7%) patients, 4 of whom received intravenous steroid pulses in response; serum creatinine levels decreased significantly only in 2 patients. One patient returned to dialysis within 4 months of IFN alfa therapy. No predictors of IFN-induced graft injury could be identified. Shu et al28 treated 11 RT recipients with chronic HCV infection with ultra low-dose IFN alfa (1 ⫻ 10 U subcutaneously 3 ⫻ wk) plus ribavirin (600 mg/day) for 48 weeks. Despite the low dose of IFN used, acute graft failure developed in 1 patient. An SVR was obtained in 3 patients (27.3%). Tang et al29 treated 4 RT recipients with acute HCV infection with IFN plus ribavirin for 48 weeks, resulting in an SVR in 3 without inducing allograft dysfunction. Ribavirin monotherapy for HCV also has been explored in RT recipients. Fontaine et al30 treated 13 RT recipients with hepatic fibrosis with ribavirin alone for a
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mean monotherapy period of 22 months. Although transaminase levels decreased significantly there was no significant decrease in serum HCV RNA levels. Comparison of pretreatment and on-treatment biopsy specimens showed a significant decrease in necroinflammatory activity, with a trend toward a decrease in fibrosis. In contrast, Kamar et al31 evaluated ribavirin monotherapy prospectively in 16 RT recipients with 32 HCVpositive untreated controls. Although therapy resulted in a decrease in liver enzyme and serum creatinine levels and a lessening of proteinuria if present, no decrease in HCV viremia occurred. Hemoglobin levels decreased significantly despite recombinant erythropoietin therapy and in 3 cases ribavirin had to be stopped. No improvement in liver inflammation scores occurred and a significant progression of liver fibrosis was detected on repeat liver biopsy examination. The results of these various treatment regimens suggest that IFN therapy for HCV is effective in at least some RT recipients although at the risk of graft viability. As in other settings, ribavirin monotherapy for HCV has little or no role. IFN therapy at this time cannot be recommended for routine treatment of HCV after RT except in exceptional circumstances.
Hepatitis C Virus–Associated Glomerulonephritis An important indication for antiviral therapy in patients with HCV infection is to ameliorate extrahepatic manifestations including GN. A number of groups reported the use of IFN monotherapy in patients with cryoglobulinemia associated with HCV infection with features such as microscopic hematuria, hypertension, proteinuria, or mild-to-moderate renal failure.32,33 Antiviral response was accompanied typically by improvement in reduction in renal dysfunction but was limited to the duration of therapy. More recently, IFN plus ribavirin therapy has been described in HCV-associated cryoglobulinemic GN. In a series of 3 patients with HCV-related cryoglobulinemic GN who were treated with IFN-alfa and ribavirin for 12 months, all 3 patients achieved an SVR with improvement in clinical, biochemical, and histologic features. In contrast, some immunologic features, such as serum levels of C4 and rheumatoid factor activity, did not normalize.34 Early reports describing treatment with the pegylated IFNs for this form of GN indicated that SVR leads to long-term improvement of the glomerular disease.35,36
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Conclusions HCV is an important cause of decreased patient survival in patients with ESRD and limits recipient and graft survival after RT. IFN-based therapy is effective in patients on chronic HD with durable virologic responses even after subsequent RT and results in a reduction in graft GN. Ribavirin can be used cautiously in patients with ESRD in combination with IFN. The risk for graft rejection and possible loss remains a major deterrent to the use of IFN in RT recipients. At present, the identification and treatment of HCV in RT candidates is the most effective strategy to manage HCV in this population; longer-term strategies will involve further reducing the spread of HCV within dialysis units. Cryoglobulinemic GN associated with HCV improves with response to antiviral response and is an important albeit relatively uncommon indication for antiviral therapy.
References 1. Finelli L, Miller JT, Tokars JI, et al. National surveillance of dialysis-associated diseases in the United States, 2002. Semin Dial 2005;18:52– 61. 2. Fissell RB, Bragg-Gresham JL, Woods JD, et al. Patterns of HCV prevalence and seroconversion in hemodialysis units from three continents: the DOPPS Study. Kidney Int 2004;65:2335–2342. 3. Jadoul M, Poignet JL, Geddes C, et al. The changing epidemiology of hepatitis C virus (HCV) in hemodialysis: European multicenter study. Nephrol Dial Transplant 2004;19:904 –909. 4. Fabrizi F, Poordad FF, Martin P. Hepatitis C infection and the patient with end-stage renal disease. Hepatology 2002;36:3–10. 5. Marcelli D, Stannard D, Conte F, et al. ESRD patient mortality with adjustment for comorbid conditions in Lombardy (Italy) versus the United States. Kidney Int 1996;50:1013–1018. 6. Maisonneuve P, Agodoa L, Gellert R, et al. Cancer in patients on dialysis for end-stage renal disease: an international collaborative study. Lancet 1999;354:93–99. 7. Stehman-Breen CO, Emerson S, Gretch D, et al. Risk of death among chronic dialysis patients infected with hepatitis C virus. Am J Kidney Dis 1998;32:629 – 634. 8. Nakayama E, Akiba T, Marumo F, et al. Prognosis of anti-hepatitis C virus antibody-positive patients on regular hemodialysis therapy. J Am Soc Nephrol 2000;11:1896 –1902. 9. Fabrizi F, Martin P, Dixit V, et al. Meta-analysis: effect of hepatitis C virus infection on mortality in dialysis. Aliment Pharmacol Ther 2004;20:1271–1277. 10. Bloom RD, Sayer G, Fa K, et al. Outcome of hepatitis C virusinfected kidney transplant candidates who remain on the waiting list. Am J Transplant 2005;4:139 –144. 11. Fabrizi F, Dulai G, Dixit V, et al. Meta-analysis: interferon for the treatment of chronic hepatitis C in dialysis patients. Aliment Pharmacol Ther 2003;18:1071–1081. 12. Russo MW, Goldsweig CD, Jacobson IM, et al. 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. 13. Bruchfeld A, Stahle L, Andersson J, et al. Ribavirin treatment in dialysis patients with chronic hepatitis C virus infection—a pilot study. J Viral Hepat 2001;8:287–292. 14. Tan AC, Brouwer JT, Glue P, et al. Safety of interferon and ribavirin therapy in haemodialysis patients with chronic hepatitis C: results of a pilot study. Nephrol Dial Transplant 2001;16:193–195.
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15. Annicchiarico BE, Siciliano M. Pegylated interferon-alpha 2b monotherapy for haemodialysis patients with chronic hepatitis C. Aliment Pharmacol Ther 2004;20:123–124. 16. Sporea I, Sirli R, Golea O, et al. Peg-interferon alfa 2a (40kDa) in patients on chronic haemodialysis with chronic C hepatitis. Preliminary results. Rom J Gastroenterol 2004;13:99 –102. 17. Wolfe RA, Ashby VB, Milford E, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999;341:1725–1730. 18. Casanovas-Taltavull T, Baliellas C, Benasco C, et al. Efficacy of interferon for chronic hepatitis C virus-related hepatitis in kidney transplant candidates on hemodialysis: results after transplantation. Am J Gastroenterol 2001;96:1170 –1177. 19. Huraib S, Iqbal A, Tanimu D, et al. Sustained virological and histological response with pretransplant interferon therapy in renal transplant patients with chronic viral hepatitis C. Am J Nephrol 2001;21:435– 440. 20. Campistol JM, Esforzado N, Martinez J, et al. Efficacy and tolerance of interferon-alpha(2b) in the treatment of chronic hepatitis C virus infection in haemodialysis patients. Pre- and post-renal transplantation assessment. Nephrol Dial Transplant 1999;14: 2704 –2709. 21. Bunnapradist S, Fabrizi F, Vierling J, et al. Hepatitis C therapy with long term remission after renal transplantation. Int J Artif Organs 2002;25:1189 –1193. 22. Cruzado JM, Casanovas-Taltavull T, Torres J, et al. Pretransplant interferon prevents hepatitis C associated glomerulonephritis in renal allografts by HCV RNA clearance. Am J Transplant 2003;3: 357–360. 23. Legendre C, Garrigue V, Le Bihan C, et al. Harmful long term impact of hepatitis C virus infection in kidney transplant recipients. Transplantation 1998;65:667– 670. 24. Mathurin P, Mouquet C, Poynard T, et al. Impact of hepatitis B and C virus on kidney transplant outcome. Hepatology 1999;29: 257–263. 25. Fabrizi F, Martin P, Dixit V, et al. Hepatitis C virus antibody status and survival after renal transplant: meta-analysis of observational studies. Am J Transplant 2005;5:452– 461. 26. Kovarik J, Mayer G, Pokanta E, et al. Adverse effect of low dose
TREATMENT OF CHRONIC HEPATITIS C INFECTION
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
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prophylactic human recombinant leukocyte interferon-alpha in renal transplant recipients. Transplantation 1988;45:402– 405. Rostaing L, Izopet J, Baron E, et al. Treatment of chronic hepatitis C with recombinant interferon alpha in kidney transplant recipients. Transplantation 1995;59:1426 –1431. Shu KH, Lan JL, Wu MJ, et al. Ultralow-dose alpha-interferon plus ribavirin for the treatment of active hepatitis C in renal transplant recipients. Transplantation 2004;77:1894 –1896. Tang S, Cheng IK, Leung VK, et al. Successful treatment of hepatitis C after kidney transplantation with combined interferon alpha-2b and ribavirin. J Hepatol 2003;39:875– 878. Fontaine H, Vallet-Pichard A, Equi-Andrade C, et al. Histopathologic efficacy of ribavirin monotherapy in kidney allograft recipients with chronic hepatitis C. Transplantation 2004;78:853– 857. Kamar N, Sandres-Saune K, Selves J, et al. Long-term ribavirin therapy in hepatitis C virus-positive renal transplant patients: effects on renal function and liver histology. Am J Kidney Dis 2003;42:184 –192. Misiani R, Bellavita P, Fenili D, et al. Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 1994;330:751–756. Johnson RJ, Gretch DR, Couser WG, et al. Hepatitis C virusassociated glomerulonephritis. Effect of alpha-interferon therapy. Kidney Int 1994;46:1700 –1704. Rossi P, Bertani T, Baio P, et al. Hepatitis C virus-related cryoglobulinemic glomerulonephritis: long-term remission after antiviral therapy. Kidney Int 2003;63:2236 –2241. Alric L, Plaisier E, Thebault S, et al. Influence of antiviral therapy in HCV-associated cryoglobulinemia MPGN. Am J Kidney Dis 2004;43:617– 623. Mazzaro C, Zanel F, Caizzi M, et al. Treatment with pegylated interferon alpha 2b and ribavirin of HCV-associated mixed cryoglobulinemia: a pilot study. J Hepatol 2005;42:632– 636.
Address requests for reprints to: Paul Martin, MD, Box 1104, Mount Sinai School of Medicine, New York, New York 10029. e-mail: [email protected]; fax: (212) 996-9688. Dr Martin has been an Investigator and Consultant for Schering and Roche.