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• W2051259076 abstract "Commentary on Liu CH, Huang CF, Liu CJ, et al. Pegylated interferon-α2a with or without low-dose ribavirin for treatment-naive patients with hepatitis C virus genotype 1 receiving hemodialysis: a randomized trial. Ann Intern Med. 2013;159(11):729-738. The worldwide hepatitis C virus (HCV) epidemic has received great attention in recent years and HCV treatment has been the subject of numerous recent trials of novel agents with the goal of eradicating the virus.1Liang T.J. Ghany M.G. Current and future therapies for hepatitis C virus infection.N Engl J Med. 2013; 368: 1907-1917Crossref PubMed Scopus (366) Google Scholar As is often the case, due to multiple comorbid conditions and altered drug pharmacokinetics, patients with kidney failure have been excluded from most trials, thus leading to a significant lag time before new therapeutics are introduced to the populations managed by nephrologists. This is particularly unfortunate in the case of HCV because a disproportionate number of patients undergoing hemodialysis (HD) are HCV infected, estimated at 13.5% of HD patients in developed countries.2Fissell R.B. Bragg-Gresham J.L. Woods J.D. et al.Patterns of hepatitis C prevalence and seroconversion in hemodialysis units from three continents: the DOPPS.Kidney Int. 2004; 65: 2335-2342Crossref PubMed Scopus (351) Google Scholar Moreover, despite the assumption that HD patients are less likely to achieve viral eradication than non-HD patients, the majority of evidence to date suggests the converse. Of HD patients treated with the older regimen of interferon monotherapy, 37%-41% achieve a sustained virologic response (SVR),3Gordon C.E. Uhlig K. Lau J. Schmid C.H. Levey A.S. Wong J.B. Interferon treatment in hemodialysis patients with chronic hepatitis C virus infection: a systematic review of the literature and meta-analysis of treatment efficacy and harms.Am J Kidney Dis. 2008; 51: 263-277Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 4Fabrizi F. Dulai G. Dixit V. Bunnapradist S. Martin P. Meta-analysis: interferon for the treatment of chronic hepatitis C in dialysis patients.Aliment Pharmacol Ther. 2003; 18: 1071-1081Crossref PubMed Scopus (138) Google Scholar the accepted surrogate outcome for successful treatment and a rate significantly higher than the 9%-22% observed in non-HD patients.5McHutchison J.G. Gordon S.C. Schiff E.R. et al.Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group.N Engl J Med. 1998; 339: 1485-1492Crossref PubMed Scopus (3351) Google Scholar, 6Poynard T. Marcellin P. Lee S.S. et al.Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT).Lancet. 1998; 352: 1426-1432Abstract Full Text Full Text PDF PubMed Scopus (2400) Google Scholar, 7Zeuzem S. Teuber G. Naumann U. et al.Randomized, double-blind, placebo-controlled trial of interferon alfa2a with and without amantadine as initial treatment for chronic hepatitis C.Hepatology. 2000; 32: 835-841Crossref PubMed Scopus (83) Google Scholar Similar rates of SVR are achieved with pegylated interferon monotherapy in HD patients,3Gordon C.E. Uhlig K. Lau J. Schmid C.H. Levey A.S. Wong J.B. Interferon treatment in hemodialysis patients with chronic hepatitis C virus infection: a systematic review of the literature and meta-analysis of treatment efficacy and harms.Am J Kidney Dis. 2008; 51: 263-277Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 8Liu C.H. Liang C.C. Lin J.W. et al.Pegylated interferon alpha-2a versus standard interferon alpha-2a for treatment-naive dialysis patients with chronic hepatitis C: a randomised study.Gut. 2008; 57: 525-530Crossref PubMed Scopus (65) Google Scholar, 9Russo M.W. Ghalib R. Sigal S. Joshi V. Randomized trial of pegylated interferon alpha-2b monotherapy in haemodialysis patients with chronic hepatitis C.Nephrol Dial Transplant. 2006; 21: 437-443Crossref PubMed Scopus (81) Google Scholar, 10Kose S. Gurkan A. Akman F. Kelesoglu M. Uner U. Treatment of hepatitis C in hemodialysis patients using pegylated interferon alpha-2a in Turkey.J Gastroenterol. 2009; 44: 353-358Crossref PubMed Scopus (15) Google Scholar, 11Covic A. Maftei I.D. Mardare N.G. et al.Analysis of safety and efficacy of pegylated-interferon alpha-2a in hepatitis C virus positive hemodialysis patients: results from a large, multicenter audit.J Nephrol. 2006; 19: 794-801PubMed Google Scholar but to date, only small cohort studies have looked at combination pegylated interferon and ribavirin,12Bruchfeld A. Lindahl K. Reichard O. Carlsson T. Schvarcz R. Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients.J Viral Hepat. 2006; 13: 316-321Crossref PubMed Scopus (126) Google Scholar, 13Rendina M. Schena A. Castellaneta N.M. et al.The treatment of chronic hepatitis C with peginterferon alfa-2a (40 kDa) plus ribavirin in haemodialysed patients awaiting renal transplant.J Hepatol. 2007; 46: 768-774Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 14Carriero D. Fabrizi F. Uriel A.J. Park J. Martin P. Dieterich D.T. Treatment of dialysis patients with chronic hepatitis C using pegylated interferon and low-dose ribavirin.Int J Artif Organs. 2008; 31: 295-302PubMed Google Scholar, 15van Leusen R. Adang R.P. de Vries R.A. et al.Pegylated interferon alfa-2a (40 kD) and ribavirin in haemodialysis patients with chronic hepatitis C.Nephrol Dial Transplant. 2008; 23: 721-725Crossref PubMed Scopus (64) Google Scholar the gold-standard treatment regimen prior to the recent development of direct-acting antiviral agents. Clinicians have been reluctant to use ribavirin in patients with chronic kidney disease (CKD) and HD patients because of concerns about high rates of ribavirin-induced hemolytic anemia due to its kidney clearance despite SVR rates being higher in these studies. A recent publication in the Annals of Internal Medicine described the largest experience worldwide with combination pegylated interferon and ribavirin treatment in HCV-infected HD patients.16Liu C.H. Huang C.F. Liu C.J. et al.Pegylated interferon-alpha2a with or without low-dose ribavirin for treatment-naive patients with hepatitis C virus genotype 1 receiving hemodialysis: a randomized trial.Ann Intern Med. 2013; 159: 729-738Crossref PubMed Scopus (78) Google Scholar The study was a multicenter, open-label, randomized, controlled trial in Taiwan of 205 HCV-infected treatment-naive patients undergoing HD. Notably, the investigators treated patients with only HCV genotype 1, the least likely to respond to therapy.1Liang T.J. Ghany M.G. Current and future therapies for hepatitis C virus infection.N Engl J Med. 2013; 368: 1907-1917Crossref PubMed Scopus (366) Google Scholar Patients were randomly assigned to treatment with pegylated interferon and ribavirin versus pegylated interferon monotherapy for 48 weeks, the standard duration for HCV genotype 1. Dosing for pegylated interferon-α2a was 135 μg weekly, and for ribavirin, was 200 mg daily, both reduced compared to the general population, but typical for studies of HD patients. The SVR with pegylated interferon monotherapy was 33%, comparable to rates in prior meta-analyses,3Gordon C.E. Uhlig K. Lau J. Schmid C.H. Levey A.S. Wong J.B. Interferon treatment in hemodialysis patients with chronic hepatitis C virus infection: a systematic review of the literature and meta-analysis of treatment efficacy and harms.Am J Kidney Dis. 2008; 51: 263-277Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar whereas the SVR with pegylated interferon and ribavirin was 64% (P < 0.001 for difference). The benefit of combination therapy was observed across prespecified subgroups separated by baseline viral load, patient sex, and degree of cirrhosis. The relationship between each of these factors and SVR was consistent with previous studies of predictors of SVR.1Liang T.J. Ghany M.G. Current and future therapies for hepatitis C virus infection.N Engl J Med. 2013; 368: 1907-1917Crossref PubMed Scopus (366) Google Scholar, 17Gordon C.E. Uhlig K. Lau J. Schmid C.H. Levey A.S. Wong J.B. Interferon for hepatitis C virus in hemodialysis—an individual patient meta-analysis of factors associated with sustained virological response.Clin J Am Soc Nephrol. 2009; 4: 1449-1458Crossref PubMed Scopus (27) Google Scholar To date, studies of interferon or pegylated interferon monotherapy in patients undergoing HD have consistently demonstrated higher SVR rates than seen in the general population. However, only one-third of patients will achieve an SVR with these treatments, a relatively low rate for a long treatment course with high toxicity. The experience with combination pegylated interferon and ribavirin treatment in HD patients suggests higher SVR rates than with monotherapy, but previously was limited to small observational studies.12Bruchfeld A. Lindahl K. Reichard O. Carlsson T. Schvarcz R. Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients.J Viral Hepat. 2006; 13: 316-321Crossref PubMed Scopus (126) Google Scholar, 13Rendina M. Schena A. Castellaneta N.M. et al.The treatment of chronic hepatitis C with peginterferon alfa-2a (40 kDa) plus ribavirin in haemodialysed patients awaiting renal transplant.J Hepatol. 2007; 46: 768-774Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 14Carriero D. Fabrizi F. Uriel A.J. Park J. Martin P. Dieterich D.T. Treatment of dialysis patients with chronic hepatitis C using pegylated interferon and low-dose ribavirin.Int J Artif Organs. 2008; 31: 295-302PubMed Google Scholar, 15van Leusen R. Adang R.P. de Vries R.A. et al.Pegylated interferon alfa-2a (40 kD) and ribavirin in haemodialysis patients with chronic hepatitis C.Nephrol Dial Transplant. 2008; 23: 721-725Crossref PubMed Scopus (64) Google Scholar Liu et al16Liu C.H. Huang C.F. Liu C.J. et al.Pegylated interferon-alpha2a with or without low-dose ribavirin for treatment-naive patients with hepatitis C virus genotype 1 receiving hemodialysis: a randomized trial.Ann Intern Med. 2013; 159: 729-738Crossref PubMed Scopus (78) Google Scholar have demonstrated an SVR rate of 64% with combination therapy despite all patients having HCV genotype 1. The high SVR rate is consistent with earlier studies of combination therapy in HD patients12Bruchfeld A. Lindahl K. Reichard O. Carlsson T. Schvarcz R. Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients.J Viral Hepat. 2006; 13: 316-321Crossref PubMed Scopus (126) Google Scholar, 13Rendina M. Schena A. Castellaneta N.M. et al.The treatment of chronic hepatitis C with peginterferon alfa-2a (40 kDa) plus ribavirin in haemodialysed patients awaiting renal transplant.J Hepatol. 2007; 46: 768-774Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 14Carriero D. Fabrizi F. Uriel A.J. Park J. Martin P. Dieterich D.T. Treatment of dialysis patients with chronic hepatitis C using pegylated interferon and low-dose ribavirin.Int J Artif Organs. 2008; 31: 295-302PubMed Google Scholar, 15van Leusen R. Adang R.P. de Vries R.A. et al.Pegylated interferon alfa-2a (40 kD) and ribavirin in haemodialysis patients with chronic hepatitis C.Nephrol Dial Transplant. 2008; 23: 721-725Crossref PubMed Scopus (64) Google Scholar and higher than the 45%-56% observed for the same regimen in non-HD patients with HCV genotype 1.18Fried M.W. Shiffman M.L. Reddy K.R. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5884) Google Scholar, 19Manns M.P. McHutchison J.G. Gordon S.C. et al.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5902) Google Scholar However, these results should be interpreted with caution in terms of their applicability to HD populations in other nations because the patients in this study had high frequencies of the T/T genotype of interleukin 28B (ie, homozygous for thymine at the site specified by the single-nucleotide polymorphism identifier rs8099917), which is associated with high SVR rates1Liang T.J. Ghany M.G. Current and future therapies for hepatitis C virus infection.N Engl J Med. 2013; 368: 1907-1917Crossref PubMed Scopus (366) Google Scholar and is more common in patients of Asian ancestry.16Liu C.H. Huang C.F. Liu C.J. et al.Pegylated interferon-alpha2a with or without low-dose ribavirin for treatment-naive patients with hepatitis C virus genotype 1 receiving hemodialysis: a randomized trial.Ann Intern Med. 2013; 159: 729-738Crossref PubMed Scopus (78) Google Scholar Moreover, patients had a relatively low mean body mass index of 22.5 kg/m2, also a predictor of SVR.1Liang T.J. Ghany M.G. Current and future therapies for hepatitis C virus infection.N Engl J Med. 2013; 368: 1907-1917Crossref PubMed Scopus (366) Google Scholar Finally, the 7% rate of treatment discontinuation due to adverse events with combination therapy was lower than in prior studies, an important observation because completing the intended treatment course is an important predictor of SVR.17Gordon C.E. Uhlig K. Lau J. Schmid C.H. Levey A.S. Wong J.B. Interferon for hepatitis C virus in hemodialysis—an individual patient meta-analysis of factors associated with sustained virological response.Clin J Am Soc Nephrol. 2009; 4: 1449-1458Crossref PubMed Scopus (27) Google Scholar All these factors raise questions about the generalizability of these findings to HD patients worldwide. Nevertheless, several hypotheses exist for why HD patients have a more favorable response to HCV treatment. First, although interferon and ribavirin dosing are reduced in HD patients, plasma drug levels likely are higher, possibly explaining the high SVR and adverse-event rates.3Gordon C.E. Uhlig K. Lau J. Schmid C.H. Levey A.S. Wong J.B. Interferon treatment in hemodialysis patients with chronic hepatitis C virus infection: a systematic review of the literature and meta-analysis of treatment efficacy and harms.Am J Kidney Dis. 2008; 51: 263-277Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 17Gordon C.E. Uhlig K. Lau J. Schmid C.H. Levey A.S. Wong J.B. Interferon for hepatitis C virus in hemodialysis—an individual patient meta-analysis of factors associated with sustained virological response.Clin J Am Soc Nephrol. 2009; 4: 1449-1458Crossref PubMed Scopus (27) Google Scholar This phenomenon also may explain the observed higher SVR rates in women17Gordon C.E. Uhlig K. Lau J. Schmid C.H. Levey A.S. Wong J.B. Interferon for hepatitis C virus in hemodialysis—an individual patient meta-analysis of factors associated with sustained virological response.Clin J Am Soc Nephrol. 2009; 4: 1449-1458Crossref PubMed Scopus (27) Google Scholar and individuals with low body mass index.1Liang T.J. Ghany M.G. Current and future therapies for hepatitis C virus infection.N Engl J Med. 2013; 368: 1907-1917Crossref PubMed Scopus (366) Google Scholar Additionally, pretreatment HCV RNA levels, a powerful predictor of SVR, generally are lower in HD patients compared with the general population,1Liang T.J. Ghany M.G. Current and future therapies for hepatitis C virus infection.N Engl J Med. 2013; 368: 1907-1917Crossref PubMed Scopus (366) Google Scholar, 17Gordon C.E. Uhlig K. Lau J. Schmid C.H. Levey A.S. Wong J.B. Interferon for hepatitis C virus in hemodialysis—an individual patient meta-analysis of factors associated with sustained virological response.Clin J Am Soc Nephrol. 2009; 4: 1449-1458Crossref PubMed Scopus (27) Google Scholar possibly due to endogenous interferon production caused by the chronic inflammation of kidney failure20Badalamenti S. Catania A. Lunghi G. et al.Changes in viremia and circulating interferon-alpha during hemodialysis in hepatitis C virus-positive patients: only coincidental phenomena?.Am J Kidney Dis. 2003; 42: 143-150Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar or HCV adsorption onto the dialyzer membrane.21Mizuno M. Higuchi T. Yanai M. Kanmatsuse K. Esumi M. Dialysis-membrane-dependent reduction and adsorption of circulating hepatitis C virus during hemodialysis.Nephron. 2002; 91: 235-242Crossref PubMed Scopus (34) Google Scholar This study adds to the evidence base suggesting that the previously high threshold for treating HCV-infected HD patients should be lowered, particularly for HD patients with few comorbid conditions and those who are candidates for kidney transplantation.22Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease.Kidney Int Suppl. 2008; 109: S1-S99PubMed Google Scholar However, caution is necessary because of ribavirin-induced hemolytic anemia and other treatment-related toxicities. This study and the earlier studies of combination therapy support the safety of low-dose ribavirin with careful anemia monitoring. Ribavirin dosing in studies of HD patients varied from 200 mg 3 times weekly to 200 mg daily, with anemia managed using erythropoiesis-stimulating agents. Nephrologists managing HCV-infected HD patients who are treatment candidates should work closely with hepatologists to co-manage these patients so the burden of close observation for treatment-related adverse events is shared. Perhaps there is an advantage here because nephrologists typically see HD patients several times per month in addition to the close observation afforded by HD nurses, who can become partners in managing HCV treatment. However, currently, only a small proportion of HCV-infected HD patients are treated with interferon or ribavirin.23Goodkin D.A. Bieber B. Gillespie B. Robinson B.M. Jadoul M. Hepatitis C infection is very rarely treated among hemodialysis patients.Am J Nephrol. 2013; 38: 405-412Crossref PubMed Scopus (121) Google Scholar Future research in this area should seek to confirm or refute the findings in this study and understand the mechanisms behind the higher SVR rates in HD patients. In addition, there are a number of agents newly approved by the US Food and Drug Administration to treat HCV that, although only now starting to become available, have been studied infrequently in HD patients. A small case series from France was the first to describe a regimen of pegylated interferon, ribavirin, and the protease inhibitor telaprevir, in which 3 of 4 patients achieved SVR and the only reported adverse event was anemia attributed to ribavirin and managed with increasing doses of an erythropoiesis-stimulating agent.24Dumortier J. Guillaud O. Gagnieu M.C. et al.Anti-viral triple therapy with telaprevir in haemodialysed HCV patients: is it feasible?.J Clin Virol. 2013; 56: 146-149Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar Meanwhile, the armamentarium of HCV treatments is growing at a rapid pace and newer agents such as sofosbuvir, a nucleotide polymerase inhibitor, have shown great efficacy in non-HD patients, with SVR rates > 90% in some populations.25Lawitz E. Mangia A. Wyles D. et al.Sofosbuvir for previously untreated chronic hepatitis C infection.N Engl J Med. 2013; 368: 1878-1887Crossref PubMed Scopus (1428) Google Scholar However, sofosbuvir is renally cleared, is minimally cleared by dialysis, and cannot be recommended in patients with CKD stages 4-5. However, as more novel treatments with different mechanisms of actions and pharmacokinetics become available, they will require study in patients with kidney failure. Finally, HCV treatment has been studied infrequently in patients with earlier stages of CKD, including kidney transplant recipients. The long-held belief that interferon treatment in kidney transplant recipients is associated with an unacceptably high rate of transplant loss from acute rejection22Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease.Kidney Int Suppl. 2008; 109: S1-S99PubMed Google Scholar has been challenged recently in a study of 32 kidney transplant recipients treated with pegylated interferon and ribavirin, of whom 38% achieved SVR with no acute rejection episodes in the 16 patients who underwent biopsy.26Sanai F.M. Mousa D. Al-Mdani A. et al.Safety and efficacy of peginterferon-alpha2a plus ribavirin treatment in renal transplant recipients with chronic hepatitis C.J Hepatol. 2013; 58: 1096-1103Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar This finding requires confirmation, although perhaps as new agents are developed, we may be able to treat kidney transplant recipients with interferon-free protocols. There still is a paucity of data available for HCV treatment in patients with CKD, a somewhat surprising omission given the high prevalence of HCV infection.27Butt A.A. Wang X. Fried L.F. HCV infection and the incidence of CKD.Am J Kidney Dis. 2011; 57: 396-402Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Given the consistent observation of high SVR rates in HD patients, perhaps this also would be seen in earlier stages of CKD. Regardless, the future of HCV treatment in the general population, as well as in patients with CKD, looks increasingly promising. Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests." @default.
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• W2051259076 title "Hepatitis C Treatment in Dialysis Patients: Is a New Dawn Approaching?" @default.
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