Forewarned is forearmed
Authors: Stefan Zeuzem
Journal: Journal of Hepatology (2009)

Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis CJournal of HepatologyVol. 51Issue 4PreviewWhile several risk factors for the histological progression of chronic hepatitis C have been identified, the contribution of HCV genotypes to liver fibrosis evolution remains controversial. The aim of this study was to assess independent predictors for fibrosis progression. Full-Text PDF The hepatitis C virus comprises 6 genotypes and more than 100 subtypes. While differences in the virologic response rates to peginterferon alfa plus ribavirin combination therapy are well established, less evidence has been accumulated regarding whether HCV genotypes are associated with differences in the natural course of disease. No clinically relevant differences with respect to symptoms and extrahepatitic manifestations of chronic hepatitis C according to HCV genotypes are reported. The published data on the impact of HCV genotypes on fibrosis progression rates, development of cirrhosis, and the risk for hepatocellular carcinoma are somewhat conflicting leading to the overall perception that clinically relevant differences are non-existant. Studies on the possible association of HCV genotype with the fibrosis progression rates are complicated by confounding factors, e.g. by the fact that HCV-1b infected patients in several regions are older than HCV-1a and HCV-3a infected patients and typically show substantial differences with respect to transmission risk factors [1Seeff L.B. The natural history of chronic hepatitis C virus infection.Clin Liver Dis. 1997; 1: 587-602Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 2Lauer G.M. Walker B.D. Hepatitis C virus infection.N Engl J Med. 2001; 345: 41-52Crossref PubMed Scopus (2474) Google Scholar, 3Zeuzem S. Teuber G. Lee J.H. Rüster B. Roth W.K. Risk factors for the transmission of hepatitis C.J Hepatol. 1996; 24: S3-S10PubMed Google Scholar].The study by Bochud et al. [[4]Bochud P.-Y. Cai T. Overbeck K. Bochud M. Dufour J-F. Müllhaupt B. et al.Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C.J Hepatol. 2009; 51: 655-666Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar] is one of the largest data sets on the association of HCV genotypes and fibrosis progression rates. The data of this study indicate a faster fibrosis progression rate in patients infected with HCV genotype 3 compared with patients infected with HCV genotype 1, supporting some previous smaller studies which showed a similar trend [5Poynard T. Bedossa P. Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups.Lancet. 1997; 349: 825-832Abstract Full Text Full Text PDF PubMed Scopus (2755) Google Scholar, 6Adinolfi L.E. Gambardella M. Andreana A. Tripodi M.F. Utili R. Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity.Hepatology. 2001; 33: 1358-1364Crossref PubMed Scopus (949) Google Scholar].The methodology of the study by Bochud et al. is sound since the authors used both a stage-constant and a stage-specific estimation of fibrosis progression rates according to different HCV genotypes, together with cumulative incidence curves. The concordant observation that HCV genotype 3 was associated with accelerated fibrosis both in stage-specific and stage-constant fibrosis rate estimates in a large cohort of well-characterized patients make the data appear robust. A possible limitation of the study as outlined in the discussion of the paper [[4]Bochud P.-Y. Cai T. Overbeck K. Bochud M. Dufour J-F. Müllhaupt B. et al.Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C.J Hepatol. 2009; 51: 655-666Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar] is the fact that the estimated duration of infection was based on the first event at risk, which may not be accurate. Furthermore, biopsy specimens were not read by a central pathologist and the authors cannot rule out other confounding factors, e.g. that patients infected with HCV genotype 3 infection may have had a higher exposure to liver-toxic agents beyond alcohol (e.g. continuous use of illicit drugs). Thus, some concerns remain as in most studies with a cross-sectional design, and the data should be confirmed in other cohorts and if at all possible in prospectively designed trials.What are the practical consequences if indeed fibrosis progression rates are faster in patients infected with HCV genotype 3 ? First, comprehensive counselling of patients with respect to proven (alcohol consumption) or suspected concomitant factors (overweight, iron overload) is mandatory. Second, reluctance to defer or delay antiviral therapy may not be appropriate. Generally, sustained virologic response rates in patients chronically infected with HCV genotype 3 are high. Combination therapy with peginterferon alfa and ribavirin for 24 weeks achieves sustained virologic response rates of 70–80% [7Andriulli A. Mangia A. Iacobellis A. Ippolito A. Leandro G. Zeuzem S. Meta-analysis: the outcome of anti-viral therapy in HCV genotype 2 and genotype 3 infected patients with chronic hepatitis.Aliment Pharmacol Ther. 2008; 28: 397-404Crossref PubMed Scopus (103) Google Scholar, 8Hadziyannis S.J. Sette Jr., H. Morgan T.R. Balan V. Diago M. Marcellin P. et al.Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.Ann Intern Med. 2004; 140: 346-355Crossref PubMed Scopus (2740) Google Scholar]. In patients with low baseline viral load (<800,000 IU/mL) and a rapid virologic response treatment duration can be shortened to 16 weeks without compromising SVR rates [[9]Shiffman M.L. Suter F. Bacon B.R. Nelson D. Harley H. Solá R. et al.Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3.N Engl J Med. 2007; 357: 124-134Crossref PubMed Scopus (510) Google Scholar]. However, in patients with high baseline viral load (>800,000 IU/mL) and/or without a rapid virologic response virologic relapse rates after 24 weeks of combination therapy are high [9Shiffman M.L. Suter F. Bacon B.R. Nelson D. Harley H. Solá R. et al.Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3.N Engl J Med. 2007; 357: 124-134Crossref PubMed Scopus (510) Google Scholar, 10Zeuzem S. Hultcrantz R. Bourliere M. Goeser T. Marcellin P. Sanchez-Tapias J. et al.Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3.J Hepatol. 2004; 40 (Erratum in: J Hepatol 2005;42:434): 993-999Abstract Full Text Full Text PDF PubMed Google Scholar]. Retrospective analyses suggest that this subpopulation may benefit from 48 weeks of combination therapy including higher doses of ribavirin (1000–1200 mg/day) [8Hadziyannis S.J. Sette Jr., H. Morgan T.R. Balan V. Diago M. Marcellin P. et al.Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.Ann Intern Med. 2004; 140: 346-355Crossref PubMed Scopus (2740) Google Scholar, 11Willems B. Hadziyannis S.J. Morgan T.R. Diago M. Marcellin P. Bernstein D. et al.Should treatment with peginterferon plus ribavirin be intensified in patients with HCV genotype 2/3 without a rapid virologic response?.J Hepatol. 2007; 46: S6Abstract Full Text PDF PubMed Google Scholar]. Prospective trials are ongoing to finally answer this open question. No study has yet specifically studied treatment success in HCV genotype 3-infected patients with liver cirrhosis, but clinical experience shows that SVR is difficult to achieve in this population.Due to marked improvement in SVR rates for HCV-1 infected patients treated with peginterferon alfa, ribavirin, and a NS3 serine protease inhibitor [12McHutchison J.G. Everson G.T. Gordon S.C. Jacobson I.M. Sulkowski M. Kauffman R. et al.Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection.N Engl J Med. 2009; 360: 1827-1838Crossref PubMed Scopus (995) Google Scholar, 13Hézode C. Forestier N. Dusheiko G. Ferenci P. Pol S. Goeser T. et al.Telaprevir and peginterferon with or without ribavirin for chronic HCV infection.N Engl J Med. 2009; 360: 1839-1850Crossref PubMed Scopus (968) Google Scholar, 14Kwo P. Lawitz E. McCone J. Schiff E. Vierling J. Pound D. et al.HCV Sprint-1 final results: SVR 24 from a phase 2 study of boceprevir plus PegIntronTM (peginterferon alfa-2b)/ribavirin in treatment-naive subjects with genotype-1 chronic hepatitis C.J Hepatol. 2009; 50: S4Abstract Full Text PDF PubMed Google Scholar], treatment is currently delayed in many patients to await approval of these specifically targeted antiviral therapies (STAT-C drugs). All physicians treating patients with chronic hepatitis C, however, should be reminded that the clinically most advanced protease inhibitors telaprevir and boceprevir are mainly active against HCV genotypes 1 (and 2) and less active against HCV genotypes 3 and 4 [15Foster G.R. Hezode C. Bronowicki J.-P. Carosi G. Weiland O. Verlinden L. et al.Activity of telaprevir alone or in combination with peginterferon alfa-2a and ribavirin in treatment-naive genotype 2 and 3 hepatitis-C patients: interim results of study C209.J Hepatol. 2009; 50: S22Abstract Full Text PDF Google Scholar, 16Benhamou Y. Moussalli J. Ratziu V. Lebray P. Gysen V. de Backer K. et al.Results of a proof of concept study (C210) of telaprevir monotherapy and in combination with peginterferon alfa-2a and ribavirin in treatment naive genotype 4 HCV patients.J Hepatol. 2009; 50: S6Abstract Full Text PDF Google Scholar]. Similarly, non-nucleoside polymerase inhibitors are generally active against HCV-1 isolates [[17]Soriano V. Peters M.G. Zeuzem S. New therapies for hepatitis C virus infection.Clin Infect Dis. 2009; 48: 313-320Crossref PubMed Scopus (151) Google Scholar]. Activity against HCV-3 isolates has yet been documented only for nucleoside polymerase inhibitors (e.g. R7128) and cyclophilin inhibitors (e.g. Debio-025) [18Gane E.J. Rodriguez-Torres M. Nelson D.R. Jacobson I.M. McHutchison J.G. Jeffers L. et al.Antiviral activity of the HCV nucleoside polymerase inhibitor R7128 in HCV genotype 2 and 3 prior non-responders: interim results of R7128 1500 mg bid with PEG-IFN and ribavirin for 28 days.Hepatology. 2008; 48: 1024AGoogle Scholar, 19Flisiak R. Feinman S.V. Jablkowski M. Horban A. Kryczka W. Pawlowska M. et al.The cyclophilin inhibitor Debio 025 combined with PEG IFNalpha2a significantly reduces viral load in treatment-naı¨ve hepatitis C patients.Hepatology. 2009; 49: 1460-1468Crossref PubMed Scopus (217) Google Scholar]. Taken together, combination of peginterferon alfa and ribavirin could remain the key treatment option for patients infected with HCV genotype 3 in the years to come. If indeed fibrosis progression in patients infected with HCV genotype 3 is faster than in HCV-1 infected patients, waiting for new treatment options should be strongly discouraged in this patient population. The hepatitis C virus comprises 6 genotypes and more than 100 subtypes. While differences in the virologic response rates to peginterferon alfa plus ribavirin combination therapy are well established, less evidence has been accumulated regarding whether HCV genotypes are associated with differences in the natural course of disease. No clinically relevant differences with respect to symptoms and extrahepatitic manifestations of chronic hepatitis C according to HCV genotypes are reported. The published data on the impact of HCV genotypes on fibrosis progression rates, development of cirrhosis, and the risk for hepatocellular carcinoma are somewhat conflicting leading to the overall perception that clinically relevant differences are non-existant. Studies on the possible association of HCV genotype with the fibrosis progression rates are complicated by confounding factors, e.g. by the fact that HCV-1b infected patients in several regions are older than HCV-1a and HCV-3a infected patients and typically show substantial differences with respect to transmission risk factors [1Seeff L.B. The natural history of chronic hepatitis C virus infection.Clin Liver Dis. 1997; 1: 587-602Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 2Lauer G.M. Walker B.D. Hepatitis C virus infection.N Engl J Med. 2001; 345: 41-52Crossref PubMed Scopus (2474) Google Scholar, 3Zeuzem S. Teuber G. Lee J.H. Rüster B. Roth W.K. Risk factors for the transmission of hepatitis C.J Hepatol. 1996; 24: S3-S10PubMed Google Scholar]. The study by Bochud et al. [[4]Bochud P.-Y. Cai T. Overbeck K. Bochud M. Dufour J-F. Müllhaupt B. et al.Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C.J Hepatol. 2009; 51: 655-666Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar] is one of the largest data sets on the association of HCV genotypes and fibrosis progression rates. The data of this study indicate a faster fibrosis progression rate in patients infected with HCV genotype 3 compared with patients infected with HCV genotype 1, supporting some previous smaller studies which showed a similar trend [5Poynard T. Bedossa P. Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups.Lancet. 1997; 349: 825-832Abstract Full Text Full Text PDF PubMed Scopus (2755) Google Scholar, 6Adinolfi L.E. Gambardella M. Andreana A. Tripodi M.F. Utili R. Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity.Hepatology. 2001; 33: 1358-1364Crossref PubMed Scopus (949) Google Scholar]. The methodology of the study by Bochud et al. is sound since the authors used both a stage-constant and a stage-specific estimation of fibrosis progression rates according to different HCV genotypes, together with cumulative incidence curves. The concordant observation that HCV genotype 3 was associated with accelerated fibrosis both in stage-specific and stage-constant fibrosis rate estimates in a large cohort of well-characterized patients make the data appear robust. A possible limitation of the study as outlined in the discussion of the paper [[4]Bochud P.-Y. Cai T. Overbeck K. Bochud M. Dufour J-F. Müllhaupt B. et al.Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C.J Hepatol. 2009; 51: 655-666Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar] is the fact that the estimated duration of infection was based on the first event at risk, which may not be accurate. Furthermore, biopsy specimens were not read by a central pathologist and the authors cannot rule out other confounding factors, e.g. that patients infected with HCV genotype 3 infection may have had a higher exposure to liver-toxic agents beyond alcohol (e.g. continuous use of illicit drugs). Thus, some concerns remain as in most studies with a cross-sectional design, and the data should be confirmed in other cohorts and if at all possible in prospectively designed trials. What are the practical consequences if indeed fibrosis progression rates are faster in patients infected with HCV genotype 3 ? First, comprehensive counselling of patients with respect to proven (alcohol consumption) or suspected concomitant factors (overweight, iron overload) is mandatory. Second, reluctance to defer or delay antiviral therapy may not be appropriate. Generally, sustained virologic response rates in patients chronically infected with HCV genotype 3 are high. Combination therapy with peginterferon alfa and ribavirin for 24 weeks achieves sustained virologic response rates of 70–80% [7Andriulli A. Mangia A. Iacobellis A. Ippolito A. Leandro G. Zeuzem S. Meta-analysis: the outcome of anti-viral therapy in HCV genotype 2 and genotype 3 infected patients with chronic hepatitis.Aliment Pharmacol Ther. 2008; 28: 397-404Crossref PubMed Scopus (103) Google Scholar, 8Hadziyannis S.J. Sette Jr., H. Morgan T.R. Balan V. Diago M. Marcellin P. et al.Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.Ann Intern Med. 2004; 140: 346-355Crossref PubMed Scopus (2740) Google Scholar]. In patients with low baseline viral load (<800,000 IU/mL) and a rapid virologic response treatment duration can be shortened to 16 weeks without compromising SVR rates [[9]Shiffman M.L. Suter F. Bacon B.R. Nelson D. Harley H. Solá R. et al.Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3.N Engl J Med. 2007; 357: 124-134Crossref PubMed Scopus (510) Google Scholar]. However, in patients with high baseline viral load (>800,000 IU/mL) and/or without a rapid virologic response virologic relapse rates after 24 weeks of combination therapy are high [9Shiffman M.L. Suter F. Bacon B.R. Nelson D. Harley H. Solá R. et al.Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3.N Engl J Med. 2007; 357: 124-134Crossref PubMed Scopus (510) Google Scholar, 10Zeuzem S. Hultcrantz R. Bourliere M. Goeser T. Marcellin P. Sanchez-Tapias J. et al.Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3.J Hepatol. 2004; 40 (Erratum in: J Hepatol 2005;42:434): 993-999Abstract Full Text Full Text PDF PubMed Google Scholar]. Retrospective analyses suggest that this subpopulation may benefit from 48 weeks of combination therapy including higher doses of ribavirin (1000–1200 mg/day) [8Hadziyannis S.J. Sette Jr., H. Morgan T.R. Balan V. Diago M. Marcellin P. et al.Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.Ann Intern Med. 2004; 140: 346-355Crossref PubMed Scopus (2740) Google Scholar, 11Willems B. Hadziyannis S.J. Morgan T.R. Diago M. Marcellin P. Bernstein D. et al.Should treatment with peginterferon plus ribavirin be intensified in patients with HCV genotype 2/3 without a rapid virologic response?.J Hepatol. 2007; 46: S6Abstract Full Text PDF PubMed Google Scholar]. Prospective trials are ongoing to finally answer this open question. No study has yet specifically studied treatment success in HCV genotype 3-infected patients with liver cirrhosis, but clinical experience shows that SVR is difficult to achieve in this population. Due to marked improvement in SVR rates for HCV-1 infected patients treated with peginterferon alfa, ribavirin, and a NS3 serine protease inhibitor [12McHutchison J.G. Everson G.T. Gordon S.C. Jacobson I.M. Sulkowski M. Kauffman R. et al.Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection.N Engl J Med. 2009; 360: 1827-1838Crossref PubMed Scopus (995) Google Scholar, 13Hézode C. Forestier N. Dusheiko G. Ferenci P. Pol S. Goeser T. et al.Telaprevir and peginterferon with or without ribavirin for chronic HCV infection.N Engl J Med. 2009; 360: 1839-1850Crossref PubMed Scopus (968) Google Scholar, 14Kwo P. Lawitz E. McCone J. Schiff E. Vierling J. Pound D. et al.HCV Sprint-1 final results: SVR 24 from a phase 2 study of boceprevir plus PegIntronTM (peginterferon alfa-2b)/ribavirin in treatment-naive subjects with genotype-1 chronic hepatitis C.J Hepatol. 2009; 50: S4Abstract Full Text PDF PubMed Google Scholar], treatment is currently delayed in many patients to await approval of these specifically targeted antiviral therapies (STAT-C drugs). All physicians treating patients with chronic hepatitis C, however, should be reminded that the clinically most advanced protease inhibitors telaprevir and boceprevir are mainly active against HCV genotypes 1 (and 2) and less active against HCV genotypes 3 and 4 [15Foster G.R. Hezode C. Bronowicki J.-P. Carosi G. Weiland O. Verlinden L. et al.Activity of telaprevir alone or in combination with peginterferon alfa-2a and ribavirin in treatment-naive genotype 2 and 3 hepatitis-C patients: interim results of study C209.J Hepatol. 2009; 50: S22Abstract Full Text PDF Google Scholar, 16Benhamou Y. Moussalli J. Ratziu V. Lebray P. Gysen V. de Backer K. et al.Results of a proof of concept study (C210) of telaprevir monotherapy and in combination with peginterferon alfa-2a and ribavirin in treatment naive genotype 4 HCV patients.J Hepatol. 2009; 50: S6Abstract Full Text PDF Google Scholar]. Similarly, non-nucleoside polymerase inhibitors are generally active against HCV-1 isolates [[17]Soriano V. Peters M.G. Zeuzem S. New therapies for hepatitis C virus infection.Clin Infect Dis. 2009; 48: 313-320Crossref PubMed Scopus (151) Google Scholar]. Activity against HCV-3 isolates has yet been documented only for nucleoside polymerase inhibitors (e.g. R7128) and cyclophilin inhibitors (e.g. Debio-025) [18Gane E.J. Rodriguez-Torres M. Nelson D.R. Jacobson I.M. McHutchison J.G. Jeffers L. et al.Antiviral activity of the HCV nucleoside polymerase inhibitor R7128 in HCV genotype 2 and 3 prior non-responders: interim results of R7128 1500 mg bid with PEG-IFN and ribavirin for 28 days.Hepatology. 2008; 48: 1024AGoogle Scholar, 19Flisiak R. Feinman S.V. Jablkowski M. Horban A. Kryczka W. Pawlowska M. et al.The cyclophilin inhibitor Debio 025 combined with PEG IFNalpha2a significantly reduces viral load in treatment-naı¨ve hepatitis C patients.Hepatology. 2009; 49: 1460-1468Crossref PubMed Scopus (217) Google Scholar]. Taken together, combination of peginterferon alfa and ribavirin could remain the key treatment option for patients infected with HCV genotype 3 in the years to come. If indeed fibrosis progression in patients infected with HCV genotype 3 is faster than in HCV-1 infected patients, waiting for new treatment options should be strongly discouraged in this patient population.