Heterogeneous virologic response rates to interferon-based therapy in patients with chronic hepatitis C: who responds less well?

The introduction of new agents and regimens for the treatment of chronic hepatitis C, such as pegylated interferons and combination therapy with ribavirin, has resulted in substantial improvements in sustained virologic response rates. However, treatment remains a challenge, particularly for certain patient populations, because several virus-related and patient-related factors are associated with a lower virologic response to therapy. Hepatitis C virus genotype 1 and a high baseline viral load are the major viral factors associated with lower response. Patient-related factors include previous relapse or nonresponse to treatment, the presence of cirrhosis, African-American ethnicity, older age, contraindications to treatment, and obesity. This article reviews the data on interferon-based therapies among patients with lower chances for sustained virologic response and discusses the potential of the new pegylated interferons.

[1]  A. Weiner,et al.  Hepatitis C virus (HCV) circulates as a population of different but closely related genomes: quasispecies nature of HCV genome distribution , 1992, Journal of virology.

[2]  P. Marcellin,et al.  Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. , 2004, Annals of internal medicine.

[3]  A S Perelson,et al.  Differences in viral dynamics between genotypes 1 and 2 of hepatitis C virus. , 2000, The Journal of infectious diseases.

[4]  C. Garret,et al.  A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia. , 1999, Gastroenterology.

[5]  A. Alberti,et al.  Therapy of hepatitis C: Re‐treatment with alpha interferon , 1997, Hepatology.

[6]  P. Marcellin,et al.  Treatment of hepatitis C. The 2002 French consensus , 2003, Gut.

[7]  T. Berg,et al.  Triple therapy with amantadine in treatment‐naive patients with chronic hepatitis C: A placebo‐controlled trial , 2003, Hepatology.

[8]  L. Rostaing,et al.  Evidence that clearance of hepatitis C virus RNA after alpha-interferon therapy in dialysis patients is sustained after renal transplantation. , 2003, Journal of the American Society of Nephrology : JASN.

[9]  A. Perelson,et al.  Viral dynamics and response differences in HCV‐infected African American and white patients treated with IFN and ribavirin , 2003, Hepatology.

[10]  M. Fried.  Side effects of therapy of hepatitis C and their management , 2002 .

[11]  S. Zeuzem.  Hepatitis C virus: kinetics and quasispecies evolution during anti-viral therapy. , 2000, Forum.

[12]  M. Brook,et al.  Treatment of hepatitis. , 1988, The Journal of hospital infection.

[13]  Kenneth Koury,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group , 2022 .

[14]  P. Marcellin,et al.  Randomised trial of interferon α2b plus ribavirin for 48 weeks or for 24 weeks versus interferon α2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus , 1998, The Lancet.

[15]  A. Neumann,et al.  Viral kinetics in patients with chronic hepatitis C treated with standard or peginterferon alpha2a. , 2001, Gastroenterology.

[16]  G. Tomlinson,et al.  High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C , 2003, Hepatology.

[17]  J. Wong,et al.  Interferon and ribavirin for patients with chronic hepatitis C who did not respond to previous interferon therapy: A meta‐analysis of controlled and uncontrolled trials , 2001, Hepatology.

[18]  S. Goodman,et al.  Interferon and ribavirin vs interferon alone in the re-treatment of chronic hepatitis C previously nonresponsive to interferon: A meta-analysis of randomized trials. , 2001, JAMA.

[19]  M. Katze,et al.  To interfere and to anti-interfere: the interplay between hepatitis C virus and interferon. , 2002, Viral immunology.

[20]  S. Zeuzem,et al.  The kinetics of hepatitis C virus infection. , 2001, Clinics in liver disease.

[21]  A. Bruchfeld,et al.  Ribavirin treatment in dialysis patients with chronic hepatitis C virus infection – a pilot study , 2001, Journal of viral hepatitis.

[22]  T. Berg,et al.  Randomized, double‐blind, placebo‐controlled trial of interferon Alfa2a with and without amantadine as initial treatment for chronic hepatitis C , 2000, Hepatology.

[23]  P. Marcellin,et al.  Treatment of Hepatitis C Virus Genotype 4–Related Cirrhosis: Ribavirin and Interferon Combination Compared With Interferon Alone , 2002, Journal of clinical gastroenterology.

[24]  William M. Lee,et al.  Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. , 1998, The New England journal of medicine.

[25]  K. Reddy,et al.  Hepatitis C Virus Genotypes in the United States: Epidemiology, Pathogenicity, and Response to Interferon Therapy , 1996, Annals of Internal Medicine.

[26]  E. Schiff,et al.  A randomized, double‐blind trial comparing pegylated interferon alfa‐2b to interferon alfa‐2b as initial treatment for chronic hepatitis C , 2001, Hepatology.

[27]  M. Andreoni,et al.  A randomized 4‐arm multicenter study of interferon alfa‐2b plus ribavirin in the treatment of patients with chronic hepatitis C relapsing after interferon monotherapy , 2002, Hepatology.

[28]  C. Grunfeld,et al.  Steatosis in chronic hepatitis C: Relative contributions of obesity, diabetes mellitus, and alcohol , 2002, Hepatology.

[29]  N. Kato,et al.  Humoral immune response to hypervariable region 1 of the putative envelope glycoprotein (gp70) of hepatitis C virus , 1993, Journal of virology.

[30]  P. Marcellin,et al.  Long-Term Histologic Improvement and Loss of Detectable Intrahepatic HCV RNA in Patients with Chronic Hepatitis C and Sustained Response to Interferon- Therapy , 1997, Annals of Internal Medicine.

[31]  M. Manns,et al.  Early virologic response to treatment with peginterferon alfa‐2b plus ribavirin in patients with chronic hepatitis C , 2003, Hepatology.

[32]  M. Shiffman,et al.  Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. , 2000, The New England journal of medicine.

[33]  M. Manns,et al.  Effect of treatment with peginterferon or interferon alfa‐2b and ribavirin on steatosis in patients infected with hepatitis C , 2003, Hepatology.

[34]  J. Hoofnagle,et al.  Hepatitis C in African Americans: summary of a workshop. , 2000, Gastroenterology.

[35]  M. Manns,et al.  Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. , 2002, Gastroenterology.

[36]  H. Fusamoto,et al.  Hepatitis C viral complexity detected by single-strand conformation polymorphism and response to interferon therapy. , 1995, Gastroenterology.

[37]  B. Pereira.  Hepatitis C virus infection in dialysis: a continuing problem. , 1999, Artificial organs.

[38]  T. Hassanein,et al.  Optimized virologic response in hepatitis C virus genotype 4 with peginterferon-alpha2a and ribavirin. , 2004, Annals of internal medicine.

[39]  D. R. Taylor,et al.  Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. , 1999, Science.

[40]  K. Sugimoto,et al.  Suppression of HCV‐specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection , 2003, Hepatology.

[41]  Dieter Häussinger,et al.  Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. , 2002, The New England journal of medicine.

[42]  F. Fabrizi,et al.  Hepatitis C infection and the patient with end‐stage renal disease , 2002, Hepatology.

[43]  J. Pawlotsky.  Use and interpretation of virological tests for hepatitis C , 2002, Hepatology.

[44]  K. Lindsay.  Introduction to therapy of hepatitis C , 2002, Hepatology.

[45]  S. Mishiro,et al.  The degree of variability in the amino terminal region of the E2/NS1 protein of hepatitis C virus correlates with responsiveness to interferon therapy in viremic patients , 1992, Hepatology.

[46]  Yasuyuki Arakawa,et al.  Interferon Therapy Reduces the Risk for Hepatocellular Carcinoma: National Surveillance Program of Cirrhotic and Noncirrhotic Patients with Chronic Hepatitis C in Japan , 1999, Annals of Internal Medicine.

[47]  D. Purdie,et al.  Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis C , 2002, Gut.

[48]  A. Neumann,et al.  Hepatitis C Virus Kinetics , 1999, Antiviral therapy.

[49]  G. Foster,et al.  189 Treatment of chronic hepatitis C with peginterferon ALFA-2A (40KD) (PEGASYS®) and ribavirin (COPEGUS®): patient age has a marked influence on the individual estimated probability of achieving a sustained virological response , 2003 .

[50]  P. Heagerty,et al.  Racial differences in the relationship between hepatitis C infection and iron stores , 2003, Hepatology.

[51]  O. Weiland,et al.  Interferon-ribavirin for chronic hepatitis C with and without cirrhosis: analysis of individual patient data of six controlled trials. Eurohep Study Group for Viral Hepatitis. , 1999, Gastroenterology.

[52]  A. Andriulli,et al.  A randomized trial of amantadine and interferon versus interferon alone as initial treatment for chronic hepatitis C , 2001, Hepatology.

[53]  C. Bréchot,et al.  Infection with hepatitis C virus genotype 4 is associated with a poor response to interferon-alpha. , 2000, Annals of internal medicine.

[54]  M. Berenguer,et al.  Contribution of obesity to hepatitis C-related fibrosis progression , 2002, American Journal of Gastroenterology.

[55]  Z. Goodman,et al.  Is an “à la carte” combination interferon alfa‐2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C? , 2000, Hepatology.

[56]  F. González-Roncero,et al.  Outcome of kidney transplant in chronic hepatitis C virus patients: effect of pretransplantation interferon-alpha2b monotherapy. , 2003, Transplantation proceedings.

[57]  P. Marcellin,et al.  Pretreatment serum hepatitis C virus RNA levels and hepatitis C virus genotype are the main and independent prognostic factors of sustained response to interferon alfa therapy in chronic hepatitis C , 1995, Hepatology.

[58]  J. Albrecht,et al.  The impact of interferon plus ribavirin on response to therapy in black patients with chronic hepatitis C. The International Hepatitis Interventional Therapy Group. , 2000, Gastroenterology.

[59]  E. Herrmann,et al.  Quasispecies heterogeneity of the carboxy-terminal part of the E2 gene including the PePHD and sensitivity of hepatitis C virus 1b isolates to antiviral therapy. , 2001, Virology.

[60]  J. Pawlotsky,et al.  Standardization of Hepatitis C Virus RNA Quantification , 2000, Hepatology.

[61]  M. Buti,et al.  Extending combination therapy with peginterferon alfa‐2b plus ribavirin for genotype 1 chronic hepatitis C late responders: A report of 9 cases , 2003, Hepatology.

[62]  N Enomoto,et al.  Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. , 1996, The New England journal of medicine.

[63]  T. Wright.  Treatment of patients with hepatitis C and cirrhosis , 2002, Hepatology.

[64]  L. Skakni,et al.  Hepatitis C genotypes and subtypes in Saudi Arabia , 1999, Journal of medical virology.

[65]  T. Berg,et al.  328 Comparison of 48 or 72 weeks of treatment with peginterferon alfa-2A (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) in treatment-naive patients with chronic hepatitis C infected with HCV genotype 1 , 2003 .

[66]  E. Herrmann,et al.  Hepatitis C Virus Nonstructural 5A Protein and Interferon Resistance: a New Model for Testing the Reliability of Mutational Analyses , 2002, Journal of Virology.

[67]  E. Herrmann,et al.  Pharmacokinetics of Peginterferons , 2003, Seminars in liver disease.

[68]  P. Marcellin,et al.  Improved response to ribavirin interferon combination compared with interferon alone in patients with type 4 chronic hepatitis C without cirrhosis. , 2000, Liver.

[69]  A. Pittenger,et al.  Single‐Dose Pharmacokinetics and Safety of Pegylated Interferon‐α2b in Patients with Chronic Renal Dysfunction , 2002, Journal of clinical pharmacology.

[70]  Interferon monotherapy for dialysis patients with chronic hepatitis C: an analysis of the literature on efficacy and safety , 2003 .

[71]  Angelo Balestrieri,et al.  Early changes in hepatitis C viral quasispecies during interferon therapy predict the therapeutic outcome , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[72]  William M. Lee,et al.  Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. , 2002, Gastroenterology.

[73]  J. Hoefs,et al.  Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group. , 1998, The New England journal of medicine.

[74]  J. Pawlotsky,et al.  Quasispecies heterogeneity and constraints on the evolution of the 5' noncoding region of hepatitis C virus (HCV): relationship with HCV resistance to interferon-alpha therapy. , 2002, Virology.

[75]  R. Purcell,et al.  Genetic Heterogeneity of Hepatitis C Virus: Quasispecies and Genotypes , 1995, Seminars in liver disease.

[76]  P. Simmonds,et al.  Viral heterogeneity of the hepatitis C virus. , 1999, Journal of hepatology.

[77]  J. Reichen,et al.  Peginterferon alfa-2a in patients with chronic hepatitis C. , 2000, The New England journal of medicine.

[78]  Attia Ma.  Prevalence of hepatitis B and C in Egypt and Africa. , 1998 .