Gastroenterology

Gastroenterology

Volume 140, Issue 3, March 2011, Pages 830-839.e3
Gastroenterology

Clinical—Liver, Pancreas, and Biliary Tract
S-Adenosyl Methionine Improves Early Viral Responses and Interferon-Stimulated Gene Induction in Hepatitis C Nonresponders

https://doi.org/10.1053/j.gastro.2010.09.010Get rights and content

Background & Aims

Less than half of patients infected with hepatitis C virus (HCV) achieve sustained viral clearance after pegylated interferon (peginterferon) and ribavirin therapy. S-adenosyl methionine (SAMe) improves interferon signaling in cell culture. We assessed the effect of SAMe on the kinetics of the early antiviral response and interferon signaling in nonresponders to previous antiviral therapy and investigated the mechanisms involved.

Methods

Nonresponders with HCV genotype 1 were given peginterferon alfa-2a and ribavirin for 2 weeks (course A, baseline/control). After 1 month, patients received SAMe (1600 mg daily) for 2 weeks and then peginterferon and ribavirin for 48 weeks (course B; completed by 21 of 24 patients). Viral kinetics and interferon-stimulated gene (ISG) expression in peripheral blood mononuclear cells (PBMCs) were compared between courses.

Results

The decrease in HCV RNA from 0 to 48 hours (phase 1) was similar with and without SAMe. However, the second phase slope of viral decline was improved with SAMe (course A, 0.11 ± 0.04 log10 IU/mL/wk; course B, 0.27 ± 0.06; P = .009); 11 patients (53%) achieved an early virological response, and 10 (48%) had undetectable HCV RNA by week 24. Induction of ISGs in PBMCs was significantly greater during course B. In cultured cells, SAMe increased induction of ISGs and the antiviral effects of interferon by increasing STAT1 methylation, possibly affecting STAT1-DNA binding.

Conclusions

The addition of SAMe to peginterferon and ribavirin improves the early viral kinetics and increases ISG induction in nonresponders to previous therapy. SAMe might be a useful adjunct to peginterferon-based therapies in chronic HCV infection.

Section snippets

Patients

Patients with a documented history of nonresponse to combination treatment with standard interferon or peginterferon and ribavirin were eligible for enrollment. Inclusion criteria included age 18 years or older, documented genotype 1 chronic HCV infection, and a history of at least 3 months of combination antiviral therapy (with interferon or peginterferon plus ribavirin) and failure to achieve an early virological response (EVR), defined as a 2-log10 IU/mL decline in HCV RNA levels by week 12

Results

Twenty-four patients were enrolled (Table 1) between October 2007 and April 2009. Eighteen (75%) had a liver biopsy specimen available, which showed advanced fibrosis (Ishak score ≥3) in 8 (44%) and cirrhosis in 5 (21%). Baseline viral levels ranged from 5.0 to 7.9 log10 IU/mL. Three patients (13%) completed course A only; one patient developed a severe rash attributed to ribavirin, one patient experienced a relapse of benzodiazepine abuse during the initial course, and one patient withdrew

Discussion

Peginterferon and ribavirin are likely to remain the backbone of antiviral treatment for chronic HCV for many years, even once new direct antivirals become available.8, 9 As a result, improving the response to interferon-based therapy remains a major priority. Results from this pilot study show that addition of SAMe to standard therapy improves early viral kinetics, likely by improving interferon signaling.

Previous in vitro data suggested that SAMe may improve interferon signaling and antiviral

Acknowledgments

J.J.F. and A.A.M. contributed equally to this study.

References (32)

  • D.M. Jensen et al.

    Re-treatment of patients with chronic hepatitis C who do not respond to peginterferon-alpha2b: a randomized trial

    Ann Intern Med

    (2009)
  • J.G. McHutchison et al.

    Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection

    N Engl J Med

    (2009)
  • C. Hezode et al.

    Telaprevir and peginterferon with or without ribavirin for chronic HCV infection

    N Engl J Med

    (2009)
  • M. Gale et al.

    Evasion of intracellular host defence by hepatitis C virus

    Nature

    (2005)
  • T. Kawai et al.

    Innate immune recognition of viral infection

    Nat Immunol

    (2006)
  • J.J. Feld et al.

    Mechanism of action of interferon and ribavirin in treatment of hepatitis C

    Nature

    (2005)
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    Conflicts of interest The authors disclose the following: Dr Feld is on the advisory board of Roche Pharmaceuticals and Schering-Plough (Merck) Pharmaceuticals. The remaining authors disclose no conflicts.

    Funding Supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. Pharmavite LLC provided SAMe for the study but had no involvement in study design, data analysis, or manuscript preparation.

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