S-adenosyl methionine improves early viral responses and interferon-stimulated gene induction in hepatitis C nonresponders.
OBJECTIVE
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 log(10) 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.
Feld
Jordan J
JJ
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1800, USA.
Modi
Apurva A
AA
El-Diwany
Ramy
R
Rotman
Yaron
Y
Thomas
Emmanuel
E
Ahlenstiel
Golo
G
Titerence
Rachel
R
Koh
Christopher
C
Cherepanov
Vera
V
Heller
Theo
T
Ghany
Marc G
MG
Park
Yoon
Y
Hoofnagle
Jay H
JH
Liang
T Jake
TJ
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D006526:Hepatitis C / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D064547:Myxovirus Resistance Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010766:Phosphorylation; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage*; D012436:S-Adenosylmethionine / Q000008:administration & dosage*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D017211:Treatment Failure; D014452:Ubiquitins / Q000235:genetics; D019562:Viral Load; D000090123:Viperin Protein
D000998:Antiviral Agents; D016207:Cytokines; D019204:GTP-Binding Proteins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D064547:Myxovirus Resistance Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011092:Polyethylene Glycols; D011506:Proteins; D012333:RNA, Messenger; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; D012436:S-Adenosylmethionine; D050794:STAT1 Transcription Factor; D014452:Ubiquitins; C494079:STAT1 protein, human; C074034:ISG15 protein, human; C444427:RSAD2 protein, human; D000090123:Viperin Protein; C100416:peginterferon alfa-2a