TY - JOUR
T1 - Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C
AU - Rotman, Yaron
AU - Noureddin, Mazen
AU - Feld, Jordan J.
AU - Guedj, Jeremie
AU - Witthaus, Michael
AU - Han, Hwalih
AU - Park, Yoon J.
AU - Park, Su-Hyung
AU - Heller, Theo
AU - Ghany, Marc G.
AU - Doo, Edward
AU - Koh, Christopher
AU - Abdalla, Adil
AU - Gara, Naveen
AU - Sarkar, Souvik
AU - Thomas, Emmanuel
AU - Ahlenstiel, Golo
AU - Edlich, Birgit
AU - Titerence, Rachel
AU - Hogdal, Leah
AU - Rehermann\, Barbara
AU - Barbara, Harel
AU - Dahari, Harel
AU - Perelson, Alan S.
AU - Hoofnagle, Jay H.
PY - 2014
Y1 - 2014
N2 - Objective: Ribavirin improves treatment response to pegylated-interferon (PEG-IFN) in chronic hepatitis C but the mechanism remains controversial. We studied correlates of response and mechanism of action of ribavirin in treatment of hepatitis C. Design: 70 treatment-naive patients were randomised to 4 weeks of ribavirin (1000–1200 mg/d) or none, followed by PEG-IFNα-2a and ribavirin at standard doses and durations. Patients were also randomised to a liver biopsy 24 h before or 6 h after starting PEG-IFN. Hepatic gene expression was assessed by microarray and interferon-stimulated gene (ISG) expression quantified by nCounter platform. Temporal changes in ISG expression were assessed by qPCR in peripheral-blood mononuclear cells (PBMC) and by serum levels of IP-10. Results: After 4 weeks of ribavirin monotherapy, hepatitis C virus (HCV) levels decreased by 0.5±0.5 log10 (p=0.009 vs controls) and ALT by 33% (p<0.001). Ribavirin pretreatment, while modestly augmenting ISG induction by PEG-IFN, did not modify the virological response to subsequent PEG-IFN and ribavirin treatment. However, biochemical, but not virological, response to ribavirin monotherapy predicted response to subsequent combination treatment (rapid virological response, 71% in biochemical responders vs 22% non-responders, p=0.01; early virological response, 100% vs 68%, p=0.03; sustained virological response 83% vs 41%, p=0.053). Ribavirin monotherapy lowered serum IP-10 levels but had no effect on ISG expression in PBMC. Conclusions: Ribavirin is a weak antiviral but its clinical effect seems to be mediated by a separate, indirect mechanism, which may act to reset IFN-responsiveness in HCV-infected liver.
AB - Objective: Ribavirin improves treatment response to pegylated-interferon (PEG-IFN) in chronic hepatitis C but the mechanism remains controversial. We studied correlates of response and mechanism of action of ribavirin in treatment of hepatitis C. Design: 70 treatment-naive patients were randomised to 4 weeks of ribavirin (1000–1200 mg/d) or none, followed by PEG-IFNα-2a and ribavirin at standard doses and durations. Patients were also randomised to a liver biopsy 24 h before or 6 h after starting PEG-IFN. Hepatic gene expression was assessed by microarray and interferon-stimulated gene (ISG) expression quantified by nCounter platform. Temporal changes in ISG expression were assessed by qPCR in peripheral-blood mononuclear cells (PBMC) and by serum levels of IP-10. Results: After 4 weeks of ribavirin monotherapy, hepatitis C virus (HCV) levels decreased by 0.5±0.5 log10 (p=0.009 vs controls) and ALT by 33% (p<0.001). Ribavirin pretreatment, while modestly augmenting ISG induction by PEG-IFN, did not modify the virological response to subsequent PEG-IFN and ribavirin treatment. However, biochemical, but not virological, response to ribavirin monotherapy predicted response to subsequent combination treatment (rapid virological response, 71% in biochemical responders vs 22% non-responders, p=0.01; early virological response, 100% vs 68%, p=0.03; sustained virological response 83% vs 41%, p=0.053). Ribavirin monotherapy lowered serum IP-10 levels but had no effect on ISG expression in PBMC. Conclusions: Ribavirin is a weak antiviral but its clinical effect seems to be mediated by a separate, indirect mechanism, which may act to reset IFN-responsiveness in HCV-infected liver.
UR - http://handle.westernsydney.edu.au:8081/1959.7/uws:41868
U2 - 10.1136/gutjnl-2012-303852
DO - 10.1136/gutjnl-2012-303852
M3 - Article
SN - 0017-5749
VL - 63
SP - 161
EP - 169
JO - Gut
JF - Gut
IS - 1
ER -
