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Effects of Ribavirin Monotherapy on ALT, HCV Viral Levels, Serum Cytokines,
and Hepatic Interferon - Stimulated Gene Expression in Chronic Hepatitis C
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Reported by Jules Levin
AASLD Nov 2 2010 Boston
M.Noureddin; Y.Rotman; J.Feld; E.Thomas; C.Koh; A.Abdalla; L.Holz; S.Park; Y.Park; M.G.Ghany; E.Doo;
T.Heller; B.Rehermann; J.H.Hoofnagle; T.Liang NIDDK, Bethesda, MD
Background: Ribavirin improves the response rate to peginterferon (Peg-IFN) therapy of chronic hepatitis C, yet by itself, ribavirin has minimal effect on HCV RNA levels. In vitro, ribavirin appears to augment induction of IFN-stimulated genes (ISGs). The effect of ribavirin on liver gene expression in humans has not been examined.
Aims: To elucidate the mechanism of action of ribavirin by assessing its effects on serum enzymes,
HCV RNA levels, serum cytokines and hepatic gene expression.
Methods: 42 treatment-na ve patients with chronic hepatitis C were randomized to receive weight-based ribavirin (1200 or 1000 mg/d) or no treatment for 4 weeks, after which standard combination therapy with Peg-IFN-alfa-2a and ribavirin was started. RNA was extracted from liver biopsies of 6 patients on no treatment, 6 patients after 4 weeks of ribavirin alone prior to the first Peg-IFN injection and 6 patients 6 hours after the first Peg-IFN injection (and no ribavirin). Gene expression was assessed (genotype 1 only) using the Affymetrix U133 Plus 2.0 array. Serum HCV titers, ALT and serum levels of selected cytokines (interferon-gamma-inducible protein-10 [IP10], monokine induced by interferon-gamma [MIG], and monocyte chemoattractant protein 1 [MCP1]) were measured before and at the end of 4 weeks of ribavirin.
Results: The 2 groups were similar in baseline factors and genotype distribution (60% genotype 1, 40% genotypes 2/3).
After 4 weeks of ribavirin treatment, HCV RNA levels decreased by a mean of 0.59 log10 (p<0.001) and serum ALT by 30 U/L (p<0.001).
Patients with genotype 2/3 had a greater decline than those with genotype 1 (HCV 0.83 vs. 0.45 log10, p=NS; ALT 47 vs. 22 U/L, p=0.036).
Serum IP10 levels declined by a mean of 253 pg/mL after 4 weeks of ribavirin (p<0.001), in correlation with the decreases in HCV RNA and ALT. MIG and MCP1 levels did not change. As expected, serum ISG levels increased after the dosing of PEG-IFN. In untreated patients, there was no change in HCV titers, ALT or serum cytokine levels. Microarray analysis of hepatic gene expression showed that ribavirin alone caused upregulation of ISG RNA levels and down-regulation of genes inhibited by IFN, in a manner similar to Peg-IFN but to a lesser degree. There was a strong positive correlation between the patterns of hepatic gene induction by ribavirin and PEG-IFN (r2=0.24, p<0.001).
Conclusion: A 4 weeks course of ribavirin alone decreased HCV RNA and ALT levels (with a corresponding decrease in serum IP10), possibly through weak induction of ISGs. These results support the potentiating effect of ribavirin in enhancing the antiviral action of IFN in HCV therapy.
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