Early immune-mediated response to ribavirin combined with IFN in patients with chronic hepatitis C

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University School of Medicine, 6-11-1 Omorinishi, Otaku, Tokyo 143, Japan.
Hepatology Research (Impact Factor: 2.74). 02/2006; 34(1):15-22. DOI: 10.1016/j.hepres.2005.09.039
Source: PubMed


This study was to investigate the immunomodulatory effects of ribavirin combined with interferon (IFN)-alpha 2b (R+IFN) compared with consensus IFN monotherapy (IFN-Con) in chronic hepatitis C (CHC) patients.
Thirty-four adult patients with biopsy-proven CHC, who were infected with HCV genotype 2a or 2b, were studied. A 24-week regimen of IFN-alpha 2b (6MU daily for 2 weeks followed by 6MU tiw for 22 weeks) and ribavirin (600-800mg/day for 24 weeks) was given to 17 patients. The other 17 patients were treated with a 24-week regimen of IFN-Con (18MU daily for 2 weeks followed by 18MU tiw for 22 weeks). Flow cytometric determination of cytoplasmic IFN-gamma and IL-4 expression in peripheral blood CD4+ T cells was performed, and the percentage of IFN-gamma+ and IL-4- (Th1), IFN-gamma- and IL-4+ (Th2) cells were calculated before and 3, 7, 14, and 28 days after the start of therapy.
In the R+IFN group, the percentage of Th1 cell peaked on day 3, and then decreased to near baseline by day 14, while the percentage of Th2 cell did not change. In the IFN-Con group, the percentage of Th1 cell peaked on day 14 and the percentage of Th2 cell peaked on day 3, and then decreased to near baseline by day 14.
Our results suggest that ribavirin induces an early immune response by peripheral blood CD4+ T cells in CHC patients.

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    • "By contrast, treatment with PEG-IFN∝ and ribavirin will result in sustained viral response rates (SVR) of 80–90% after 6 months therapy for HCV genotypes II [36-38] while ~50% of patients with genotype I [3,35], or over double the rate for IFN alone, will experience SVR after 48 weeks PEG-IFN∝ and ribavirin. Paradoxically, despite having little impact on HCV RNA levels, ribavirin does improve serum alanine aminotransferase (ALT) levels in a significant number of patients, with about 30% of patients normalizing their ALT after 24 weeks ribavirin monotherapy and some improvement in ALT levels in 55% [135-138], an observation difficult to reconcile with the notion ribavirin acts as a direct immunomodulator; if ribavirin does alter the CD4+ lymphocyte TH1/TH2 subset balance [139,140] to favour a TH1 response an increased cell-mediated immune response with enhanced clearance of infected cells and an increased ALT might be expected. "
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    ABSTRACT: While improved drug regimens have greatly enhanced outcomes for patients with chronic viral infection, antiviral therapy is still not ideal due to drug toxicities, treatment costs, primary drug failure and emergent resistance. New antiviral agents, alternative treatment strategies and a better understanding of viral pathobiology, host responses and drug action are desperately needed. Interferon (IFN) and ribavirin, are effective drugs used to treat hepatitis C (HCV), but the mechanism(s) of their action are uncertain. Error catastrophe (EC), or precipitous loss of replicative fitness caused by genomic mutation, is postulated to mediate ribavirin action, but is a deeply flawed hypothesis lacking empirical confirmation. Paradoxically ribavirin, a proven RNA mutagen, has no impact on HCV viraemia long term, suggesting real viruses, replicating in-vitro, as opposed to mathematical models, replicating in-silico, are likely to resist EC by highly selective replication of fit (~consensus sequence) genomes mediated, in part, by replicative homeostasis (RH), an epicyclic mechanism that dynamically links RNApol fidelity and processivity and other viral protein functions. Replicative homeostasis provides a rational explanation for the various responses seen during treatment of HCV, including genotype-specific and viral load-dependent differential response rates, as well as otherwise unexplained phenomena like the transient inhibition and rebound of HCV viraemia seen during ribavirin monotherapy. Replicative homeostasis also suggests a primarily non-immunological mechanism that mediates increased immune responsiveness during treatment with ribavirin (and other nucleos(t)ide analogues), explicating the enhanced second-phase clearance of HCV ribavirin promotes and, thus, the apparent immunomodulatory action of ribavirin. More importantly, RH suggests specific new antiviral therapeutic strategies.
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