Article

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: 2.2). 02/2006; 34(1):15-22. DOI:10.1016/j.hepres.2005.09.039 pp.15-22
Source: PubMed

ABSTRACT 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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    Article: Replicative homeostasis III: implications for antiviral therapy and mechanisms of response and non-response.
    Richard Sallie
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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.
    Virology Journal 02/2007; 4:29. · 2.34 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

2 weeks
 
24-week regimen
 
6MU tiw
 
biopsy-proven CHC
 
CHC patients
 
chronic hepatitis C
 
consensus IFN monotherapy
 
cytoplasmic IFN-gamma
 
Flow cytometric determination
 
HCV genotype 2a
 
IFN)-alpha 2b
 
IFN-alpha 2b
 
IFN-Con
 
IFN-Con group
 
IL-4 expression
 
immunomodulatory effects
 
R+IFN group
 
ribavirin induces
 
Th1 cell
 
Th2 cell