Mechanism of action of ribavirin in the combination treatment of chronic HCV infection

Lau, Johnson Y. N.; Tam, Robert C.; Liang, T. Jake; Hong, Zhi

doi:10.1053/jhep.2002.32672

Cited by 317 publications

(257 citation statements)

References 43 publications

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“…5 Pegylation is a recent modification that sustains interferon's half-life in vivo. 6 Ribavirin is a nucleoside analog with pleiotropic effects, 7 including mutagenic potential that may degrade the ability of HCV to sustain reliable replication. 8 Despite the improved efficacy of combined drug therapy, around half of patients infected with genotype 1 HCV fail to show a sustained virologic response and remain chronically infected.…”

Section: Commentsmentioning

confidence: 99%

Evasive maneuvers by hepatitits C virus

Lindenbach

Rice

2003

Hepatology

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The hepatitis C virus (HCV) serine protease is necessary for viral replication and represents a valid target for developing new therapies for HCV infection. Potent and selective inhibitors of this enzyme have been identified and shown to inhibit HCV replication in tissue culture. The optimization of these inhibitors for clinical development would greatly benefit from in vitro systems for the identification and the study of resistant variants. We report the use of HCV subgenomic replicons to isolate and characterize mutants resistant to a protease inhibitor. Taking advantage of the replicons' ability to transduce resistance to neomycin, we selected replicons with decreased sensitivity to the inhibitor by culturing the host cells in the presence of the inhibitor and neomycin. The selected replicons replicated to the same extent as those in parental cells. Sequence analysis followed by transfection of replicons containing isolated mutations revealed that resistance was mediated by amino acid substitutions in the protease. These results were confirmed by in vitro experiments with mutant enzymes and by modeling the inhibitor in the three-dimensional structure of the protease.

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Section: Commentsmentioning

confidence: 99%

Evasive maneuvers by hepatitits C virus

Lindenbach

Rice

2003

Hepatology

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“…66,68,69 Polarization of a T H 1 response would be expected to enhance both cytokine-and CTL-mediated clearance of HCV-in- …”

Section: Ifn-␣mentioning

confidence: 99%

The clinical and immunologic impact of using interferon and ribavirin in the immunosuppressed host

Braun

Vierling

2003

Liver Transplantation

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C irrhosis caused by chronic hepatitis C virus (HCV) infection is the leading indication for cadaver and living donor liver transplantation. 1 Recurrent HCV infection, which occurs within days in virtually all allografts, is associated with a 10-to 20-fold increase in serum HCV RNA levels because of enhanced replication stimulated by immunosuppression. 2,3 A majority develop acute hepatitis C 1 to 4 months post-orthotopic liver transplantation (OLT) that is characterized by lymphocytic infiltration and hepatocyte apoptosis. Progression to chronic hepatitis C is associated with: (1) decline in HCV RNA levels observed in the acute phase because of effects of HCVspecific CD4 T helper subtype 1 (T H 1) and CD8 cell responses, (2) profibrotic effects of interferon-␥ (IFN-␥), and (3) proapoptotic effects of increased hepatocyte expression of Fas. 3 Progression of chronic hepatitis C is accelerated in immunosuppressed patients post OLT, resulting in a cumulative probability of cirrhosis in 30% by 5 years. 4 In addition, a minority develop severe, usually fatal, cholestatic hepatitis C within the first 6 months after OLT that is characterized by a direct cytopathic effect of excessive intrahepatic replication of HVC, intrahepatic anti-inflammatory T H 2 cytokine expression, and absence of an HCV-specific immune response. 3 Studies of the impact of different immunosuppressive regimens on recurrent hepatitis C also have been performed in an attempt to reduce hepatitis C progression while preventing acute cellular rejection (ACR). 5 Overall, HCV infection significantly reduces graft and patient survival compared with patients who undergo OLT for non-HCV-related indications. 6 Results of re-OLT are poor, 7 and this is an increasingly unrealistic option in view of the shortage of organ donors.To prevent morbidity and mortality associated with recurrent hepatitis C, many centers have used interferon alfa (IFN-␣) and/or ribavirin (RVN) as either antiviral prophylaxis or treatment of established hepatitis C or hepatitis B. Regimens have ranged from

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“…[1][2][3] The mode of action of ribavirin is not firmly established. 4 Furthermore, data regarding the correlation between the dose and the resulting concentration of ribavirin are limited, and the optimal dose is not known. For the treatment of chronic HCV, ribavirin is currently dosed according to body weight, usually between 800 and 1,200 mg daily.…”

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confidence: 99%

High-dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C

et al. 2005

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Improved treatment regimens for patients with chronic hepatitis C, genotype 1 and high viral load are needed. Increasing the dose of ribavirin has increased the response rate, but experience with doses of more than 1,200 mg/day is limited. The aim of this study was to investigate the safety and tolerance to treatment with a high and individualized dose of ribavirin in combination with peginterferon. Ten patients with chronic hepatitis C, genotype 1 and high viral load were treated with peginterferon alfa-2a and ribavirin for 48 weeks in a prospective trial. The initial ribavirin dose was individualized and calculated from a pharmacokinetic formula based mainly on renal function. Ribavirin plasma concentrations were monitored, and the dose was adjusted to reach the target concentration. Hemoglobin was monitored, and patients were treated with erythropoietin and blood transfusions when indicated. After dose adjustments, the mean dose of ribavirin was 2,540 mg/day (range, 1,600-3,600) at week 24. The main side effect was anemia, which was controlled with erythropoietin. Two patients required blood transfusions. One patient was withdrawn at week 24 because of a lack of viral response, and one patient at week 39 because of side effects, primarily interferon associated. A lthough improvements have been made in the antiviral therapy of chronic hepatitis C virus (HCV), patients with genotype 1 infection with a high level of HCV RNA still pose a therapeutic challenge. The standard combination treatment with 12 months of peginterferon combined with ribavirin results in a sustained virological response rate of approximately 40% for this subset of patients. [1][2][3]

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Mechanism of action of ribavirin in the combination treatment of chronic HCV infection

Cited by 317 publications

References 43 publications

Evasive maneuvers by hepatitits C virus

Evasive maneuvers by hepatitits C virus

The clinical and immunologic impact of using interferon and ribavirin in the immunosuppressed host

High-dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C

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