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Thuluvath, Paul J.; Pande, Hemant; Maygers, Joyce

doi:10.1023/a:1022509304694

Cited by 19 publications

(1 citation statement)

References 24 publications

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“…These include amantidine, IL-10, IL-12 and histamine dihydrochloride. Treatment with amantidine has mainly been studied in patients who have previously failed interferon monotherapy or in combination with ribavirin, with response rates varying from 13% (n=3/23) to 40% (n=4/10) and 48% (n=19/40) in three separate investigations [76][77][78]. IL-10 appears to have limited efficacy in the management of HCV disease and may in fact have deleterious effects by shifting the cytokine profile to that of a T H 2 profile [79].…”

Section: Acute Hcvmentioning

confidence: 99%

Anti-Viral Therapies for Hepatitis C Virus Infection: Current Options and Evolving Candidate Drugs

Fanning

2005

LDDD

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Chronic hepatitis C is a ubiquitous disease, affecting approximately 170 million globally. The hepatitis C virus (HCV) is spread by parenteral transmission of body fluids, primarily blood or blood products. The hepatitis C viral genome is a positive-sense, single-stranded RNA molecule approximately 9.4kb in length, which encodes a polyprotein of about 3100 amino acids. There are 6 main genotypes of HCV, with each further stratified by subtype. Hepatitis C virus exists as a heterogeneous mixture of closely related viruses called quasispecies. The continuous evolution of new variant glycoproteins is a major mechanism of viral evasion of the immune system. The quasispecies diversity collapses to oligoclonality or homogeneity prior to clearance. Substantial evidence indicates that HCV genotype is clinically important with respect to efficacy of anti-viral therapy. The dual drug regime currently used to treat HCV infection consists of pegylated-interferon (peg-IFN) and the guanosine nucleoside analog ribavirin. Mutations in the viral genome are likely to contribute in large measure to the emergence of "resistance" during interferon-based therapy.The HCV genome codes for 10 proteins. The structural proteins of core, E1, E2 and P7 are positioned immediately downstream of the 5'UTR. These proteins are cleaved from the polyprotein by host-encoded proteases. The remaining proteins are released from the polyprotein by a process of autocatalytic cleavage or by the protease activity of NS3. The RNA dependent RNA polymerase (NS5B) is position immediately downstream of the 3'UTR. The current cytokine based treatment modality is based on a shotgun approach of up regulation of cellular anti-viral pathways. The net effect of IFN signalling is the down regulation of protein translation. The cellular signalling pathways induced by IFN engagement of the cognate receptor are not specific for the elimination of HCV. HCV has evolved mechanisms that hinder IFN signalling and the induction of nuclease activity that would otherwise destroy the viral genome. The net benefit to the virus is that it potentiates the establishment of persistence.The activity of the host encoded proteases necessary for the cleavage of Core-P7, the proteolytic activity of NS3, the helicase activity of NS3 and the polymerase activity of NS5B are all potential targets for the development of adjunct options for the treatment of hepatitis C virus infections. The development of novel antivirals suitable for use against HCV has learnt a great deal from the research and development of drugs used to treat HIV disease. Like HIV, HCV has the propensity to produce greater than 10 10 virions per day. Each genome will have a fitness potential to survive each unique selection pressure (endogenous and/or exogenous) and it is to be expected that again like HIV, HCV will have the potential to evolve drug resistant mutants. The goal of highly active antiretroviral therapy in HIV disease is viral suppression. However, it would appear that elimination, rather than suppression of vir...

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Section: Acute Hcvmentioning

confidence: 99%

Anti-Viral Therapies for Hepatitis C Virus Infection: Current Options and Evolving Candidate Drugs

Fanning

2005

LDDD

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Placebo-controlled trial of 400 mg amantadine combined with peginterferon alfa-2a and ribavirin for 48 weeks in chronic hepatitis C virus-1 infection

Wagner¹,

Hofmann²,

Teuber³

et al. 2008

Hepatology

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The impact of amantadine on virologic response rates of interferon-based treatment of chronic hepatitis C is controversial. The aim of this study was to compare virological response rates in patients with chronic hepatitis C virus (HCV)-1 infection treated with 400 mg amantadine or placebo in combination with peginterferon alfa-2a (40 kD) and ribavirin for 48 weeks. Seven hundred four previously untreated chronically HCV-1-infected patients (mean age, 46 ؎ 12 years) were randomized to (A) amantadine-sulphate (400 mg/day) (n ‫؍‬ 352) or (B) placebo (n ‫؍‬ 352), both in combination with 180 g peginterferon alfa-2a once weekly and ribavirin (1000-1200 mg/day) for 48 weeks. End of treatment and sustained virological response after a 24-week follow-up period were assessed by qualitative reverse transcription polymerase chain reaction (RT-PCR) (sensitivity, 50 IU/mL). Demographic and baseline virological parameters were similar in both treatment groups. In groups A and B, 231 of 352 patients (66%) and 256 of 352 patients (72%) achieved an end of treatment response, and 171 of 352 patients (49 %) and 186 of 352 patients (53 %) a sustained virological response, respectively. On-treatment dropout rate in the amantadine group was significantly higher than in the placebo group (32% versus 23%; P ‫؍‬ 0.01). However, adverse events and laboratory abnormalities were similar between both groups. Per-protocol analysis revealed similar sustained virological response rates in both treatment groups (53% versus 55%). Conclusion: In this large placebo-controlled multicenter study, amantadine even at a dose of 400 mg/day did not improve virological response rates of peginterferon alfa-2a and ribavirin in patients with chronic genotype HCV-1 infection. (HEPATOLOGY 2008;

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Chronic hepatitis

Hepatology Principles and Practice

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Cited by 19 publications

References 24 publications

Anti-Viral Therapies for Hepatitis C Virus Infection: Current Options and Evolving Candidate Drugs

Anti-Viral Therapies for Hepatitis C Virus Infection: Current Options and Evolving Candidate Drugs

Placebo-controlled trial of 400 mg amantadine combined with peginterferon alfa-2a and ribavirin for 48 weeks in chronic hepatitis C virus-1 infection

Chronic hepatitis

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