TITLE

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

AUTHOR(S)
Fanning, Liam J.
PUB. DATE
March 2005
SOURCE
Letters in Drug Design & Discovery;Mar2005, Vol. 2 Issue 2, p150
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
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 1010 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 viral replication, in HCV disease is achievable at least in a proportion of patients. The phenomenon of quasispecies is likely responsible for the ineffectiveness of isolate-specific vaccines and will challenge the development of pangenotype antiviral therapies. New strategies based on antisense and ribozyme technologies may hold future promise as therapeutic adjuncts in the treatment of HCV infection.
ACCESSION #
16266316

 

Related Articles

  • Duration and Dose of Antiviral Treatment for Chronic Hepatitis C.  // Annals of Internal Medicine;3/2/2004, Vol. 140 Issue 5, pI67 

    Reports on the duration and dose of antiviral treatment for Chronic Hepatitis C. Effective combination of a long-acting immunity-boosting protein with another antiviral drug in ridding the body of HCV; Requirement of higher ribavirin doses by the patients with chronic hepatitis and HCV genotype 1.

  • Therapy of Acute Hepatitis C: A Review of Literature. Santantonio, T.; Fasano, M. // Current Pharmaceutical Design;Jun2008, Vol. 14 Issue 17, p1686 

    The goal of treatment for acute hepatitis C patients is to eradicate the virus in the early phase of infection, thus preventing progression to chronicity. Early interferon (IFN) monotherapy has been shown to significantly reduce this risk, and therefore it has been recommended by international...

  • PEG INF-α-2a/ribavirin cost effective for mild-chronic hep C.  // PharmacoEconomics & Outcomes News;1/28/2006, Issue 495, p4 

    Discusses research being done on the use of Peginterferon-alpha-2a/ribavirin for treating mild-chronic hepatitis C. Reference to study being done by J. Hornberger et al, which appeared in the October 2006 issue of the journal "Hepatology"; Therapeutic use and mechanism of action of the drugs;...

  • Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 in Patients With Unfavorable Treatment Characteristics. Osinusi, Anuoluwapo; Meissner, Eric G.; Yu-Jin Lee; Bon, Dimitra; Heytens, Laura; Nelson, Amy; Sneller, Michael; Kohli, Anita; Barrett, Lisa; Proschan, Michael; Herrmann, Eva; Shivakumar, Bhavana; Wenjuan Gu; Kwan, Richard; Teferi, Geb; Talwani, Rohit; Silk, Rachel; Kotb, Colleen; Wroblewski, Susan; Fishbein, Dawn // JAMA: Journal of the American Medical Association;8/28/2013, Vol. 310 Issue 8, p804 

    IMPORTANCE The efficacy of directly acting antiviral agents in interferon-free regimens for the treatment of chronic hepatitis C infections needs to be evaluated in different populations. OBJECTIVE To determine the efficacy and safety of sofosbuvir with weight-based or low-dose ribavirin among a...

  • Pegylated-interferon plus ribavirin treatment does not alter the prevalence of resistance-associated substitutions to direct-acting antivirals in HCV genotype la patients. Zhi-wei Chen; Xi-chen Pang; Zhao Li; Hong Ren; Peng Hu // Infection & Drug Resistance;Aug2017, Vol. 10, p275 

    Background: Direct-acting antiviral (DAA) resistance-associated substitutions (RASs) can jeopardize the effectiveness of DAAs in patients with hepatitis C virus (HCV). The selection pressure by pegylated-interferon (Peg-IFN) plus ribavirin (P/R) treatment may enhance HCV genome variation....

  • Peginterferon/ribavirin/telaprevir.  // Reactions Weekly;1/11/2014, Issue 1483, p80 

    The article presents a case report on the adverse effects of peginterferon, ribavirin, and telaprevir to 12 patients who experienced toxicities after receiving the treatment for their hepatitis C.

  • New developments in the treatment of hepatitis C. Rossi, S.J.; Wright, T.L. // Gut;May2003, Vol. 52 Issue 5, p756 

    Reports on developments in the treatment of hepatitis C. Factors that hinder the development of effective antiviral agents for the disease; Features of the process of pegylation; Comparators used in the clinical trials of peginterferon in combination with ribavirin.

  • A retrospective cohort study of partial splenic embolization for antiviral therapy in chronic hepatitis C with thrombocytopenia. Tahara, Hiroki; Takagi, Hitoshi; Sato, Ken; Shimada, Yasushi; Tojima, Hiroki; Hirokawa, Tomoyuki; Ohyama, Tatsuya; Horiuchi, Katsuhiko; Naganuma, Atsushi; Arai, Hirotaka; Kakizaki, Satoru; Mori, Masatomo // Journal of Gastroenterology;Aug2011, Vol. 46 Issue 8, p1010 

    Background: Although partial splenic embolization (PSE) is reportedly effective prior to interferon (IFN)-based therapy, the number of subjects in these studies is small, and the appropriate candidates and disease prognosis remain unknown. Methods: PSE was performed in 30 patients with advanced...

  • Efficacy of re-treatment with pegylated interferon plus ribavirin combination therapy for patients with chronic hepatitis C in Japan. Oze, Tsugiko; Hiramatsu, Naoki; Yakushijin, Takayuki; Mochizuki, Kiyoshi; Oshita, Masahide; Hagiwara, Hideki; Mita, Eiji; Ito, Toshifumi; Inui, Yoshiaki; Fukui, Hiroyuki; Hijioka, Taizo; Katayama, Kazuhiro; Tamura, Shinji; Yoshihara, Harumasa; Inoue, Atsuo; Imai, Yasuharu; Hayashi, Eijiro; Kato, Michio; Hosui, Atsushi; Miyagi, Takuya // Journal of Gastroenterology;Aug2011, Vol. 46 Issue 8, p1031 

    Background: It is still not known which patients with chronic hepatitis C who failed to respond to previous pegylated interferon (Peg-IFN) plus ribavirin therapy can benefit from re-treatment. Methods: Seventy-four patients (HCV genotype 1, n = 56, genotype 2, n = 18) were re-treated with...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics