Mechanisms of drug resistance to current and future antiviral therapies for hepatitis C virus infection
The treatment of chronic hepatitis C is currently based on the pegylated interferon alpha and ribavirin combination. Despite this treatment, a significant number of patients still fail to eradicate the virus. The mechanisms underlying this failure are unknown, but indirect evidence suggests that chronic infection is associated with phenomena that protect hepatitis C virus (HCV) from the antiviral action of interferon alpha and hinder the clearance of infected cells. Viral factors responsible for true "HCV resistance" probably play a partial role. Numerous new HCV drugs are currently at the developmental stage. It is foreseeable that specific HCV inhibitors will select resistant viral variants. As a result, combination therapy will probably become the standard of care in chronic hepatitis C.
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References and Recommended Reading
- 1.McHutchison J, Davis GL, Esteban-Mur R, et al.: Durability of sustained virologic response in patients with chronic hepatitis C after treatment with interferon alfa-2b alone or in combination with ribavirin. Hepatology 2001, 34:244A.Google Scholar
- 17.Blindenbacher A, Duong FH, Hunziker L, et al.: Expression of hepatitis C virus proteins inhibits interferon alpha signaling in the liver of transgenic mice. Gastroenterology 2003, 124:1465–1475. Describes inhibition of the Jak-Stat pathway upstream of PKR by the HCV polyprotein expressed in transgenic mice.PubMedCrossRefGoogle Scholar
- 24.Polyak SJ, Khabar KS, Paschal DM, et al.: Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response. J Virol 2001, 75:6095–6106. Provides the first demonstration that NS5A transcriptional activation may be functional during infection. It suggests that NS5A transcriptional activation of the interleukin-8 gene may play a role in IFN alpha treatment failure, through mechanisms that remain to be elucidated.PubMedCrossRefGoogle Scholar
- 25.Foy E, Li K, Wang C, et al.: Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 2003, 300:1145–1148. On the basis of in vitro experiments, this article suggests that the IFN regulatory factor-3 could be inhibited by the HCV NS3 serine proteinase and that this would constitute a mean by which the virus would antagonize IFN antiviral effect. It is not known whether such an interaction exists in vivo and plays a role in IFN alpha treatment failure.PubMedCrossRefGoogle Scholar
- 27.Jinushi M, Takehara T, Kanto T, et al.: Critical role of MHC class I-related chain A and B expression on IFN-alphastimulated dendritic cells in NK cell activation: impairment in chronic hepatitis C virus infection. J Immunol 2003, 170:1249–1256. Shows that natural killer cell activation is impaired during HCV infection.PubMedGoogle Scholar
- 32.Soler M, Penin F, Ray S, et al.: Hepatitis C virus NS3 serine protease variability and evolution are strongly constrained by the need for structural and functional conservation [abstract]. J Hepatol 2002, 36(suppl 1):5. Describes HCV NS3 proteinase natural variability and suggests that the NS3 proteinase, an obvious target for specific HCV inhibitors, could be prone to the selection of resistant variants by these drugs.CrossRefGoogle Scholar
- 36.Young KC, Lindsay KL, Lee KJ, et al.: Identification of a ribavirin-resistant NS5B mutation of hepatitis C virus during ribavirin monotherapy. Hepatology 2003, 38:869–878. This is an intriguing article suggesting that ribavirin selects resistant variants when administered for several months in HCV-infected patients. These data need to be confirmed.PubMedGoogle Scholar
- 37.Bronowicki JP, Ouzan D, Asselah T, et al.: Efficacy and safety of 22 weeks of maintenance therapy with peginterferon alfa-2a (40 kD) (Pegasys) alone versus peginterferon alfa-2a (40kD) plus ribavirin (Copegus) in naive patients with chronic hepatitis C and genotype 1 who responded to a 24-week course of peginterferon alfa-2a (40 kD) plus ribavirin: an open, multicenter randomized trial. Hepatology 2003, 38:244A.CrossRefGoogle Scholar
- 38.Pawlotsky JM, McHutchison JG: Hepatitis C new drug and clinical trials development: promises and pitfalls. Hepatology 2004, in press. Summarizes a recent Single Topic Conference organized by the American Association for the Study of Liver Diseases at which the current therapeutic approaches in preclinical and clinical development for HCV have been presented.Google Scholar
- 42.Lin C, Lin K, Gates CA, et al.: VX-950, a HCV protease inhibitor, retains potency against BILN-2061 resistant replicon cells [abstract]. Hepatology 2003, 38:638A. Describes the in vitro selection of resistant proteinases by two specific inhibitors of the NS3 serine proteinase currently at the preclinical or clinical developmental phase.CrossRefGoogle Scholar