Viral Determinants of Resistance to Treatment in Patients with Hepatitis C

Abstract

SUMMARY Chronic hepatitis C virus (HCV) infection affects more than 170 million persons worldwide and is responsible for the development of liver cirrhosis in many cases. Standard treatment with pegylated alpha interferon (IFN-α) in combination with the nucleoside analogue ribavirin leads to a sustained virologic response in approximately half of the patients. IFN-α is classified as an indirect treatment, as it interacts with the host's immune response. The mechanism of action of ribavirin is still unknown. The benefit of triple therapy by adding other antiviral agents, e.g., amantadine, is controversial. Currently, new direct antiviral drugs (HCV protease/polymerase inhibitors) are being evaluated in phase 1/phase 2 trials. Phenotypic resistance to antiviral therapy has been attributed to amino acid variations within distinct regions of the HCV polyprotein. While sensitivity to IFN-α-based antiviral therapy in vivo is clearly correlated with the number of mutations within the HCV NS5A protein, the underlying functional mechanisms for this association are unknown. In turn, in vitro, several mechanisms to circumvent the host immune defense or to block treatment-induced antiviral activities have been described for different HCV proteins. By the introduction of direct antiviral drugs, hepatitis C therapy now is entering a new era in which the development of resistance may become the most important parameter for treatment success or failure.

RETRACTED: Selection of cyclic peptide aptamers to HCV IRES RNA using mRNA display

“…This treatment is effective in Ϸ50% of patients (1, 3). Resistance to IFN and ribavirin (4), and HCV persistence after SVR in the form of ''occult'' hepatitis C (3,5) makes HCV frequently incurable. The virus effectively avoids the host immune response and no vaccine for hepatitis C is currently available (6,7).…”

The Distribution of Genotype and Allelic Frequency of IL28B Gene Polymorphism in Andhra Pradesh, India

“…The PCR products were purified and sequenced individually on both strands ( RNA concentration of HCV, age, gender, body mass index (BMI), fibrosis stage, alanine aminotransferase (ALT), gamma-glutamyl-transpeptidase (GGT) levels, insulin resistance, and host genetic polymorphism of several genes (human leukocyte antigen, chemokines, ILs, and IFNstimulated genes) are associated with SVR. 16,17 Presently, in clinical practice guidelines, only the HCV genotype and concentration of HCV-RNA at baseline are recommended to be used in determining treatment duration but still the therapy is frequently complicated by treatment-limiting side effects. [18][19][20][21] The most recent genome-wide association studies reported association of different SNPs of IL28B gene (IFN-λ gene region) with response to antiviral therapy, where SNP, rs12979860(C/T) of IL28B gene, was reported to be strongly associated.…”

Host-Based Ribavirin Resistance Influences Hepatitis C Virus Replication and Treatment Response

“…Despite a significant research effort, only half of patients infected with HCV genotype 1 respond to therapy (50). IFN clearly plays an important role in HCV treatment response.…”