Hepatitis C virus (HCV) of genotype 1b is the most prevalent worldwide, and the least responsive to interferon-based treatments. A combination therapy with two direct-acting antivirals has shown promising results in patients with HCV-1b, but the prevalence of drug-resistant variants before treatment is not known in the Japanese population.
To detect HCV variants resistant to NS3 protease inhibitors or the NS5A inhibitor (BMS-790052) in hepatitis patients infected with HCV-1b.
Drug-resistant mutations were determined in the 362 hepatitis patients infected with HCV-1b who had not received direct-acting antivirals before.
Amino-acid substitutions resistant to NS3 inhibitors (V36A, T54S, Q80H and D168E) were detected in 15 of the 307 (4.9%) patients, who had been examined, and T54S (3.3%) predominated over V36A (0.3%), Q80R (0.7%) and D168E (0.7%) in them. Amino-acid substitutions resistant to BMS-790052 (L31M and/or Y93H) were detected in 33 of the 294 (11.2%) patients, and Y93H (8.2%) predominated over L31M (2.7%). One of the 239 (0.4%) patients, who had been examined for amino-acid substitutions in both NS3 and NS5A regions, possessed HCV-1b variants resistant to NS3 inhibitors (T54S) and BMS-790052 (L31M).
Mutations conferring resistance to NS3 inhibitors or BMS-790052 were frequent in our treatment-naive study population, but double mutants with possible resistance to both drugs were rare. Since single mutations did not result in treatment failure in a previous pilot trial combining BMS-790052 and an NS3 inhibitor, larger trials of this drug regimen appear warranted in the Japanese population.
"It should be underlined that while the Q54H + Y93H combination has already been reported  to provide moderate resistance to Daclatasvir, the other combinations have never been investigated, and their level of resistance is not known. In general, greater heterogeneity was confirmed in HCV genotype 1b strains [26,27]. "
[Show abstract][Hide abstract] ABSTRACT: Direct-acting antiviral (DAA) agents target HCV proteins; some of these have already been approved for the treatment of HCV infection, while others are in development. However, selection of DAA-resistant viral variants may hamper treatment. The aim of this study was to illustrate potential natural DAA-resistance mutations in the HCV NS5A and NS5B regions of HCV genotypes 1a and 1b from DAA-naive patients.
Direct sequencing of HCV NS5A and NS5B regions was performed in 32 patients infected with HCV genotype 1a and 30 patients infected with HCV genotype 1b; all subjects were naive to DAAs.
In genotype 1a strains, resistance mutations in NS5A (M28V, L31M and H58P) were observed in 4/32 (12.5%) patients, and resistance mutations in NS5B (V321I, M426L, Y448H, Y452H) were observed in 4/32 (12.5%) patients. In genotype 1b, resistance mutations in NS5A (L28V, L31M, Q54H, Y93H and I280V) were observed in 16/30 (53.3%) patients, while resistance mutations in NS5B (L159F, V321I, C316N, M426L, Y452H, R465G and V499A) were observed in 27/30 (90%) patients.
Mutations conferring DAA resistance were detected in NS5A and NS5B of HCV genotypes 1a and 1b from DAA-naive patients. Although some mutations confer only a low level of resistance, the presence at baseline of mutated HCV variants should be taken into consideration in the context of DAA therapy.
[Show abstract][Hide abstract] ABSTRACT: Viral resistance corresponds to the selection, during treatment, of pre-existing viral variants less susceptible to the drug’s inhibitory activity because they bear amino acid substitutions altering the drug target. Hepatitis C virus (HCV) drugs in development can be split into two groups according to their barrier to resistance. Direct-acting antiviral drugs with a low barrier to resistance include first-generation NS3-4A protease inhibitors, non-nucleoside inhibitors of HCV RNA-dependent RNA polymerase and first-generation NS5A inhibitors. HCV drugs with a high barrier to resistance include nucleoside/nucleotide analogues, possibly second-generation protease and NS5A inhibitors, and host-targeted agents, such as cyclophilin inhibitors or microRNA-122 antagonists. This article reviews recent findings that add to our knowledge and understanding of HCV resistance to direct-acting antiviral drugs and discusses them in the context of new therapeutic strategies, with and without pegylated interferon-α and/or ribavirin.
Current Hepatitis Reports 09/2012; 11(3). DOI:10.1007/s11901-012-0139-1
[Show abstract][Hide abstract] ABSTRACT: Two oral direct-acting antivirals (DAA) are now available for the treatment of chronic hepatitis C infection and several generations of DAA are in development. Expectations are that, at some time in the near future, hepatitis C will be 'curable' with an all-oral DAA regimen. This article reviews the current problems associated with interferon-based hepatitis C treatments that are combined with DAAs, including adverse events and complications of therapy, contraindications, drug-drug interactions and cost. The article further discusses difficulties with new drug development and provides an opinion on the research issues still to be dealt with and the requirements for the successful implementation of such a strategy. These include lack of efficacy in certain populations, unexpected side effects, antiviral resistance, late relapse, lack of cooperation between drug developers and cost.
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