Prevalence of hepatitis C virus variants resistant to NS3 protease inhibitors or the NS5A inhibitor (BMS-790052) in hepatitis patients with genotype 1b

Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology (Impact Factor: 3.47). 06/2012; 54(4):352-4. DOI: 10.1016/j.jcv.2012.04.024
Source: PubMed

ABSTRACT 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.

1 Follower
  • [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.
    Drugs 08/2012; 72(14):1825-31. DOI:10.2165/11635560-000000000-00000 · 4.13 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV) is a modern-day pandemic; 2-3% of the world's population are thought to be infected with the virus and are subsequently at risk of developing end-stage liver diseases. The traditional standard of care (SOC) for HCV-infected patients has been limited to a regimen of pegylated-interferon alpha (pegIFN) and ribavirin; displaying low cure rates in a majority of patients and severe side effects. However, in 2011 the first direct-acting antivirals (DAA) were licensed to treat HCV-infected patients in combination with SOC, which served to elevate treatment response rates. The HCV drug development pipeline is currently populated with many additional and improved DAAs; primarily molecules that target the virus-encoded protease or polymerase enzymes. These molecules are being evaluated both in combination with the traditional SOC and together with other DAAs as all-oral pegIFN-free regimens with the ultimate goal of developing multiple DAA-containing HCV therapies that do not rely on an pegIFN backbone. A recent addition to the arsenal of HCV inhibitors in development is represented by an entirely new DAA class; molecules that target the HCV-encoded non-enzymatic NS5A protein. NS5A is essential for HCV propagation and, although its actual functions are largely unknown, it is likely a key regulator of viral genome replication and virion assembly. The protein is exquisitely sensitive to small molecule-mediated inhibition; NS5A-targeting molecules are probably the most potent antiviral molecules ever discovered and exhibit a number of other attractive drug-like properties, including activity against many HCV genotypes/subtypes and once-daily dosing potential. Although their mechanism of action is unclear, NS5A-targeting molecules are already proving their utility in clinical evaluation; particularly as components of pegIFN-sparring DAA combination regimens. This review will aim to amalgamate our current understanding and knowledge of NS5A-targeting molecules; their discovery, properties, applications, and insight into their future impact as components of all-oral pegIFN-free DAA combination therapies to combat HCV infection.
    Virus Research 09/2012; 170(1-2). DOI:10.1016/j.virusres.2012.09.007 · 2.83 Impact Factor
Show more