کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5908125 1570159 2016 13 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
HCV1b genome evolution under selective pressure of the cyclophilin inhibitor alisporivir during the DEB-025-HCV-203 phase II clinical trial
کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم کشاورزی و بیولوژیک بوم شناسی، تکامل، رفتار و سامانه شناسی
پیش نمایش صفحه اول مقاله
HCV1b genome evolution under selective pressure of the cyclophilin inhibitor alisporivir during the DEB-025-HCV-203 phase II clinical trial
چکیده انگلیسی
Major advances have revolutionized the HCV antiviral treatment field, with interferon-free combinations of direct-acting antivirals (DAAs) resulting into success rates of > 90% for all HCV genotypes. Nevertheless, viral eradication at a global level stills remains challenging, stimulating the continued search for new affordable pan-genotypic drugs. To overcome selection of drug resistant variants, targeting host proteins can be an attractive mechanism of action. Alisporivir (Debio 025) is a potent pan-genotypic host-targeting antiviral agent, acting on cyclophilin A, which is necessary for HCV replication. The efficacy and safety of three different oral doses of alisporivir in combination with pegylated interferon-α2a given over a period of four weeks, was investigated in a randomized, double-blind and placebo-controlled phase IIa clinical trial, in 90 treatment-naïve subjects infected with chronic hepatitis C, wherefrom 58 HCV1b samples were selected for genetic sequencing purposes. Sequencing results were used to study the HCV genome for amino acid changes potentially related with selective pressure and resistance to alisporivir. By comparing baseline and on-treatment sequences, a large variation in proportion of amino acid changes was detected in all treatment arms. The NS5A variant D320E, which was previously identified during in vitro resistance selection and resulted in 3.6-fold reduced alisporivir susceptibility, emerged in two subjects in the alisporivir monotherapy arm. However, emergence of D320E appeared to be associated only with concurrent viral load rebound in one subject with 0.8 log10 IU/ml increase in HCV RNA. In general, for all datasets, low numbers of positions under positive selective pressure were observed, with no significant differences between naïve and treated sequences. Additionally, incomplete sequence information for some of the 22 patients and the low number of individuals per treatment arm, is limiting the power to assess the association of alisporivir or interferon treatment with the observed amino acid changes.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Infection, Genetics and Evolution - Volume 44, October 2016, Pages 169-181
نویسندگان
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