Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients.
Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients.
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DOI：
10.1002/hep.22549
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发表时间：
2008-12
期刊：
影响因子：
13.5
通讯作者：
Allen, Todd M.
中科院分区：
文献类型：
--
作者：
Kuntzen, Thomas;Timm, Joerg;Berical, Andrew;Lennon, Niall;Berlin, Aaron M.;Young, Sarah K.;Lee, Bongshin;Heckerman, David;Carlson, Jonathan;Reyor, Laura L.;Kleyman, Marianna;McMahon, Cory M.;Birch, Christopher;Wiesch, Julian Schulze zur;Ledlie, Timothy;Koehrsen, Michael;Kodira, Chinnappa;Roberts, Andrew D.;Lauer, Georg M.;Rosen, Hugo R.;Bihl, Florian;Cerny, Andreas;Spengler, Ulrich;Liu, Zhimin;Kim, Arthr Y.;Xing, Yanming;Schneidewind, Arne;Madey, Margaret A.;Fleckenstein, Jaquelyn F.;Park, Vicki M.;Galagan, James E.;Nusbaum, Chad;Walker, Bruce D.;Lake-Bakaar, Gerond V.;Daar, Eric S.;Jacobson, Ira M.;Gomperts, Edivard D.;Edlin, Brian R.;Donfield, Sharyne M.;Chung, Raymond T.;Talal, Andrew H.;Marion, Tony;Birren, Bruce W.;Henn, Mattliew R.;Allen, Todd M.
HCV NS 3蛋白酶抑制剂的耐药突变使<1% of the viral quasispecies may still allow >治疗后病毒载量降低1000倍，与其报告的体外复制适应性降低一致。然而，最近，R155 K蛋白酶突变被报道为未接受过治疗的个体中的优势准种，引起了对可能的完全耐药性的担忧。为了调查人群中显性STAT-C耐药突变的患病率，我们分析了来自美国、德国和瑞士的507例未经治疗的HCV基因型1感染患者的HCV基因组序列。系统发生序列分析和病毒载量数据用于确定人群中复制能力、耐药病毒株的可能传播，并推断这些突变对体内病毒复制的影响。描述为赋予对蛋白酶抑制剂特拉匹韦、BILN 2061、ITMN-191、SCH 6和博西普韦、NS 5 B聚合酶抑制剂AG-021541和NS 4A拮抗剂ACH-806的耐药性的突变大多作为散发的、不相关的病例观察到，在人群中的频率在0.3%至2.8%之间，包括2例可能具有多药耐药性的患者。然而，总的来说，8.6%的基因型1a和1.4%的基因型1b感染患者携带至少一个显性耐药突变。大多数患者的病毒载量较高，表明耐药病毒株可能在体内达到与非耐药病毒相当的复制水平。结论：自然发生的显性STAT-C耐药突变在HCV基因1型感染的初治患者中很常见。它们对治疗结果的影响应进一步表征，以评估当治疗选择因既往对聚乙二醇干扰素和利巴韦林无应答而受到限制时，耐药性检测对个体定制药物组合的可能益处。
Resistance mutations to HCV NS3 protease inhibitors in <1% of the viral quasispecies may still allow >1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant STAT-C resistance mutations in the population we analyzed HCV genome sequences from 507 treatment-naïve HCV genotype 1 infected patients from the US, Germany and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication competent, drug resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir, the NS5B polymerase inhibitor AG-021541, and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multi-drug resistance. Collectively, however, 8.6% of the genotype 1a and 1.4% of the genotype 1b infected patients carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug resistant viral strains might achieve replication levels comparable to non-resistant viruses in vivo. Conclusion: Naturally occurring dominant STAT-C resistance mutations are common in HCV genotype 1 infected treatment-naïve patients. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous non-response to peginterferon and ribavirin.
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影响因子：
13.5
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通讯作者：
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