Naturally occurring resistance mutations to inhibitors of HCV NS5A region and NS5B polymerase in DAA treatment-naïve patients.
Naturally occurring resistance mutations to inhibitors of HCV NS5A region and NS5B polymerase in DAA treatment-naïve patients.
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DOI：
10.1186/1743-422x-10-355
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发表时间：
2013-12-17
期刊：
影响因子：
4.8
通讯作者：
Baldanti F
中科院分区：
文献类型：
--
作者：
Paolucci S;Fiorina L;Mariani B;Gulminetti R;Novati S;Barbarini G;Bruno R;Baldanti F
直接作用的抗病毒（DAA）药物靶向HCV蛋白;其中一些已经被批准用于治疗HCV感染，而另一些正在开发中。然而，DAA抗性病毒变体的选择可能妨碍治疗。本研究的目的是阐明来自DAA初治患者的HCV基因型1a和1b的HCV NS 5A和NS 5 B区域中潜在的天然DAA耐药突变。在32例感染HCV基因型1a的患者和30例感染HCV基因型1b的患者中进行了HCV NS 5A和NS 5 B区域的直接测序;所有受试者均未接受过DAA。在基因型1a菌株中，在4/32例（12.5%）患者中观察到NS 5A（M28 V、L31 M和H58 P）耐药突变，在4/32例（12.5%）患者中观察到NS 5 B（V321 I、M426 L、Y 448 H、Y 452 H）耐药突变。在基因型1b中，在16/30例（53.3%）患者中观察到NS 5A（L28 V、L31 M、Q54 H、Y 93 H和I280 V）的耐药突变，而在27/30例（90%）患者中观察到NS 5 B（L159 F、V321 I、C316 N、M426 L、Y 452 H、R465 G和V499 A）的耐药突变。在DAA初治患者的HCV基因型1a和1b的NS 5A和NS 5 B中检测到赋予DAA抗性的突变。虽然一些突变仅赋予低水平的耐药性，但在DAA治疗的背景下，应考虑基线时突变的HCV变体的存在。
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-naïve 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 naïve 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-naïve 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.