Naturally occurring mutations associated with resistance to HCV NS5B polymerase and NS3 protease inhibitors in treatment-naïve patients with chronic hepatitis C.
Naturally occurring mutations associated with resistance to HCV NS5B polymerase and NS3 protease inhibitors in treatment-naïve patients with chronic hepatitis C.
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DOI：
10.1186/s12985-015-0414-1
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发表时间：
2015-11-14
期刊：
影响因子：
4.8
通讯作者：
Ciccaglione AR
中科院分区：
文献类型：
--
作者：
Costantino A;Spada E;Equestre M;Bruni R;Tritarelli E;Coppola N;Sagnelli C;Sagnelli E;Ciccaglione AR
HCV慢性感染treatment-naïve患者对新型直接作用抗病毒药物（DAAs）基线耐药突变的检测可能对其管理和预后预测具有重要意义。在这项研究中，我们调查了treatment-naïve患者血清中突变的存在，这些突变先前被报道与HCV聚合酶（NS5B）和HCV蛋白酶（NS3）区域对DAAs的耐药性相关。对感染不同HCV基因型（21、1a、21、1b、2、2a、60、2c、22、3a、25、4d和1、4k）的152例naïve患者（84%为意大利人，16%为各国移民）的HCV RNA进行序列分析。分别对152例和28例HCV基因组NS5B区（nt 8256-8640）和NS3区（nt 3420-3960）进行扩增和测序。来自基因型1b感染患者的21个分析序列中有9个（43%）检测到与索非布韦耐药相关的NS5B区C316N/H多态性。在100%的感染2c和4亚型的患者中观察到NS3蛋白酶区自然发生的突变V36L和M175L。在本研究中评估的相关比例的naïve基因型1b感染患者存在N316多态性，可能对索非布韦治疗反应较差。由于索非布韦已在美国和欧洲（包括意大利）被批准用于治疗HCV慢性感染，因此应考虑对基因型1b naïve患者进行N316多态性的治疗前检测。
The detection of baseline resistance mutations to new direct-acting antivirals (DAAs) in HCV chronically infected treatment-naïve patients could be important for their management and outcome prevision. In this study, we investigated the presence of mutations, which have been previously reported to be associated with resistance to DAAs in HCV polymerase (NS5B) and HCV protease (NS3) regions, in sera of treatment-naïve patients. HCV RNA from 152 naïve patients (84 % Italian and 16 % immigrants from various countries) infected with different HCV genotypes (21,1a; 21, 1b; 2, 2a; 60, 2c; 22, 3a; 25, 4d and 1, 4k) was evaluated for sequence analysis. Amplification and sequencing of fragments in the NS5B (nt 8256–8640) and NS3 (nt 3420–3960) regions of HCV genome were carried out for 152 and 28 patients, respectively. The polymorphism C316N/H in NS5B region, associated with resistance to sofosbuvir, was detected in 9 of the 21 (43 %) analysed sequences from genotype 1b-infected patients. Naturally occurring mutations V36L, and M175L in the NS3 protease region were observed in 100 % of patients infected with subtype 2c and 4. A relevant proportion of treatment naïve genotype 1b infected patients evaluated in this study harboured N316 polymorphism and might poorly respond to sofosbuvir treatment. As sofosbuvir has been approved for treatment of HCV chronic infection in USA and Europe including Italy, pre-treatment testing for N316 polymorphism on genotype 1b naïve patients should be considered for this drug.