意大利 HCV 基因 1-4 型中 NS3、NS5A 和 NS5B 单一和多种耐药相关取代的流行情况。
Prevalence of Single and Multiple Natural NS3, NS5A and NS5B Resistance-Associated Substitutions in Hepatitis C Virus Genotypes 1-4 in Italy.
机构信息
Department Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00133, Rome, Italy.
Hepatology Unit, University Hospital of Rome "Tor Vergata", 00133, Rome, Italy.
出版信息
Sci Rep. 2018 Jun 12;8(1):8988. doi: 10.1038/s41598-018-26862-y.
Natural resistance-associated substitutions (RASs) are reported with highly variable prevalence across different HCV genotypes (GTs). Frequency of natural RASs in a large Italian real-life cohort of patients infected with the 4 main HCV-GTs was investigated. NS3, NS5A and NS5B sequences were analysed in 1445 HCV-infected DAA-naïve patients. Sanger-sequencing was performed by home-made protocols on 464 GT1a, 585 GT1b, 92 GT2c, 199 GT3a, 16 GT4a and 99 GT4d samples. Overall, 20.7% (301/1455) of patients showed natural RASs, and the prevalence of multiclass-resistance was 7.3% (29/372 patients analysed). NS3-RASs were particularly common in GT1a and GT1b (45.2-10.8%, respectively), mainly due to 80K presence in GT1a (17%). Almost all GTs showed high prevalence of NS5A-RASs (range: 10.2-45.4%), and especially of 93H (5.1%). NS5A-RASs with fold-change >100x were detected in 6.8% GT1a (30H/R-31M-93C/H), 10.3% GT1b (31V-93H), 28.4% GT2c (28C-31M-93H), 8.5% GT3a (30K-93H), 45.5% GT4a (28M-30R-93H) and 3.8% GT4d (28V-30S-93H). Sofosbuvir RAS 282T was never detected, while the 159F and 316N RASs were found in GT1b (13.4-19.1%, respectively). Natural RASs are common in Italian patients infected with HCV-GTs 1-4. High prevalence of clinically-relevant RASs (such as Y93H) supports the appropriateness of HCV resistance-test to properly guide DAA-based therapy.
自然耐药相关取代（RAS）在不同 HCV 基因型（GT）中报道的流行率差异很大。本研究旨在调查意大利一个大型 HCV 感染患者的自然 RAS 频率。对 1445 例 DAA 初治 HCV 感染患者的 NS3、NS5A 和 NS5B 序列进行了分析。464 例 GT1a、585 例 GT1b、92 例 GT2c、199 例 GT3a、16 例 GT4a 和 99 例 GT4d 样本采用自制方案进行 Sanger 测序。总的来说，1455 例患者中有 20.7%（301/1455）出现自然 RAS，372 例分析患者中有 7.3%（29/372）出现多药耐药。GT1a 和 GT1b 中的 NS3-RAS 特别常见（分别为 45.2-10.8%），主要归因于 GT1a 中 80K 的存在（17%）。几乎所有 GT 都显示出 NS5A-RAS 的高流行率（范围：10.2-45.4%），特别是 93H（5.1%）。在 6.8%的 GT1a（30H/R-31M-93C/H）、10.3%的 GT1b（31V-93H）、28.4%的 GT2c（28C-31M-93H）、8.5%的 GT3a（30K-93H）、45.5%的 GT4a（28M-30R-93H）和 3.8%的 GT4d（28V-30S-93H）中检测到 NS5A-RAS 折叠变化>100x。从未检测到索非布韦 RAS282T，而 GT1b 中发现了 159F 和 316N RAS（分别为 13.4-19.1%）。意大利 HCV GT1-4 感染患者中自然 RAS 很常见。临床相关 RAS（如 Y93H）的高流行率支持 HCV 耐药性检测的合理性，以适当指导基于 DAA 的治疗。
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