Nguyen Linh Thuy, Gray Emma, Dean Jonathan, Carr Michael, Connell Jeff, De Gascun Cillian, Nguyen Lan Anh, O'Leary Aisling, Bergin Colm, Hall William, Norris Suzanne
Ireland Vietnam Blood-Borne Virus Initiative (IVVI), Dublin, Ireland and Hanoi, Vietnam.
Antivir Ther. 2015;20(8):865-9. doi: 10.3851/IMP2964. Epub 2015 Apr 29.
The HCV NS3/4A serine protease inhibitors (PIs) boceprevir (BOC), telaprevir (TVR) and simeprevir (SMV) are approved for treatment of chronic hepatitis C infection in combination with pegylated interferon and ribavirin. The present study investigated the prevalence of HCV NS3 drug resistance mutations (DRMs) associated with HCV genotype-1-infected individuals at baseline and in viral breakthrough following BOC and TVR treatment.
HCV genotype-1-infected individuals were enrolled in a multicentre, prospective outcomes study. The HCV NS3 viral protease was analysed for DRMs at baseline (n=164) and at viral breakthrough (n=18) following BOC/TVR treatment.
Viral NS3 protease subtype analysis showed 65.2% (107/164) were HCV subtype-1a and 34.8% (57/164) were HCV subtype-1b infections. Naturally occurring PI DRMs in NS3 (V36L, T54S, V55A, Q80K/R and I132V) were identified in 57.3% (94/164) cases at baseline. The NS3 Q80K polymorphism was found in 43/107 (40.2%) of HCV subtype-1a and exclusively in clade 1 (43/82; 52.4%) versus clade 2 viruses (0/25; 0%, P<10(-6)). The pretreatment I132V variant was found in 78.9% (45/57) of subtype-1b. Of 18 patients who had viral breakthrough, the majority was subtype-1a (77.8%, 14/18). BOC/TVR-associated DRMs were detected in 94.4% (17/18), of which 64.7% (11/17) emerged on-treatment.
To ensure the most appropriate direct-acting antiviral-based treatment regimen is employed, baseline reporting of clade and resistance mutations for HCV subtype-1a using nucleotide sequence-based analysis is warranted prior to commencement of therapy.
丙型肝炎病毒（HCV）NS3/4A丝氨酸蛋白酶抑制剂（PIs）博赛匹韦（BOC）、特拉匹韦（TVR）和西米普明（SMV）已被批准与聚乙二醇干扰素和利巴韦林联合用于治疗慢性丙型肝炎感染。本研究调查了基线时以及接受BOC和TVR治疗后病毒突破时，与HCV基因1型感染个体相关的HCV NS3耐药突变（DRMs）的发生率。
HCV基因1型感染个体被纳入一项多中心前瞻性结局研究。在基线时（n = 164）以及接受BOC/TVR治疗后的病毒突破时（n = 18），对HCV NS3病毒蛋白酶进行DRMs分析。
病毒NS3蛋白酶亚型分析显示，65.2%（107/164）为HCV 1a亚型感染，34.8%（57/164）为HCV 1b亚型感染。在基线时，57.（94/164）的病例中检测到NS3中天然存在的PI DRMs（V36L、T54S、V55A、Q80K/R和I132V）。在43/107（40.2%）的HCV 1a亚型中发现了NS3 Q80K多态性，并且仅在进化枝1（43/82；52.4%）中发现，而在进化枝2病毒中未发现（0/25；0%，P < 10(-6)）。在78.9%（45/57）的1b亚型中发现了治疗前I132V变异。在18例发生病毒突破的患者中，大多数为1a亚型（77.8%，14/18）。在94.4%（17/18）的患者中检测到与BOC/TVR相关的DRMs，其中64.7%（11/17）在治疗期间出现。
为确保采用最合适的基于直接作用抗病毒药物的治疗方案，在开始治疗前，有必要使用基于核苷酸序列的分析对HCV 1a亚型的进化枝和耐药突变进行基线报告。
