Tong Xiao, Li Lewyn, Haines Kristin, Najera Isabel
Infectious Diseases Discovery, Hoffmann-La Roche, Nutley, New Jersey, USA.
Infectious Diseases Discovery, Hoffmann-La Roche, Nutley, New Jersey, USA
Antimicrob Agents Chemother. 2014 Jun;58(6):3105-14. doi: 10.1128/AAC.02672-13. Epub 2014 Mar 17.
Baseline and posttreatment samples from hepatitis C virus (HCV) genotype (GT) 1-infected patients who received a combination of danoprevir and mericitabine from a phase II clinical study (INFORM-SVR) were analyzed. In addition to resistance monitoring, sequencing and phenotypic assays were combined with statistical analysis to identify potential novel amino acid substitutions associated with treatment outcome. The NS5B S282T substitution associated with mericitabine resistance was identified in 2/30 viral breakthrough patients and was replaced by wild-type viruses after cessation of drug treatment (during follow-up). The NS3 R155K substitution associated with danoprevir resistance was also observed in these 2 patients. All 69 GT 1a-infected patients who experienced viral breakthrough on treatment or relapsed during follow-up (relapsers) developed NS3 R155K. Among GT 1b-infected patients, substitutions at the danoprevir resistance locus NS3 D168 were observed in 15/20 subjects, whereas substitutions at the danoprevir resistance locus NS3 R155 were observed in 5/20 subjects. Interestingly, the baseline polymorphism NS5B Q47H was more prevalent in GT 1a-infected patients who achieved a sustained virologic response at follow-up week 24 (SVR24) than in non-SVR24 patients (2/13 versus 0/72), and a postbaseline NS3 S122G substitution was more prevalent in GT 1a-infected patients with viral breakthrough than in relapsers (4/22 versus 0/47). Neither substitution conferred resistance to danoprevir or mericitabine, but the substitutions reduced (NS5B Q47H) or improved (NS3 S122G) replication capacity by 2- to 4-fold. The NS5B S282T mericitabine-resistant variant was rare and did not persist once drug was discontinued. NS5B Q47H and NS3 S122G are two newly identified substitutions that affected replication capacity and were enriched in distinct treatment response groups. (This study has been registered at ClinicalTrials.gov under registration no. NCT01278134.).
对来自一项II期临床研究（INFORM-SVR）中接受达诺普韦和美利他滨联合治疗的丙型肝炎病毒（HCV）基因1型（GT1）感染患者的基线和治疗后样本进行了分析。除了耐药性监测外，还将测序和表型分析与统计分析相结合，以确定与治疗结果相关的潜在新氨基酸替代。在2/30例病毒突破患者中鉴定出与美利他滨耐药相关的NS5B S282T替代，在停药后（随访期间）被野生型病毒取代。在这2例患者中还观察到与达诺普韦耐药相关的NS3 R155K替代。所有69例在治疗期间发生病毒突破或在随访期间复发（复发者）的GT1a感染患者均出现NS3 R155K。在GT1b感染患者中，15/20例患者在达诺普韦耐药位点NS3 D168处出现替代，而5/20例患者在达诺普韦耐药位点NS3 R155处出现替代。有趣的是，基线多态性NS5B Q47H在随访第24周实现持续病毒学应答（SVR24）的GT1a感染患者中比未实现SVR24的患者更常见（2/13对0/72），并且基线后NS3 S122G替代在发生病毒突破的GT1a感染患者中比复发者更常见（4/22对0/47）。这两种替代均未赋予对达诺普韦或美利他滨的耐药性，但这些替代使复制能力降低（NS5B Q47H）或提高（NS3 S122G）2至4倍。NS5B S282T美利他滨耐药变异罕见，停药后不再持续存在。NS5B Q47H和NS3 S122G是两个新鉴定的影响复制能力的替代，且在不同治疗反应组中富集。（本研究已在ClinicalTrials.gov注册，注册号为NCT01278134。）
