Jagjit Singh Gurmit Kaur, Kaye Steve, Abbott James C, Boesecke Christoph, Rockstroh Juergen, McClure Myra O, Nelson Mark
a Department of HIV and Sexual Health , Chelsea and Westminster Hospital NHS Foundation Trust , London , UK.
b Division of Infectious Diseases , Imperial College London , London , UK.
HIV Clin Trials. 2018 Apr;19(2):46-51. doi: 10.1080/15284336.2018.1439714. Epub 2018 Mar 1.
Background The epidemic of acute HCV infection among HIV-infected men who have sex with men (MSM) is ongoing. Transmission of drug-resistant variants (DRVs) after HCV treatment failure could pose a major threat to the effectiveness of future therapies. We determined the baseline prevalence of pre-existing DRVs in the HCV NS3 protease gene and their effects on the addition of telaprevir (TVR) to standard pegylated interferon and ribavirin (PEG-IFN/RBV) for acute HCV infection in individuals enrolled in a multicentre randomized controlled trial (2013 and 2014). Methods The HCV NS3 viral protease was analyzed using Sanger and next-generation sequencing (NGS) for DRVs at baseline (n = 31), and at viral breakthrough following TVR-based treatment (n = 3) or PEG-IFN/RBV alone (n = 2). Results Sequence analysis indicated that all individuals were infected with HCV genotype 1a. Complete (100%) concordance was seen between Sanger and NGS for high levels of mutant viral populations. The simeprevir-associated Q80K variant was present at high frequency in the German samples (7/11-64%) and infrequently in the UK samples (1/20-5%). In the three TVR-based treatment failures, V36M/l and R155K/T emerged, but not R155G which was detectable at low levels in two individuals at baseline. Failure rate at week 24 was 26.7% (with baseline DRVs) vs. 6.3% (without baseline DRVs), p = 0.17). Comparison of sequences pre- and post-therapy in 5 who failed therapy revealed the emergence of not previously described variants V193G, E176K, P189S (on TVR), and V181S in one instance each. Conclusion The presence of baseline DRVs for the NS3 protease gene of HCV genotype 1a did not appear to predict treatment failure in our patient cohort. Where detected, Q80K was present at high levels (>98%), but had no effect on outcomes and remained high after failure.
背景 艾滋病毒感染的男男性行为者（MSM）中急性丙型肝炎病毒（HCV）感染的流行仍在持续。HCV治疗失败后耐药变异株（DRV）的传播可能对未来治疗的有效性构成重大威胁。我们确定了参加一项多中心随机对照试验（2013年和2014年）的个体中，HCV NS3蛋白酶基因中预先存在的DRV的基线患病率及其对在标准聚乙二醇化干扰素和利巴韦林（PEG-IFN/RBV）基础上加用特拉匹韦（TVR）治疗急性HCV感染的影响。方法 使用桑格测序法和下一代测序（NGS）分析HCV NS3病毒蛋白酶的基线（n = 31）以及基于TVR治疗后的病毒突破期（n = 3）或单独使用PEG-IFN/RBV后的病毒突破期（n = 2）的DRV情况。结果 序列分析表明所有个体均感染HCV 1a基因型。对于高水平的突变病毒群体，桑格测序法和NGS的结果完全（100%）一致。simeprevir相关的Q80K变异株在德国样本中高频出现（7/11 - 64%），在英国样本中出现频率较低（1/20 - 5%）。在3例基于TVR的治疗失败病例中，出现了V36M/l和R155K/T变异，但未出现基线时在2例个体中低水平检测到的R155G变异。第24周时的失败率为26.7%（有基线DRV）对比6.3%（无基线DRV），p = 0.17）。对5例治疗失败患者治疗前后的序列比较显示出现了之前未描述的变异株V193G、E176K、P189S（在TVR治疗中）以及各有1例出现的V181S变异。结论 在我们的患者队列中，HCV 1a基因型NS3蛋白酶基因基线DRV的存在似乎不能预测治疗失败。在检测到的病例中，Q80K变异株高水平存在（>98%），但对治疗结果无影响，治疗失败后仍保持高水平。
