Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase.
Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase.
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DOI：
10.1038/s41467-020-19801-x
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发表时间：
2020-12-01
影响因子：
16.6
通讯作者：
Gupta RK
中科院分区：
文献类型：
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作者：
Siedner MJ;Moorhouse MA;Simmons B;de Oliveira T;Lessells R;Giandhari J;Kemp SA;Chimukangara B;Akpomiemie G;Serenata CM;Venter WDF;Hill A;Gupta RK
关于预处理耐药(PDR)对第二代整合酶抑制剂疗效的影响，目前知之甚少。我们对来自高级试验(NCT03122262)的预处理血浆样本进行了测序。我们的主要结果是96周的病毒学成功，定义为12周后持续的病毒载量为1000拷贝/毫升，24周后为200拷贝/毫升，48周后为50拷贝/毫升。在这里，我们报告了由世界卫生组织(WHO)突变列表定义的PDR如何影响这一结果。在1053名试验参与者中，874人(83%)测序成功，其中289人(33%)随机接受基于EFV的治疗，585人(67%)随机接受基于DTG的治疗。14%(12 2/874)具有世卫组织定义的≥1突变，其中98%(12 0/12 2)为NNRTI突变。病毒学抑制率分别为65%(73/112vs85%)、EFV组(60%[12/20]vs86%[214/248]，P=0.002)和DTG组(61/92[66%]vs84%[391/465]P<；0.001，P<0.01)。在根据临床特征和依从性进行调整的多变量模型中，结果相似。治疗前对NNRTI的耐药性与含有整合酶抑制剂的一线方案的长期失败有关，并预示着撒哈拉以南非洲一线方案的高失败率。在这里，作者结合先进临床试验参与者血浆的下一代测序与病毒学和后续数据，调查治疗前对非核苷类逆转录酶抑制剂(NNRTI)的耐药性(PDR)对第二代整合酶抑制剂(NNRTI)疗效的影响，并找到治疗前NNRTI耐药性与长期治疗之间的联系。
Little is known about the impact of pretreatment drug resistance (PDR) on the efficacy of second generation integrase inhibitors. We sequenced pretreatment plasma specimens from the ADVANCE trial (NCT03122262). Our primary outcome was 96-week virologic success, defined as a sustained viral load <1000 copies/mL from 12 weeks onwards, <200 copies/mL from 24 weeks onwards, and <50 copies/mL after 48 weeks. Here we report how this outcome was impacted by PDR, defined by the World Health Organization (WHO) mutation list. Of 1053 trial participants, 874 (83%) have successful sequencing, including 289 (33%) randomized to EFV-based therapy and 585 (67%) randomized to DTG-based therapy. Fourteen percent (122/874) have ≥1 WHO-defined mutation, of which 98% (120/122) are NNRTI mutations. Rates of virologic suppression are lower in the total cohort among those with PDR 65% (73/112) compared to those without PDR (85% [605/713], P < 0.001), and for those on EFV-based treatment (60% [12/20] vs 86% [214/248], P = 0.002) and for those on DTG-based treatment (61/92 [66%] vs 84% [391/465] P < 0.001, P for interaction by regimen 0.49). Results are similar in multivariable models adjusted for clinical characteristics and adherence. NNRTI resistance prior to treatment is associated with long-term failure of integrase inhibitor-containing first-line regimens, and portends high rates of first-line failure in sub Saharan Africa. Here the authors combine next generation sequencing on plasma from participants of the ADVANCE clinical trial with virological and follow-up data to investigate the impact of pre-treatment drug resistance (PDR) to non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the efficacy of second-generation integrase inhibitors and find an association between NNRTI resistance prior to treatment and long-term treatment.