Minority Quasispecies of Drug-Resistant HIV-1 That Lead to Early Therapy Failure in Treatment-Naive and -Adherent Patients
Minority Quasispecies of Drug-Resistant HIV-1 That Lead to Early Therapy Failure in Treatment-Naive and -Adherent Patients
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DOI：
10.1086/595703
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发表时间：
2009-01-15
影响因子：
11.8
通讯作者：
Cavassini, Matthias
中科院分区：
文献类型：
--
作者：
Metzner, Karin J.;Giulieri, Stefano G.;Cavassini, Matthias
背景。抗逆转录病毒治疗的早期病毒学失败与在初治患者中选择耐药人类免疫缺陷病毒 1 型相关，这一点非常关键，因为病毒学失败会显着增加后续失败的风险。因此，我们评估了 1 型耐药人类免疫缺陷病毒的少数准种对于早期病毒学失败的可能作用，这些准种在基线时通过群体测序无法检测到。我们研究了 4 名在拉米夫定、替诺福韦、依非韦伦或奈韦拉平一线治疗方案中经历早期病毒学失败的患者，以及 18 名接受类似治疗但未出现病毒学失败的对照患者。通过在早期病毒学治疗失败之前和期间对血浆样本进行等位基因特异性实时聚合酶链反应，对逆转录酶中的关键突变 K65R、K103N、Y181C、M184V 和 M184I 进行定量。结果。治疗前，在标准基因型分析中，没有一种病毒显示出任何耐药性的证据。在 18 名对照患者中，有 3 名检测到带有 M184V 突变或 M184I 突变的少数准种。相比之下，治疗失败的4名患者在治疗前均存在低频率耐药病毒，频率范围为0.07%-2.0%。每个患者的病毒中均检测到 1-4 个突变。在患者开始抗逆转录病毒治疗后几周内，大多数少数准种被迅速选择并代表主要病毒种群。所有 4 名患者均表现出良好的治疗依从性。在 2 个单独的评估时间，所有 4 名患者的非核苷类逆转录酶抑制剂血浆浓度均处于正常范围。结论。在基线时检测到的少数耐药病毒准种可以迅速生长并成为主要病毒种群，并随后导致接受具有低遗传耐药屏障的抗逆转录病毒治疗方案的初治患者的早期治疗失败。
Background. Early virological failure of antiretroviral therapy associated with the selection of drug-resistant human immunodeficiency virus type 1 in treatment-naive patients is very critical, because virological failure significantly increases the risk of subsequent failures. Therefore, we evaluated the possible role of minority quasispecies of drug-resistant human immunodeficiency virus type 1, which are undetectable at baseline by population sequencing, with regard to early virological failure.Methods. We studied 4 patients who experienced early virological failure of a first-line regimen of lamivudine, tenofovir, and either efavirenz or nevirapine and 18 control patients undergoing similar treatment without virological failure. The key mutations K65R, K103N, Y181C, M184V, and M184I in the reverse transcriptase were quantified by allele-specific real-time polymerase chain reaction performed on plasma samples before and during early virological treatment failure.Results. Before treatment, none of the viruses showed any evidence of drug resistance in the standard genotype analysis. Minority quasispecies with either the M184V mutation or the M184I mutation were detected in 3 of 18 control patients. In contrast, all 4 patients whose treatment was failing had harbored drug-resistant viruses at low frequencies before treatment, with a frequency range of 0.07%-2.0%. A range of 1-4 mutations was detected in viruses from each patient. Most of the minority quasispecies were rapidly selected and represented the major virus population within weeks after the patients started antiretroviral therapy. All 4 patients showed good adherence to treatment. Nonnucleoside reverse-transcriptase inhibitor plasma concentrations were in normal ranges for all 4 patients at 2 separate assessment times.Conclusions. Minority quasispecies of drug-resistant viruses, detected at baseline, can rapidly outgrow and become the major virus population and subsequently lead to early therapy failure in treatment-naive patients who receive antiretroviral therapy regimens with a low genetic resistance barrier.