Rapid accumulation of HIV-1 thymidine analogue mutations and phenotypic impact following prolonged viral failure on zidovudine-based first-line ART in sub-Saharan Africa
Rapid accumulation of HIV-1 thymidine analogue mutations and phenotypic impact following prolonged viral failure on zidovudine-based first-line ART in sub-Saharan Africa
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DOI：
10.1093/jac/dkw583
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发表时间：
2017-05-01
影响因子：
5.2
通讯作者：
Gupta, Ravindra K.
中科院分区：
文献类型：
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作者：
Goodall, Ruth L.;Dunn, David T.;Gupta, Ravindra K.
背景：已知缺乏ART病毒载量监测与从失败的方案转换较慢，从而导致较高的多药耐药HIV-1流行率有关。许多国家继续使用胸苷类似物，尽管建议将替诺福韦与胞嘧啶类似物联合使用，并将NNRTI作为一线抗逆转录病毒药物。累积的胸腺嘧啶核苷类似物突变(TAMS)对表型耐药的影响在非洲环境中一直没有得到很好的描述。患者和方法：在Nora(NeviRapine或Abacavir)研究中，对48至96周持续病毒失败的个体进行了回顾性分析。我们分析了48周和96周一线抗逆转录病毒疗法的36对基因型(14例用齐多夫定/拉米夫定/奈韦拉平治疗，22例用齐多夫定/拉米夫定/阿巴卡韦治疗)。结果：在96周时，接受奈韦拉平和阿巴卡韦治疗的患者中分别有50%和73%的患者出现广泛的TAMS(>；=3个突变)。服用奈韦拉平的受试者在48周至96周期间累积的TAMs的平均(SE)数为1.50(0.37)，服用阿巴卡韦的受试者为1.82(0.26)。总体而言，在48周[几何平均折叠变化(FC)1.3]至96周(3.4，P=0.01)之间，病毒对齐多夫定的敏感性降低。替诺福韦的敏感性略有下降(FC分别为0.7和1.0，P=0.18)。结论：一线抗逆转录病毒药物治疗的持续失败与耐药性的迅速增加有关，有效的病毒载量监测可以缓解这种情况。
Background: Lack of viral load monitoring of ART is known to be associated with slower switch from a failing regimen and thereby higher prevalence of MDR HIV-1. Many countries have continued to use thymidine analogue drugs despite recommendations to use tenofovir in combination with a cytosine analogue and NNRTI as firstline ART. The effect of accumulated thymidine analogue mutations (TAMs) on phenotypic resistance over time has been poorly characterized in the African setting.Patients and methods: A retrospective analysis of individuals with ongoing viral failure between weeks 48 and 96 in the NORA (Nevirapine OR Abacavir) study was conducted. We analysed 36 genotype pairs from weeks 48 and 96 of first-line ART (14 treated with zidovudine/lamivudine/nevirapine and 22 treated with zidovudine/lamivudine/abacavir). Phenotypic drug resistance was assessed using the Antivirogram assay (v.2.5.01, Janssen Diagnostics).Results: At 96 weeks, extensive TAMs (>= 3mutations) were present in 50% and 73% of nevirapine-and abacavir-treated patients, respectively. The mean (SE) number of TAMs accumulating between week 48 and week 96 was 1.50 (0.37) in nevirapine-treated participants and 1.82 (0.26) in abacavir-treated participants. Overall, zidovudine susceptibility of viruses was reduced between week 48 [ geometric mean fold change (FC) 1.3] and week 96 (3.4, P = 0.01). There was a small reduction in tenofovir susceptibility (FC 0.7 and 1.0, respectively, P = 0.18).Conclusions: Ongoing viral failure with zidovudine-containing first-line ART is associated with rapidly increasing drug resistance that could be mitigated with effective viral load monitoring.