HIV-1 reverse transcriptase (RT) genotype and susceptibility to RT inhibitors during abacavir monotherapy and combination therapy
HIV-1 reverse transcriptase (RT) genotype and susceptibility to RT inhibitors during abacavir monotherapy and combination therapy
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DOI：
10.1097/00002030-200001280-00012
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发表时间：
2000-01-28
期刊：
影响因子：
3.8
通讯作者：
Tisdale, M
中科院分区：
文献类型：
--
作者：
Miller, V;Ait-Khaled, M;Tisdale, M
目的：研究在最初的阿巴卡韦单药治疗阶段加上齐多夫定和拉米夫定后HIV-1易感性（基因型和表型）的变化。设计：60名HIV-1感染、未接受抗逆转录病毒治疗的受试者随机接受100,300或600mg阿巴卡韦，每日两次。完成24周随机治疗或符合方案定义的转换标准的受试者可以切换到开放标签的阿巴卡韦/齐多夫定/拉米夫定。方法：在基线、第12周和ABC单药治疗的最后一个时间点进行血浆HIV-1逆转录酶基因分型。使用重组病毒试验分析基线和随后具有足够HIV-1 RNA水平的样品的药物敏感性。病毒学应答（第24周）与第24周基因型相关。结果：除1例受试者外，12周前未检出突变病毒。在阿巴卡韦单药治疗的最新时间点（范围，6-48周），43名受试者中有21名携带具有耐药突变的病毒，包括K65R、L74V、Y115F和M184V的单、双和三重组合。最常见的突变模式为L74V + M184V（11/21例）。在21名分离株含有阿巴卡韦病毒相关突变的受试者中，有20人达到了48周，在添加拉米夫定/齐多夫定后，20人中有16人（80%）的48周血浆hiv -1 rna低于400拷贝/ml。第48周，获得46个基因型中的16个；其中一个是野生型；其中15只含有M184V，或与K65R和/或L74V和/或Y115F联合，或与胸腺嘧啶类似物相关突变。这15名受试者第48周的病毒载量水平较低(中位数为3.43 log（10) copies/ml或比基线减少-1.99 log(10) copies/ml）。基因型与ABC抗性表型相关；具有3个阿巴卡韦相关突变的4个样本具有高水平的阿巴卡韦耐药性（8倍），具有2个或3个突变的6个样本显示中等水平的阿巴卡韦耐药性（4-8倍）。所有具有单突变的样本都保留了完全的ABC易感性。结论：在单药治疗阶段，对阿巴卡韦产生耐药性的突变相对较慢，并不妨碍阿巴卡韦/拉米夫定/齐多夫定长达48周的持久疗效。(C) 2000 Lippincott Williams & Wilkins。
Objective: To examine changes in HIV-1 susceptibility (genotype and phenotype) during an initial abacavir monotherapy phase followed by the addition of zidovudine and lamivudine.Design: Sixty HIV-1 infected, antiretroviral therapy-naive subjects were randomized to receive 100, 300 or 600 mg abacavir twice daily. Subjects completing 24 weeks of randomized therapy or meeting a protocol defined switch criterion could switch to open label abacavir/zidovudine/lamivudine.Methods: Plasma HIV-1 reverse transcriptase was genotyped at baseline, week 12, and at the last time point on ABC monotherapy. Drug susceptibility was analysed at baseline and on subsequent samples with sufficient HIV-1 RNA levels using the recombinant virus assay. Virological responses (week 24) were correlated to week 24 genotypes.Results: Mutant viruses were not detected before week 12 with the exception of one subject. At the latest time point on abacavir monotherapy (range, weeks 6-48), 21 out of 43 subjects harboured virus with resistance conferring mutations including single, double and triple combinations of K65R, L74V, Y115F and M184V. The most common mutational pattern was L74V + M184V (11/21 cases). Twenty of the 21 subjects with isolates containing abacavir-associated mutations reached week 48, and upon addition of lamivudine/zidovudiine, 16 out of 20 (80%) had week 48 plasma HIV-1-RNA below 400 copies/ml. At week 48, 16 out of 46 genotypes were obtained; one of these was wild-type; 15 contained M184V either alone, in combination with K65R and/or L74V and/or Y115F or with thymidine analogue-associated mutations. Week 48 viral load levels for these 15 subjects was low (median 3.43 log(10) copies/ml or -1.99 log(10) copies reduction from baseline). Genotype correlated well with phenotypic resistance to ABC; four samples with three abacavir-associated mutations had high level abacavir resistance (> 8-fold) and six samples with two or three mutations showed intermediate (4-8-fold) resistance. All samples with single mutations retained full ABC susceptibility.Conclusions: Resistance conferring mutations to abacavir were relatively slow to develop during the monotherapy phase, and did not preclude durable efficacy of abacavir/lamivudine/zidovudine up to 48 weeks. (C) 2000 Lippincott Williams & Wilkins.