The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy.
The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy.
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DOI：
10.1097/qad.0b013e32832ac34e
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发表时间：
2009-06-01
期刊：
影响因子：
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通讯作者：
Kumwenda J
中科院分区：
文献类型：
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作者：
Hosseinipour MC;van Oosterhout JJ;Weigel R;Phiri S;Kamwendo D;Parkin N;Fiscus SA;Nelson JA;Eron JJ;Kumwenda J
超过15万马拉维人已经开始抗逆转录病毒疗法(ART)，其中一线疗法是司他夫定/拉米夫定/奈韦拉平。在马拉维的利隆圭和布兰太尔，我们根据临床或免疫学标准评估了未能通过一线抗逆转录病毒治疗的患者的耐药性模式。对2006年1月至2007年7月期间符合抗逆转录病毒治疗失败定义(新的或进展性的4期疾病，CD4细胞计数下降超过30%，CD4细胞计数低于治疗前)的患者进行评估。对HIVRNA>1000拷贝/ml的患者进行基因分型。对于复杂的基因分型，进行表型分析。确定了96名确诊的抗逆转录病毒治疗失败患者。CD_4细胞计数中位数(四分位数)为68个/μ(23~174)，HIV-1RNA中位数为4.72拷贝/ml(4.26~5.16)，ART持续时间为36.5月(26.6~49.8)。93%的样本有非核苷类逆转录酶抑制物突变，81%的样本有M184V突变。最常见的模式包括M184V和非核苷逆转录酶抑制物突变，以及至少一个胸腺嘧啶核苷类似物突变(56%)。23%的患者获得了与替诺福韦耐药相关的K70E或K65R突变；17%的患者具有与K65R或K70E相对应的泛核苷耐药和额外的耐药突变，最常见的是151复合体。K65R和K70E突变的出现与L的CD_4细胞计数低于100cell/μ有关(优势比为6.1)，与齐多夫定的使用呈负相关(优势比为0.18)。表型敏感性数据显示，后续治疗中活性最高的核苷逆转录酶抑制剂骨架是齐多夫定/拉米夫定/替诺福韦，其次是拉米夫定/替诺福韦，然后是阿巴卡韦/地达诺辛。当临床和CD4细胞计数标准被用来监测一线ART失败时，出现了广泛的核苷逆转录酶抑制剂和非核苷逆转录酶抑制剂耐药性，大多数患者的耐药性特征明显损害了二线ART的活性。
Over 150 000 Malawians have started antiretroviral therapy (ART), in which first-line therapy is stavudine/lamivudine/nevirapine. We evaluated drug resistance patterns among patients failing first-line ART on the basis of clinical or immunological criteria in Lilongwe and Blantyre, Malawi. Patients meeting the definition of ART failure (new or progressive stage 4 condition, CD4 cell count decline more than 30%, CD4 cell count less than that before treatment) from January 2006 to July 2007 were evaluated. Among those with HIV RNA of more than 1000 copies/ml, genotyping was performed. For complex genotype patterns, phenotyping was performed. Ninety-six confirmed ART failure patients were identified. Median (interquartile range) CD4 cell count, log10 HIV-1 RNA, and duration on ART were 68 cells/μl (23–174), 4.72 copies/ml (4.26–5.16), and 36.5 months (26.6–49.8), respectively. Ninety-three percent of samples had nonnucleoside reverse transcriptase inhibitor mutations, and 81% had the M184V mutation. The most frequent pattern included M184V and nonnucleoside reverse transcriptase inhibitor mutations along with at least one thymidine analog mutation (56%). Twenty-three percent of patients acquired the K70E or K65R mutations associated with tenofovir resistance; 17% of the patients had pan-nucleoside resistance that corresponded to K65R or K70E and additional resistance mutations, most commonly the 151 complex. Emergence of the K65R and K70E mutations was associated with CD4 cell count of less than 100 cells/μl (odds ratio 6.1) and inversely with the use of zidovudine (odds ratio 0.18). Phenotypic susceptibility data indicated that the nucleoside reverse transcriptase inhibitor backbone with the highest activity for subsequent therapy was zidovudine/lamivudine/tenofovir, followed by lamivudine/tenofovir, and then abacavir/didanosine. When clinical and CD4 cell count criteria are used to monitor first-line ART failure, extensive nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor resistance emerges, with most patients having resistance profiles that markedly compromise the activity of second-line ART.