Low-frequency nevirapine resistance at multiple sites may predict treatment failure in infants on nevirapine-based treatment.
Low-frequency nevirapine resistance at multiple sites may predict treatment failure in infants on nevirapine-based treatment.
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DOI：
10.1097/qai.0b013e3182515730
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发表时间：
2012-07-01
期刊：
影响因子：
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通讯作者：
Overbaugh J
中科院分区：
文献类型：
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作者：
Lehman DA;Wamalwa DC;McCoy CO;Matsen FA;Langat A;Chohan BH;Benki-Nugent S;Custers-Allen R;Bushman FD;John-Stewart GC;Overbaugh J
耐药性通常发生在接触单剂量奈韦拉平（sdNVP）以预防母婴传播（PMTCT）的婴儿中。虽然K103N和Y181C在sdNVP后很常见，但多种其他突变也会产生nvp抗性。目前尚不清楚特异性nvp耐药突变或突变组合是否能预测婴儿在nvp治疗前低频率出现的病毒学失败。研究人员对20名暴露于sdnvp的婴儿进行了检查，这些婴儿随后接受了基于nvp的高效抗逆转录病毒治疗（HAART）。采用K103N和Y181C等位基因特异性PCR （ASPCR）和所有NVP原发突变的超深焦磷酸测序（UDPS）检测预处理血浆样本是否存在NVP耐药突变。在长达24个月的NVP-HAART治疗中，每3个月检测一次病毒水平。Cox比例风险模型用于确定病毒衰竭的相关因素。应用ASPCR检测6例患儿治疗前血浆样本中NVP耐药突变K103N或Y181C。在接受检测的20名婴儿中，有10名通过UDPS检测到这些或其他位点的NVP耐药性。检测到任何NVP耐药突变的婴儿中有50%发生病毒学失败，而无耐药的婴儿中只有20%发生病毒失败，但差异无统计学意义（p=0.19）。UDPS检测到的婴儿NVP耐药突变数量的增加与病毒学失败风险的增加显著相关（HR=1.79 (95%CI: 1.07, 2.99), p=0.027）。除了K103N和Y181C外，在基于NVP的治疗前存在于婴儿中的多种NVP耐药突变的低频率可能预测治疗结果。
Resistance commonly arises in infants exposed to single-dose nevirapine (sdNVP) for prevention of mother to child transmission (PMTCT). While K103N and Y181C are common following sdNVP, multiple other mutations also confer NVP-resistance. It remains unclear whether specific NVP-resistance mutations or combinations of mutations predict virologic failure in infants when present at low frequencies prior to NVP-based treatment. Twenty sdNVP-exposed infants who were subsequently treated with NVP-based highly active antiretroviral therapy (HAART) were examined. Pre-treatment plasma samples were tested for the presence of NVP-resistance mutations by allele-specific PCR (ASPCR) for K103N and Y181C and ultra-deep pyrosequencing (UDPS) for all primary NVP mutations. Viral levels were determined every 3 months for up to 24months on NVP-HAART. Cox proportional hazard models were used to determine correlates of viral failure. The NVP resistance mutations K103N or Y181C were detected in pre-treatment plasma samples in 6 infants by ASPCR. NVP resistance at these or other sites was detectable by UDPS in 10 out of 20 infants tested. Virologic failure occurred in 50% of infants with any NVP resistance mutations detected, while only 20% of infants without resistance experienced viral failure, but the difference was not significant (p=0.19). An increase in the number of NVP resistance mutations detectable by UDPS in an infant was significantly associated with an increased risk of virologic failure (HR=1.79 (95%CI: 1.07, 2.99), p=0.027). Low frequencies of multiple NVP resistance mutations, in addition to K103N and Y181C, present in infants before NVP-based treatment may predict treatment outcome.