Nevirapine Resistance in Women who Received Nevirapine for PMTCT HIV

描述(申请人提供)：艾滋病毒-1在南部非洲流行的特点是由C亚型引起的感染占主导地位，这是博茨瓦纳的主要亚型，那里的成年人艾滋病毒流行率估计为37%。世界卫生组织的目标是到2005年向300万人提供抗逆转录病毒药物，这将使大量人有机会变得健康，并在艾滋病毒携带者中过上富有成效的生活。然而，在引入抗逆转录病毒药物的同时，需要对非B亚型分支中的病毒耐药性进行进一步研究，因为关于这些亚型中的耐药性的知识有限。需要检验的中心假设是，更灵敏的检测方法可以检测接受奈韦拉平预防母婴传播(PMTCT)的妇女的病毒耐药性，并且一旦妇女开始抗逆转录病毒药物，这一信息可以预测临床结果。为了解决这一假设，我们正在优化寡核苷酸连接分析和等位基因特异性实时聚合酶链式反应技术，对已知包含耐药突变的样本进行检测。这些针对HIV-1C的检测将用于临床样本，以检测导致奈韦拉平耐药性的两个最常见部位的突变。将探索微小变异耐药性的临床相关性，因为这些技术将应用于接受PMTCT后常规基因分型技术未检测到耐药性突变的女性样本。如果通过这些更敏感的方法检测到导致临床病毒学失败的微小变异，这些变异可能在解释接受非核苷逆转录酶抑制剂治疗的患者的病毒学失败方面发挥重要作用。进行的分析还将解决诸如突变随时间的持久性以及在单剂量奈韦拉平后不同病毒库的耐药性模式变化等问题。这项研究的公共卫生意义重大，因为它将提供更全面的了解单剂量奈韦拉平后的耐药性，并将其与接受这种疗法然后开始服用ARV的妇女的临床结果相关联。研究单剂后奈韦拉平的耐药性及其对未来孕产妇健康的影响，有助于增加关于非B亚型艾滋病毒耐药性问题的知识基金，有助于制定有关预防母婴传播的公共政策，并有助于在资源匮乏的环境中迅速扩大抗逆转录病毒使用期间改善对患者的护理。

DESCRIPTION (provided by applicant): The epidemic of HIV-1 in southern Africa is characterized by the predominance of infections caused by subtype C. This is the major subtype in Botswana where HIV prevalence in adults is estimated to be 37%. The goals of the World Health Organization to provide antiretrovirals (ARVs) to three million people by 2005 will provide an opportunity for great numbers of people to become healthy and live productive lives with HIV. This introduction of ARVs, however, needs to be accompanied by further research into viral resistance in the non-subtype B clades as limited knowledge exists about resistance in these subtypes. The central hypothesis to be examined is that more sensitive assays can detect viral resistance in women who have received nevirapine for the prevention of mother-to-child transmission (PMTCT) and that this information can predict clinical outcomes once the women commence ARVs. To address this hypothesis, we are optimizing both an oligonucleotide ligation assay and allele specific real time-polymerase chain reaction technique on samples which are known to contain resistant mutations. These assays, specific to HIV-1 C, will be used on clinical samples to detect mutations at the two most common sites which confer nevirapine resistance. The clinical relevance of minor variant resistance will be explored as these techniques will be applied to samples from women in whom conventional genotyping techniques have not detected resistance mutations after receiving PMTCT. If minor variants causing clinical virologic failure are detected by these more sensitive methods, these variants may have an important role in explaining virologic failure in patients receiving nonnucleoside reverse transcriptase inhibitor therapy. The analyses conducted will also address issues such as the persistence of mutations over time and variations in resistance patterns across different viral reservoirs after single-dose nevirapine. The public health implications of this research are significant in that it will provide a more complete understanding of resistance after single-dose nevirapine and correlate it with clinical outcomes for the women who receive this therapy and then start on ARVs. Research into nevirapine resistance after single-dose and its impact on future maternal health can help to increase the fund of knowledge about issues of resistance in non-subtype B HIV, help with public policy decisions about PMTCT, and serve to improve the care of patients during the rapid expansion of ARV use in resource-poor settings.