Novel Strategy for HIV Drug Resistance Monitoring in Developing Countries.

说明(申请人提供)：全球抗逆转录病毒治疗艾滋病毒感染的使用增加，这是一项非常必要和有价值的成就，因为治疗的迅速扩大拯救了数千人的生命。增加使用这些药物的一个自然副产品是在治疗失败的患者中获得耐药性，最终将导致传播性耐药性。传播耐药性增加的时间尚不清楚，从而影响国家抗逆转录病毒疗法(ART)计划，但在资源有限的地区，在进入护理时检测所有人的耐药性是不可行的，因此需要替代战略来监测耐药性。我们假设，在博茨瓦纳可以通过新的策略监测传播的耐药性。在具体目标1中，我们建议使用世界卫生组织(WHO)开发的监测方法，以及我们汇集样本和应用高灵敏分析来检测对一线抗逆转录病毒治疗至关重要的耐药性突变的新策略，在博茨瓦纳连续四年进行艾滋病毒传播耐药性监测。这一战略将通过世卫组织方案获得的标准基因分型结果进行验证。在具体目标2中，我们将这种汇集样本的方法仅限于那些最近感染艾滋病毒的人，以了解这是否提高了我们监测传播耐药的能力，并将密切评估传播对，以了解伴侣之间的传播动态。在具体目标3中，我们将比较检测艾滋病毒耐药性的汇集策略和标准的内部基因分型技术，以确定这种基因分型方法是否在抗逆转录病毒治疗启动之前提供有意义的、成本效益高的结果。通过这项技术产生的数据将再次集中在与一线ART相关的突变上，以帮助临床医生预测这种治疗的成功。将在这项研究中进行的研究将通过传统和新技术描述博茨瓦纳传播耐药性的现状，并确定在资源有限的地区监测艾滋病毒耐药性出现的新战略的可行性；监测的基本组成部分，以确保博茨瓦纳的抗逆转录病毒治疗计划继续成功。 公共卫生相关性：随着更多的抗逆转录病毒疗法的出现，在资源有限的地区，传播的艾滋病毒耐药性无疑将增加，这种耐药性将影响国家抗逆转录病毒计划的成功。这项建议的目标是：1)除了使用世卫组织推荐的监测方法外，评估博茨瓦纳传播的耐药性的程度；以及(3)评估在启动抗逆转录病毒治疗之前，是否可用一种新的、成本更低的方法来确定对一线抗逆转录病毒治疗至关重要的耐药突变；2)仅评估那些最近感染艾滋病毒的人，以加强我们监测传播耐药性的能力和研究病毒在伴侣之间传播的动态；3)评估在开始抗逆转录病毒治疗之前类似技术是否可作为基因分型的低成本替代方法。这些结果将扩大我们对博茨瓦纳艾滋病毒耐药性现状的了解，并可能提供成本较低的监测耐药性的战略。

DESCRIPTION (provided by applicant): The increase in antiretroviral use globally to treat HIV infections has been a much needed and worthy achievement as many thousands of lives have been saved by the rapid expansion of treatment. A natural byproduct of the increased use of these medications is the acquisition of drug resistance in patients failing therapy that will ultimately result in transmitted drug resistance. The timing of the increase in transmitted resistance, so that it impacts national antiretroviral therapy (ART) programs, is unclear, but in resource-limited regions, where it is not feasible to test all individuals for drug resistance at the time they enter care, alternative strategies to monitor resistance are needed. We hypothesize that transmitted drug resistance can be monitored with novel strategies in Botswana. In Specific Aim 1, we propose to conduct surveillance for transmitted HIV drug resistance in Botswana for four consecutive years using a surveillance method developed by the World Health Organization (WHO) in addition to our novel strategy of pooling samples and applying highly sensitive assays to detect drug resistance mutations critical to 1st line ART. This strategy will be validated by the standard genotyping results obtained by the WHO protocol. In Specific Aim 2, we restrict this method of pooling samples to only those individuals with recent HIV infection to see if this improves our ability to monitor transmitted drug resistance and also will closely evaluate transmission pairs to learn about the dynamics of transmission between partners. In Specific Aim 3, we will compare a pooling strategy to detect HIV drug resistance with a standard in-house genotyping technique to determine if this approach to genotyping provides meaningful, cost-effective, results prior to ART initiation. The data generated by this technique would again focus on those mutations relevant to 1st line ART to aid clinicians in predicting success of this therapy. The studies to be performed in this research will characterize the current state of transmitted drug resistance in Botswana by conventional and novel techniques and determine the feasibility of new strategies to monitor for the emergence of HIV drug resistance in resource-limited regions; essential components of monitoring to ensure the continued success of the ART program in Botswana. PUBLIC HEALTH RELEVANCE: Transmitted HIV drug resistance will undoubtedly increase in resource-limited regions as more antiretroviral therapy becomes available and this resistance will impact the success of national antiretroviral programs. The goals of this proposal are to: 1) Evaluate the extent of transmitted drug resistance in Botswana using the WHO recommended surveillance method in addition to a novel, less expensive approach that identifies those resistance mutations critical to 1st line antiretroviral therapy; 2) To evaluate only those with recent HIV infection to enhance our ability to monitor transmitted drug resistance and to study the dynamics of viral transmission between partners; and 3) To assess if similar techniques can serve as a low cost alternative to genotyping prior to the initiation of antiretroviral treatment. These results will expand our knowledge about the current state of HIV drug resistance in Botswana and possibly provide less expensive strategies to monitor for resistance.