Novel virologic and pharmacologic assays to predict clinical outcomes after first-line ART failure in sub-Saharan Africa

项目摘要 2014年，联合国艾滋病规划署推出了艾滋病毒控制的“90-90-90”目标，其中包括90%的抗逆转录病毒治疗者是 病毒学抑制。为了实现这些治疗目标，需要在以下方面取得更多进展： 撒哈拉以南非洲，据报道，一线抗逆转录病毒治疗失败率高达三分之一 个体和增加的耐药性率使有效治疗这些患者的努力复杂化。 对于在一线ART治疗中发生病毒学失败（VF）的患者，目前尚不确定 个体应维持其一线ART方案，并应转换为二线 方案.多项研究表明，传统的基于桑格的基因型检测可能不准确， 预测这些情况下的临床结果。VF通常发生在那些服用高血糖方案的患者中。 通过标准桑格测序技术测定的基因型易感性评分（GSS），和 相反，病毒学抑制常常发生在接受低GSS方案的患者中。这项研究带来了 来自美国的经验丰富的临床研究人员、病毒学家、药理学家和生物统计学家团队 美国和非洲确定维持一线ART或维持一线ART后VF的预测因子 本研究将利用现有临床试验的储存样本， 创新的病毒测序和药理学技术，以评估任何一种方法的VF风险。的 拟议的研究将直接解决与耐药性和药物治疗有关的关键知识差距 依从性，并最终旨在改善一线ART失败患者的临床管理 于撒哈拉以南非洲的在这一人群中优化治疗策略对于预防药物滥用至关重要。 抵抗力，控制流行病，并确保艾滋病毒项目的长期可持续性。

PROJECT SUMMARY In 2014, UNAIDS introduced the “90-90-90” targets for HIV control, including that 90% of those on ART are virologically suppressed. In order to reach these treatment goals, additional progress will need to be made in sub-Saharan Africa, where rates of 1st-line antiretroviral treatment (ART) failure are reportedly as high as 1 in 3 individuals and increasing rates of drug resistance are complicating efforts to effectively treat these patients. For patients experiencing virologic failure (VF) on 1st-line ART, there is currently uncertainty over which individuals should be maintained on their 1st-line ART regimen and who should be switched to a 2nd-line regimen. Multiple studies have indicated that traditional Sanger-based genotypic testing might not accurately predict clinical outcomes in these situations. VF commonly occurs in those taking regimens with a high genotypic susceptibility scores (GSS) as determined by standard Sanger sequencing techniques, and conversely, virologic suppression often occurs in patients on regimens with a low GSS. This study brings together an experienced team of clinical researchers, virologists, pharmacologists, and biostatisticians from the United States and Africa to determine the predictors of VF either with maintenance of 1st-line ART or after switch to 2nd-line ART. This study will leverage stored samples from existing clinical trials combined with innovative viral sequencing and pharmacologic technologies to assess the risk of VF with either approach. The proposed studies will directly address key knowledge gaps related to drug resistance and medication adherence, and are ultimately intended to improve the clinical management of patients with 1st-line ART failure in sub-Saharan Africa. Optimizing treatment strategies in this population is critical for preventing drug resistance, controlling the epidemic, and ensuring the long-term sustainability of HIV programs.