ACTION: Study of ACuTe Infections On Novel HIV Prevention Modalities

项目摘要/摘要 用于治疗和预防的抗逆转录病毒(ARV)药物将是结束艾滋病毒流行的关键。虽然是口头的 暴露前预防(PrEP)非常有效，较少依赖日常依从性的新选项包括 需要最大限度地发挥影响力。长效PrEP时代已经到来，2022年将推出两款新产品。 每月自行植入的达皮韦林阴道环(DVR)正在撒哈拉以南非洲实施，以及 可注射卡波替格韦(CAB)每8周给药一次，现在已得到美国FDA的批准。尽管有…的承诺 这些减少艾滋病毒发病率的方式，急性艾滋病毒感染(AHI)发生在PrEP使用者中，并被看到 在硬盘录像机和出租车试验中。PrEP模式下发生AHI的潜在原因包括ARV依从性不足/ 对PrEP试剂的暴露和抗性。随着口服和长效PrEP的扩大，300,000 AHI可能 在未来5年内在PrEP用户中发生。DVR在试验中显示出适度的疗效和较高的环粘附性 将是至关重要的。具有高水平的循环ARV耐药性(来自用于治疗的同一类别的ARV)， DVR可能无法阻止抗药性病毒的感染。虽然CAB的疗效在试验中很高，但发生了AHI 尽管按时注射，但仍产生了耐药性。因为同样的药物类别正被用于治疗艾滋病毒 预防和治疗，CAB的耐药性可能使美国和全球成为一线抗逆转录病毒治疗 (ART)养生法无效。此外，CAB水平在药代动力学(PK)尾部持续1年以上 可能进一步增加耐药风险。随着DVR和CAB规模的扩大，关键的知识差距必须 已解决：1)在部署环境中，DVR和CAB上出现AHI的原因是什么？2)哪些行为因素 在AHI之前导致DVR/CAB不合规？3)DVR/CAB抵抗的风险是什么？4)什么是 随后的艾滋病毒治疗结果如何？这项应用促使人们深入研究DVR上AHI的原因 和CAB，利用三项研究，从肯尼亚西部和 在美国进行样本收集、调查、访谈和艺术成果评估。创新的方法将是 用于检测耐药性(下一代测序)、识别新的突变(全基因组 测序)，在诊断前回顾测量ARV暴露(切成 反映连续两周间隔暴露的分段)，并了解DVR/CAB遵守情况 AHI和ART坚持(纵向混合法)。建议的目标是：1)确定 肯尼亚使用DVR的妇女中的艾滋病毒感染情况。2)找出人感染爱滋病毒的原因 在美国使用CAB进行预防3)评估艾滋病毒感染后抗逆转录病毒治疗的后续结果 使用PrEP模式的人。总的来说，这些目标将提供第一次也是最大规模的原因分析 以及在部署设置中对DVR和CAB进行AHI后的结果。这项研究将为解决 关于使用CAB或DVR后的新耐药性以及出现耐药性的药物水平的关键问题，以及 将为DVR、CAB和下一代PrEP模式的最佳实施战略提供参考。

PROJECT SUMMARY/ABSTRACT Antiretroviral (ARV) agents for treatment and prevention will be key to Ending the HIV Epidemic. Although oral pre-exposure prophylaxis (PrEP) is highly effective, new options less dependent on day-to-day adherence are needed to maximize impact. The era of long-acting PrEP has arrived, with rollout of two new products in 2022. The dapivirine vaginal ring (DVR), self-inserted monthly, is being implemented in sub-Saharan Africa, and injectable cabotegravir (CAB), given every 8 weeks, is now approved by the U.S. FDA. Despite the promise of these modalities to reduce HIV incidence, acute HIV infections (AHI) occur among PrEP users and were seen in DVR and CAB trials. Potential causes of AHI on PrEP modalities include inadequate ARV adherence/ exposure and resistance to the PrEP agent. As oral and long-acting PrEP are scaled up, 300,000 AHI could occur among PrEP users in the next 5 years. DVR showed modest efficacy in trials and high ring adherence will be critical. With high levels of circulating ARV resistance (from ARVs in the same class used for treatment), DVR could fail to block infection with resistant virus. While CAB efficacy was high in trials, AHI occurred despite on-time injections and resulted in resistance. Because the same drug classes are being used for HIV prevention and treatment, resistance from CAB could render U.S. and global first-line antiretroviral therapy (ART) regimens ineffective. Moreover, CAB levels persist for over 1 year in a pharmacokinetic (PK) tail that could further increase resistance risk. As DVR and CAB are scaled up, key knowledge gaps must be addressed: 1) What are causes of AHI on DVR and CAB in rollout settings? 2) What behavioral factors contribute to DVR/CAB non-adherence prior to AHI? 3) What is the risk of DVR/CAB resistance? 4) What are subsequent HIV treatment outcomes? This application proposes intensive studies of causes of AHI on DVR and CAB, leveraging three studies enrolling persons with AHI from large PrEP programs in western Kenya and the U.S. for sample collection, surveys, interviews, and ART outcomes assessment. Innovative methods will be deployed to detect drug resistance (next-generation sequencing), identify novel mutations (full-genome sequencing), retrospectively measure ARV exposure before diagnosis (PK analysis of hair samples cut into segments reflecting exposure over sequential 2-week intervals), and understand DVR/CAB adherence prior to AHI and ART adherence (longitudinal mixed methods). The proposed aims are: 1) To determine the causes of HIV infection among women using DVR in Kenya. 2) To identify the causes of HIV infection among persons using CAB for prevention in the U.S. 3) To evaluate subsequent outcomes on ART after HIV infection among persons using PrEP modalities. Collectively, these aims will provide the first and largest analysis of causes of and outcomes following AHI on DVR and CAB in rollout settings. This study will pave the way to address crucial questions on novel resistance after CAB or DVR use and drug levels at which resistance emerges, and will inform optimal implementation strategies for DVR, CAB, and next-generation PrEP modalities.