ACTION: Study of ACuTe Infections On Novel HIV Prevention Modalities

行动：针对新型 HIV 预防方式的 ACuTe 感染研究

基本信息

批准号：
10653261
负责人：
Catherine Anne Stimets Koss
金额：
$ 77.72万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653261
关键词：
AIDS prevention Acceleration Acute Address Adherence Africa South of the Sahara Anti-Retroviral Agents Antiretroviral resistance Behavior Behavior assessment Behavioral Clinical Dapivirine Data Diagnosis Diagnostic Drug Kinetics Drug resistance Enrollment Epidemic FDA approved Failure Future HIV HIV Infections HIV diagnosis Hair Health Incidence Individual Infection Injectable Injections Interview Kenya Knowledge Laboratories Lead Measures Methods Modality Mutation Oral Outcome Outcome Assessment Participant Persons Pharmaceutical Preparations Phenotype Plasma Population Study Prevention Public Health Recording of previous events Regimen Research Personnel Resistance Risk Risk Reduction Sampling Sapphire Services Surveys Tail Testing Time Treatment outcome United States Vaginal Ring Viral Viremia Virus Woman acute infection antiretroviral therapy drug testing genome sequencing implementation strategy improved innovation next generation next generation sequencing novel population health pre-exposure prophylaxis programs resistance mutation sample collection scale up success therapy adherence therapy outcome whole genome

项目摘要

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.

项目概要/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，新的选择较少依赖于日常依从性需要最大限度地发挥影响力。长效 PrEP 时代已经到来，两款新产品将于 2022 年推出。每月自行置入的达匹韦林阴道环 (DVR) 正在撒哈拉以南非洲实施，每 8 周注射一次的卡博特韦 (CAB) 现已获得美国 FDA 批准。尽管许诺这些方法可降低 HIV 发病率，但 PrEP 使用者中发生急性 HIV 感染 (AHI)，并且已被观察到在 DVR 和 CAB 试验中。 PrEP 模式中 AHI 的潜在原因包括 ARV 依从性不足/ PrEP 剂的暴露和耐药性。随着口服和长效 PrEP 的规模扩大，300,000 AHI 可以未来 5 年内，这种情况将在 PrEP 用户中发生。 DVR 在试验中显示出适度的功效，并且环依从性很高将是至关重要的。具有高水平的循环抗逆转录病毒药物耐药性（来自用于治疗的同类抗逆转录病毒药物）， DVR 可能无法阻止耐药病毒的感染。虽然试验中 CAB 的疗效很高，但发生了 AHI 尽管按时注射并导致耐药性。因为相同的药物类别正在用于治疗艾滋病毒预防和治疗，CAB 耐药性可能使美国和全球成为一线抗逆转录病毒治疗（ART）治疗方案无效。此外，CAB 水平在药代动力学 (PK) 尾部持续超过 1 年，可能会进一步增加抵抗风险。随着 DVR 和 CAB 的规模扩大，关键知识差距必须得到解决已解决：1) 在部署设置中 DVR 和 CAB 上出现 AHI 的原因是什么？ 2）哪些行为因素 AHI 之前是否会导致 DVR/CAB 不依从？ 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？该应用建议深入研究 DVR 上 AHI 的原因和 CAB，利用三项研究，招募来自肯尼亚西部大型 PrEP 项目的 AHI 患者，美国进行样本收集、调查、访谈和 ART 结果评估。创新方法将用于检测耐药性（下一代测序）、识别新突变（全基因组测序），在诊断前回顾性测量 ARV 暴露（对剪成的头发样本进行 PK 分析）反映连续两周间隔内的暴露情况的片段），并在之前了解 DVR/CAB 的遵守情况 AHI 和 ART 依从性（纵向混合方法）。拟议的目标是： 1) 确定造成问题的原因肯尼亚使用 DVR 的妇女感染艾滋病毒。 2) 查明人类感染艾滋病毒的原因在美国使用 CAB 进行预防 3) 评估 HIV 感染后 ART 的后续结果使用 PrEP 方式的人。总的来说，这些目标将提供对问题原因的首次也是最大的分析。以及部署设置中 DVR 和 CAB 上的 AHI 后的结果。这项研究将为解决这一问题铺平道路关于使用 CAB 或 DVR 后出现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 模式的最佳实施策略提供信息。