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

• 批准号: 10547683
• 负责人: Catherine Anne Stimets Koss
• 金额: $ 81.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/10547683
• 关键词: AIDS prevention; Acute; Address; Adherence; Africa South of the Sahara; Anti-Retroviral Agents; Antiretroviral resistance; Behavior; Behavioral; Centers for Disease Control and Prevention (U.S.); Clinical; Dapivirine; Data; Diagnosis; Diagnostic; Drug Kinetics; Drug resistance; Enrollment; Epidemic; FDA approved; Failure; Future; HIV; HIV Infections; HIV antiretroviral; 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; Sampling; Sapphire; Services; Surveys; Tail; Testing; Time; Treatment outcome; United States; Vaginal Ring; Viral; Viremia; Virus; Woman; acute infection; antiretroviral therapy; 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; therapy resistant; whole genome

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.

项目总结/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。虽然口服 暴露前预防（PrEP）是非常有效的，新的选择较少依赖于日常的坚持， 需要最大化影响。长效PrEP的时代已经到来，2022年将推出两款新产品。 目前正在撒哈拉以南非洲实施每月自行插入的达匹韦林阴道环， 每8周注射一次的cabotegravir（CAB）现已获得美国FDA的批准。尽管承诺 这些方式，以减少艾滋病毒的发病率，急性艾滋病毒感染（AHI）发生在PrEP用户，并被认为是 在DVR和CAB试验中。PrEP模式下AHI的潜在原因包括抗逆转录病毒药物依从性不足/ 暴露和抵抗PrEP试剂。随着口服和长效PrEP的规模扩大，30万AHI可以 在未来5年内，PrEP用户中发生。DVR在试验中显示出适度的有效性和高环依从性 将至关重要。由于抗逆转录病毒药物的耐药性很高（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CAB在试验中的疗效很高，但AHI发生了 尽管按时注射并导致耐药性。因为同样的药物类别被用于艾滋病毒 预防和治疗，来自CAB的耐药性可能使美国和全球的一线抗逆转录病毒治疗 (ART)治疗无效。此外，CAB水平在药代动力学（PK）尾部持续超过1年， 可能会进一步增加耐药风险。随着DVR和CAB规模的扩大，关键的知识差距必须得到解决。 解决：1）在推出设置中，DVR和CAB上的AHI的原因是什么？2)什么行为因素 在AHI之前是否导致DVR/CAB不依从？3)DVR/CAB电阻的风险是什么？4)是什么 艾滋病后续治疗效果如何？本申请建议深入研究DVR上AHI的原因 和CAB，利用三项研究，从肯尼亚西部的大型PrEP项目中招募AHI患者， 在美国进行样本收集、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），识别新的突变（全基因组测序）， 测序），在诊断前回顾性测量ARV暴露（将头发样本切成 反映连续2周间隔内暴露的片段），并在 AHI和ART依从性（纵向混合方法）。建议的目标是：1）确定的原因， 肯尼亚使用DVR的妇女中的艾滋病毒感染。2)查明艾滋病毒感染者的原因 3）评估艾滋病毒感染后ART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个和最大的分析原因， 和结果后，AHI的DVR和CAB在推出设置。这项研究将为解决以下问题铺平道路 关于CAB或DVR使用后新耐药性的关键问题以及出现耐药性的药物水平，以及 将为DVR、CAB和下一代PrEP模式的最佳实施策略提供信息。