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: 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
• 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

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.

项目摘要/摘要 用于治疗和预防的抗逆转录病毒（ARV）剂将是结束HIV流行的关键。虽然口服 暴露前预防（PREP）是非常有效的，新的选择较少依赖日常遵守 需要最大程度地影响影响。长效准备的时代已经到来，在2022年推出了两种新产品。 Dapivirine阴道环（DVR），每月自插，正在撒哈拉以南非洲实施， 每8周给出一次可注射的Cabotegravir（CAB），现在已由美国FDA批准。尽管承诺 这些降低艾滋病毒发病率的方式，急性艾滋病毒感染（AHI）发生在准备用户中，并被发现 在DVR和驾驶室试验中。 AHI以准备方式的潜在原因包括ARV依从性不足/ 对准备剂的暴露和阻力。随着口头和长效准备的规模，300,000 AHI可以 在未来5年中，预备用户之间发生。 DVR在试验和高环依从性中显示出适中的功效 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中的ARV）， DVR可能无法用抗性病毒阻止感染。虽然驾驶室功效在试验中很高，但发生了AHI 尽管按时注射并导致阻力。因为同一药物类用于艾滋病毒 预防和治疗，CAB的阻力可以使美国和全球一线抗逆转录病毒疗法 （艺术）方案无效。此外，驾驶室水平在药代动力学（PK）尾巴中持续1年以上 可能会进一步增加抵抗风险。随着DVR和CAB的扩展，关键知识差距必须是 地址：1）DVR和CAB在推出设置中的AHI原因是什么？ 2）什么行为因素 在AHI之前有助于DVR/CAB不遵守？ 3）DVR/CAB阻力的风险是什么？ 4）是什么 随后的HIV治疗结果？该申请提出了对DVR的AHI原因的深入研究 和出租车，利用三项研究在肯尼亚西部的大型预备计划中招募AHI的研究和 美国进行样本收集，调查，访谈和艺术成果评估。创新方法将是 部署以检测耐药性（下一代测序），识别新型突变（全基因组 测序），回顾性测量诊断之前的ARV暴露（PK分析头发样品 反映在连续2周间隔内暴露暴露的段），并在之前了解DVR/CAB的依从性 AHI和艺术依从性（纵向混合方法）。拟议的目的是：1）确定 使用肯尼亚DVR的妇女中的艾滋病毒感染。 2）确定患者之间艾滋病毒感染的原因 使用CAB在美国预防3）评估艾滋病毒感染后随后的艺术结果 使用准备方式的人。总的来说，这些目标将提供第一和最大的原因分析 以及在DVR上AHI和CAB的结果，在推出设置中。这项研究将为解决 关于出现抗药性后出现抗药性后新型阻力的关键问题，其抗药性出现，并且 将为DVR，CAB和下一代准备模式提供最佳实施策略。