Chemoprophylaxis for HIV Prevention: Analysis of Bone and Metabolic Effects

预防艾滋病毒的化学预防：骨和代谢影响分析

• 批准号: 8992519
• 负责人: DAVID V. GLIDDEN
• 金额: $ 7.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-19 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8992519
• 关键词: AIDS prevention; Adherence; Biological; Biological Assay; Body Composition; Body mass index; Bone Density; Chemoprophylaxis; Clinical Trials; Controlled Clinical Trials; Data; Data Set; Data Sources; Dose; Drug Exposure; Dual-Energy X-Ray Absorptiometry; Effectiveness; Enrollment; Exercise; Exhibits; Funding; HIV; HIV Infections; Hip region structure; Label; Lead; Measurement; Measures; Metabolic; Nature; Oral; Participant; Patients; Persons; Pharmaceutical Preparations; Placebo Control; Placebos; Plasma; Population; Positioning Attribute; Prophylactic treatment; Randomized; Recovery; Research Personnel; Risk; Roentgen Rays; Safety; Sampling; Scanning; Signal Transduction; Subgroup; Tenofovir; Toxic effect; United States Food and Drug Administration; United States National Institutes of Health; Ursidae Family; Vertebral column; Work; antiretroviral therapy; arm; base; bone; bone loss; emtricitabine; follow-up; men; men who have sex with men; novel strategies; open label; partial recovery; prevent; public health relevance; randomized placebo controlled trial; response; risk benefit ratio; sex; trend; truvada

 DESCRIPTION (provided by applicant): HIV Pre-exposure prophylaxis (PrEP) with co-formulated emtricitabine tenofovir (FTC/TDF) in HIV negative persons is a powerful strategy for preventing HIV infection. While FTC/TDF has an excellent overall safety profile, it does produce subtle decreases in bone mineral density (BMD). Men who have sex with men (MSM) bear a major burden of HIV infection worldwide and have been shown to have low bone mineral density even in the absence of FTC/TDF treatment. Hence, understanding the nature of BMD effects of FTC/TDF is important optimizing the risk benefit ratio of PrEP. The investigators have conducted a NIH-funded project that included a randomized placebo controlled trial of FTC/TDF v. placebo for PrEP in a global sample of HIV- MSM at risk of acquiring HIV infection and an open label extension to that trial. As a part of that study, we conducted a substudy of bone and body composition effects in approximately 20% of the study participants who underwent dual x-ray absorptiometry (DEXA) scans. We recently concluded an open-label extension to the original trial. The trial found that PrEP was effective in preventing HIV infection with intent-to-treat effects of a 42% reduction in HIV infection. Comparing the randomization arm in the DEXA substudy found a mean decrease in BMD of 0.6% in the hip and 0.9% in the spine on FTC/TDF compared to placebo. The study had low overall adherence (55% at week 8) and so biological effects of FTC/TDF on bone may be underestimated. Preliminary indications are this decrement is stronger among US-enrolled participants and those with higher bone mineral density but it unclear if this is a differential response to FTC/TDF or merely a surrogate for higher adherence. There is an indication that the decrement in BMD, begins to rebound after FTC/TDF is stopped; however, we have only examined this in the first 6 months after stopping drug. An additional follow-up one year of off-drug follow-up is now available as a part of the open-label extension. We propose to combine data for our randomized study and open label extension to examine changes in BMD after discontinuation of FTC/TDF, explore subgroups most vulnerable to BMD loss from FTC/TDF and attempting to estimate the mean BMD changes expected under perfect adherence. The project concluded in late 2014. Funding this proposal will allow us to pursue important outstanding questions from an available data source.

 描述（由申请方提供）：在HIV阴性人群中使用联合配制的恩曲他滨替诺福韦（FTC/TDF）进行HIV暴露前预防（PrEP）是预防HIV感染的有效策略。虽然FTC/TDF具有良好的整体安全性，但它确实会导致骨矿物质密度（BMD）轻微降低。男男性行为者（MSM）在全球范围内承担着艾滋病毒感染的主要负担，即使在没有FTC/TDF治疗的情况下，也显示出骨密度低。因此，了解FTC/TDF的BMD效应的性质对于优化PrEP的风险效益比非常重要。研究人员进行了一项NIH资助的项目，其中包括在全球有HIV感染风险的HIV- MSM样本中进行FTC/TDF与PrEP安慰剂的随机安慰剂对照试验，以及该试验的开放标签扩展。作为该研究的一部分，我们对大约20%接受双X线吸收测定法（DEXA）扫描的研究参与者进行了骨和身体成分影响的子研究。我们最近完成了对原始试验的开放标签扩展。该试验发现，PrEP可有效预防HIV感染，其意向治疗效果可使HIV感染减少42%。在DEXA子研究中比较随机分组组发现，与安慰剂组相比，FTC/TDF组髋部BMD平均降低0.6%，脊柱BMD平均降低0.9%。该研究的总体依从性较低（第8周为55%），因此可能低估了FTC/TDF对骨的生物学效应。初步迹象表明，这种降低在美国入组的受试者和骨密度较高的受试者中更强，但尚不清楚这是否是对FTC/TDF的差异反应或仅仅是更高依从性的替代。有迹象表明，在停止FTC/TDF后，BMD的下降开始反弹;然而，我们仅在停药后的前6个月内对此进行了检查。作为开放标签扩展的一部分，现在可额外进行为期一年的停药随访。我们建议将联合收割机随机研究和开放标签扩展的数据结合起来，以检查停止FTC/TDF后BMD的变化，探索最容易因FTC/TDF而导致BMD丢失的亚组，并试图估计在完全依从性下预期的平均BMD变化。该项目于2014年底结束。为这项提案提供资金将使我们能够从现有的数据来源中探讨重要的悬而未决的问题。