Chemoprophylaxis for HIV Prevention: Analysis of Bone and Metabolic Effects

 描述(由申请人提供)：在艾滋病毒阴性者中联合使用恩曲他滨替诺福韦(FTC/TDF)的暴露前预防(PrEP)是预防艾滋病毒感染的有效策略。虽然FTC/TDF具有极好的整体安全性，但它确实会在骨密度(BMD)方面产生微小的下降。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，而且已被证明即使在没有接受FTC/TDF治疗的情况下，骨密度也很低。因此，了解FTC/TDF对骨密度影响的本质，对优化PrEP的风险收益比具有重要意义。研究人员进行了一项由美国国立卫生研究院资助的项目，其中包括在全球有感染艾滋病毒风险的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%接受双重X射线吸收扫描(DEXA)的研究参与者进行了一项关于骨和身体成分影响的子研究。我们最近结束了对最初试验的开放标签扩展。试验发现，PrEP在预防艾滋病毒感染方面是有效的，意向治疗的效果是将艾滋病毒感染减少42%。在DEXA亚研究中比较随机组发现，与安慰剂相比，服用FTC/TDF的患者髋部骨密度平均降低0.6%，脊柱骨密度平均降低0.9%。这项研究的总体粘附率较低(8周时为55%)，因此FTC/TDF对骨骼的生物学效应可能被低估。初步迹象表明，这种减少在美国登记的参与者和那些骨密度较高的人中更明显，但尚不清楚这是对FTC/TDF的不同反应，还是仅仅是更高粘附性的替代。有迹象表明，在FTC/TDF停药后，BMD开始反弹；然而，我们只在停药后的前6个月对此进行了检查。作为开放标签延期的一部分，现在还提供了一年的非药物后续跟进。我们建议结合我们的随机研究和开放标签扩展的数据来检查FTC/TDF停用后BMD的变化，探索最容易受到FTC/TDF骨密度丢失影响的亚组，并试图估计在完全遵守的情况下预期的平均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可用的数据来源中寻找重要的悬而未决的问题。

 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.