Incidence and Implications of Subclinical Kidney Injury with Tenofovir based PrEP

基于替诺福韦的 PrEP 亚临床肾损伤的发生率和影响

• 批准号: 8658574
• 负责人: CHRISTINA M WYATT
• 金额: $ 61.93万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658574
• 关键词: AIDS prevention; Adherence; Adult; Alkaline Phosphatase; Anti-Retroviral Agents; Archives; Biological Assay; Biological Markers; Biopsy; Bone Density; Bone Resorption; C-telopeptide; Chronic; Chronic Disease; Clinical Trials; Couples; Creatinine; Creatinine clearance measurement; Critiques; Data; Databases; Documentation; Drug toxicity; Early Diagnosis; Excretory function; FDA approved; Fracture; Fumarates; Functional disorder; Future; Glomerular Filtration Rate; Glycosuria; Goals; HIV; HIV Infections; HIV-1; Heterosexuals; Hormones; Incidence; Individual; Injury; Kenya; Kidney; Measurement; Measures; Metabolism; Minerals; Monitor; N-telopeptide; N-terminal; Nested Case-Control Study; Osteocalcin; Osteogenesis; Parathyroid gland; Participant; Persons; Pharmaceutical Preparations; Phosphorus Acids; Placebo Control; Placebos; Population; Procollagen; Prophylactic treatment; Proteinuria; Qualifying; Randomized; Renal function; Research; Resources; Risk; Risk Factors; Safety; Sampling; Sentinel; Serum; Specimen; Subgroup; Tenofovir; Testing; Toxic effect; Tubular formation; Uganda; Uric Acid; Urine; Visit; Vitamin D; Woman; antiretroviral therapy; base; bone; bone metabolism; bone turnover; clinically relevant; cohort; design; drug development; emtricitabine; high risk; member; men; novel; pre-clinical; preclinical study; prevent; prospective; public health relevance; randomized placebo controlled trial; risk benefit ratio; standard measure; tartrate-resistant acid phosphatase

Project Summary Antiretroviral pre-exposure prophylaxis (PrEP) with tenofovir disoproxyl fumarate (TDF)/ emtricitabine (TDF/FTC) reduces the risk of HIV acquisition in high-risk HIV-uninfected individuals. However, a major critique of TDF/FTC PrEP is the potential for kidney and bone toxicity. Although overt kidney toxicity is rare, subclinical kidney injury is common in HIV-infected individuals on TDF-containing antiretroviral therapy. TDF has also been associated with altered bone metabolism, including declines in bone mineral density, increased markers of bone turnover, and increased fracture risk, but the relationship with kidney injury is not known. We hypothesize that TDF/FTC PrEP causes subclinical kidney injury in HIV-uninfected adults, and that subclinical proximal tubular injury promotes clinically relevant declines in kidney function and alterations in bone mineral metabolism. We will investigate this hypothesis using data and banked specimens from the Partners PrEP Study, a randomized, placebo-controlled trial that demonstrated efficacy of TDF/FTC PrEP in 4758 HIV-uninfected members of heterosexual HIV-1 serodiscordant couples in Uganda and Kenya. The prospective documentation of serum creatinine in all Partners PrEP Study participants and the measurement of noninvasive biomarkers of proximal tubular dysfunction and bone turnover in a nested subgroup of participants will allow us to determine whether TDF/FTC PrEP causes clinically relevant kidney injury and alterations in bone metabolism. In nested case-control studies, we will determine whether subclinical proximal tubular injury is a risk factor for decline in glomerular filtration rate or increased bone turnover. We will also leverage the unique opportunity to study cumulative TDF-induced kidney injury in healthy adults in order to identify urine biomarkers of drug-induced kidney injury with potential applications in drug development and toxicity monitoring. The results of the proposed research are expected to have significant implications for the implementation of antiretroviral PrEP and alternative approaches to HIV prevention. The identification of new biomarkers of drug- induced kidney injury is expected to accelerate future drug development for HIV and other chronic diseases.

项目摘要 抗逆转录病毒前预防前预防（PREP）用替诺福韦毒氧基（TDF）/ Emtricerabine（TDF/FTC）降低了高风险艾滋病毒未感染的HIV获取风险 个人。但是，对TDF/FTC准备的主要批评是肾脏和 骨毒性。尽管明显的肾脏毒性很少见，但亚临床肾脏损伤很常见 在含TDF的抗逆转录病毒疗法的HIV感染者中。 TDF也是 与骨代谢改变有关，包括骨矿物质密度下降， 增加了骨转换标记，并增加了断裂风险，但与 肾脏损伤尚不清楚。我们假设TDF/FTC准备会导致亚临床 HIV未感染的成年人和亚临床近端损伤的肾脏损伤 促进肾功能的临床相关下降和骨矿物质的改变 代谢。我们将使用数据和从 合作伙伴准备研究，一项随机的安慰剂对照试验，证明了 TDF/FTC PREP在4758 HIV未感染的异性恋HIV-1成员中的功效 乌干达和肯尼亚的Serodiscordant夫妇。血清的前瞻性文档 所有合作伙伴准备研究参与者的肌酐和非侵入性的测量 嵌套亚组的近端管状功能障碍和骨转换的生物标志物 参与者将允许我们确定TDF/FTC准备是否会导致临床相关 肾脏损伤和骨代谢的改变。在嵌套的病例对照研究中，我们将 确定亚临床近端管状损伤是否是下降的危险因素 肾小球滤过率或骨转换增加。我们还将利用独特的 研究健康成年人的累积TDF诱导肾脏损伤的机会 鉴定药物诱导的肾损伤的尿液生物标志物，并在药物中使用潜在的应用 发展和毒性监测。预计拟议研究的结果是 对实施抗逆转录病毒PREP具有重要意义 预防艾滋病毒的替代方法。鉴定药物的新生物标志物 预计诱发肾脏损伤将加速艾滋病毒的未来药物开发 其他慢性疾病。