Kidney Tubular Dysfunction in Hepatitis B Mono-Infected Women Receiving a Short Tenofovir Disoproxil Fumarate Course in Pregnancy and Postpartum Period to Prevent Mother to Child Transmission

乙型肝炎单一感染女性的肾小管功能障碍在妊娠期和产后期间接受富马酸替诺福韦二吡呋酯短期疗程以预防母婴传播

• 批准号: 9790974
• 负责人: Gonzague Joseph Jourdain
• 金额: $ 5.31万
• 依托单位: INSTITUTE OF RESEARCH AND DEVELOPMENT
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9790974
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adult; Adverse effects; Affect; Anti-Retroviral Agents; Biological Markers; Bone Density; Bone Development; Bone Growth; Breast Feeding; Calcium; Cells; Centers for Disease Control and Prevention (U.S.); Chronic; Chronic Hepatitis B; Clinical Data; Clinical Trials; Controlled Clinical Trials; Country; Creatinine clearance measurement; Data; Development; Disease; Double-Blind Method; Enrollment; Ensure; Epithelial Cells; Exposure to; Fanconi Syndrome; Fumarates; Functional disorder; Glomerular Filtration Rate; Goals; HIV; HIV Infections; Hepatitis B; Hepatitis B Transmission; Hepatitis B Virus; Human Milk; Immunoglobulins; Impairment; Infant; Injury; Ions; Kidney; Knowledge; Lactation; Lead; Maternal Exposure; Mitochondria; Monitor; Mother-to-child HIV transmission; Mothers; National Institute of Child Health and Human Development; Perinatal transmission; Pharmaceutical Preparations; Phosphorus; Physiologic calcification; Physiological; Placebos; Plasma; Population; Postpartum Period; Pregnancy; Pregnant Women; Prevalence; Prevention; Process; Proximal Kidney Tubules; Randomized; Randomized Clinical Trials; Reporting; Resources; Risk; Safety; Sampling; Tenofovir; Testing; Thailand; Time; Toxic effect; Tubular formation; Urine; Vaccines; Vertebral column; Vertical Disease Transmission; Vitamin D; Woman; World Health Organization; antiretroviral therapy; arm; base; biobank; bone mass; bone turnover; calcium metabolism; double-blind placebo controlled trial; early detection biomarkers; kidney dysfunction; men; novel therapeutics; phosphorus metabolism; pregnant; prevent; renal tubular dysfunction; urinary; viral DNA

PROJECT SUMMARY The proposed study will assess kidney tubular dysfunction in hepatitis B virus (HBV) mono-infected women who receive a short tenofovir diprosoxil fumarate (TDF) course for the prevention of HBV mother-to-child transmission. Although this treatment has been shown generally well tolerated, previous studies have showed a possible deficit in maternal and infant bone mineral density. This deficit is likely a consequence of the toxicity on the kidney proximal tubule but the extent of this adverse effect during this specific period is not known. TDF is frequently used in combination with other antiretroviral drugs in HIV infected women to prevent mother- to-child transmission of HIV. It has been also increasingly used for the prevention of mother-to-child transmission of hepatitis B virus. TDF elimination is mainly renal, partly through proximal tubular secretion. The accumulation of TDF in epithelial cells is associated with mitochondrial toxicity leading to the development of tubular dysfunction responsible for a loss of phosphorus and ions in urine, adversely affecting bone mineralization. During the pregnancy and lactating periods, the maternal bone turnover is increased to supply large amounts of calcium needed for infant bone growth. This process can lead to a loss of 5 to 10% of the maternal bone mass. Tubular dysfunction may interfere with this process and modify the composition of breast milk, which may in turn impact infant bone development. We recently completed in Thailand a multicenter, placebo-controlled, double blind, randomized clinical trial (iTAP), which assessed the efficacy of a 5-month TDF maternal treatment, in a setting where infants received HB vaccine and immune globulin (HBIg). We hypothesize that a short maternal exposure to tenofovir is associated with at least transitory maternal proximal tubular dysfunction, which is strongly predictive of BMD abnormalities. Our primary objective is to assess the risk of proximal tubular dysfunction using urinary biomarkers in pregnant women/mothers who received TDF 300 mg once a day from 28 weeks pregnancy to 2 months post partum. For this purpose, we will assess and compare between arms biomarkers of tubular dysfunction in maternal urine samples collected at several time points during the iTAP study (prior to exposure to study treatment, during, at the end of exposure and 10 months after discontinuation). In addition, we will assess the relationship between maternal tenofovir exposure and the risk of tubular proximal dysfunction. TDF will be increasingly used in HBV infected pregnant women to prevent mother-to-child transmission of HBV, all over the world but especially in resource-limited countries. Also, the number of HIV infected pregnant women on TDF has dramatically increased in high endemic countries during the last decade (from 36% in 2009 to 80% in 2015). It is therefore essential to better characterize TDF renal toxicity in this setting to prevent consequences of such disorders, awaiting new drugs better tolerated and shown safe during pregnancy.

项目摘要 这项研究将评估B型肝炎病毒（HBV）单一感染女性的肾小管功能障碍 接受短疗程替诺福韦酯（TDF）预防HBV母婴传播的患者 传输虽然这种治疗通常表现出良好的耐受性，但以前的研究表明， 孕妇和婴儿骨矿物质密度可能不足。这种缺陷可能是毒性的结果 对肾脏近端小管的影响，但在这一特定时期这种不良影响的程度尚不清楚。 TDF经常与其他抗逆转录病毒药物联合用于感染艾滋病毒的妇女，以防止母婴传播。 艾滋病毒的儿童传播。它也越来越多地用于预防母婴传播 B型肝炎病毒的传播TDF主要通过肾脏消除，部分通过近端肾小管分泌。的 TDF在上皮细胞中的积累与线粒体毒性相关，导致 一种肾小管功能障碍，导致尿中磷和离子的丢失，对骨骼产生不利影响 成矿在妊娠期和哺乳期，母体骨转换增加， 婴儿骨骼生长所需的大量钙。这个过程可能会导致5%到10%的损失。 母体骨量。肾小管功能障碍可能会干扰这一过程，并改变乳腺的组成， 牛奶，这反过来可能会影响婴儿的骨骼发育。 我们最近在泰国完成了一项多中心、安慰剂对照、双盲、随机临床试验 （iTAP），评估了5个月TDF母体治疗的疗效，在婴儿接受 乙肝疫苗和免疫球蛋白（HBIg）。 我们推测，母亲短期接触替诺福韦与至少暂时性的母亲 近端肾小管功能障碍，这是BMD异常的强预测。我们的首要目标是 使用尿液生物标志物评估以下孕妇/母亲近端肾小管功能障碍的风险： 孕28周至产后2个月，口服TDF 300 mg，1次/d。 为此目的，我们将评估和比较两组之间的肾小管功能障碍的生物标志物， 在iTAP研究期间的几个时间点收集尿样（在暴露于研究治疗之前， 暴露期间、暴露结束时和停药后10个月）。此外，我们还将评估 母体接触替诺福韦与肾小管近端功能障碍风险之间的关系。 TDF将越来越多地用于HBV感染的孕妇，以防止母婴传播， HBV，在世界各地，特别是在资源有限的国家。此外，感染艾滋病毒的孕妇人数 在过去十年中，在高流行国家，接受TDF治疗的妇女人数急剧增加（2011年为36%， 2015年达到80%）。因此，在这种情况下，更好地描述TDF的肾毒性是至关重要的，以防止 这些疾病的后果，等待新的药物更好地耐受，并显示在怀孕期间的安全。