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 拟议的研究将评估肝炎病毒（HBV）单感染妇女的肾小管功能障碍 他接受了短暂的Tenofovir Diprosoxil Fumarate（TDF）课程，以预防HBV母亲到孩子 传播。尽管这种治疗的耐受性良好，但先前的研究表明 母体和婴儿骨矿物质密度的可能缺陷。这种赤字可能是毒性的结果 在肾脏近端小管上，但在此特定时期内这种不良影响的程度尚不清楚。 TDF经常与HIV感染妇女中的其他抗逆转录病毒药物联合使用，以防止母亲 艾滋病毒的孩子传播。它也越来越多地用于预防母亲 丙型肝炎病毒的传播。 TDF消除主要是肾脏，部分通过近端管状分泌。这 TDF在上皮细胞中的积累与线粒体毒性有关 管状功能障碍，导致尿液中磷和离子损失，对骨骼产生不利影响 矿化。在怀孕和哺乳期间，孕产妇的骨骼更新增加以供应 婴儿骨骼生长所需的大量钙。这个过程可能导致5％至10％的损失 母体骨骼质量。管状功能障碍可能会干扰这一过程并改变乳房的组成 牛奶反过来可能会影响婴儿骨骼的发育。 我们最近在泰国完成了一个多中心，安慰剂对照，双盲，随机临床试验 （ITAP）在婴儿接受的环境中评估了5个月TDF母体治疗的功效 HB疫苗和免疫球蛋白（HBIG）。 我们假设短期母亲接触替诺福韦至少与临时母体有关 近端肾小管功能障碍，这是BMD异常的强烈预测。我们的主要目标是 在孕妇/母亲中使用尿生物标志物评估近端管状功能障碍的风险 每天28周怀孕到分组后2个月接受TDF 300毫克。 为此，我们将评估和比较母体管状功能障碍的臂生物标志物 在ITAP研究期间，在几个时间点收集的尿液样本（在暴露于研究治疗之前， 在暴露结束时和中断后10个月结束时）。此外，我们将评估关系 在母体替诺福韦的暴露和管状近端功能障碍的风险之间。 TDF将越来越多地用于HBV感染的孕妇，以防止母亲到孩子的传播 HBV，全世界，尤其是在资源有限的国家中。另外，感染了孕妇的艾滋病毒的数量 在过去的十年中 2009年至2015年的80％）。因此，在这种情况下更好地表征TDF肾脏毒性以防止 这种疾病的后果，等待新药在怀孕期间得到更好的耐受性和安全性。