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

项目总结 这项拟议的研究将评估单一感染乙肝病毒的女性的肾小管功能障碍。 接受富马酸替诺福韦(TDF)预防母婴传播的短期疗程 变速箱。尽管这种疗法已被证明总体耐受性良好，但先前的研究表明 母婴骨密度可能存在不足。这种缺陷很可能是毒性的结果。 对肾脏近端小管的影响，但这种不良反应在这一特定时期的程度尚不清楚。 TDF经常与其他抗逆转录病毒药物联合用于艾滋病毒感染的妇女，以防止母亲- 艾滋病毒的儿童传播。它也越来越多地被用于预防母婴传播。 乙肝病毒的传播。TDF的排出主要通过肾脏，部分通过近端肾小管分泌物。这个 TDF在上皮细胞中的积聚与线粒体毒性有关，从而导致糖尿病的发生 肾小管功能障碍导致尿磷和离子丢失，对骨骼造成不利影响 矿化作用。在妊娠期和哺乳期，母体的骨周转率增加以供应 婴儿骨骼生长所需的大量钙。这一过程可能会导致5%到10%的损失 母体骨量。小管功能障碍可能会干扰这一过程，并改变乳房的组成 牛奶，这可能反过来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)，该组织评估了为期5个月的TDF孕产妇治疗的疗效，在婴儿接受 乙肝疫苗和免疫球蛋白(HBIg)。 我们假设，母亲短期接触替诺福韦至少与暂时性母亲有关。 近端小管功能障碍，这是骨密度异常的强烈预测。我们的主要目标是 使用尿生物标记物评估孕妇/母亲近端肾小管功能障碍的风险 从妊娠28周到产后2个月，每天服用TDF300 mg。 为此，我们将评估和比较母体肾小管功能障碍的ARM生物标志物。 在ITAP研究期间的几个时间点收集的尿样(在暴露于研究治疗之前， 在接触期间、接触结束时和停药后10个月)。此外，我们还将评估两国关系 母亲暴露于替诺福韦与肾小管近端功能障碍风险之间的关系。 TDF将越来越多地用于感染乙肝病毒的孕妇，以防止母婴传播 乙肝病毒，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数量 在过去十年中，在高度流行的国家中，服用TDF的妇女大幅增加(从#年的36% 从2009年的80%增加到2015年的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 这类疾病的后果，等待新药更好地耐受，并在怀孕期间被证明是安全的。

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.