Impact of maternal HAART on HIV-infected breastfeeding infants: Malawi

描述（由申请人提供）：在非洲的许多环境中，艾滋病毒感染状况不明的妇女在怀孕后期或分娩时出现，产后时期是咨询、检测和评估抗逆转录病毒（ARV）治疗的主要切入点。孕妇和哺乳期妇女使用抗逆转录病毒药物对母亲和婴儿有明显的好处。此外，如果婴儿已经感染艾滋病毒，母乳喂养被视为对婴儿没有风险，并大力鼓励妇女继续母乳喂养，以尽量延长婴儿的存活时间。然而，在母乳喂养的妇女中使用高效抗逆转录病毒疗法（HAART）可能会通过将抗逆转录病毒菌株从母亲转移给婴儿，或通过将婴儿暴露于具有生物学意义但低于治疗量的抗逆转录病毒药物，导致在已经感染抗逆转录病毒易感艾滋病毒的婴儿中选择抗逆转录病毒耐药艾滋病毒。艾滋病毒感染婴儿对一种以上的抗逆转录病毒药物产生耐药性（多类耐药性）可能会显著降低他们对挽救生命的抗逆转录病毒治疗产生反应的机会。这项研究的假设是，母亲HAART诱导多类抗逆转录病毒药物在大多数艾滋病毒感染的母乳喂养的婴儿。将使用在马拉维布兰太尔进行的婴儿暴露后预防（PEPI）试验的样本和数据对这一假设进行检验。在PEPI中，大约90名产后开始HAART的妇女有感染艾滋病毒的婴儿。参与PEPI的妇女和婴儿接受抗逆转录病毒药物，以预防艾滋病毒母婴传播。大多数女性（~70%）接受单剂量奈韦拉平（sdNVP）。所有婴儿均接受sdNVP和1周齐多夫定（对照方案）。婴儿在出生时随机接受对照方案单独治疗，或对照方案加长达14周的每日NVP延长治疗或每日NVP延长治疗加每日ZDV延长治疗。对于确诊感染艾滋病毒的婴儿，这些方案立即停止。因为已知这些pMTCT方案会导致一些妇女和一些HIV感染婴儿选择NVP耐药HIV，所以我们的分析将考虑pMTCT方案的暴露。该提案的具体目标是：目标1：测试产后母亲HAART的启动是否与HIV感染的母乳喂养婴儿中出现多类耐药相关。目的2：分析HAART妇女母乳样本中的HIV病毒载量、ARV药物水平和HIV耐药性。这些研究将量化母亲开始HAART治疗后婴儿血浆和母乳中多类耐药的患病率，并将确定与HIV感染的母乳喂养婴儿中多类耐药发展相关的因素。这些研究还将评估这种情况下的婴儿是否更有可能从母亲（从她的HAART方案中选择）传播耐药HIV或从母乳中暴露于ARV药物中获得多类耐药性。这些信息将有助于在资源有限的情况下设计和执行艾滋病毒预防和治疗战略。

DESCRIPTION (provided by applicant): In many settings in Africa, women with unknown HIV status present late in pregnancy or in labor, and the postpartum period represents a major entry point for counseling, testing, and assessment for antiretroviral (ARV) treatment. ARV use in pregnant and breastfeeding women has clear benefits for mothers and infants. Furthermore, if an infant is already HIV-infected, breastfeeding is seen as posing no risk to the infant, and women are strongly encouraged to continue breastfeeding to maximize survival of the infant. However, use of highly active antiretroviral therapy (HAART) in breastfeeding women may induce ARV resistance in some HIV-infected infants, either through transfer of ARV-resistant strains from the mother to the infant, or by exposing the infant to biologically significant but sub-therapeutic amounts of ARV drugs, leading to selection of ARV-resistant HIV in infants who are already infected with ARV-susceptible HIV. Development of ARV resistance to more than one class of ARV drugs (multi-class resistance) in HIV-infected infants is likely to significantly reduce their chance of responding to life-saving ARV therapy. The hypothesis of this study is that maternal HAART induces multi-class ARV resistance in the majority of HIV-infected breastfeeding infants. This hypothesis will be tested using samples and data from the Post-Exposure Prophylaxis of Infants (PEPI) trial that was conducted in Blantyre, Malawi. In PEPI, approximately 90 women who initiated HAART postpartum had infants who were HIV-infected. Women and infants in PEPI received ARV drugs for prevention of mother-to-child transmission of HIV (pMTCT). Most women (~70%) received single dose nevirapine (sdNVP). All infants received sdNVP and 1 week of zidovudine (control regimen). Infants were then randomized at birth to receive either the control regimen alone, or the control regimen plus up to 14 weeks of extended daily NVP or extended daily NVP plus extended daily ZDV. These regimens were stopped immediately in infants with confirmed HIV infection. Because these pMTCT regimens are known to cause selection of NVP-resistant HIV in some women and some HIV-infected infants, exposure to pMTCT regimens will be considered in our analysis. The Specific Aims of this proposal are: Aim 1: Test whether initiation of maternal HAART postpartum is associated with emergence of multi-class resistance in HIV- infected breastfeeding infants. Aim 2: Analyze HIV viral load, ARV drug levels, and HIV drug resistance in breast milk samples from women on HAART. These studies will quantify the prevalence of multi-class resistance in infant plasma and breast milk after maternal HAART initiation, and will identify factors associated with development of multi-class resistance in HIV-infected breastfeeding infants. These studies will also assess whether infants in this setting are more likely to acquire multi-class resistance from transmission of resistant HIV from the mother (selected from her HAART regimen), or from exposure to ARV drugs in breast milk. This information will facilitate the design and implementation of strategies for HIV prevention and treatment in resource-constrained settings.