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，在怀孕后期或分娩期间，以及产后时期，艾滋病毒感染状况未知的妇女是抗逆转录病毒（ARV）治疗咨询、检测和评估的主要切入点。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，如果婴儿已经感染了艾滋病毒，则认为母乳喂养不会对婴儿构成危险，因此强烈鼓励妇女继续母乳喂养，以最大限度地提高婴儿的存活率。然而，在母乳喂养妇女中使用高活性抗逆转录病毒疗法（HAART）可能导致一些感染艾滋病毒的婴儿对抗逆转录病毒产生耐药性，要么是通过将抗抗逆转录病毒菌株从母亲传给婴儿，要么是通过使婴儿接触生物学上显著但低于治疗量的抗逆转录病毒药物，导致已经感染抗逆转录病毒易感艾滋病毒的婴儿选择抗抗逆转录病毒艾滋病毒。感染艾滋病毒的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），可能会大大降低他们对挽救生命的抗逆转录病毒治疗作出反应的机会。本研究的假设是，在大多数感染艾滋病毒的母乳喂养婴儿中，母体HAART诱导了多级别ARV耐药。将使用在马拉维布兰太尔进行的婴儿接触后预防试验的样本和数据来检验这一假设。在PEPI，大约90名产后开始HAART治疗的妇女的婴儿感染了艾滋病毒。PEPI的妇女和婴儿获得了抗逆转录病毒药物，以预防艾滋病毒母婴传播。大多数妇女（约70%）接受单剂量奈韦拉平（sdNVP）治疗。所有婴儿均接受snvp和1周的齐多夫定（对照方案）治疗。然后，婴儿在出生时随机接受单独的对照方案，或对照方案加上长达14周的延长每日NVP或延长每日NVP加上延长每日ZDV。在确诊感染艾滋病毒的婴儿中，这些方案立即停止。由于已知这些预防母婴传播方案会在一些妇女和一些感染艾滋病毒的婴儿中导致nvp抗性艾滋病毒的选择，因此我们的分析将考虑到预防母婴传播方案的暴露情况。本建议的具体目的是：目的1：检验母亲产后开始HAART治疗是否与感染HIV的母乳喂养婴儿出现多级别耐药有关。目的2：分析接受HAART治疗妇女母乳样本中的HIV病毒载量、抗逆转录病毒药物水平和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级别耐药的流行情况，并将确定与艾滋病毒感染的母乳喂养婴儿中多级别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）传播耐药艾滋病毒，或从母乳中暴露于抗逆转录病毒药物中获得多级别耐药性。这些信息将有助于在资源有限的情况下设计和实施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. PUBLIC HEALTH RELEVANCE: In resource-limited settings, many HIV-infected women are diagnosed with HIV infection during pregnancy or shortly after delivery, and many begin HIV treatment with antiretroviral drugs while they are still breastfeeding. We will determine whether initiation of treatment in breastfeeding women poses any risk to breastfeeding infants who are HIV-infected, by inducing resistance to antiretroviral drugs in the infant's virus.