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，艾滋病毒状况不明的妇女在怀孕后期或分娩中，产后是抗逆转录病毒(ARV)治疗咨询、检测和评估的主要切入点。在孕妇和哺乳妇女中使用抗逆转录病毒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，母乳喂养被视为不会对婴儿构成风险，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，在哺乳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毒株从母亲转移到婴儿身上，或者通过使婴儿接触到具有生物学意义但低于治疗量的抗逆转录病毒药物，从而在已经感染了抗逆转录病毒病毒的婴儿中选择抗逆转录病毒病毒的艾滋病毒，从而在一些感染艾滋病毒的婴儿中诱导抗逆转录病毒病毒。感染艾滋病毒的婴儿对多种抗逆转录病毒药物产生抗药性(多抗药性)可能会显著降低他们对挽救生命的抗逆转录病毒疗法的反应机会。这项研究的假设是，母体HAART在大多数感染艾滋病毒的母乳喂养婴儿中诱导了多类ARV耐药。这一假设将使用在马拉维布兰太尔进行的暴露后婴儿预防(PEPI)试验的样本和数据进行验证。在佩皮，大约90名产后开始HAART的妇女的婴儿感染了艾滋病毒。佩皮的妇女和婴儿接受了预防艾滋病毒母婴传播的抗逆转录病毒药物(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sdNVP和1周的齐多夫定(对照方案)治疗。然后，婴儿在出生时被随机分成两组，一组只接受对照方案，另一组在对照组的基础上加用长达14周的每日NVP，或每日NVP加ZDV。对于确诊感染艾滋病毒的婴儿，这些方案立即停止。由于已知这些预防母婴传播方案会导致一些妇女和一些感染艾滋病毒的婴儿选择耐NVP的艾滋病毒，因此在我们的分析中将考虑接触预防母婴传播方案。这项建议的具体目的是：目的1：测试母亲产后开始HAART是否与感染艾滋病毒的母乳喂养婴儿出现多类耐药有关。目的2：分析接受HAART治疗的妇女母乳样本中的HIV病毒载量、抗逆转录病毒药物水平和抗药性。这些研究将量化母体HAART启动后婴儿血浆和母乳中多类耐药性的流行情况，并将确定与感染艾滋病毒的母乳喂养婴儿中多类耐药性发展相关的因素。这些研究还将评估在这种环境下的婴儿是否更有可能因母亲传播耐药艾滋病毒(从她的HAART方案中挑选)或接触母乳中的抗逆转录病毒药物而获得多类抗药性。这些信息将有助于在资源有限的情况下制定和执行艾滋病毒预防和治疗战略。 公共卫生相关性：在资源有限的情况下，许多感染艾滋病毒的妇女在怀孕期间或分娩后不久被诊断为艾滋病毒感染，许多人在仍在母乳喂养时就开始使用抗逆转录病毒药物治疗艾滋病毒。我们将通过诱导婴儿病毒对抗逆转录病毒药物的抗药性来确定开始治疗母乳喂养的妇女是否会对感染艾滋病毒的母乳喂养婴儿构成任何风险。

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.