Resistance in HIV-infected infants after extended ARV prophylaxis: PEPI-Malawi

描述（由申请人提供）：许多资源贫乏的国家必须依靠简化的抗逆转录病毒（ARV）方案来预防艾滋病毒母婴传播（MTCT）。不幸的是，这些方案并不完全有效，并且对通过母乳喂养传播艾滋病毒提供的保护很少，母乳喂养至少占所有儿科艾滋病毒感染的三分之一。这种情况可能会得到改善，因为最近的两项研究表明，通过向母乳喂养的婴儿提供奈韦拉平（NVP）或奈韦拉平加齐多夫定（ZDV）的延长每日预防，可以大大降低产后艾滋病毒传播的风险。因此，在母乳喂养对婴儿健康至关重要的资源贫乏国家，扩大的母婴传播方案可能成为预防母婴传播方案的关键组成部分。不幸的是，一项研究的数据显示，尽管有预防措施，但婴儿感染艾滋病毒时，接受单剂量NVP （sdNVP）加上每天长达6周的NVP的婴儿的NVP耐药率高于单独接受sdNVP的婴儿；在接受延长NVP治疗方案的婴儿中，NVP耐药性也更有可能持续一段时间。在资源贫乏的环境中，大多数针对感染艾滋病毒儿童的一线抗逆转录病毒药物治疗方案包括NVP。因此，在接受长期NVP预防的婴儿中存在NVP耐药HIV毒株可能会显著降低他们未来ARV治疗成功的机会。拟议研究的假设是，在延长的NVP预防中加入延长的ZDV将减少在接受预防后感染艾滋病毒的母乳喂养婴儿中NVP耐药性的出现和持续存在。我们将通过分析马拉维婴儿暴露后预防试验（PEPI-Malawi）的样本和数据来检验这一假设。在pepi -马拉维，大多数妇女在分娩时接受了sdNVP， 3352名婴儿被随机分为三个研究组：(1)对照组[sdNVP加1周每日ZDV]，(2)延长NVP组[控制方案加每日NVP至14周龄]，或(3)延长NVP/ZDV组[控制方案加每日NVP和每日ZDV至14周龄]。在9个月时，出生时未感染艾滋病毒的婴儿出生后艾滋病毒传播的估计风险在对照组为10.6%，在扩展NVP组为5.2% (p<0.001)，在扩展NVP/ZDV组为6.4% （p=0.002）。在延长的NVP和延长的NVP/ZDV组中，在24个月时仍然观察到艾滋病毒传播的减少。在拟议的研究中，我们将分析pepi -马拉维出生时未感染艾滋病毒但在14周龄时感染艾滋病毒的婴儿中NVP耐药性的出现和持久性。我们将比较延长NVP组和延长NVP/ZDV组的NVP耐药性，并将确定影响婴儿NVP耐药性出现和持续的因素。我们还将评估NVP耐药性是否会影响婴儿健康。这些信息将有助于在非洲和其他地方设计和实施预防产后母婴传播的规划。公共卫生相关性：这些研究将评估降低母乳喂养期间艾滋病毒传播风险的抗逆转录病毒药物方案。这些研究将有助于在资源贫乏的环境中设计和实施预防艾滋病毒母婴传播的方案。

DESCRIPTION (provided by applicant): Many resource-poor countries must rely on simplified antiretroviral (ARV) regimens to prevent HIV mother-to- child transmission (MTCT). Unfortunately, these regimens are not fully effective and offer little protection against HIV transmission by breastfeeding, which accounts for at least 1/3 of all pediatric HIV infections. This situation is likely to improve, since two recent studies show that the risk of post-natal HIV transmission can be greatly reduced by providing breastfeeding infants with extended daily prophylaxis with nevirapine (NVP) or NVP plus zidovudine (ZDV). Therefore, extended NVP is likely to become a key component in regimens used to prevent MTCT in resource-poor countries where breastfeeding is critical for infant health. Unfortunately, data from one study shows that when infants are HIV-infected despite prophylaxis, those who received single dose NVP (sdNVP) plus up to 6 weeks of daily NVP had higher rates of NVP resistance than infants who received sdNVP alone; NVP resistance was also more likely to persist over time in infants who received the extended NVP regimen. In resource-poor settings, most first-line ARV treatment regimens for HIV-infected children include NVP. Therefore, the presence of NVP-resistant HIV strains in infants who received extended NVP prophylaxis may significantly reduce their chance of future ARV treatment success. The hypothesis of the proposed studies is that the addition of extended ZDV to extended NVP prophylaxis will reduce emergence and persistence of NVP resistance in breastfeeding infants who become HIV-infected despite having received prophylaxis. We will test this hypothesis by analyzing samples and data from the Post-Exposure Prophylaxis of Infants in Malawi trial (PEPI-Malawi). In PEPI-Malawi, most women received sdNVP in labor, and 3,352 infants were randomized to one of three study arms: (1) the control arm [sdNVP plus 1 week of daily ZDV], (2) the extended NVP arm [control regimen plus daily NVP to 14 weeks of age], or (3) the extended NVP/ZDV arm [control regimen plus daily NVP and daily ZDV to 14 weeks of age]. At 9 months, the estimated risk of post- natal HIV transmission among infants who were HIV-uninfected at birth was 10.6% in the control arm, 5.2% in the extended NVP arm (p<0.001), and 6.4% in the extended NVP/ZDV arm (p=0.002). The reduction in HIV transmission in the extended NVP and extended NVP/ZDV arms was still observed at 24 months. In the proposed studies, we will analyze emergence and persistence of NVP resistance in infants in PEPI-Malawi who were HIV-uninfected at birth, but became HIV-infected by 14 weeks of age. We will compare NVP resistance in the extended NVP arm and the extended NVP/ZDV arm, and will identify factors that influence emergence and persistence of NVP resistance in infants. We will also assess whether NVP resistance influences infant health. This information will facilitate the design and implementation of programs for prevention of post-natal MTCT in Africa and elsewhere. PUBLIC HEALTH RELEVANCE: These studies will evaluate antiretroviral drug regimens that reduce the risk of HIV transmission during breastfeeding. These studies will facilitate the design and implementation of programs for prevention of HIV mother-to-child transmission in resource-poor settings.