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）疗法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，对母乳喂养的艾滋病毒传播几乎没有保护作用，母乳喂养至少占所有儿科艾滋病毒感染的1/3。这种情况可能会得到改善，因为最近的两项研究表明，通过为母乳喂养的婴儿提供奈韦拉平（NVP）或NVP加齐多夫定（ZDV）的日常预防，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的国家，扩大NVP很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，当婴儿在预防治疗后仍感染HIV时，接受单剂量NVP（sdNVP）加每日NVP治疗长达6周的婴儿的NVP耐药率高于接受sdNVP单独治疗的婴儿;接受延长NVP方案的婴儿的NVP耐药也更可能随着时间的推移而持续。在资源匮乏的环境中，大多数感染艾滋病毒儿童的一线抗逆转录病毒治疗方案包括NVP。因此，在接受NVP延长预防的婴儿中存在NVP耐药HIV毒株可能会显着降低他们未来ARV治疗成功的机会。拟定研究的假设是，在延长NVP预防中添加延长ZDV将减少尽管接受预防但仍感染HIV的母乳喂养婴儿中NVP耐药性的出现和持续。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-Malawi中，大多数女性在分娩时接受sdNVP，3，352名婴儿被随机分配至三个研究组之一：（1）对照组[sdNVP +1周每日ZDV]，（2）扩展NVP组[对照方案+每日NVP至14周龄]，或（3）扩展NVP/ZDV组[对照方案+每日NVP和每日ZDV至14周龄]。在9个月时，出生时未感染HIV的婴儿的纳塔尔HIV传播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24个月时，仍观察到延长NVP和延长NVP/ZDV组的HIV传播减少。在拟议的研究中，我们将分析NVP耐药性的出现和持久性的婴儿在PEPI-马拉维谁是艾滋病毒未感染的出生时，但成为艾滋病毒感染的14周龄。我们将比较扩展NVP组和扩展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抗性是否影响婴儿健康。这一信息将有助于在非洲和其他地方设计和执行预防产后母婴传播的方案。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匮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.