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

延长抗逆转录病毒药物预防后艾滋病毒感染婴儿的耐药性：PEPI-马拉维

• 批准号: 7682012
• 负责人: SUSAN H ESHLEMAN
• 金额: $ 8.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7682012
• 关键词: AIDS prevention; Accounting; Address; Africa; Age; Age-Months; Anti-Retroviral Agents; Biological Assay; Birth; Breast Feeding; Child; Clinical; Complement; Country; Data; Dose; Future; Genotype; HIV; HIV Infections; Infant; Infant Health; Malawi; Mutation; Nevirapine; Outcome; Pharmaceutical Preparations; Point Mutation; Population; Positioning Attribute; Prevention; Prevention program; Prophylactic treatment; Randomized; Research Personnel; Resistance; Resources; Risk; Risk Estimate; Safety; Sampling; Testing; Time; Treatment Protocols; Upper arm; Vertical Disease Transmission; Viral; Woman; Zidovudine; Zidovudine resistance; design; follow-up; high risk; improved; nevirapine resistance; pediatric human immunodeficiency virus infection; prevent; public health relevance; resistant strain; success; transmission process

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.

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）方案来防止艾滋病毒母亲传播（MTCT）。不幸的是，这些方案没有完全有效，几乎没有保护艾滋病毒传播的母乳喂养，这占所有儿科艾滋病毒感染的至少1/3。这种情况可能会改善，因为最近的两项研究表明，通过为婴儿提供延长的每日预防症的母乳喂养，可以大大降低产后艾滋病毒后传播的风险，以纳维拉平（NVP）或NVP加上Zidovudine（ZDV）。因此，扩展的NVP可能会成为用于防止母乳喂养对婴儿健康至关重要的资源贫乏国家中MTCT的关键组成部分。不幸的是，一项研究的数据表明，当婴儿感染了HIV时，接受单剂量NVP（SDNVP）的人加上每日6周的NVP的NVP耐药率要比单独接受SDNVP的婴儿更高。在接受NVP延长方案的婴儿中，随着时间的流逝，NVP抗性也更有可能持续。在资源贫乏的环境中，艾滋病毒感染儿童的大多数一线ARV治疗方案包括NVP。因此，在接受NVP预防的扩展的婴儿中，NVP抗HIV菌株的存在可能会大大减少其未来ARV治疗成功的机会。拟议的研究的假设是，在扩展NVP预防中加长ZDV将减少NVP耐药性在母乳喂养的婴儿中的出现和持久性，这些婴儿尽管接受了预防，但受到HIV感染的婴儿。我们将通过分析马拉维试验（PEPI-Malawi）婴儿预防后预防的样本和数据来检验这一假设。 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周龄]。在9个月时，在对照组中，艾滋病毒未感染的艾滋病毒未感染的婴儿的估计风险为10.6％，延长的NVP ARM为5.2％（P <0.001），在扩展的NVP/ZDV ARM中为6.4％（P = 0.002）。在24个月的时间里，仍观察到延长的NVP和延长的NVP/ZDV臂的HIV传播减少。在拟议的研究中，我们将分析在出生时艾滋病毒未感染的pepi-malawi婴儿中NVP耐药性的出现和持久性，但在14周龄时感染了HIV。我们将比较扩展的NVP臂和扩展的NVP/ZDV臂中的NVP耐药性，并将确定影响婴儿NVP抗性的出现和持续性的因素。我们还将评估NVP抗性是否影响婴儿健康。这些信息将促进预防非洲和其他地方产后MTCT计划的设计和实施。公共卫生相关性：这些研究将评估抗逆转录病毒药物方案，以降低母乳喂养期间艾滋病毒传播的风险。这些研究将促进预防资源贫乏环境中预防艾滋病毒母亲传播计划的计划。