Lopinavir/ritonavir + zidovudine to prevent perinatal HIV in Thailand

洛匹那韦/利托那韦齐多夫定在泰国预防围产期艾滋病毒

• 批准号: 7338907
• 负责人: MARC J LALLEMANT
• 金额: $ 42.85万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-10 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7338907
• 关键词: AIDS prevention; Anti-Retroviral Agents; Appendix; Applications Grants; Asia; Birth; Breast Feeding; CD4 Lymphocyte Count; Cesarean section; Child; Class; Clinical Research; Combined Modality Therapy; Consent; Developed Countries; Developing Countries; Dose; Drug Combinations; Drug Kinetics; End Point; Enrollment; Enzymes; Evaluable Disease; Evolution; Fetus; France; Future; Goals; Guidelines; HIV; HIV Infections; HIV-1; Head; Health; Height; Hepatitis B Prevalence; Highly Active Antiretroviral Therapy; Hospitals; Hour; Immune; Immunocompromised Host; Incidence; Individual; Infant; Infant formula; Infection; Interruption; Labor Onset; Lamivudine/Zidovudine; Lead; Light; Lopinavir; Lopinavir/Ritonavir; Maps; Monitor; Morbidity - disease rate; Mothers; Mutation; Nevirapine; Nucleosides; Oral; Perinatal; Pharmaceutical Preparations; Phase; Population; Postpartum Period; Pregnancy; Pregnant Women; Prevention; Prevention Guidelines; Principal Investigator; Prophylactic treatment; Protease Inhibitor; Public Health; Public Hospitals; Publishing; Randomized Clinical Trials; Randomized Controlled Trials; Rate; Recommendation; Research Personnel; Resistance; Resources; Rest; Reverse Transcriptase Inhibitors; Risk; Ritonavir; Safety; Second Pregnancy Trimester; Standards of Weights and Measures; Testing; Thailand; Thinking; Time; Treatment Protocols; Universities; Upper arm; Vertical Disease Transmission; Viral; Viral Load result; Week; Woman; World Health Organization; Zidovudine; antiretroviral therapy; base; clinical research site; comparative; cost; day; feeding; mortality; neonate; non-nucleoside reverse transcriptase inhibitors; prevent; programs; response; risk selection; transmission process

DESCRIPTION (provided by applicant): World Health Organization guidelines for Prevention of HIV infection in infants in resource-limited settings recommend single dose nevirapine (SD-NVP) at onset of labor and to infants at 48-72 hours in addition to zidovudine (ZDV) from 28 weeks' gestation (ZDV28w/SD-NVP), for non immunocompromised women. While this regimen reduces perinatal HIV transmission to ¿2%, post exposure resistance mutations to NVP in mothers and infected children raised concerns regarding future efficacy of Non Nucleoside Reverse Transcriptase Inhibitor (NNRTI) based treatments. In industrialized countries similarly low transmission rates are obtained using highly active antiretroviral therapy (HAART) regardless of women's immune status. Such regimens have not been rigorously compared for efficacy and safety with simpler regimens. With the increasing availability of protease inhibitors in resource limited settings and the concerns with use of SD- NVP, we propose to evaluate a simple HAART regimen, ZDV + ritonavir boosted lopinavir (ZDV+LPV/r28w), for prevention of mother to child HIV transmission (PMTCT) in a non-breastfeeding population. The primary objective of this study is to compare the efficacy, long term safety for infants and mothers, and feasibility of ZDV+LPV/r28w versus ZDV28w/SD-NVP for PMTCT. All infants will receive one week ZDV and will be formula fed. Secondary objectives are to: (1) evaluate the mortality, morbidity, CD4 evolution and time to treatment initiation in women up to 24 months after ZDV+LPV/r prophylaxis interruption; (2) assess the incidence of HIV resistance mutations in women after delivery and in HIV infected children; (3) study the pharmacokinetics of LPV/r in Thai pregnant women; and (4) monitor the virological response to ZDV+LPV/r. This multicenter, phase III, randomized, controlled trial will build upon an existing two-arm study, PHPT-5a, with a third arm to be compared with the reference arm (ZQV28w/SD-NVP). The revised study will enroll a total of 2097 consenting HIV-1 infected pregnant women, with CD4 count >250/mm3 (699 per arm including 5% non evaluable; alpha 5%; power: 80%; delta for non-inferiority testing between groups: 1.5%). The primary endpoint is infant HIV status based on confirmed DNA-PCR results at birth, 1, 2, 4 and 6 months. The study represents a collaborative effort of Harvard University, the Institut de Recherche pour le Developpement (France), the Thai Ministry of Public Health, and Mahidol and Chiang Mai Universities, through a network of 45 public hospitals in Thailand. If the simple ZDV+LPV/r28w regimen proves to be efficacious and safe for PMTCT, avoiding risks of resistance mutations to NNRTIs for both mothers and infected children and therefore preserving their future drug options, this study will have important public health imolications for industrialized and developing countries.

描述（由申请方提供）：世界卫生组织关于预防资源有限环境中婴儿HIV感染的指南建议，对于非免疫功能低下的女性，除了齐多夫定（ZDV）（ZDV 28 w/SD-NVP）外，还应在分娩开始时和婴儿48-72小时时给予单剂量奈韦拉平（SD-NVP）。虽然该方案将围产期艾滋病毒传播率降低至2%，但母亲和感染儿童暴露后对NVP的耐药性突变引发了人们对基于非核苷逆转录酶抑制剂（NNRTI）的治疗未来疗效的担忧。在工业化国家，无论妇女的免疫状况如何，使用高效抗逆转录病毒疗法也同样获得了较低的传播率。这些方案尚未与更简单的方案进行有效性和安全性的严格比较。随着资源有限环境中蛋白酶抑制剂的可用性增加以及对使用SD-NVP的担忧，我们建议评估一种简单的HAART方案，ZDV +利托那韦加强的洛匹那韦（ZDV+LPV/r28 w），用于预防非母乳喂养人群中的母婴HIV传播（PMTCT）。本研究的主要目的是比较ZDV+LPV/r28 w与ZDV 28 w/SD-NVP用于PMTCT的疗效、婴儿和母亲的长期安全性和可行性。所有婴儿将接受为期一周的ZDV，并将接受配方奶粉喂养。次要目的是：（1）评价ZDV+LPV/r预防中断后24个月内女性的死亡率、发病率、CD 4演变和至开始治疗的时间;（2）评估分娩后女性和HIV感染儿童中HIV耐药突变的发生率;（3）研究LPV/r在泰国孕妇中的药代动力学;（4）监测对ZDV+LPV/r的病毒学应答。这项多中心、III期、随机、对照试验将建立在现有的两组研究PHPT-5a的基础上，第三组将与参考组（ZQV 28 w/SD-NVP）进行比较。修订后的研究将招募总计2097名同意的HIV-1感染孕妇，CD 4计数>250/mm 3（每组699名，包括5%不可评估; α 5%;功效：80%;组间非劣效性检验的δ：1.5%）。主要终点是基于出生时、1个月、2个月、4个月和6个月时确认的DNA-PCR结果的婴儿艾滋病毒状态。这项研究是哈佛大学、发展研究所（法国）、泰国公共卫生部、玛希隆大学和清迈大学通过泰国45家公立医院网络开展的一项合作努力。如果简单的ZDV+LPV/r28 w方案被证明对PMTCT有效且安全，避免母亲和感染儿童对NNRTI的耐药突变风险，从而保留他们未来的药物选择，则该研究将对工业化国家和发展中国家具有重要的公共卫生意义。