Lopinavir/ritonavir + zidovudine to prevent perinatal HIV in Thailand

描述(申请人提供)：世界卫生组织在资源有限的环境中预防婴儿艾滋病毒感染指南建议，对于非免疫功能受损的妇女，在分娩开始时单剂奈韦拉平(SD-NVP)，在妊娠28周起给予齐多夫定(ZDV28w/SD-NVP)的基础上，婴儿在48-72小时内服用单剂量奈韦拉平(SD-NVP)。虽然这种方案将围产期艾滋病毒的传播率降低到2%，但母亲和受感染儿童暴露后对NVP的耐药性突变引发了对基于非核苷逆转录酶抑制物(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(HAART)都能获得同样低的传播率。这样的方案还没有被严格地与更简单的方案进行疗效和安全性的比较。随着蛋白水解酶抑制剂在资源有限的环境下越来越多的可用，以及对SD-NVP使用的关注，我们建议评估一种简单的HAART方案，ZDV+利托那韦促进的洛匹那韦(ZDV+LPV/r28w)，用于在非母乳喂养人群中预防母婴HIV传播(PMTCT)。本研究的主要目的是比较ZDV+LPV/r28w和ZDV28w/SD-NVP用于PMTCT的有效性、对婴儿和母亲的长期安全性以及可行性。所有婴儿将接受一周的ZDV，并将接受配方奶喂养。次要目标是：(1)评估ZDV+LPV/r预防中断后长达24个月的妇女的死亡率、发病率、CD4的演变和开始治疗的时间；(2)评估分娩后妇女和艾滋病毒感染儿童中艾滋病毒耐药突变的发生率；(3)研究LPV/r在泰国孕妇中的药代动力学；以及(4)监测ZDV+LPV/r的病毒学应答。这项多中心、III期的随机对照试验将建立在现有的两组研究PHPT-5a的基础上，第三组试验将与参考ARM(ZQV28w/SD-NVP)进行比较。修订后的研究将纳入2097名自愿接受HIV-1感染的孕妇，CD4计数和GT；250/mm3(每支手臂699支，其中5%不可评估；阿尔法5%；能力：80%；组间非劣势测试：增量：1.5%)。主要终点是根据出生时、1个月、2个月、4个月和6个月的确认DNA-PCR结果确定的婴儿艾滋病毒状况。这项研究是哈佛大学、法国发展研究所、泰国公共卫生部以及Mahidol大学和清迈大学通过泰国45家公立医院组成的网络共同努力的结果。如果简单的ZDV+LPV/r28w方案被证明对预防母婴传播有效且安全，避免了母亲和受感染儿童对NNRTIs的耐药性突变风险，从而保护了他们未来的药物选择，这项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。

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.