Malaria treatment outcomes and pharmacokinetics in HIV-infected pregnant women

描述（由申请人提供）：蒿甲醚-苯芴醇是世界卫生组织（WHO）推荐用于治疗由恶性疟原虫引起的无并发症疟疾的主要药物。已在非妊娠成人和儿童中确立了蒿甲醚-本芴醇的高疗效、良好耐受性和可接受的安全性特征。然而，尽管在许多疟疾流行国家，按照世卫组织的建议，孕妇越来越多地使用这种药物，但孕妇对蒿甲醚-本芴醇的药代动力学、安全性和疗效的了解极为有限，特别是那些感染艾滋病毒的人，他们的疟疾负担要高得多，在疟疾流行的非洲国家，艾滋病毒在孕妇中的流行率一直高于一般人群。目前尚不清楚蒿甲醚-本芴醇的高疗效和良好安全性的显著记录是否能在这一脆弱人群中持续下去。现有数据表明，妊娠和HIV相关的免疫抑制和继发于妊娠诱导的药物处置加速的次优药代动力学可能会妨碍蒿甲醚-本芴醇的疗效。公共卫生和研究界的成员也一再表示关切抗疟药物和抗逆转录病毒药物之间的潜在相互作用会改变抗疟药物在这一人群中的疗效和安全性，因为在过去5年中，随着普及抗逆转录病毒治疗的有力推动，发展中国家抗逆转录病毒药物的使用和供应增加了一倍。本提案的总体公共卫生目标是确定标准剂量的蒿甲醚-本芴醇对正在服用以奈韦拉平为基础的抗逆转录病毒疗法治疗艾滋病毒的孕妇是否安全有效。主要研究目标是评估蒿甲醚-本芴醇治疗感染艾滋病毒的孕妇与艾滋病毒阴性孕妇和感染艾滋病毒的非孕妇的单纯疟疾的疗效。次要目的是评估安全性，并评价药代动力学（可能通过妊娠相关变化和/或与奈韦拉平的相互作用进行修改）、耐药性和获得性免疫（可能通过妊娠和HIV相关免疫抑制进行修改）在治疗结局中的相对贡献。我们与马里和布基纳法索的同事密切合作，设计了一项临床试验，以比较蒿甲醚-苯芴醇在三个队列（艾滋病毒感染孕妇、艾滋病毒阴性孕妇和艾滋病毒感染非孕妇）中的治疗效果和安全性。蒿甲醚和本芴醇的药代动力学以及已知或疑似与恶性疟原虫耐药性相关的分子标志物将与治疗结果一起进行评价。将保存样本，以评估免疫力受损在治疗效果中的作用，单独供资。 公共卫生相关性（由申请人提供）：拟议的临床试验将侧重于感染艾滋病毒的孕妇，她们也有患疟疾的风险。由于担心对胎儿造成伤害，无论是否感染艾滋病毒的孕妇通常都被排除在临床药物试验之外，导致几乎完全缺乏指导妊娠期药物治疗的科学证据，这是一种可能影响药物安全性、药代动力学和疗效的状态。研究结果将为疟疾-艾滋病毒合并感染流行的西非的公共卫生专业人员和决策者提供直接和直接的相关性，提供临床证据，以确定蒿甲醚-苯芴醇标准疟疾治疗在这一特定人群中是否安全有效，以及足够的药代动力学数据，以仔细开发基于药代动力学的适当给药方案，从而优化临床疗效和安全性（如有必要）。

DESCRIPTION (provided by applicant): Artemether-lumefantrine is the leading drug recommended by the World Health Organization (WHO) for the treatment of uncomplicated malaria caused by Plasmodium falciparum. High treatment efficacy, good tolerability, and an acceptable safety profile of artemether-lumefantrine have been established in non-pregnant adults and children. However, despite increasing use of the drug in pregnant women in many endemic countries following the WHO recommendation, knowledge on the pharmacokinetics, safety and efficacy of artemether-lumefantrine is extremely limited in the pregnant population, especially in those living with HIV who carry a significantly higher burden of malaria, in malaria-endemic African nations where the prevalence of HIV is consistently higher in the pregnant than the general population. It is not known whether the remarkable record of high efficacy and good safety of artemether- lumefantrine is sustained in this vulnerable population. Available data suggest that pregnancy- and HIV-related immune suppression and suboptimal pharmacokinetics secondary to pregnancy-induced acceleration in drug disposition may hamper the efficacy of artemether-lumefantrine. Members of the public health and research communities have also repeatedly expressed concern about potential interactions between antimalarial and antiretroviral drugs modifying antimalarial drug efficacy and safety in this population, since the use and availability of antiretroviral drugs in developing nations has doubled in the last 5 years, with the powerful push for universal access to antiretroviral treatment. The overall public health objective of this proposal is to determine if standard doses of artemether- lumefantrine are safe and efficacious in pregnant women who are taking nevirapine-based ART for the treatment of HIV. The primary research objective is to assess the efficacy of artemether-lumefantrine in the treatment of uncomplicated malaria in HIV-infected pregnant women in comparison with HIV-negative pregnant and HIV-infected non-pregnant women. The secondary objectives are to assess safety, and to evaluate the relative contributions of pharmacokinetics (which may be modified by pregnancy-related changes and/or interaction with nevirapine), drug resistance, and acquired immunity (which may be modified by pregnancy- and HIV-related immunosuppression) in the treatment outcomes. In close collaboration with our colleagues in Mali and Burkina Faso, we have designed a clinical trial to compare the treatment efficacy and safety of artemether-lumefantrine in three cohorts of (HIV-infected pregnant, HIV-negative pregnant, and HIV-infected non-pregnant women). The pharmacokinetics of artemether and lumefantrine, and molecular markers known or suspected to be associated with falciparum drug resistance will be evaluated in association with the treatment outcomes. Samples will be preserved to assess the role of impaired immunity in therapeutic efficacy, under separate funding. PUBLIC HEALTH RELEVANCE (provided by applicant): The proposed clinical trial will focus on pregnant women living with HIV who are also at risk of malaria. Pregnant women, with or without HIV, are typically excluded from clinical drug trials for fear of harm to the fetus, resulting in an almost complete lack of scientific evidence to guide drug treatment in pregnancy, a state in which drug safety, pharmacokinetics and efficacy may be affected. Study findings will be of immediate and direct relevance for public health professionals and policy makers in West Africa where malaria-HIV co- infection is prevalent, by providing clinical evidence to determine whether the standard malaria treatment with artemether-lumefantrine is safe and effective in this specific population, and adequate pharmacokinetic data to carefully develop a pharmacokinetic-based appropriate dosing regimen to optimize clinical efficacy and safety if necessary.