Malaria treatment outcomes and pharmacokinetics in HIV-infected pregnant women

描述(申请人提供)：蒿甲醚-鲁米芬是世界卫生组织(WHO)推荐的治疗恶性疟原虫引起的无并发症疟疾的主要药物。在未怀孕的成人和儿童中，已经建立了蒿甲醚-鲁米芬的高疗效、良好的耐受性和可接受的安全性概况。然而，尽管遵循世卫组织的建议，许多流行国家的孕妇越来越多地使用该药物，但在怀孕人群中，尤其是在携带疟疾负担明显更高的艾滋病毒携带者中，在艾滋病毒感染率始终高于一般人群的疟疾流行非洲国家，对蒿甲醚-鲁米芬的药代动力学、安全性和有效性的了解极其有限。目前尚不清楚蒿甲醚-鲁米芬净的高疗效和良好安全性的显著记录是否在这一脆弱人群中保持下去。现有数据表明，妊娠和艾滋病毒相关的免疫抑制以及妊娠引起的药物处置加速继发的次优药代动力学可能会阻碍蒿甲醚-鲁米芬的疗效。公共卫生界和研究界成员也一再对抗疟疾药物和抗逆转录病毒药物之间的潜在相互作用表示关切，这些药物改变了这一人群的抗疟疾药物疗效和安全性，因为在过去5年中，发展中国家抗逆转录病毒药物的使用和可获得性翻了一番，大力推动普遍获得抗逆转录病毒治疗。这项建议的总体公共卫生目标是确定标准剂量的蒿甲醚-鲁米芬净对正在服用奈韦拉平ART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-鲁米芬对感染艾滋病毒的孕妇中无并发症疟疾的治疗效果，并与艾滋病毒阴性孕妇和感染艾滋病毒的非孕妇进行比较。次要目标是评估安全性，并评估药物动力学(可能会因妊娠相关的变化和/或与奈韦拉平的相互作用而改变)、耐药性和获得性免疫(可能因妊娠和艾滋病毒相关的免疫抑制而改变)在治疗结果中的相对贡献。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-鲁米芬净在三组(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。蒿甲醚和鲁米芬的药代动力学，以及已知或怀疑与恶性疟原虫耐药性有关的分子标记，将根据治疗结果进行评估。样本将被保存，以评估免疫受损在治疗效果中的作用，由单独的资金提供。 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。无论是否携带艾滋病毒的孕妇，由于担心对胎儿造成伤害，通常都被排除在临床药物试验之外，导致几乎完全缺乏科学证据来指导怀孕期间的药物治疗，这种状态下的药物安全性、药代动力学和疗效可能会受到影响。研究结果将与疟疾和艾滋病毒共同感染盛行的西非的公共卫生专业人员和政策制定者直接相关，提供临床证据，以确定蒿甲醚-鲁米芬净的标准疟疾治疗在这一特定人群中是否安全有效，并提供足够的药代动力学数据，以便在必要时仔细制定基于药代动力学的适当剂量方案，以优化临床疗效和安全性。

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.