Malaria treatment outcomes and pharmacokinetics in HIV-infected pregnant women

艾滋病毒感染孕妇的疟疾治疗结果和药代动力学

• 批准号: 7977134
• 负责人: Myaing Myaing Nyunt
• 金额: $ 25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7977134
• 关键词: Acceleration; Adult; Adverse effects; Affect; Africa; African; Anti-Retroviral Agents; Antimalarials; Artemisinins; Blood; Budgets; Burkina Faso; Child; Clinical; Clinical Protocols; Clinical Trials; Collaborations; Communities; Consent Forms; Country; Data; Developing Countries; Disease; Dose; Drug Kinetics; Drug resistance; Drug usage; Falciparum Malaria; Fetus; Fright; Funding; Gene Dosage; General Population; Genes; Genetic Polymorphism; HIV; HIV Infections; Health Professional; Immunity; Immunologics; Immunosuppression; Individual; Infection; Institution; Investigational Drugs; Knowledge; Laboratory Procedures; Language; Life; Malaria; Mali; Manuals; Monitor; Morbidity - disease rate; Nevirapine; Parasites; Pharmaceutical Preparations; Plasmodium falciparum; Policy Maker; Population; Predisposition; Pregnancy; Pregnant Women; Prevalence; Protocols documentation; Public Health; Recommendation; Regimen; Relative (related person); Research; Research Ethics Committees; Resistance; Risk; Role; Safety; Sampling; Secondary to; Single Nucleotide Polymorphism; Site; Training; Treatment Efficacy; Treatment Failure; Treatment outcome; United States Food and Drug Administration; Vulnerable Populations; Woman; World Health Organization; acquired immunity; artemether; artemisinine; base; benflumetol; clinical efficacy; cohort; comparative efficacy; data management; design; drug efficacy; improved; member; molecular marker; mortality; open label; pregnant; prospective; public health relevance; public health research; response; treatment effect; treatment response

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.

描述（申请人提供）：蒿甲醚-本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单纯性疟疾的主要药物。蒿甲醚-本芴醇在非妊娠成人和儿童中的治疗效果高、耐受性好、安全性可接受。然而，尽管按照世界卫生组织的建议，许多流行国家的孕妇越来越多地使用该药物，但孕妇对蒿甲醚-本芴醇的药代动力学、安全性和有效性的了解极为有限，尤其是那些疟疾负担明显较高的艾滋病毒感染者，在疟疾流行的非洲国家，这些国家的孕妇艾滋病毒感染率始终高于一般人群。目前尚不清楚蒿甲醚-苯芴醇在这一弱势群体中是否能保持高效和良好安全性的卓越记录。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对抗疟药和抗逆转录病毒药物之间潜在的相互作用表示担忧，这些相互作用会改变该人群的抗疟药物疗效和安全性，因为在过去五年中，随着抗逆转录病毒治疗的普遍获得，发展中国家的抗逆转录病毒药物的使用和供应量增加了一倍。该提案的总体公共卫生目标是确定标准剂量的蒿甲醚-苯芴醇对于正在服用基于奈韦拉平的抗逆转录病毒疗法治疗艾滋病毒的孕妇是否安全有效。主要研究目的是与 HIV 阴性孕妇和 HIV 感染非孕妇相比，评估蒿甲醚-本芴醇治疗 HIV 感染孕妇单纯性疟疾的疗效。次要目标是评估安全性，并评估药代动力学（可能因妊娠相关变化和/或与奈韦拉平相互作用而改变）、耐药性和获得性免疫（可能因妊娠和 HIV 相关免疫抑制而改变）对治疗结果的相对贡献。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，比较蒿甲醚-本芴醇在三组（HIV 感染孕妇、HIV 阴性孕妇和 HIV 感染非孕妇）中的治疗效果和安全性。将结合治疗结果评估蒿甲醚和苯芴醇的药代动力学，以及已知或怀疑与恶性疟原虫耐药性相关的分子标志物。将在单独的资助下保存样本，以评估免疫受损在治疗效果中的作用。 公共卫生相关性（由申请人提供）：拟议的临床试验将重点关注感染艾滋病毒且也面临疟疾风险的孕妇。孕妇，无论是否患有艾滋病毒，通常都会因担心对胎儿造成伤害而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，在妊娠期药物的安全性、药代动力学和疗效可能会受到影响。研究结果将对疟疾-艾滋病毒合并感染流行的西非公共卫生专业人员和政策制定者具有直接和直接的意义，通过提供临床证据来确定蒿甲醚-本芴醇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，以仔细制定基于药代动力学的适当剂量方案，以在必要时优化临床疗效和安全性。