Optimizing ACT use for African children in the setting of HIV and malnutrition

在艾滋病毒和营养不良的情况下优化非洲儿童 ACT 的使用

• 批准号: 10440222
• 负责人: FRANCESCA T. AWEEKA
• 金额: $ 4.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440222
• 关键词: AIDS/HIV problem; Address; Administrative Supplement; Adopted; Africa; Africa South of the Sahara; African; Aftercare; Age; Anti-Retroviral Agents; Antimalarials; Artemisinins; CYP3A4 gene; Cardiotoxicity; Caring; Child; Childhood; Chronic; Clinical; Combination Drug Therapy; Combined Modality Therapy; Communicable Diseases; Data; Development; Dose; Drug Exposure; Drug Interactions; Drug Kinetics; Ensure; Evaluation; Exposure to; Family member; Fostering; Foundations; Funding; Goals; Grant; HIV; Infrastructure; Integrase Inhibitors; Lead; Lopinavir/Ritonavir; Malaria; Malnutrition; Medicine; Neural Tube Defects; Outcome; Patients; Pediatrics; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Phase; Policies; Population; Pregnancy; Pregnant Women; Recommendation; Recurrence; Regimen; Research; Research Design; Resistance; Risk; Safety; Speed; Toxic effect; Treatment Efficacy; Treatment outcome; UGT1A1 gene; Uganda; Update; Vulnerable Populations; absorption; antiretroviral therapy; artemether; base; benflumetol; clinically relevant; college; design; efavirenz; experience; follow-up; genetic resistance; high risk; improved; pharmacokinetics and pharmacodynamics; prospective; randomized trial; treatment guidelines; treatment optimization

Abstract Dihydroartemisinin-piperaquine (DP), an artemisinin-based combination therapy, is one of the most important drugs for the treatment of uncomplicated malaria, yet fundamental questions remain for assuring its optimal use in our most vulnerable populations, especially for children, and in the context of interacting antiretroviral therapies. Dolutegravir (DTG), now a first-line HIV treatment option per the updated HIV treatment guidelines, has never been studied in children in the setting of concomitant DP and its impact on DP pharmacokinetics is unknown, while lopinavir/ritonavir (LPV/r, another HIV treatment), is known to increase maximum piperaquine concentrations but the magnitude and associated risk of cardiotoxicity in children is still unclear. We plan to expand our current grant to allow us to study potential interactions between DTG and DP and to also more carefully, and safely, evaluate the potentially detrimental interaction between LPV/r and DP. This administrative supplement is requesting support to allow the study of DTG as one of three antiretrovirals that will be under evaluation. Specifically we are requesting support for the expansion of control children to include a broader age range which is necessary to age-match children who are managed on DTG. Additionally, this supplement is requesting support to permit a two phase study design that will allow us to complete a safe evaluation of the likely interaction between LPV/r / and DP (i.e. LPV/r is expected to increase piperaquine concentrations which has been associated with QTc prolongation). These two requests are to provide infrastructure support in Uganda. In summary, the results of our study has the potential to significantly impact treatment guidelines for HIV and malaria in children through this definitive study of pharmacokinetics and pharmacodynamics of DP in the setting of these antiretroviral therapies. Our overaching goal is to inform optimized DP dosing strategies for children.

抽象的 双氢青蒿素哌喹（DP）是一种以青蒿素为基础的联合疗法，是最重要的治疗药物之一。 治疗单纯性疟疾的药物，但确保其最佳效果的基本问题仍然存在 在我们最脆弱的人群中使用，特别是儿童，以及在相互作用的抗逆转录病毒药物的背景下使用 疗法。根据更新的艾滋病毒治疗指南，多替拉韦 (DTG) 现在是一线艾滋病毒治疗选择， 尚未在伴有 DP 的儿童中进行过研究，其对 DP 药代动力学的影响是 未知，而洛匹那韦/利托那韦（LPV/r，另一种 HIV 治疗方法）已知会增加哌喹的最大浓度 但儿童心脏毒性的严重程度和相关风险仍不清楚。我们计划 扩大我们当前的资助，使我们能够研究 DTG 和 DP 之间的潜在相互作用，以及更多 仔细、安全地评估 LPV/r 和 DP 之间潜在的有害相互作用。本次行政 补充材料请求支持，以允许将 DTG 作为三种抗逆转录病毒药物之一进行研究，该药物将在 评估。具体来说，我们请求支持扩大控制儿童的范围，以涵盖更广泛的范围 年龄匹配 DTG 管理的儿童所必需的年龄范围。另外，本补充 正在请求支持以允许进行两阶段研究设计，这将使我们能够完成对 LPV/r / 和 DP 之间可能存在相互作用（即 LPV/r 预计会增加哌喹浓度，从而 与 QTc 延长有关）。这两个要求是提供基础设施支持 乌干达。总之，我们的研究结果有可能对以下疾病的治疗指南产生重大影响： 通过这项针对 DP 的药代动力学和药效学的权威研究，儿童中的 HIV 和疟疾 这些抗逆转录病毒疗法的背景。我们的首要目标是为以下患者提供优化的 DP 剂量策略： 孩子们。

项目成果

In vitro metabolism of piperaquine is primarily mediated by CYP3A4.

哌喹的体外代谢主要由CYP3A4介导。

• 发表时间: 2012-11
• 作者: Lee, Tina Ming;Huang, Liusheng;Johnson, Marla K;Lizak, Patricia;Kroetz, Deanna;Aweeka, Francesca;Parikh, Sunil
• 通讯作者: Parikh, Sunil

Long-Term SARS-CoV-2-Specific Immune and Inflammatory Responses Across a Clinically Diverse Cohort of Individuals Recovering from COVID-19.

从 COVID-19 中恢复的临床多样化个体群体中的长期 SARS-CoV-2 特异性免疫和炎症反应。

• 发表时间: 2021-03-01
• 作者: Peluso, Michael J;Deitchman, Amelia N;Torres, Leonel;Iyer, Nikita S;Nixon, Christopher C;Munter, Sadie E;Donatelli, Joanna;Thanh, Cassandra;Takahashi, Saki;Hakim, Jill;Turcios, Keirstinne;Janson, Owen;Hoh, Rebecca;Tai, Viva;Hernandez, Yanel
• 通讯作者: Hernandez, Yanel

Population Pharmacokinetics of Piperaquine in Young Ugandan Children Treated With Dihydroartemisinin-Piperaquine for Uncomplicated Malaria.

用二氢青蒿素-哌喹治疗单纯性疟疾的乌干达幼儿中哌喹的群体药代动力学。

• 发表时间: 2015-07
• 影响因子: 6.7
• 作者: Sambol, N C;Yan, L;Creek, D J;McCormack, S A;Arinaitwe, E;Bigira, V;Wanzira, H;Kakuru, A;Tappero, J W;Lindegardh, N;Tarning, J;Nosten, F;Aweeka, F T;Parikh, S
• 通讯作者: Parikh, S

Determination of artemether and dihydroartemisinin in human plasma with a new hydrogen peroxide stabilization method.

采用新的过氧化氢稳定方法测定人血浆中的蒿甲醚和双氢青蒿素。

• DOI: 10.4155/bio.13.91
• 发表时间: 2013-06
• 期刊: Bioanalysis
• 影响因子: 1.8
• 作者: Huang L;Olson A;Gingrich D;Aweeka FT
• 通讯作者: Aweeka FT

Antiretroviral Choice for HIV Impacts Antimalarial Exposure and Treatment Outcomes in Ugandan Children.

HIV 抗逆转录病毒选择会影响乌干达儿童的抗疟药物暴露和治疗结果。

• 发表时间: 2016-08-01
• 作者: Parikh, Sunil;Kajubi, Richard;Huang, Liusheng;Ssebuliba, Joshua;Kiconco, Sylvia;Gao, Qin;Li, Fangyong;Were, Moses;Kakuru, Abel;Achan, Jane;Mwebaza, Norah;Aweeka, Francesca T
• 通讯作者: Aweeka, Francesca T