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.

摘要 双氢青蒿素-哌喹（DP）是一种以青蒿素为基础的联合治疗药物， 治疗简单疟疾的药物，但确保其最佳效果的根本问题仍然存在。 在我们最脆弱的人群中，特别是儿童中，以及在相互作用的抗逆转录病毒药物的背景下， 治疗Dolutegravir（DTG），现在是根据更新的艾滋病毒治疗指南的一线艾滋病毒治疗选择， 尚未在儿童中研究伴随DP的情况，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，另一种艾滋病毒治疗），已知增加最大哌喹 目前，这些药物在儿童中的浓度尚不清楚，但儿童心脏毒性的程度和相关风险仍不清楚。我们计划 扩大我们目前的拨款，使我们能够研究DTG和DP之间的潜在相互作用， 仔细、安全地评价LPV/r和DP之间潜在的有害相互作用。这一行政 补充要求支持DTG作为三种抗逆转录病毒药物之一的研究， 评价具体来说，我们正在请求支持扩大控制儿童，以包括更广泛的 年龄范围，这是必要的年龄匹配的儿童谁是DTG管理。此外，该补充 正在请求支持，以允许两个阶段的研究设计，这将使我们能够完成一个安全的评估， LPV/r /和DP之间可能的相互作用（即LPV/r预计会增加哌喹浓度， 与QTc间期延长有关）。这两项要求是提供基础设施支助， 乌干达总之，我们的研究结果有可能显著影响治疗指南， 通过这项DP在儿童中的药代动力学和药效学的确定性研究， 这些抗逆转录病毒疗法的设置。我们的总体目标是为优化DP给药策略提供信息， 孩子

项目成果

Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms.

从急性后症状和没有急性后症状的患者中，长期SARS-COV-2特异性免疫和炎症反应。

• DOI: 10.1016/j.celrep.2021.109518
• 发表时间: 2021-08-10
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Peluso MJ;Deitchman AN;Torres L;Iyer NS;Munter SE;Nixon CC;Donatelli J;Thanh C;Takahashi S;Hakim J;Turcios K;Janson O;Hoh R;Tai V;Hernandez Y;Fehrman EA;Spinelli MA;Gandhi M;Trinh L;Wrin T;Petropoulos CJ;Aweeka FT;Rodriguez-Barraquer I;Kelly JD;Martin JN;Deeks SG;Greenhouse B;Rutishauser RL;Henrich TJ
• 通讯作者: Henrich TJ

Disposition of amodiaquine and desethylamodiaquine in HIV-infected Nigerian subjects on nevirapine-containing antiretroviral therapy.

在接受奈韦拉平抗逆转录病毒治疗的艾滋病毒感染尼日利亚受试者中阿莫地喹和去乙基阿莫地喹的处置。

• DOI: 10.1093/jac/dkt513
• 发表时间: 2014
• 期刊: The Journal of antimicrobial chemotherapy
• 作者: Scarsi,KimberlyK;Fehintola,FataiA;Ma,Qing;Aweeka,FrancescaT;Darin,KristinM;Morse,GeneD;Akinola,IbrahimTemitope;Adedeji,WaheedA;Lindegardh,Niklas;Tarning,Joel;Ojengbede,Oladosu;Adewole,IsaacF;Taiwo,Babafemi;Murphy,Robert
• 通讯作者: Murphy,Robert

Population Pharmacokinetics and Pharmacodynamics of Lumefantrine in Young Ugandan Children Treated With Artemether-Lumefantrine for Uncomplicated Malaria.

• DOI: 10.1093/infdis/jiw338
• 发表时间: 2016-10-15
• 期刊: The Journal of infectious diseases
• 作者: Tchaparian E;Sambol NC;Arinaitwe E;McCormack SA;Bigira V;Wanzira H;Muhindo M;Creek DJ;Sukumar N;Blessborn D;Tappero JW;Kakuru A;Bergqvist Y;Aweeka FT;Parikh S
• 通讯作者: Parikh S

The epidemiological impact of HIV antiretroviral therapy on malaria in children.

• DOI: 10.1097/qad.0000000000000550
• 发表时间: 2015-02-20
• 期刊: AIDS (London, England)
• 作者: Greenhalgh S;Ndeffo M;Galvani AP;Parikh S
• 通讯作者: Parikh S

Determination of the antimalarial drug piperaquine in small volume pediatric plasma samples by LC-MS/MS.

• DOI: 10.4155/bio.14.254
• 发表时间: 2014
• 期刊: Bioanalysis
• 影响因子: 1.8
• 作者: Kjellin LL;Dorsey G;Rosenthal PJ;Aweeka F;Huang L
• 通讯作者: Huang L