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Pharmacokinetics and Pharmacodynamics of Dolutegravir in Children Weighing ≥20 Kg Living with HIV with and without TB Coinfection

Award Number: R21AI158263
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/07/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Pharmacokinetics and Pharmacodynamics of Dolutegravir in Children Weighing ≥20 Kg Living with HIV with and without TB Coinfection - ABSTRACT Children and adolescents living with human immunodeficiency virus (HIV) infection are a distinct key population from adults who have not fully benefited from the recent advances in antiretroviral therapy (ART) because of lack of age-appropriate drug formulations as well as relevant research that informs dosing recommendations for the newer antiretrovirals. Dolutegravir (DTG) is a novel second-generation integrase strand transfer inhibitor (INSTI) that is highly efficacious, safer and easy to use with a higher genetic barrier to the emergence of HIV drug resistance. The World Health Organization (WHO) updated guidelines in 2019 recommend DTG-containing regimens as preferred for the treatment of HIV in adults, adolescents and children weighing ≥20 kg. In Africa, DTG is available as the fixed-dose combination (FDC) tenofovir disoproxil fumarate (TDF) 300 mg/lamivudine (3TC) 300 mg/DTG 50 mg (TLD) and standalone 50 mg tablet. Thus, TLD is the only formulation that will be prescribed to children in the African region despite lack of supportive evidence from clinical trials or pharmacokinetics/pharmacodynamics (PK/PD) studies that it will be safe and effective. While it is expected that TLD will to be efficacious in children, verification that it achieves desired PK and safety profile in children is important. A second issue is that tuberculosis (TB) is a common comorbidity of HIV in Africa. Double dose DTG is also recommended for TB/HIV coinfection in children weighing ≥20 kg. To date, DTG 50 mg twice a day has not been studied in children with TB/HIV coinfection on rifampin-containing TB therapy. Dolutegravir is primarily metabolized by UDP-glucuronosyltransferase 1A1 (UGT1A1) with minor contribution (~10%) from cytochrome P450 3A4 (CYP3A4). Genetic variations in UGT1A1, ABCG2 and NR1I2 genes has been identified as significant covariates of DTG PK. Not only is DTG susceptible to potential drug-drug interactions due to enzyme induction, there may be additional variability due to effects of genetic and biologic covariates such as age, malnutrition and comorbidities that influence drug absorption in children in Africa. In this exploratory R21, we propose to rapidly examine the PK and safety of DTG in eligible children and adolescents as the drug is rolled out in Ghana. Our primary goal is to determine the PK and safety of DTG in children weighing ≥20 kg living with HIV with or without TB coinfection. In aim 1, we will evaluate the PK and safety of dolutegravir in ARV-naïve and ARV-experienced children and adolescents living with HIV who are prescribed TLD. In aim 2, we will evaluate the PK and safety of DTG 50 mg twice a day during rifampin- containing anti-tuberculosis therapy compared to 50 mg a day after stopping anti-Tb treatment in children and adolescents with TB/HIV coinfection. Successful completion of these aims will provide timely evidence for rational use DTG in children. The proposed studies are not only significant and innovative, they address NIH priorities of implementation of next generation HIV therapies with better safety and ease of use in a key population and challenges of HIV-associated TB coinfection therapy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	2	4/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	2	11/8/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $206,434 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	2	11/2/2021	NON-COMPETING CONTINUATION	$206,434
														Subtotal = $206,434

Issue Date FY: 2021 ( Subtotal = $178,764 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	1	12/3/2020	NEW	$178,764
														Subtotal = $178,764

Grand Total All Awards = $385,198

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Pharmacokinetics and Pharmacodynamics of Dolutegravir in Children Weighing ≥20 Kg Living with HIV with and without TB Coinfection

Award Number: R21AI158263

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/07/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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