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.
