Clinical trial NCT03800394: Pharmacokinetics of Intracellular TFV-DP and FTC-TP in HIV-infected Adolescents
Official title: Pharmacokinetics of Anti-tuberculosis and Antiretroviral Drugs in Children
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Human Immunodeficiency Virus (HIV)
Tuberculosis
Coinfection
Keywords: Pharmacokinetic
Pharmacogenomic
Tenofovir diphosphate
Emtricitabine triphosphate
Adolescents
Lead sponsor: University of Florida
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2019-01-11
Enrollment: 52
Sex: ALL
Minimum age (years): 10
Maximum age (years): 19
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Adolescents aged 10-19 years with HIV with or without TB co-infection.

Brief summary: Tenofovir (TFV) disoproxil fumarate (TDF) plus emtricitabine (FTC) or lamivudine (3TC) is the preferred nucleoside backbone of first-line antiretroviral therapy (ART) for adolescents in sub-Saharan Africa. In addition, TDF/FTC is recommended for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection in adolescents at substantial risk of acquisition of HIV infection, as well as for hepatitis B virus (HBV) treatment in those with HBV/HIV coinfection. The efficacy TDF and FTC are dependent on intracellular concentrations of the active phosphate anabolites, called TFV diphosphate (TFV-DP) and FTC triphosphate (FTC-TP). However, the intracellular pharmacokinetics of TFV-DP and FTC-TP to examine the adequacy of current dosages in African adolescents has not been previously studied. Thus, examining the pharmacokinetics (PK) of these widely used antiretrovirals in African adolescents is important as ART outcomes remain poor and the recommended dosages of these drugs for children and adolescent were extrapolated from drug approval clinical trials in adult in the United States and Europe.

Detailed description: This study will evaluate the intracellular PK of TFV-DP and FTC-TP in Ghanaian HIV-infected adolescents with and without TB coinfection. As the clinical effects of TDF and FTC are related to the intracellular concentrations of the phosphate anabolites, called TFV-DP and FTC-TP, there is a need to understand the cellular pharmacology of TDF interactions in African HIV-infected adolescents with and without TB, as the study team cannot extrapolate from US patients not on antituberculosis (anti-TB) drugs. This study will enroll HIV-infected adolescents aged 10 to 18 years old with and without TB coinfection who are already established on ART. The study team hypothesize that younger age, adenosine triphosphate (ATP)-binding cassette subfamily C (ABCC) single nucleotide polymorphisms (SNPs) and anti-TB therapy may influence the intracellular TFV-DP and FTC-TP concentrations in adolescents.

Eligibility criteria: Inclusion Criteria:

* HIV-infected adolescents aged 10 to 19 years old who are stable on antiretroviral regimen containing TDF/FTC (300/200 mg daily) for at least 8 weeks.

Exclusion Criteria:

* Unable to obtain informed signed consent from parent(s) or legal guardian.
* Pregnant or breast feeding.
* Require therapy for other opportunistic infections other than tuberculosis (TB).

Primary outcomes:
measure: Average concentration (Cav) of intracellular TFV-DP and FTC-TP in Ghanaian HIV-infected adolescents.
timeFrame: After at least 8 weeks of HIV therapy.
measure: Area under the time-concentration curve 0-24 hours (AUC0-24h) of intracellular TFV-DP and FTC-TP in Ghanaian HIV-infected adolescents.
timeFrame: After at least 8 weeks of HIV therapy.
measure: Cav of TFV-DP and FTC-TP PK in HIV-infected adolescents with and without TB coinfection.
timeFrame: After at least 8 weeks of HIV therapy.
measure: AUC0-24h of TFV-DP and FTC-TP PK in HIV-infected adolescents with and without TB coinfection.
timeFrame: After at least 8 weeks of HIV therapy.
Secondary outcomes:
measure: Effect of age on TFV-DP and FTC-TP Cav.
timeFrame: After at least 8 weeks of HIV therapy.
measure: Effect of age on TFV-DP and FTC-TP AUC0-24h .
timeFrame: After at least 8 weeks of HIV therapy.
measure: Intracellular TFV-DP and FTC-TP Cav in adolescents compared to that in historical adult controls.
timeFrame: After at least 8 weeks of HIV therapy.
measure: Intracellular TFV-DP and FTC-TP AUC0-24h in adolescents compared to that in historical adult controls.
timeFrame: After at least 8 weeks of HIV therapy.
measure: Relationship between Adenosine triphosphate (ATP)-binding cassette subfamily C, member 2 (ABCC2), member 4 (ABCC4) and member 10 (ABCC10) SNPs and TFV-DP and FTC-TP AUC0-24h.
timeFrame: After at least 8 weeks of HIV therapy.
measure: Prevalence and covariates of intracellular TFV-DP Cav < 95 fmol/106 cells in adolescents.
timeFrame: After at least 8 weeks of HIV therapy.
Other outcomes:
Locations:
city: Kumasi
country: Ghana
facility: Kwame Nkrumah University of Science and Technology
Study officials:
affiliation: University of Florida
name: Awewura Kwara, MD
role: PRINCIPAL_INVESTIGATOR
References: