Safety, Pharmacokinetics and Efficacy of Dolutegravir in Treatment-experienced HIV-1 Infected Adolescents: Forty-eight-week Results from IMPAACT P1093

Pediatr Infect Dis J. 2015 Nov;34(11):1207-13. doi: 10.1097/INF.0000000000000848.

Abstract

Objective: To assess the pharmacokinetics (PK), safety and efficacy of dolutegravir plus optimized background regimen in HIV-infected treatment-experienced adolescents.

Methods: Children older than 12 to younger than 18 years received dolutegravir weight-based fixed doses at approximately 1.0 mg/kg once daily in a phase I/II multicenter open label 48-week study. Intensive PK evaluation was done at steady state after dolutegravir was added to a failing regimen or started at the end of a treatment interruption. Safety and HIV RNA and CD4 cell count assessments were performed through week 48.

Results: Twenty-three adolescents were enrolled and 22 (96%) completed the 48-week study visit. Median age and weight were 15 years and 52 kg, respectively. Median [interquartile range (IQR)] baseline CD4+ cell count was 466 cells/μL (297, 771). Median (IQR) baseline HIV-1 RNA log10 was 4.3 log10 copies/mL (3.9, 4.6). Dolutegravir geometric mean of the area under the plasma concentration-time curve from time of administration to 24 hours after dosing (AUC0-24) and 24 hour postdose concentration (C24) were 46.0 μg hours/mL and 0.90 μg/mL, respectively, which were within the study targets based on adult PK ranges. Virologic success with an HIV RNA <400 copies/mL was achieved in 74% [95% confidence interval (CI): 52-90%] at week 48. Additionally, 61% (95% CI: 39-80%) had an HIV RNA <50 copies/mL at week 48. Median (IQR) gain in CD4 cell count at week 48 was 84 cells/μL (-81, 238). Dolutegravir was well tolerated, with no grade 4 adverse events, serious adverse events or discontinuations because of serious adverse events.

Conclusions: Dolutegravir achieved target PK exposures in adolescents. Dolutegravir was safe and well tolerated, providing good virologic efficacy through week 48.

Trial registration: ClinicalTrials.gov NCT01302847.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Female
  • HIV Infections / drug therapy*
  • HIV Infections / epidemiology
  • HIV Integrase Inhibitors* / adverse effects
  • HIV Integrase Inhibitors* / pharmacokinetics
  • HIV Integrase Inhibitors* / therapeutic use
  • Heterocyclic Compounds, 3-Ring* / adverse effects
  • Heterocyclic Compounds, 3-Ring* / pharmacokinetics
  • Heterocyclic Compounds, 3-Ring* / therapeutic use
  • Humans
  • Male

Substances

  • HIV Integrase Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • dolutegravir

Associated data

  • ClinicalTrials.gov/NCT01302847