Safety, Pharmacokinetics and Efficacy of Dolutegravir in Treatment-experienced HIV-1 Infected Adolescents

Abstract

Objective To assess the pharmacokinetic (PK), safety and efficacy of dolutegravir plus optimized background regimen (OBR) in HIV infected treatment-experienced adolescents. Methods Children ≥12 to < 18 years received dolutegravir weight-based fixed doses at ~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 (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 AUC(0–24) and C24 were 46.0 µg.h/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% CI: 52% to 90%) at Week 48. Additionally, 61% (95% CI: 39% to 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 AEs, SAEs or discontinuations due to AEs. Conclusions Dolutegravir achieved target PK exposures in adolescents. Dolutegravir was safe and well tolerated, providing good virologic efficacy through Week 48.

Use of Integrase Inhibitors in HIV-Infected Children and Adolescents

“…The drug was well-tolerated, with no Grade 4 adverse events noted and no discontinuation of the drug secondary to any adverse events. All six subjects with virological failure reported suboptimal adherence and there was no emergence of mutations conferring integrase inhibitor resistance [16].…”

“…Data from the younger cohort enrolled in IMPAACT P1093 have recently been presented [87]. Eleven HIV-infected children between the ages of 6 and 12 years of age failing ART with a screening HIV RNA [1000 copies/mL received dolutegravir tablets at a dosage of 1 mg/kg once a day based on a weight band utilizing 10, 25, or 50 mg tablets with OBT.…”

“…IMPAACT P1093 is an ongoing phase I/II multicenter open-label study assessing the safety, pharmacokinetics, and efficacy of dolutegravir in combination with OBT in children and adolescents between 4 weeks and 18 years of age [16]. HIV-infected, treatment-experienced adolescents between the ages of 12 and 18 years with a HIV RNA C1000 copies/mL at screening were enrolled in the adolescent cohort [16].…”

“…HIV-infected, treatment-experienced adolescents between the ages of 12 and 18 years with a HIV RNA C1000 copies/mL at screening were enrolled in the adolescent cohort [16]. At baseline, the median HIV RNA was 4.3 log 10 copies/mL, and the median CD4?…”

“…As a class, integrase inhibitors have a potentially higher threshold for developing resistance than other antiretroviral agents, as well as a lower risk of cross-resistance given their unique mechanism of action [10][11][12]. These drugs as a whole have demonstrated utility in salvage regimens in both children and adults and as initial therapy in adults [13][14][15][16][17]. They provide rapid control of viral replication and have a favorable adverse effect profile overall [10-12, 17, 18].…”