Background: EVG/COBI/FTC/tenofovir alafenamide (TAF) [E/C/F/TAF] is an integrase inhibitor-based single tablet regimen in clinical development for use in HIV-infected adolescents. Pharmacokinetics, safety and efficacy from a planned interim analysis of the first clinical trial of E/C/F/TAF in adolescents are reported.
Methods: Treatment-naïve 12 to <18 year-olds weighing ≥35 kg with HIV-1 RNA >1000 copies/mL (c/mL), CD4 >100 cells/μL and eGFR>90 mL/min/1.73m2 received E/C/F/TAF once daily in a prospective, 2-part, 48-week, single-arm, open-label trial. Steady-state pharmacokinetic (PK) parameters were compared to an adult reference population by ANOVA, and related to the range of exposures associated with antiviral activity in adults. Adverse events (AE), laboratory tests, and the proportion of subjects with HIV-1 RNA < 50 c/mL were assessed through Week 24. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry.
Results: The trial enrolled 48 adolescents with a median age of 15 years, median weight of 52 kg, 58% female, 88% Black, 13% Asian, 67% vertically infected, 35% with HIV-1 RNA > 100,000 c/mL, median CD4 count 468 cells/μL, and median serum creatinine [sCr] 0.57 mg/dL. TAF, TFV, EVG, COBI, and FTC PK profiles of adolescents were consistent with those in adults. Of 23 subjects followed to Week 24, 21 (91%) had HIV-1 RNA <50 c/mL (Figure). No deaths or AE-related discontinuations occurred. The most frequent AEs were nausea (23%), upper respiratory infection (21%), and diarrhea (17%). One serious AE of visual impairment and intermediate uveitis occurred and resolved without interruption of E/C/F/TAF. The median change in sCr was +0.08 mg/dL at Week 24, consistent with cobicistat’s inhibition of renal tubular Cr secretion. No renal failure or proximal renal tubulopathy occurred. From baseline to Week 24, the change in median spine BMD was +2.8% with a change in height-adjusted (HA) Z-score of +0.02 and 2/23 subjects (9%) having a decrease of ≥4%. The change in median total body less head BMD was +0.3% with a change in HA Z-score of +0.09 and no decreases of ≥4%. No fractures occurred.
Conclusions: Therapeutic plasma concentrations of all components of E/C/F/TAF were achieved, consistent with potent antiviral activity of the regimen. Treatment was generally well-tolerated through 24 weeks with a favorable renal and bone safety profile. These promising findings support E/C/F/TAF’s eventual use in adolescents and its further evaluation in other pediatric populations.