Nucleoside/nucleotide reverse transcriptase inhibitor sparing regimen with once daily integrase inhibitor plus boosted darunavir is non-inferior to standard of care in virologically-suppressed children and adolescents living with HIV - Week 48 results of the randomised SMILE Penta-17-ANRS 152 clinical trial.

Abstract

Integrase inhibitor (INSTI) with boosted darunavir (DRV/r), a regimen with a high-resistance barrier, avoiding NRTI toxicities, might be a switching option in children living with HIV (CLWHIV). SMILE is a randomised non-inferiority trial evaluating safety and antiviral efficacy of once-daily INSTI+DRV/r vs. continuing on current standard-of-care (SOC) triple ART (2NRTI+boosted PI/NNRTI) in virologically-suppressed CLWHIV aged 6-18 years. The primary outcome is the proportion with confirmed HIV-RNA ≥50 copies/mL by week 48, estimated by Kaplan-Meier method. Non-inferiority margin was 10%. Registration number for SMILE are: ISRCTN11193709, NCT #: NCT02383108. Between 10th June 2016 and 30th August 2019, 318 participants were enrolled from Africa 53%, Europe 24%, Thailand 15% and Latin America 8%, 158 INSTI+DRV/r [153 Dolutegravir (DTG); 5 Elvitegravir (EVG)], 160 SOC. Median (range) age was 14.7 years (7.6-18.0); CD4 count 782cells/mm3 (227-1647); 61% female. Median follow-up was 64.3 weeks with no loss to follow-up. By 48 weeks, 8 INSTI+DRV/r vs. 12 SOC had confirmed HIV-RNA ≥50 copies/mL; difference (INSTI+DRV/r-SOC)-2.5% (95% CI:-7.6, 2.5%), showing non-inferiority. No major PI or INSTI resistance mutations were observed. There were no differences in safety between arms. By week 48, difference (INSTI+DRV/r-SOC) in mean CD4 count change from baseline was-48.3cells/mm3 (95% CI:-93.4,-3.2; p=0.036). Difference (INSTI+DRV/r-SOC) in mean HDL change from baseline was-4.1mg/dL (95% CI:-6.7,-1.4; p=0.003). Weight and Body Mass Index (BMI) increased more in INSTI+DRV/r than SOC [difference: 1.97kg (95% CI: 1.1, 2.9; p<0.001), 0.66kg/m2 (95% CI: 0.3, 1.0; p<0.001)]. In virologically-suppressed children, switching to INSTI+DRV/r was non-inferior virologically, with similar safety profile, to continuing SOC. Small but significant differences in CD4, HDL-cholesterol, weight and BMI were observed between INSTI+DRV/r vs. SOC although clinical relevance needs further investigation. SMILE data corroborate adult findings and provide evidence for this NRTI-sparing regimen for children and adolescents. Fondazione Penta Onlus, Gilead, Janssen, INSERM/ANRS and UK MRC. ViiV-Healthcare provided Dolutegravir.