Once-daily integrase inhibitor (INSTI) with boosted darunavir is non-inferior to standard of care in virologically suppressed children, Week 48 results of the SMILE PENTA-17 TRIAL


BACKGROUND: INSTI+Darunavir/r, a regimen with a high-resistance barrier, avoiding NRTI toxicities, might be a switching option in children LWHIV.
METHODS: SMILE is a randomised non-inferiority trial evaluating safety and antiviral effect of once-daily INSTI+Darunavir/r versus standard-of-care (SOC) in HIV-1 infected, virologically-suppressed children 6-<18 years. The primary outcome is the proportion with confirmed HIV-RNA'¥50c/mL up to week 48. Analyses were intention-to-treat, using Kaplan-Meier method (10% non-inferiority margin).
RESULTS: 318 participants were randomised (Africa 53%, Europe 24%, Thailand 15%, Latin America 8%), INSTI+DRV/r:158(DTG: 153, EVG: 5); SOC:160. Median (range) age was 14.7years (7.6-18.0); weight 47.8kg (22.1-96.3); CD4 count 782cells/mm3 (227-1647); 61% female; 59% NNRTI; 41% PI.
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'¥50c/mL; difference (INSTI+DRV/r-SOC) -2.5% (95% CI: -7.7, 2.6), showing non-inferiority. No major PI (0/11) or INSTI (0/6) resistance mutations were observed. There was 1 new severe CDC stage B event in INSTI+DRV/r and none in SOC. There were 4 SAEs (4 participants) in INSTI+DRV/r vs 5(4) in SOC (p=0.986); 13 grade 3/4 AEs (13 participants) in INSTI+DRV/r vs 25(19) in SOC (p=0.280). Self-reported mood/sleep disorders were infrequent and similar between arms.
By week 48, difference between arms (INSTI+DRV/r-SOC) in mean CD4 count change from baseline was 48.3cells/mm3 (95% CI: -93.4,-3.2; p=0.036); numbers with CD4 count '¤500cells/mm3 were low and similar between arms [21(14%) INSTI+DRV/r vs 15(10%) SOC; p=0.234]; no significant differences were observed for CD8%, CD8 count and CD4%/CD8% ratio. Difference between arms (INSTI+DRV/r-SOC) in mean LDL and HDL change from baseline was +4.7mg/dL (95% CI: -0.7, 10; p=0.088) and -4.1mg/dL (95% CI: -6.7,-1.4; p=0.003), respectively. Weight and 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)].
CONCLUSIONS: In virologically-suppressed children, switching to INSTI+DRV/r was non-inferior virologically, with similar safety profile, to continuing SOC. Changes in CD4%, CD4 count, HDL-cholesterol, weight and BMI were slightly different in INSTI+DRV/r vs SOC although clinical relevance needs further investigation. SMILE data corroborate adult findings and provide evidence for an alternative NRTI-sparing regimen for children and adolescents.