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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

Title
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
Presenter
Alexandra Compagnucci
Authors
A. Compagnucci * (1), M. Chan (2), Y. Saïdi (1), T. Cressey (3), A. Bamford (2), Y. Riault (1), A. Coelho (1), A. Nolan (2), S. Chalermpantmetagul (3), P. Amuge (4), V. Musiime (5), A. Violari (6), M. Cotton (7), S. Kanjanavanit (8), A. Volokha (9), R. Bologna (10), N. Pavia Ruz (11), L. Tato Prieto (12), P. Paioni (13), L. Marques (14), V. Reliquet (15), S. Welch (16), D. Ford (2), C. Giaquinto (17), D. Gibb (2), A. Babiker (2), J.T. Ramos Amador (18), and the SMILE-PENTA 17 Trial Group
Institutions
(1) INSERM, SC10-US19 Clinical Trial Unit, Clinical Trials and Infectious Diseases, Villejuif, France, (2) MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London, United Kingdom, (3) AMS-CMU/IRD (PHPT), Chiang Mai, Thailand, (4) Baylor College of Medicine Children's Foundation, Kampala, Uganda, (5) Joint Clinical Research Centre (JCRC), Lubowa, Kampala, Uganda, (6) Perinatal HIV Research Unit (PHRU), Johannesburg, South Africa, (7) Family Centre for Research with Ubuntu (FAMCRU), Cape Town, South Africa, (8) Nakornping Hospital, Chiang Mai, Thailand, (9) Kiev City AIDS Center, Infectious Diseases, Kiev, Ukraine, (10) Hospital de Pediatría Garrahan, Epidemiology and Infectious Diseases, Buenos Aires, Argentina, (11) Universidad Nacional Autónoma de México, Clínica de Atención a Niños con VIH, UNAM/HGM, Mexico, Mexico, (12) Hospital Universitario 12 de Octubre, Pediatric Infectious Diseases, Madrid, Spain, (13) Kinderspital, Zurich, Switzerland, (14) Centro Materno Infantil do Norte ' CH do Porto, Oporto, Portugal, (15) CHU Hôtel Dieu, Infectious Diseases, Nantes, France, (16) University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom, (17) University of Padova, Woman''s and Child''s Health, Padova, Italy, (18) University Complutense of Madrid, Departamento de Salud Pública y Materno-Infantil-Instituto de Investigacion Biomedica Hospital Clinico San Carlos (IdISSC), Madrid, Spain

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.