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. 2023 Jun 2:60:102025.
doi: 10.1016/j.eclinm.2023.102025. eCollection 2023 Jun.

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

Alexandra Compagnucci  1 , Man K Chan  2 , Yacine Saïdi  1 , Tim R Cressey  3 , Alasdair Bamford  2   4   5 , Yoann Riault  1 , Alexandra Coelho  1 , Aoife Nolan  2 , Suwalai Chalermpantmetagul  3 , Gabija Morkunaite  6 , Pauline Amuge  7 , Victor Musiime  8   9 , Avy Violari  10 , Mark Cotton  11 , Adeodata R Kekitiinwa  7 , Elizabeth Kaudha  8 , Marisa Groenewald  11 , Afaaf A Liberty  10 , Suparat Kanjanavanit  12 , Alla Volokha  13 , Rosa Bologna  14 , Noris Pavia Ruz  15 , Luis Prieto Tato  16 , Paolo Paioni  17 , Laura Marques  18 , Véronique Reliquet  19 , Tim Niehues  20 , Steven B Welch  21 , Deborah Ford  2 , Carlo Giaquinto  22 , Diana M Gibb  2 , Abdel Babiker  2 , Jose Tomas Ramos Amador  23 ; SMILE-PENTA17-ANRS 152 Trial Group
Collaborators, Affiliations

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

Alexandra Compagnucci et al. EClinicalMedicine. .

Abstract

Background: 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).

Methods: 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.

Findings: 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 782 cells/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 -48.3 cells/mm3 (95% CI: -93.4, -3.2; p = 0.036). Difference (INSTI + DRV/r-SOC) in mean HDL change from baseline was -4.1 mg/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: 1.97 kg (95% CI: 1.1, 2.9; p < 0.001), 0.66 kg/m2 (95% CI: 0.3, 1.0; p < 0.001)].

Interpretation: 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.

Funding: Fondazione Penta Onlus, Gilead, Janssen, INSERM/ANRS and UK MRC. ViiV-Healthcare provided Dolutegravir.

Keywords: Adolescents; Children; Darunavir; Dolutegravir; Dual therapy; HIV; Maintenance; Paediatrics; Randomised; Simplification; Virological suppressed.

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Conflict of interest statement

ACom, YS, YR and ACoe declare that their institution Inserm received a grant for the trial through PENTA Foundation “agreement PENTA-Inserm” started 14th September 2014 and declare support for scientific meetings from PENTA Foundation. AVi declares funding given from PENTA Foundation to her institution for the conduct of the study. ABab declares a grant from Medical Research Council, UKRI to his Institution. PA and ADK declare sponsored study materials and participant recruitment costs from PENTA foundation. PA, ADK and CG declare a research grant for part of the study from Gilead and funded drug supply for the study from ViiV Healthcare. NPR declares a financial support for the research paid to her institution from PENTA Foundation and from Merck. NPR declares that her institution receives the drugs for the study from PENTA Foundation. NPR declares a support for attending ID week in 2022 from AstraZeneca. All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
SMILE total population CONSORT diagram. + One participant was ineligible due to interruption in recruitment due to EVG withdrawal off the market. One participant was ineligible due to viral resistance to Darunavir. ∗ 5 participants in each arm were randomised before temporary suspension due to EVG withdrawal from the market. ∗∗ During the COVID-19 pandemic, sites were advised they could conduct follow-up visits by phone if there was an additional risk to come in person. Eight participants missed the trial endpoint visit at week 48 (7 in INSTI + DRV/r; 1 in SOC); 5 out of the 8 participants came in 1–6 days late and missed week 48 max window (fell in week 60 window), 3 participants missed week 48 clinic visit/telephone follow-up.
See this image and copyright information in PMC

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