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June 01, 2023 article Open access Aachen paper

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

EClinicalMedicine, vol. 60, pp. 102025

DOI: 10.1016/j.eclinm.2023.102025 Full text (OA) OpenAlex

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/mm 3 (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/mm 3 (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/m 2 (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.

Authors 75

  1. Alexandra Compagnucci corresponding

    Inserm

    Affiliation as printed

    INSERM SC10-US19, Essais Thérapeutiques et Maladies Infectieuses, Villejuif, France

  2. Man Kam Chan

    MRC Clinical Trials Unit at UCL · University College London

    Affiliation as printed

    MRC Clinical Trials Unit at UCL, London, UK

  3. Yacine Saïdi

    Inserm

    Affiliation as printed

    INSERM SC10-US19, Essais Thérapeutiques et Maladies Infectieuses, Villejuif, France

  4. Tim Roy Cressey

    Institut de Recherche pour le Développement · Chiang Mai University

    Affiliation as printed

    AMS-CMU & IRD Research Collaboration, Faculty of Associated Medical Sciences (AMS), Chiang Mai University, Thailand

  5. Alasdair Bamford

    Great Ormond Street Hospital · Great Ormond Street Hospital for Children NHS Foundation Trust · MRC Clinical Trials Unit at UCL · University College London

    Affiliation as printed

    Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

    MRC Clinical Trials Unit at UCL, London, UK

    UCL Great Ormond Street Institute of Child Health, London, UK

  6. Yoann Riault

    Inserm

    Affiliation as printed

    INSERM SC10-US19, Essais Thérapeutiques et Maladies Infectieuses, Villejuif, France

  7. Alexandra Coelho

    Inserm

    Affiliation as printed

    INSERM SC10-US19, Essais Thérapeutiques et Maladies Infectieuses, Villejuif, France

  8. Suwalai Chalermpantmetagul

    Institut de Recherche pour le Développement · Chiang Mai University

    Affiliation as printed

    AMS-CMU & IRD Research Collaboration, Faculty of Associated Medical Sciences (AMS), Chiang Mai University, Thailand

  9. Gabija Morkunaite

    PENTA Foundation

    Affiliation as printed

    Penta Foundation, Padova, Italy

  10. Pauline Mary Amuge

    Baylor College of Medicine Children’s Foundation

    Affiliation as printed

    Baylor College of Medicine Children's Foundation, Kampala, Uganda

  11. Victor Musiime

    Joint Clinical Research Centre · Makerere University

    Affiliation as printed

    Joint Clinical Research Centre, Lubowa, Kampala, Uganda

    Makerere University, Department of Paediatrics and Child Health, Kampala, Uganda

  12. Avy Violari

    University of the Witwatersrand · Perinatal HIV Research Unit

    Affiliation as printed

    Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa

  13. Mark Fredric Cotton

    Stellenbosch University

    Affiliation as printed

    FAMCRU, Department of Paediatrics & Child Health, Family Center for Research with Ubuntu, Stellenbosch University, South Africa

  14. Adeodata Kekitiinwa

    Baylor College of Medicine Children’s Foundation

    Affiliation as printed

    Baylor College of Medicine Children's Foundation, Kampala, Uganda

  15. Elizabeth Kaudha

    Joint Clinical Research Centre

    Affiliation as printed

    Joint Clinical Research Centre, Lubowa, Kampala, Uganda

  16. Marisa M. Groenewald

    Stellenbosch University

    Affiliation as printed

    FAMCRU, Department of Paediatrics & Child Health, Family Center for Research with Ubuntu, Stellenbosch University, South Africa

  17. Afaaf Liberty

    University of the Witwatersrand · Perinatal HIV Research Unit

    Affiliation as printed

    Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa

  18. Suparat Kanjanavanit

    Nakornping Hospital

    Affiliation as printed

    Nakornping Hospital, Chiang Mai, Thailand

  19. Alla P. Volokha

    Shupyk National Healthcare University of Ukraine

    Affiliation as printed

    Shupyk National Healthcare University of Ukraine, Kyiv, Ukraine

  20. Rosa Bologna

    Garrahan Hospital

    Affiliation as printed

    Hospital Garrahan, Buenos Aires, Argentina

  21. Noris Pavia Ruz

    Hospital General de México · Universidad Nacional Autónoma de México

    Affiliation as printed

    Clínica para niños con VIH, UNAM/HGM; Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico

    Clínica para niños con VIH, UNAM/HGM

    Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico

  22. P Paioni

    University Children's Hospital Zurich

    Affiliation as printed

    Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital Zurich, Zurich, Switzerland

  23. Véronique Reliquet

    Inserm · Centre Hospitalier Universitaire de Nantes · Nantes Université

    Affiliation as printed

    Infectious Diseases Department, CHU Hôtel Dieu and INSERM UIC 1413, Nantes University, Nantes, France

  24. Tim Niehues Aachen Centre for Child Health and Adolescence

    Helios Klinikum Krefeld · RWTH Aachen University

    Affiliation as printed

    Centre for Child Health and Adolescence, Helios Klinikum Krefeld, Academic Hospital, RWTH Aachen, Krefeld, Germany

  25. Steven B. Welch

    University Hospitals Birmingham NHS Foundation Trust · Heartlands Hospital

    Affiliation as printed

    Department of Paediatrics, Heartlands Hospital, University Hospitals Birmingham, Birmingham, UK

  26. Deborah Ford

    MRC Clinical Trials Unit at UCL · University College London

    Affiliation as printed

    MRC Clinical Trials Unit at UCL, London, UK

  27. Carlo Giaquinto

    University of Padua

    Affiliation as printed

    Department of Women's and Children's Health, University of Padova, Padova, Italy

  28. Diana M. Gibb

    MRC Clinical Trials Unit at UCL · University College London

    Affiliation as printed

    MRC Clinical Trials Unit at UCL, London, UK

  29. Abdel G. Babiker

    MRC Clinical Trials Unit at UCL · University College London

    Affiliation as printed

    MRC Clinical Trials Unit at UCL, London, UK

  30. José Tomás Ramos-Amador

    Universidad Complutense de Madrid · Hospital Clínico San Carlos · Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

    Affiliation as printed

    Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC); Fundación para la Investigación Biomédica HCSC; Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain

    Fundación para la Investigación Biomédica HCSC

    Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain

    Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC)

  31. Y Saïdi

    Inserm

    Affiliation as printed

    INSERM SC10-US19, Essais Thérapeutiques et Maladies Infectieuses, Villejuif, France

  32. Loïc Picault

    Hospital General de México · Universidad Nacional Autónoma de México

    Affiliation as printed

    Clínica para niños con VIH, UNAM/HGM; Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico

  33. Laurence Meyer

    Hospital General de México · Universidad Nacional Autónoma de México

    Affiliation as printed

    Clínica para niños con VIH, UNAM/HGM; Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico

  34. Carole Cagnot

    University of Padua

    Affiliation as printed

    Department of Women's and Children's Health, University of Padova, Padova, Italy

  35. Sophie Circosta

    Universidad Complutense de Madrid · Hospital Clínico San Carlos · Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

    Affiliation as printed

    Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC); Fundación para la Investigación Biomédica HCSC; Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain

  36. L Léger

    Hospital General de México · Universidad Nacional Autónoma de México

    Affiliation as printed

    Clínica para niños con VIH, UNAM/HGM; Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico

  37. S. Simanic

    Universidad Complutense de Madrid · Hospital Clínico San Carlos · Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

    Affiliation as printed

    Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC); Fundación para la Investigación Biomédica HCSC; Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain

  38. A. Arulananthan
  39. Fleur Hudson

    MRC Clinical Trials Unit at UCL · University College London

    Affiliation as printed

    MRC Clinical Trials Unit at UCL, London, UK

  40. Lynda M. Harper

    Hospital General de México · Universidad Nacional Autónoma de México

    Affiliation as printed

    Clínica para niños con VIH, UNAM/HGM; Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico

  41. Kaja Widuch

    MRC Clinical Trials Unit at UCL · University College London

    Affiliation as printed

    MRC Clinical Trials Unit at UCL, London, UK

  42. N. Van-Looy

    MRC Clinical Trials Unit at UCL · University College London

    Affiliation as printed

    MRC Clinical Trials Unit at UCL, London, UK

  43. E. Little

    Hospital General de México · Universidad Nacional Autónoma de México

    Affiliation as printed

    Clínica para niños con VIH, UNAM/HGM; Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico

  44. Anna Turkova
  45. Stella M. Fabiane

    Universidad Complutense de Madrid · Hospital Clínico San Carlos · Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

    Affiliation as printed

    Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC); Fundación para la Investigación Biomédica HCSC; Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain

  46. Joanna Calvert

    Universidad Complutense de Madrid · Hospital Clínico San Carlos · Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

    Affiliation as printed

    Fundación para la Investigación Biomédica HCSC

    Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain

    Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC)

  47. James Blackstone

    Universidad Complutense de Madrid · Hospital Clínico San Carlos · Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

    Affiliation as printed

    Fundación para la Investigación Biomédica HCSC

    Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain

    Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC)

  48. Karen Scott

    MRC Clinical Trials Unit at UCL · University College London

    Affiliation as printed

    MRC Clinical Trials Unit at UCL, London, UK

  49. Jamie Inshaw

    Universidad Complutense de Madrid · Hospital Clínico San Carlos · Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

    Affiliation as printed

    Fundación para la Investigación Biomédica HCSC

    Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain

    Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC)

  50. Andrew Nunn
  51. Davide Bilardi

    Universidad Complutense de Madrid · Hospital Clínico San Carlos · Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

    Affiliation as printed

    Fundación para la Investigación Biomédica HCSC

    Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain

    Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC)

  52. Woottichai Khamduang

    University Hospitals Birmingham NHS Foundation Trust · Heartlands Hospital

    Affiliation as printed

    Department of Paediatrics, Heartlands Hospital, University Hospitals Birmingham, Birmingham, UK

  53. Gonzague Jourdain

    Hospital General de México · Universidad Nacional Autónoma de México

    Affiliation as printed

    Clínica para niños con VIH, UNAM/HGM; Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico

  54. Nicole Ngo Giang Huong

    MRC Clinical Trials Unit at UCL · University College London

    Affiliation as printed

    MRC Clinical Trials Unit at UCL, London, UK

  55. Dujrudee Chinwong

    Universidad Complutense de Madrid · Hospital Clínico San Carlos · Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

    Affiliation as printed

    Fundación para la Investigación Biomédica HCSC

    Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain

    Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC)

  56. Chalermpong Saenjum

    University of Padua

    Affiliation as printed

    Department of Women's and Children's Health, University of Padova, Padova, Italy

  57. Rukchanok Peongjakta

    Hospital General de México · Universidad Nacional Autónoma de México

    Affiliation as printed

    Clínica para niños con VIH, UNAM/HGM; Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico

  58. Pra-ornsuda Sukrakanchana

    Hospital General de México · Universidad Nacional Autónoma de México

    Affiliation as printed

    Clínica para niños con VIH, UNAM/HGM; Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico

  59. Laddawan Laomanit

    Hospital General de México · Universidad Nacional Autónoma de México

    Affiliation as printed

    Clínica para niños con VIH, UNAM/HGM; Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico

  60. Ampika Kaewbundit
  61. Jiraporn Khamkon

    Universidad Complutense de Madrid · Hospital Clínico San Carlos · Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

    Affiliation as printed

    Fundación para la Investigación Biomédica HCSC

    Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain

    Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC)

  62. Kanchana Than-in-at

    MRC Clinical Trials Unit at UCL · University College London

    Affiliation as printed

    MRC Clinical Trials Unit at UCL, London, UK

  63. C. Meeboon

    University of Padua

    Affiliation as printed

    Department of Women's and Children's Health, University of Padova, Padova, Italy

  64. Worathip Sripaoraya

    University Hospitals Birmingham NHS Foundation Trust · Heartlands Hospital

    Affiliation as printed

    Department of Paediatrics, Heartlands Hospital, University Hospitals Birmingham, Birmingham, UK

  65. Nitinart Krueduangkam

    MRC Clinical Trials Unit at UCL · University College London

    Affiliation as printed

    MRC Clinical Trials Unit at UCL, London, UK

  66. Namthip Kruenual

    MRC Clinical Trials Unit at UCL · University College London

    Affiliation as printed

    MRC Clinical Trials Unit at UCL, London, UK

  67. Warunee Khamjakkaew

    University Hospitals Birmingham NHS Foundation Trust · Heartlands Hospital

    Affiliation as printed

    Department of Paediatrics, Heartlands Hospital, University Hospitals Birmingham, Birmingham, UK

  68. Soraya Klinprung

    Universidad Complutense de Madrid · Hospital Clínico San Carlos · Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

    Affiliation as printed

    Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC); Fundación para la Investigación Biomédica HCSC; Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain

  69. Déborah Hirt

    Universidad Complutense de Madrid · Hospital Clínico San Carlos · Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

    Affiliation as printed

    Fundación para la Investigación Biomédica HCSC

    Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain

    Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC)

  70. Dietmar Plonné

    Universidad Complutense de Madrid · Hospital Clínico San Carlos · Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

    Affiliation as printed

    Fundación para la Investigación Biomédica HCSC

    Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain

    Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC)

  71. Constanza Morén

    University of Padua

    Affiliation as printed

    Department of Women's and Children's Health, University of Padova, Padova, Italy

  72. Telma Noguera

    Hospital General de México · Universidad Nacional Autónoma de México

    Affiliation as printed

    Clínica para niños con VIH, UNAM/HGM; Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico

  73. Solange Arazi

    Universidad Complutense de Madrid · Hospital Clínico San Carlos · Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

    Affiliation as printed

    Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC); Fundación para la Investigación Biomédica HCSC; Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain

  74. A.G. Fedullo

    Stellenbosch University

    Affiliation as printed

    FAMCRU, Department of Paediatrics & Child Health, Family Center for Research with Ubuntu, Stellenbosch University, South Africa

  75. Moira Taicz

    Universidad Complutense de Madrid · Hospital Clínico San Carlos · Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

    Affiliation as printed

    Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC); Fundación para la Investigación Biomédica HCSC; Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain

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