EClinicalMedicine (Jun 2023)
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 trialResearch in context
- Alexandra Compagnucci,
- Man K. Chan,
- Yacine Saïdi,
- Tim R. Cressey,
- Alasdair Bamford,
- Yoann Riault,
- Alexandra Coelho,
- Aoife Nolan,
- Suwalai Chalermpantmetagul,
- Gabija Morkunaite,
- Pauline Amuge,
- Victor Musiime,
- Avy Violari,
- Mark Cotton,
- Adeodata R. Kekitiinwa,
- Elizabeth Kaudha,
- Marisa Groenewald,
- Afaaf A. Liberty,
- Suparat Kanjanavanit,
- Alla Volokha,
- Rosa Bologna,
- Noris Pavia Ruz,
- Luis Prieto Tato,
- Paolo Paioni,
- Laura Marques,
- Véronique Reliquet,
- Tim Niehues,
- Steven B. Welch,
- Deborah Ford,
- Carlo Giaquinto,
- Diana M. Gibb,
- Abdel Babiker,
- Jose Tomas Ramos Amador,
- A. Compagnucci,
- Y. Saidi,
- Y. Riault,
- A. Coelho,
- C. Kouakam,
- L. Picault,
- M. Ndiaye,
- L. Meyer,
- C. Cagnot,
- S. Circosta,
- L. Léger,
- S. Simanic,
- A. Arulananthan,
- D.M. Gibb,
- A. Babiker,
- M. Chan,
- D. Ford,
- F. Hudson,
- L. Harper,
- A. Bamford,
- A. Nolan,
- K. Widuch,
- S. Townsend,
- N. Van-Looy,
- L. Gao,
- E. Little,
- A. Turkova,
- S. Fabiane,
- J. Calvert,
- J. Blackstone,
- K. Scott,
- J. Inshaw,
- A. Nunn,
- A. Nardone,
- D. Bilardi,
- T.R. Cressey,
- S. Chalermpantmetagul,
- W. Khamduang,
- G. Jourdain,
- N. Ngo Giang Huong,
- D. Chinwong,
- C. Saenjum,
- R. Peongjakta,
- P. Sukrakanchana,
- L. Laomanit,
- A. Kaewbundit,
- J. Khamkon,
- K. Than-in-at,
- C. Meeboon,
- W. Sripaoraya,
- N. Krueduangkam,
- N. Kruenual,
- W. Khamjakkaew,
- S. Klinprung,
- C. Giaquinto,
- G. Morkunaite,
- D. Hirt,
- L. Prieto Tato,
- T. Niehues,
- D. Plonné,
- C. Morén,
- T. Noguera,
- M.A. Muñoz Fernández,
- R. Bologna,
- S. Arazi,
- A.G. Fedullo,
- M. Taicz,
- E. Vicentini,
- M. Moragas,
- A. Mangano,
- M. Dell’Orso,
- M. Gatto,
- V. Reliquet,
- A. Soria,
- E. Paredes,
- N. Chereau,
- M. Tching Sin,
- L. Flet,
- A. Rodallec,
- C. Hemon,
- N. Elenga,
- M.D. Terrine,
- N. Blaise,
- S. Augustin,
- P. Mespoulhe,
- H. Pouchain,
- N. Pavia-Ruz,
- R. Muñoz- Hernández,
- A. Neri-Macias,
- M.D. Jarillo-Quijada,
- C. Espinosa-Sotero,
- L. Marques,
- C. Teixeira,
- A. Fernandes,
- R. Nunes,
- H. Nascimento,
- J. Tuna,
- A. Padrao,
- I. Ferraz,
- A.C. Mendes,
- C. Correira,
- H. Pinheiro,
- A.C. Matos,
- A.C. Sampaio,
- A. Oliveira,
- A. Caldeira,
- M. Tavares,
- A. Reis Melo,
- C. Castro,
- C. Faria,
- C. Prucha,
- R. Ribeiro,
- F. Monteiro,
- M.F. Candeias,
- T. Silva Milhiero,
- E. Gomes Neves,
- A. Oliveira,
- R. Corte-Real,
- M. Morgado,
- D. Mendes,
- M. Cardão,
- A. Violari,
- N. Ramsagar,
- A. Liberty,
- M. Nyati,
- L. Maseko,
- M. Khunene,
- S. Mkhize,
- Z. Essack,
- N. Akoojee,
- U. Singh,
- Y. Fourie,
- S. Govender,
- A. Vadee,
- R. Lakha,
- J. Erasmus,
- A. Mamiane,
- T. Daniel,
- P. Bhana,
- N. Maduna,
- M. Cotton,
- M. Groenewald,
- G. Slade,
- J. Coetzee,
- L. Ganger,
- S. Weldon,
- M. Wessels,
- L. Hoorn,
- S. Pieterse,
- C. Makola,
- K. Smith,
- M. Isaacs,
- A. Cweya,
- S. Fry,
- S. Barnabas,
- M. Theunissen,
- N. Nduna,
- M. Smuts,
- P. Rojo Conejo,
- C. Epalza,
- L. Prieto Tato,
- M. Fernández,
- M.J. Mellado Peña,
- T. Sainz Costa,
- L. Escosa García,
- P. Gomez Salcedo,
- C. Fortuny Guasch,
- T. Noguera Julian,
- C. Estepa,
- M. Cubells,
- E. Sans,
- E. Bruno,
- L. Prieto,
- P. Mendez García,
- A. Murciano Cabeza,
- M. Coto,
- R. Torrent,
- M. Torres Arauz,
- M. Navarro Gómez,
- A. Mur,
- S. Guillén Martin,
- M. Moreno,
- J.T. Ramos Amador,
- I. Garcia,
- C. Kalhert,
- T. Wachinger,
- B. Wohlwend,
- S. Hafner,
- G. Dollenmaier,
- P. Paioni,
- R. Signorell,
- J. Boni,
- A. Duppenthaler,
- B. Mann,
- C. Saegesser,
- M. Barbani,
- C. Ngampiyaskul,
- P. Greetanukroh,
- P. Khannak,
- P. Tearsansern,
- W. Chamjamrat,
- N. Chanto,
- T. Thapwai,
- K. Thungkham,
- P. Puangmalai,
- C. Ruklao,
- P. Ounchanum,
- S. Khusuwan,
- S. Denjanta,
- Y. Thaweesombat,
- J. Thewsoongnoen,
- K. Kaewmamueng,
- P. Kamboua,
- S. Pongprapass,
- W. Srisuk,
- A. Kongponoi,
- J. Limplertjareanwanich,
- S. Kanjanavanit,
- C. Saewtrakool,
- P. Yingyong,
- D. Chutima,
- R. Junkaew,
- T. Chankun,
- U. Srirompotong,
- P. Sudsaard,
- K. Kongsuk,
- T. Petpranee,
- S. Srirojana,
- D. Donngernl,
- A. Kamkoonmongkol,
- N. Na Kalasin,
- P. Phunkhum,
- A.R. Kekitiinwa,
- P. Amuge,
- D. Bbuye,
- J. Nalubwama,
- S. Namanda,
- M. Nsibuka Kisekka,
- A. Kirabira,
- L. Lawrence,
- G. Agaba,
- G. Ahimbisibwe,
- A. Nalugo,
- F. Namuli,
- R. Kadhuba,
- R. Namuddu,
- I. Nabwire,
- L. Kiyimba,
- A. Baita,
- J. Tikabibamu,
- L. Nakandi,
- G.P. Kisitu,
- N. Nabukeera Barung,
- C.M. Kityo,
- V. Musiime,
- E. Kaudha,
- A. Nanduudu,
- E. Mujyambere,
- S.P. Labeja Ocitti,
- J. Ategeka,
- E. Nambi,
- R. Nazzinda,
- D. Rutebarika,
- R. Basiimwa,
- R. Mbabazi,
- P. Kyobutungi,
- M. Nabalamba,
- A. Nakalyango,
- J. Tumusiime,
- S. Nakabuye,
- J. Mwebaza,
- S. Oruk,
- J. Namusanje,
- A. Musiime,
- L. Mugarura,
- M. Ojok,
- J. Kitabalwa,
- C. Katemba,
- M. Nannungi,
- E. Bagirigomwa,
- D. Odoch,
- E. Rubanga,
- D. Mulima,
- E.L. Babu,
- D. Baliruno,
- C. Inyakuwal,
- E.D. Williams,
- A. Mulindwa,
- A. Uyungrwoth,
- I. Raus,
- O. Mostovenko,
- T. Stepchenkova,
- A. Volokha,
- N. Primak,
- J. Kenny,
- A. Callaghan,
- M. Ahmad,
- S. Vergnano,
- M. Ross,
- F. Manyi,
- D. Nayagam,
- S. Hawkins,
- C. Ball,
- E. Hamlyn,
- C. Gilmour,
- S. Gilmour-White,
- S. Doshi,
- E. Fuller,
- A. Adebayo,
- K. Tupper,
- E. Nsirim,
- S. Welch,
- J. Daglish,
- L. Thrasyvoulou,
- E. Irvine,
- K. Gandhi,
- Y. Vaughn-Gordon,
- N. Sibanda
Affiliations
- Alexandra Compagnucci
- INSERM SC10-US19, Essais Thérapeutiques et Maladies Infectieuses, Villejuif, France; Corresponding author.
- Man K. Chan
- MRC Clinical Trials Unit at UCL, London, UK
- Yacine Saïdi
- INSERM SC10-US19, Essais Thérapeutiques et Maladies Infectieuses, Villejuif, France
- Tim R. Cressey
- AMS-CMU & IRD Research Collaboration, Faculty of Associated Medical Sciences (AMS), Chiang Mai University, Thailand
- Alasdair Bamford
- MRC Clinical Trials Unit at UCL, London, UK; Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; UCL Great Ormond Street Institute of Child Health, London, UK
- Yoann Riault
- INSERM SC10-US19, Essais Thérapeutiques et Maladies Infectieuses, Villejuif, France
- Alexandra Coelho
- INSERM SC10-US19, Essais Thérapeutiques et Maladies Infectieuses, Villejuif, France
- Aoife Nolan
- MRC Clinical Trials Unit at UCL, London, UK
- Suwalai Chalermpantmetagul
- AMS-CMU & IRD Research Collaboration, Faculty of Associated Medical Sciences (AMS), Chiang Mai University, Thailand
- Gabija Morkunaite
- Penta Foundation, Padova, Italy
- Pauline Amuge
- Baylor College of Medicine Children's Foundation, Kampala, Uganda
- Victor Musiime
- Joint Clinical Research Centre, Lubowa, Kampala, Uganda; Makerere University, Department of Paediatrics and Child Health, Kampala, Uganda
- Avy Violari
- Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa
- Mark Cotton
- FAMCRU, Department of Paediatrics & Child Health, Family Center for Research with Ubuntu, Stellenbosch University, South Africa
- Adeodata R. Kekitiinwa
- Baylor College of Medicine Children's Foundation, Kampala, Uganda
- Elizabeth Kaudha
- Joint Clinical Research Centre, Lubowa, Kampala, Uganda
- Marisa Groenewald
- FAMCRU, Department of Paediatrics & Child Health, Family Center for Research with Ubuntu, Stellenbosch University, South Africa
- Afaaf A. Liberty
- Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa
- Suparat Kanjanavanit
- Nakornping Hospital, Chiang Mai, Thailand
- Alla Volokha
- Shupyk National Healthcare University of Ukraine, Kyiv, Ukraine
- Rosa Bologna
- Hospital Garrahan, Buenos Aires, Argentina
- Noris Pavia Ruz
- 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
- Luis Prieto Tato
- Hospital Universitario 12 de Octubre, Madrid, Spain
- Paolo Paioni
- Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital Zurich, Zurich, Switzerland
- Laura Marques
- Centro Materno-Infantil do Norte, CHU Porto, Porto, Portugal
- Véronique Reliquet
- Infectious Diseases Department, CHU Hôtel Dieu and INSERM UIC 1413, Nantes University, Nantes, France
- Tim Niehues
- Centre for Child Health and Adolescence, Helios Klinikum Krefeld, Academic Hospital, RWTH Aachen, Krefeld, Germany
- Steven B. Welch
- Department of Paediatrics, Heartlands Hospital, University Hospitals Birmingham, Birmingham, UK
- Deborah Ford
- MRC Clinical Trials Unit at UCL, London, UK
- Carlo Giaquinto
- Department of Women's and Children's Health, University of Padova, Padova, Italy
- Diana M. Gibb
- MRC Clinical Trials Unit at UCL, London, UK
- Abdel Babiker
- MRC Clinical Trials Unit at UCL, London, UK
- Jose Tomas Ramos Amador
- Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC); Fundación para la Investigación Biomédica HCSC; Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain
- A. Compagnucci
- Y. Saidi
- Y. Riault
- A. Coelho
- C. Kouakam
- L. Picault
- M. Ndiaye
- L. Meyer
- C. Cagnot
- S. Circosta
- L. Léger
- S. Simanic
- A. Arulananthan
- D.M. Gibb
- A. Babiker
- M. Chan
- D. Ford
- F. Hudson
- L. Harper
- A. Bamford
- A. Nolan
- K. Widuch
- S. Townsend
- N. Van-Looy
- L. Gao
- E. Little
- A. Turkova
- S. Fabiane
- J. Calvert
- J. Blackstone
- K. Scott
- J. Inshaw
- A. Nunn
- A. Nardone
- D. Bilardi
- T.R. Cressey
- S. Chalermpantmetagul
- W. Khamduang
- G. Jourdain
- N. Ngo Giang Huong
- D. Chinwong
- C. Saenjum
- R. Peongjakta
- P. Sukrakanchana
- L. Laomanit
- A. Kaewbundit
- J. Khamkon
- K. Than-in-at
- C. Meeboon
- W. Sripaoraya
- N. Krueduangkam
- N. Kruenual
- W. Khamjakkaew
- S. Klinprung
- C. Giaquinto
- G. Morkunaite
- D. Hirt
- L. Prieto Tato
- T. Niehues
- D. Plonné
- C. Morén
- T. Noguera
- M.A. Muñoz Fernández
- R. Bologna
- S. Arazi
- A.G. Fedullo
- M. Taicz
- E. Vicentini
- M. Moragas
- A. Mangano
- M. Dell’Orso
- M. Gatto
- V. Reliquet
- A. Soria
- E. Paredes
- N. Chereau
- M. Tching Sin
- L. Flet
- A. Rodallec
- C. Hemon
- N. Elenga
- M.D. Terrine
- N. Blaise
- S. Augustin
- P. Mespoulhe
- H. Pouchain
- N. Pavia-Ruz
- R. Muñoz- Hernández
- A. Neri-Macias
- M.D. Jarillo-Quijada
- C. Espinosa-Sotero
- L. Marques
- C. Teixeira
- A. Fernandes
- R. Nunes
- H. Nascimento
- J. Tuna
- A. Padrao
- I. Ferraz
- A.C. Mendes
- C. Correira
- H. Pinheiro
- A.C. Matos
- A.C. Sampaio
- A. Oliveira
- A. Caldeira
- M. Tavares
- A. Reis Melo
- C. Castro
- C. Faria
- C. Prucha
- R. Ribeiro
- F. Monteiro
- M.F. Candeias
- T. Silva Milhiero
- E. Gomes Neves
- A. Oliveira
- R. Corte-Real
- M. Morgado
- D. Mendes
- M. Cardão
- A. Violari
- N. Ramsagar
- A. Liberty
- M. Nyati
- L. Maseko
- M. Khunene
- S. Mkhize
- Z. Essack
- N. Akoojee
- U. Singh
- Y. Fourie
- S. Govender
- A. Vadee
- R. Lakha
- J. Erasmus
- A. Mamiane
- T. Daniel
- P. Bhana
- N. Maduna
- M. Cotton
- M. Groenewald
- G. Slade
- J. Coetzee
- L. Ganger
- S. Weldon
- M. Wessels
- L. Hoorn
- S. Pieterse
- C. Makola
- K. Smith
- M. Isaacs
- A. Cweya
- S. Fry
- S. Barnabas
- M. Theunissen
- N. Nduna
- M. Smuts
- P. Rojo Conejo
- C. Epalza
- L. Prieto Tato
- M. Fernández
- M.J. Mellado Peña
- T. Sainz Costa
- L. Escosa García
- P. Gomez Salcedo
- C. Fortuny Guasch
- T. Noguera Julian
- C. Estepa
- M. Cubells
- E. Sans
- E. Bruno
- L. Prieto
- P. Mendez García
- A. Murciano Cabeza
- M. Coto
- R. Torrent
- M. Torres Arauz
- M. Navarro Gómez
- A. Mur
- S. Guillén Martin
- M. Moreno
- J.T. Ramos Amador
- I. Garcia
- C. Kalhert
- T. Wachinger
- B. Wohlwend
- S. Hafner
- G. Dollenmaier
- P. Paioni
- R. Signorell
- J. Boni
- A. Duppenthaler
- B. Mann
- C. Saegesser
- M. Barbani
- C. Ngampiyaskul
- P. Greetanukroh
- P. Khannak
- P. Tearsansern
- W. Chamjamrat
- N. Chanto
- T. Thapwai
- K. Thungkham
- P. Puangmalai
- C. Ruklao
- P. Ounchanum
- S. Khusuwan
- S. Denjanta
- Y. Thaweesombat
- J. Thewsoongnoen
- K. Kaewmamueng
- P. Kamboua
- S. Pongprapass
- W. Srisuk
- A. Kongponoi
- J. Limplertjareanwanich
- S. Kanjanavanit
- C. Saewtrakool
- P. Yingyong
- D. Chutima
- R. Junkaew
- T. Chankun
- U. Srirompotong
- P. Sudsaard
- K. Kongsuk
- T. Petpranee
- S. Srirojana
- D. Donngernl
- A. Kamkoonmongkol
- N. Na Kalasin
- P. Phunkhum
- A.R. Kekitiinwa
- P. Amuge
- D. Bbuye
- J. Nalubwama
- S. Namanda
- M. Nsibuka Kisekka
- A. Kirabira
- L. Lawrence
- G. Agaba
- G. Ahimbisibwe
- A. Nalugo
- F. Namuli
- R. Kadhuba
- R. Namuddu
- I. Nabwire
- L. Kiyimba
- A. Baita
- J. Tikabibamu
- L. Nakandi
- G.P. Kisitu
- N. Nabukeera Barung
- C.M. Kityo
- V. Musiime
- E. Kaudha
- A. Nanduudu
- E. Mujyambere
- S.P. Labeja Ocitti
- J. Ategeka
- E. Nambi
- R. Nazzinda
- D. Rutebarika
- R. Basiimwa
- R. Mbabazi
- P. Kyobutungi
- M. Nabalamba
- A. Nakalyango
- J. Tumusiime
- S. Nakabuye
- J. Mwebaza
- S. Oruk
- J. Namusanje
- A. Musiime
- L. Mugarura
- M. Ojok
- J. Kitabalwa
- C. Katemba
- M. Nannungi
- E. Bagirigomwa
- D. Odoch
- E. Rubanga
- D. Mulima
- E.L. Babu
- D. Baliruno
- C. Inyakuwal
- E.D. Williams
- A. Mulindwa
- A. Uyungrwoth
- I. Raus
- O. Mostovenko
- T. Stepchenkova
- A. Volokha
- N. Primak
- J. Kenny
- A. Callaghan
- M. Ahmad
- S. Vergnano
- M. Ross
- F. Manyi
- D. Nayagam
- S. Hawkins
- C. Ball
- E. Hamlyn
- C. Gilmour
- S. Gilmour-White
- S. Doshi
- E. Fuller
- A. Adebayo
- K. Tupper
- E. Nsirim
- S. Welch
- J. Daglish
- L. Thrasyvoulou
- E. Irvine
- K. Gandhi
- Y. Vaughn-Gordon
- N. Sibanda
- Journal volume & issue
-
Vol. 60
p. 102025
Abstract
Summary: 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.
