Article
Author: Elenga, N. ; Gibb, Diana M. ; Tuna, J. ; Little, E. ; Ford, Deborah ; Blackstone, J. ; Fortuny Guasch, C. ; Van-Looy, N. ; Fernández, M. ; Puangmalai, P. ; Saidi, Y. ; Thapwai, T. ; Wachinger, T. ; Maduna, N. ; Silva Milhiero, T. ; Teixeira, C. ; Hirt, D. ; Doshi, S. ; Khusuwan, S. ; Khamjakkaew, W. ; Namuddu, R. ; Kiyimba, L. ; Sripaoraya, W. ; Paioni, Paolo ; Sampaio, A.C. ; Lawrence, L. ; Cotton, Mark ; Kyobutungi, P. ; Amuge, Pauline ; Slade, G. ; Pongprapass, S. ; Morkunaite, G. ; Prieto Tato, L. ; Turkova, A. ; Thewsoongnoen, J. ; Ford, D. ; Kalhert, C. ; Harper, L. ; Mbabazi, R. ; Saenjum, C. ; Babiker, Abdel ; Musiime, V. ; Srirompotong, U. ; Pouchain, H. ; Bbuye, D. ; Mendes, A.C. ; Ngampiyaskul, C. ; Khunene, M. ; Uyungrwoth, A. ; Dell’Orso, M. ; Maseko, L. ; Ferraz, I. ; Sibanda, N. ; Soria, A. ; Basiimwa, R. ; Lakha, R. ; Coto, M. ; Kaudha, E. ; Kekitiinwa, A.R. ; Niehues, T. ; Riault, Y. ; Fernandes, A. ; Nannungi, M. ; Liberty, Afaaf A. ; Townsend, S. ; Pavia Ruz, Noris ; Junkaew, R. ; Primak, N. ; Mespoulhe, P. ; Babu, E.L. ; Than-in-at, K. ; Tching Sin, M. ; Nascimento, H. ; Plonné, D. ; Ramos Amador, J.T. ; Navarro Gómez, M. ; Bilardi, D. ; Bologna, R. ; Ruklao, C. ; Barnabas, S. ; Morén, C. ; Gandhi, K. ; Vicentini, E. ; Wessels, M. ; Donngernl, D. ; Chan, Man K. ; Arulananthan, A. ; Agaba, G. ; Singh, U. ; Saegesser, C. ; Coelho, A. ; Raus, I. ; Pavia-Ruz, N. ; Vaughn-Gordon, Y. ; Nabwire, I. ; Muñoz Fernández, M.A. ; Manyi, F. ; Mulindwa, A. ; Chereau, N. ; Pinheiro, H. ; Namanda, S. ; Sukrakanchana, P. ; Neri-Macias, A. ; Groenewald, M. ; Saïdi, Yacine ; Moragas, M. ; Kitabalwa, J. ; Kamkoonmongkol, A. ; Nakabuye, S. ; Hamlyn, E. ; Torres Arauz, M. ; Cubells, M. ; Mostovenko, O. ; Nabalamba, M. ; Mur, A. ; Adebayo, A. ; Candeias, M.F. ; Nduna, N. ; Cagnot, C. ; Ategeka, J. ; Akoojee, N. ; Thungkham, K. ; Jourdain, G. ; Chalermpantmetagul, Suwalai ; Kekitiinwa, Adeodata R. ; Fedullo, A.G. ; Mulima, D. ; Weldon, S. ; Fourie, Y. ; Nalubwama, J. ; Welch, Steven B. ; Ahimbisibwe, G. ; Khamkon, J. ; Chinwong, D. ; Smuts, M. ; Groenewald, Marisa ; Torrent, R. ; Daniel, T. ; Petpranee, T. ; Inyakuwal, C. ; Ganger, L. ; Bologna, Rosa ; Giaquinto, C. ; Kanjanavanit, S. ; Taicz, M. ; Faria, C. ; Vergnano, S. ; Cardão, M. ; Theunissen, M. ; Musiime, Victor ; Tumusiime, J. ; Monteiro, F. ; Meeboon, C. ; Marques, Laura ; Epalza, C. ; Mangano, A. ; Daglish, J. ; Nardone, A. ; Léger, L. ; Gilmour, C. ; Hoorn, L. ; Mann, B. ; Flet, L. ; Hafner, S. ; Nsibuka Kisekka, M. ; Niehues, Tim ; Augustin, S. ; Ngo Giang Huong, N. ; Rojo Conejo, P. ; Compagnucci, A. ; Mendes, D. ; Krueduangkam, N. ; Chamjamrat, W. ; Gao, L. ; Picault, L. ; Musiime, A. ; Srirojana, S. ; Prieto Tato, Luis ; Pieterse, S. ; Mamiane, A. ; Nambi, E. ; Kadhuba, R. ; Calvert, J. ; Baliruno, D. ; Reis Melo, A. ; Srisuk, W. ; Inshaw, J. ; Espinosa-Sotero, C. ; Isaacs, M. ; Williams, E.D. ; Ball, C. ; Oliveira, A. ; Phunkhum, P. ; Govender, S. ; Mwebaza, J. ; Meyer, L. ; Bhana, P. ; Rutebarika, D. ; Nalugo, A. ; Denjanta, S. ; Ribeiro, R. ; Tearsansern, P. ; Kongponoi, A. ; Matos, A.C. ; Liberty, A. ; Guillén Martin, S. ; Namusanje, J. ; Tikabibamu, J. ; Nolan, Aoife ; Boni, J. ; Kamboua, P. ; Blaise, N. ; Nyati, M. ; Rubanga, E. ; Nayagam, D. ; Widuch, K. ; Cotton, M. ; Hawkins, S. ; Nunes, R. ; Nabukeera Barung, N. ; Dollenmaier, G. ; Baita, A. ; Garcia, I. ; Gatto, M. ; Wohlwend, B. ; Gomes Neves, E. ; Estepa, C. ; Vadee, A. ; Ramos Amador, Jose Tomas ; Prucha, C. ; Coelho, Alexandra ; Reliquet, Véronique ; Mugarura, L. ; Cressey, T.R. ; Stepchenkova, T. ; Chalermpantmetagul, S. ; Compagnucci, Alexandra ; Sans, E. ; Ojok, M. ; Nolan, A. ; Sainz Costa, T. ; Giaquinto, Carlo ; Yingyong, P. ; Nazzinda, R. ; Violari, Avy ; Na Kalasin, N. ; Kaewbundit, A. ; Terrine, M.D. ; Volokha, A. ; Kaewmamueng, K. ; Kruenual, N. ; Corte-Real, R. ; Gibb, D.M. ; Noguera Julian, T. ; Amuge, P. ; Jarillo-Quijada, M.D. ; Limplertjareanwanich, J. ; Kaudha, Elizabeth ; Mellado Peña, M.J. ; Padrao, A. ; Caldeira, A. ; Chan, M. ; Coetzee, J. ; Duppenthaler, A. ; Tavares, M. ; Prieto, L. ; Ndiaye, M. ; Essack, Z. ; Noguera, T. ; Namuli, F. ; Kanjanavanit, Suparat ; Paioni, P. ; Arazi, S. ; Greetanukroh, P. ; Labeja Ocitti, S.P. ; Kityo, C.M. ; Muñoz- Hernández, R. ; Kongsuk, K. ; Nsirim, E. ; Babiker, A. ; Thrasyvoulou, L. ; Chanto, N. ; Correira, C. ; Morkunaite, Gabija ; Erasmus, J. ; Nanduudu, A. ; Khamduang, W. ; Khannak, P. ; Ross, M. ; Escosa García, L. ; Nunn, A. ; Reliquet, V. ; Kenny, J. ; Gilmour-White, S. ; Hemon, C. ; Barbani, M. ; Laomanit, L. ; Tupper, K. ; Gomez Salcedo, P. ; Peongjakta, R. ; Murciano Cabeza, A. ; Mujyambere, E. ; Morgado, M. ; Kisitu, G.P. ; Cweya, A. ; Nakalyango, A. ; Nakandi, L. ; Sudsaard, P. ; Bruno, E. ; Irvine, E. ; Moreno, M. ; Cressey, Tim R. ; Scott, K. ; Bamford, A. ; Paredes, E. ; Marques, L. ; Hudson, F. ; Chutima, D. ; Chankun, T. ; Ramsagar, N. ; Circosta, S. ; Callaghan, A. ; Ounchanum, P. ; Mendez García, P. ; Simanic, S. ; Klinprung, S. ; Fry, S. ; Bamford, Alasdair ; Oruk, S. ; Fuller, E. ; Smith, K. ; Makola, C. ; Thaweesombat, Y. ; Odoch, D. ; Fabiane, S. ; Kouakam, C. ; Welch, S. ; Rodallec, A. ; Violari, A. ; Saewtrakool, C. ; Katemba, C. ; Bagirigomwa, E. ; Signorell, R. ; Riault, Yoann ; Mkhize, S. ; Ahmad, M. ; Kirabira, A. ; Castro, C. ; Volokha, Alla
BackgroundIntegrase 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).MethodsSMILE 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.FindingsBetween 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)].InterpretationIn 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.FundingFondazione Penta Onlus, Gilead, Janssen, INSERM/ANRS and UK MRC. ViiV-Healthcare provided Dolutegravir.