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

Chan, M.K.; Coelho, Alexandra; Nolan, Aoife; Kekitiinwa, Adeodata; Liberty, Afaaf; Ruz, Noris Pavia; Ramos-Amador, José Tomás; Compagnucci, Alexandra; Saïdi, Yacine; Riault, Yoann; Coelho, André; Kouakam, Claude; Picault, Loïc; Ndiaye, Moustapha; Meyer, Laurence; Cagnot, Carole; Circosta, Sophie; Léger, L; Simanic, S.; Arulananthan, A.; Gibb, Diana M; Babiker, Abdel; Chan, Mei Yen; Ford, Deborah; Hudson, Fleur; Harper, Lynda; Bamford, Alasdair; Nolan, Anna; Widuch, Kaja; Townsend, S.; Van-Looy, N.; Gao, Li; Little, E.; Turkova, Anna; Fabiane, Stella M.; Calvert, Joanna; Blackstone, Jacquelyn; Scott, Karen; Inshaw, Jamie; Nunn, AJ; Nardone, Anthony; Bilardi, Davide; Cressey, Tim R.; Chalermpantmetagul, Suwalai; Khamduang, Woottichai; Jourdain, Gonzague; Huong, Nicole Ngo Giang; Chinwong, Dujrudee; Saenjum, Chalermpong; Peongjakta, Rukchanok; Sukrakanchana, Pra-ornsuda; Laomanit, Laddawan; Kaewbundit, Ampika; Khamkon, Jiraporn; Than-in-at, Kanchana; Meeboon, C.; Sripaoraya, Worathip; Krueduangkam, Nitinart; Kruenual, Namthip; Khamjakkaew, Warunee; Klinprung, Soraya; Giaquinto, Carlo; Morkunaite, Gabija; Hirt, Déborah; Niehues, Tim; Plonné, Dietmar; Morén, Constanza; Noguera, T.; Fernández, M.A. Muñoz; Bologna, Rosa; Arazi, S; Fedullo, A.G.; Taicz, Moira; Vicentini, Edoardo; Moragas, Matías; Mangano, Andrea; Dell’Orso, M.; Gatto, Mariana; Reliquet, Véronique; Soria, A; Paredes, Ernesto; Chéreau, Nathalie; Sin, Mee-Kung; Flet, Laurent; Rodallec, Audrey; Hemon, C; Elenga, Narcisse; Terrine, M.D.; Nkegoum, Blaise; Augustín, Salvador; Mespoulhe, P.; Pouchain, H.; Pavía-Ruz, Noris; Hernandez, Ricardo; Neri-Macias, Angelica; Jarillo-Quijada, Ma Dolores; Espinosa-Sotero, C.; Marquès, Laura; Teixeira, Cristina; Fernandes, Alexandre; Nunes, Raquel; Nascimento, Hugo HenriqueCosta do; Tuna, Joana; Padrao, Andreia; Ferraz, Ivan Savioli; Mendes, Ana Constança; Correira, C.; Pinheiro, H.M.; Matos, A.C.; Sampaio, A.C.; Caldeira, Ana Teresa; Tavares, Marta; Melo, A.C.V De; Castro, Cristina Grávalos; Faria, Cláudia; Prucha, Carmo; Ribeiro, Ricardo; Monteiro, Fátima; Candeias, M.; Milhiero, T. Silva; Neves, Esmeralda; Oliveira, Afonso; Côrte‐Real, Rita; Morgado, Micaela; Mendes, Diogo; Cardão, M.; Violari, Avy; Ramsagar, Nastassja; Liberty, Abigail; Nyati, Mukesh K.; Maseko, Lindiwe; Khunene, Mirriam; Mkhize, Sibongile; Essack, Zaynab; Akoojee, Nazim; Singh, Umesh; Fourie, Yolandie; Govender, S.; Vadee, Aasia; Lakha, Reshma; Erasmus, Jeremy J.; Mamiane, Angelous; Daniel, Thomas M.; Bhana, P.; Maduna, Nomfundo; Cotton, Mark F.; Groenewald, M.; Slade, George; Coetzee, J. F.; Ganger, L.; Weldon, Steven M.; Wessels, M.; Hoorn, Laura van; Pieterse, Sonja; Makola, Candice; Smith, K.; Isaacs, Michelle; Cweya, A.; Fry, Stéphanie; Barnabas, Shaun; Theunissen, Maurice; Nduna, N.; Smuts, Cornelius M.; Conejo, Pablo Rojo; Epalza, Cristina; Tato, Luis Prieto; Fernández, Marta; Peña, María José; Costa, Talia Sainz; García, L. Escosa; Salcedo, Pilar Gomez; Guasch, Claudia Fortuny; Julian, T. Noguera; Estepa, Carolina; Cubells, M. Dolors Rosines; Sans, E.; Bruno, Elisa; Prieto, Luís; Garcia, Patricia Mendez; Cabeza, A. Murciano; Blanco, Mario A.; Torrent, Rosa Bou; Arauz, M. Torres; Gómez, M. Navarro; Mur, Antonio; Martín, Sara Guillén; Moreno, Mar; Amador, José Tomás Ramos; García, I. Gómez; Kalhert, C.; Wachinger, Tanja; Wohlwend, B.; Häfner, S.; Dollenmaier, Günter; Paioni, Paolo; Signorell, Ruth; Boni, Joseph; Duppenthaler, Andrea; Mann, Bruce; Saegesser, C.; Barbani, Maria Teresa; Ngampiyaskul, Chaiwat; Greetanukroh, Pisut; Khannak, P.; Tearsansern, Pathanee; Chamjamrat, Wanna; Chanto, Nuttawut; Thapwai, Thitiwat; Thungkham, Khanungnit; Puangmalai, Patcharee; Ruklao, Chutima; Ounchanum, Pradthana; Khusuwan, Suwimon; Denjanta, S.; Thaweesombat, Yupawan; Thewsoongnoen, Jutarat; Kaewmamueng, Kanyanee; Kamboua, Phakamas; Pongprapass, Supawadee; Srisuk, W.; Kongponoi, Areerat; Limplertjareanwanich, Juthamas; Kanjanavanit, Suparat; Saewtrakool, Chayakorn; Yingyong, Pacharaporn; Chutima, Duangrat; Junkaew, Raungwit; Chankun, Thannapat; Srirompotong, Ussanee; Sudsaard, Patamawadee; Kongsuk, K.; Petpranee, Turian; Srirojana, Sakulrat; Donngernl, D.; Kamkoonmongkol, A.; Kalasin, N. Na; Phunkhum, P.; Kekitiinwa, Addy; Amuge, Pauline; Bbuye, Dickson; Nalubwama, Justine; Namanda, Sylvia; Kisekka, Muzamil Nsibuka; Kirabira, Anthony; Lawrence, Leah; Agaba, Gerald Muzorah; Ahimbisibwe, Grace Miriam; Nalugo, Annet; Namuli, Florence; Kadhuba, Rose Jacqueline; Namuddu, R.; Nabwire, I.; Kiyimba, Lameck; Baita, Antonella; Tikabibamu, Judith; Nakandi, L.; Kisitu, Grace P.; Barung, N. Nabukeera; Kityo, Cissy; Musiime, Victor; Kaudha, Elizabeth; Nanduudu, Annet; Mujyambere, Emmanuel; Ocitti, S.P. Labeja; Ategeka, Juliet; Nambi, E.; Nazzinda, Rashidah; Rutebarika, Diana; Basiimwa, R.; Mbabazi, Ritah; Kyobutungi, Priscilla; Nabalamba, Mariam; Nakalyango, A.; Tumusiime, Julius; Nakabuye, Sarah; Mwebaza, J.; Oruk, Şemsettin; Namusanje, Josephine; Musiime, Alex V.; Mugarura, Lincoln; Ojok, Martin; Kitabalwa, J.; Katemba, Chrispus; Nannungi, Maria; Bagirigomwa, Edward; Odoch, Denis; Rubanga, Eddie; Mulima, Disan; Babu, Enock; Baliruno, David; Inyakuwal, C.; Williams, Emily D.; Mulindwa, Alice; Uyungrwoth, A.; Raus, Iulian; Mostovenko, O.; Stepchenkova, T.; Volokha, Alla; Primak, N.; Kenny, Julia; Callaghan, Ann; Ahmad, Mansoor; Vergnano, Stefania; Ross, Michelle; Manyi, F.; Nayagam, D.; Hawkins, Sarah; Ball, Colin; Hamlyn, Elizabeth; Gilmour, Carol H.; Gilmour-White, Susanna K.; Doshi, Shephal K.; Fuller, Edward; Adebayo, Abiodun Humphrey; Tupper, K.; Nsirim, Eniola; Welch, S; Daglish, Jacqui; Thrasyvoulou, Laura; Irvine, E. Jan; Gandhi, Kavita; Vaughn-Gordon, Y.; Sibanda, Nokuthaba

doi:10.1016/j.eclinm.2023.102025

Cited by 5 publications

(2 citation statements)

References 21 publications

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“…DTG plus one additional ARV (Scenario 5) : Ten clinical trials examined the efficacy of a two-drug DTG-containing regimen in PLWH with VS for six or more months including six trials of DTG/3TC [ 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 ], one trial of DTG/FTC [ 91 ], one trial of DTG/rilpivirine [ 92 , 93 , 94 ], and two trials of DTG plus ritonavir-boosted darunavir (DRV/r) [ 95 , 96 , 97 ] ( Table 4 ). Among the seven trials of DTG/3TC or DTG/FTC, six enrolling 987 individuals excluded those with a history of VF or major DRMs.…”

Section: Resultsmentioning

confidence: 99%

Prevalence of Emergent Dolutegravir Resistance Mutations in People Living with HIV: A Rapid Scoping Review

Chu,

Tao,

Kouamou

et al. 2024

Viruses

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Background: Dolutegravir (DTG) is a cornerstone of global antiretroviral (ARV) therapy (ART) due to its high efficacy and favorable tolerability. However, limited data exist regarding the risk of emergent integrase strand transfer inhibitor (INSTI) drug-resistance mutations (DRMs) in individuals receiving DTG-containing ART. Methods: We performed a PubMed search using the term “Dolutegravir”, last updated 18 December 2023, to estimate the prevalence of VF with emergent INSTI DRMs in people living with HIV (PLWH) without previous VF on an INSTI who received DTG-containing ART. Results: Of 2131 retrieved records, 43 clinical trials, 39 cohorts, and 6 cross-sectional studies provided data across 6 clinical scenarios based on ART history, virological status, and co-administered ARVs: (1) ART-naïve PLWH receiving DTG plus two NRTIs; (2) ART-naïve PLWH receiving DTG plus lamivudine; (3) ART-experienced PLWH with VF on a previous regimen receiving DTG plus two NRTIs; (4) ART-experienced PLWH with virological suppression receiving DTG plus two NRTIs; (5) ART-experienced PLWH with virological suppression receiving DTG and a second ARV; and (6) ART-experienced PLWH with virological suppression receiving DTG monotherapy. The median proportion of PLWH in clinical trials with emergent INSTI DRMs was 1.5% for scenario 3 and 3.4% for scenario 6. In the remaining four trial scenarios, VF prevalence with emergent INSTI DRMs was ≤0.1%. Data from cohort studies minimally influenced prevalence estimates from clinical trials, whereas cross-sectional studies yielded prevalence data lacking denominator details. Conclusions: In clinical trials, the prevalence of VF with emergent INSTI DRMs in PLWH receiving DTG-containing regimens has been low. Novel approaches are required to assess VF prevalence with emergent INSTI DRMs in PLWH receiving DTG in real-world settings.

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Section: Resultsmentioning

confidence: 99%

Prevalence of Emergent Dolutegravir Resistance Mutations in People Living with HIV: A Rapid Scoping Review

Chu,

Tao,

Kouamou

et al. 2024

Viruses

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“…Data on effectiveness of two-drug regimens in suppressing viral replication compared with three-drug regimens in children remain scarce. SMILE, an open-label non-inferiority trial, recruited virologically suppressed children aged 6-18 years and compared a two-drug regimen of integrase inhibitor and boosted darunavir with standard triple regimen 34. The two-drug regimen was shown to be non-inferior, but it resulted in a significantly higher weight gain of 1.97 kg (95% confidence interval 1.1 to 2.9, P<0.001) and BMI increase of 0.66 kg/m 2 (0.3 to 1.0, P<0.001).…”

Section: Can These Drugs Be Given To Children and Adolescents?mentioning

confidence: 99%

Two-drug antiretroviral regimens for HIV

Thornhill,

Cromarty,

Gaddie

et al. 2023

BMJ

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Optimising Paediatric HIV Treatment: Recent Developments and Future Directions

Kamphuis,

Bamford,

Tagarro

et al. 2024

Pediatr Drugs

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Treatment options for children living with HIV have historically been less effective, less practical and more difficult to implement compared with those for adults, as the research and development of new drugs for children has lagged behind. Significant progress has been achieved in response to the paediatric HIV epidemic over the last decade. Several optimised paediatric antiretroviral formulations are currently available or in development, including fixed-dose combination tablets containing a complete World Health Organization-recommended regimen. Despite these advancements, virological suppression rates in children are generally lower than in adults. Even when oral fixed-dose combinations with the optimal target profiles are developed, for some children virological suppression is not achievable for reasons such as adherence challenges, intolerance, toxicity and genotypic resistance. New safe, effective, well-tolerated antiretroviral agents from existing and novel classes, as well as innovative administration strategies are essential. To achieve the UNAIDS target of virological suppression in 95% of children receiving antiretroviral therapy, concerted efforts are required. This includes identifying priority drugs in line with latest developments, focusing drug development studies on these priorities, ensuring a timely technical knowledge transfer between originator and generic companies, accelerating regulatory approvals and facilitating procurement and implementation in countries. Success in these efforts depends on collaboration among all stakeholders, including communities, researchers, pharmaceutical companies, guideline and policymakers, governments, funders, regulators and healthcare providers. This review outlines which paediatric antiretroviral therapies are currently available, those which are under development and the future directions of paediatric HIV treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s40272-024-00656-4.

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Cited by 5 publications

References 21 publications

Prevalence of Emergent Dolutegravir Resistance Mutations in People Living with HIV: A Rapid Scoping Review

Prevalence of Emergent Dolutegravir Resistance Mutations in People Living with HIV: A Rapid Scoping Review

Two-drug antiretroviral regimens for HIV

Optimising Paediatric HIV Treatment: Recent Developments and Future Directions

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