Once-daily dolutegravir-based antiretroviral therapy in infants and children living with HIV from age 4 weeks: results from the below 14 kg cohort in the randomised ODYSSEY trial. Issue 9 (September 2022)

• Record Type: Journal Article
• Authors: Amuge, Pauline; Lugemwa, Abbas; Wynne, Ben; Mujuru, Hilda A; Violari, Avy; Kityo, Cissy M; Archary, Moherndran; Variava, Ebrahim; White, Ellen; Turner, Rebecca M; Shakeshaft, Clare; Ali, Shabinah; Nathoo, Kusum J; Atwine, Lorna; Liberty, Afaaf; Bbuye, Dickson; Kaudha, Elizabeth; Mngqibisa, Rosie; Mosala, Modehei; Mumbiro, Vivian; Nanduudu, Annet; Ankunda, Rogers; Maseko, Lindiwe; Kekitiinwa, Adeodata R; Giaquinto, Carlo; Rojo, Pablo; Gibb, Diana M; Turkova, Anna; Ford, Deborah; Mehar (nee Abdulla), Amina Farhana; Abraham, Pattamukkil; Abrams, Elaine; Acero, Judith; Agaba, Gerald Muzorah; Ahimbisibwe, Grace; Ainebyoona, Barbara; Akobye, Winnie; Akhalwaya, Yasmeen; Akoojee, Nazim; Ali, Shabinah S.; Amuge, Pauline; Andrea, Catherine; Muñoz Fernandez, Maria Angeles; Ankunda, Rogers; Rutebarika, Diana Antonia; Anugulruengkitt, Suvaporn; Apollo, Tsitsi; Archary, Moherndran; Arendze, Ronelle; Ategeka, Juliet; Atim, Eunice; Atwine, Lorna; Babiker, Abdel; Babirye, Sarah; Babu, Enock; Bagirigomwa, Edward; Baita, Angella; Balamusani, David; Baliram, Patsy; Baliruno, David; Ball, Colin; Balwa, Henry; Bamford, Alasdair; Bandi, Srini; Barker, Dominique; Barlow-Mosha, Linda; Bbuye, Dickson; Begum, Shazia; Behuhuma, Osee; Bernays, Sarah; Besigye, Rogers; Bester, Maria; Bhiri, Joyline; Bilardi, Davide; Bird, Kristien; Bollen, Pauline; Borg, Chiara; Borges Da Silva, Anne-Marie; Brown, Jackie; Bruno, Elena; Bunupuradah, Torsak; Burger, David; Buthelezi, Nomzamo; Bwakura-Dangarembizi, Mutsa; Byaruhanga, Africanus; Calvert, Joanna; Casey, Petronelle; Cassim, Haseena; Cebekhulu, Sphiwee; Chailert, Sanuphong; Chalermpantmetagul, Suwalai; Chamjamrat, Wanna; Chan, Man; Chandiwana, Precious; Chankun, Thannapat; Chanthaburanun, Sararut; Chanto, Nuttawut; Chidziva, Ennie; Chikowore, Minenhle; Chimanzi, Joy; Chinwong, Dujrudee; Chitongo, Stuart; Chitsamatanga, Moses; Choga, Joshua; Chutima, Duangrat; Clayden, Polly; Coelho, Alexandra; Colbers, Angela; Compagnucci, Alexandra; Constança Mendes, Ana; Conway, Magda; Cotton, Mark F.; Crawley, Jane; Cressey, Tim R.; Crisp, Jacky; Matos, Ana Cristina; Dadan, Sumaya; Daglish, Jacqui; Danaviah, Siva; Daniel, Tseleng; De Rossi, Anita; Denjanta, Sukanda; Dobbels, Els; Dowie, Maria; Dube, Prosper; Dube, Benedictor; Dudakia, Nimisha; Elwana, Alice; Epalza, Cristina; Eram, David; Erasmus, Juan; Erim, Peter; Escosa Garcia, Luis; Essack, Zaakirah; Estepa, Carolina; Etima, Monica; Fernandes, Alexandre; Fernandez, Maite; Fitzgerald, Felicity; Flynn, Jacquie; Ford, Deborah; Fortuny Guasch, Claudia; Foster, Caroline; Fourie, George; Fourie, Yolandie; Foxall, Sophie; Frank, Derusha; Gandhi, Kate; Garcia, India; Gartner, Kathleen; Gasa, Joshua; Gasa, Gugu; Giaquinto, Carlo; Gibb, Diana M.; Gomez Rico, Coral; Gomez-Pena, Daniel; Gondo, Secrecy; Goodman, Anna; Gorreti Nakalema, Maria; Gozhora, Winnie; Greetanukroh, Pisut; Gregorio Maranon, Biobanco; Grossele, Tiziana; Gwande, Shamiso; Gwaze, Tapiwa; Gwenzi, Tsitsi; Hakim, James; Hakiza, Emmanuel; Kaka, Abdul Hamid; Harley, Ashley; Isaacs, Mornay; Isabirye, Richard; Ishemunyoro, Wilber; Jacobs, Tom; Jafta, Lungile; Jamil, Nasir; Janse van Rensburg, Anita Janse; Jeaven, Vinesh; Mellado Peña, Maria José; Jourdain, Gonzague; Juliet, Katabalwa; Jumpimai, Thidarat; Junkaew, Raungwit; Jupimai, Thidarat; Kaahwa, Winfred; Kabasonga, Mildred; Kaboggoza, Olivia; Kadhuba, Rose Jacqueline; Kaewbundit, Ampika; Kaewmamueng, Kanyanee; Kafufu, Bosco; Kakayi, Brenda; Kamboua, Phakamas; Kanjanavanit, Suparat; Kasangaki, Gladys; Kasipong, Naruporn; Kasozi, Miriam; Kataike, Hajira; Katemba, Chrispus; Kaudha, Elizabeth; Kekane, Nkata; Kekitiinwa, Adeodata R.; Keminyeto, Edridah; Khamduang, Woottichai; Khamjakkaew, Warunee; Khamkon, Jiraporn; Khannak, Sasipass; Khatngam, Orapin; Khayanchoomnoom, Tassawan; Khumalo, Busi; Khunene, Mirriam; Khusuwan, Suwimon; Kibalama, Phionah; Kibenge, Robinah; Kirabira, Anthony; Kityo, Cissy M.; Kiyimba, Lameck; Klein, Nigel; Klinprung, Soraya; Kobbe, Robin; Kobusingye, Olivia; Kobusungye, Josephine; Kongponoi, Areerat; Königs, Christoph; Koole, Olivier; Kouakam, Christelle; Krueduangkam, Nitinart; Kruenual, Namthip; Kunjaroenrut, Nuananong; Kyambadde, Raymonds; Kyobutungi, Priscilla; Kyomuhendo, Flavia; Kyomukama, Erinah; Lakha, Reshma; Langa, Cleopatra; Laomanit, Laddawan; Lebotsa, Emily; Leenasirimakul, Prattana; Lekku, Lawrence; Lensen, Sarah; Leroy, Valériane; Li, Jin; Liberty, Afaaf; Limplertjareanwanich, Juthamas; Little, Emma; Lugemwa, Abbas; Lutalo, Ezra; Jimenez, Jose Luis; Lyall, Hermione; MacDonald, Candice; Machache, Gladness; Madlala, Penelope; Madonsela, Tryphina; Maduna, Nomfundo; Maena, Joel; Mahanontharit, Apicha; Makanga, Collin; Makola, Candice; Makumbi, Shafic; Malgraaf, Lucille; Mamiane, Angelous; Mantkowski, Felicia; Mapfumo, Wendy; Marques, Laura; Mugagga, Agnes Mary; Maseko, Lindiwe; Masienyane, Tshepiso; Mathiba, Ruth; Matimba, Farai; Mawlana, Sajeeda; Mayanja, Emmanuel; Mayat, Fatima; Mbabazi, Ritah; Mbadaliga, Nokuthula; Mbasani, Faith; McClaughlin, Kathleen; McIlleron, Helen; Meethaisong, Watchara; Mendez Garcia, Patricia; Miwanda, Annet; Miranda, Carlota; Mkhize, Siphiwe; Mmolawa, Kgosimang; Mngqibisa, Rosie; Mohamed, Fatima; Moloantoa, Tumelo; Monametsi, Maletsatsi; Montero, Samuel; Moore, Cecilia L.; Mosia, Rejoice; Moyo, Columbus; Mthethwa, Mumsy; Mudzingwa, Shepherd; Mudzviti, Tawona; Mujuru, Hilda; Mujyambere, Emmanuel; Mukanganiki, Trust; Mukisa Williams, Cynthia; Mulder, Mark; Mulima, Disan; Mulindwa, Alice; Mumbiro, Vivian; Mupambireyi, Zivai; Murciano Cabeza, Alba; Murungi, Herbert; Murungu, Dorothy; Musarurwa, Sandra; Musiime, Victor; Musiime, Alex V.; Musisi, Maria; Musoke, Philippa; Musoke Nakirya, Barbara; Musoro, Godfrey; Musumba, Sharif; Mustafa, Sobia; Mutsai, Shirley; Mwesigwa Rubondo, Phyllis; Naabalamba, Mariam; Nagawa, Immaculate; Naidoo, Allemah; Nakabuye, Shamim; Nakabuye, Sarah; Nakalanzi, Sarah; Nalubwama, Justine; Nalugo, Annet; Nalusiba, Stella; Namajja, Clementine; Namanda, Sylvia; Namayanja, Paula; Nambi, Esther; Namuddu, Rachael Kikabi; Namukwaya, Stella; Namuli, Florence; Namusanje, Josephine; Namwanje, Rosemary; Nanan-kanjee, Anusha; Nanduudu, Annet; Nankunda, Charity; Baddokwaya, Joanita Nankya; Nannungi, Maria; Nansamba, Winnie; Nanthapisal, Kesdao; Nanyonjo, Juliet; Na-Rajsima, Sathaporn; Nasaazi, Claire; Nascimento, Helena; Nastouli, Eleni; Songtaweesin, Wipaporn Natalie; Nathoo, Kusum; Natuhurira, Ian; Nazzinda, Rashidah; Ncgaba, Thabisa; Ndigendawani, Milly; Ndlovu, Makhosonke; Nentsa, Georgina; Ngampiyaskul, Chaiwat; Ngcobo, Ntombenhle; Ngo Giang Huong, Nicole; Ngwaru, Pia; Nhema, Ruth; Ninsiima, Emily; Ninsiima, Gloria; Nkalo Phiri, Misheck; Noguera Julian, Antoni; Nolan, Monica; Noppakaorattanamanee, Thornthun; Nsibuka Kisekka, Muzamil; Nsirim, Eniola; Nundlal, Rashina; Nunes, Rosita; Nyantsa, Lungile; Nyati, Mandisa; O'Riordan, Sean; Ocitti Labeja, Paul; Odoch, Denis; Oguntimehin, Rachel; Ojok, Martin; Onen, Geoffrey; Orange, Wilma; Ounchanum, Pradthana; Ouma, Benson; Padrao, Andreia; Pako, Deborah; Parker, Anna; Pasko-Szcech, Malgorzata; Patel, Reena; Peongjakta, Rukchanok; Petpranee, Turian; Phillips, Tasmin; Philps, Jackie; Picault, Laura; Pieterse, Sonja; Pinheiro, Helena; Pongprapass, Supawadee; Pozniak, Anton; Prendergast, Andrew; Prieto Tato, Luis; Puangmalai, Patcharee; Puthanakit, Thanyawee; Rakgokong, Modiehi; Ramos, Helena; Ramsagar, Nastassja; Rau, Cornelius; Riault, Yoann; Rojo Conejo, Pablo; Clark, Basiimwa Roy; Rubanga, Eddie; Rubinga, Baker; Ruklao, Chutima; Runarassamee, Pattira; Rutebarika, Diana Antonia; Saenjum, Chalermpong; Saewtrakool, Chayakorn; Saidi, Yacine; Sainz Costa, Talia; Saisaengjan, Chutima; Sakwa, Rebecca; Sarfati, Tatiana; Sbisi, Noshalaza; Scheppers, Dihedile; Schultze-Strasser, Stephan; Schulze-Sturm, Ulf; Scott, Karen; Seeley, Janet; Serunjogi, Robert; Sewnarain, Leora; Shakeshaft, Clare; Sidhoo, Subashinie; Shibemba, Mercy; Shingadia, Delane; Singh, Sheleika; Sirirungsi, Wasna; Sithebe, Sibongile; Smit, Theresa; Smith, Kurt; Smuts, Marlize; Spyer, Moira; Sripaoraya, Worathip; Srirompotong, Ussanee; Srisuk, Warunee; Ssenyonga, Mark; Sudsaard, Patamawadee; Sukrakanchana, Praornsuda; Tearsansern, Pathanee; Teixeira, Carla; Than-in-at, Kanchana; Thapwai, Thitiwat; Thaweesombat, Yupawan; Thewsoongnoen, Jutarat; Thiébaut, Rodolphe; Thomason, Margaret; Thrasyvoulou, Laura; Thungkham, Khanungnit; Tikabibamu, Judith; Tinago, Gloria; Trairat, Ketmookda; Tudor-Williams, Gareth; Tukamushaba, Mercy; Tukwasibwe, Deogratiuos; Tumusiime, Julius; Tuna, Joana; Turkova, Anna; Turner, Rebecca; Udomvised, Arttasid; Vadee, Aasia; Van Huyssteen, Hesti; Van Looy, Nadine; Variava, Ebrahim; Vaughan-Gordon, Yvonne; Vecchia, Giulio; Violari, Avy; Vowden, Richard; Waalewijn, Hylke; Wampamba, Rebecca; Welch, Steve; Weller, Ian; Weza, Sibusisiwe; White, Ellen; White, Ian; Widuch, Kaja; Wilkes, Helen; Wimonklang, Sookpanee; Wynne, Ben; Yingyong, Pacharaporn; Nakawungu, Zaam Zinda; Zuidewind, Peter;
• Is Part Of: Lancet. Volume 9:Issue 9(2022)
• Page Start: e638
• Page End: e648
• Publication Date: 2022-09
• Subjects: HIV (Viruses) -- Periodicals; HIV infections -- Periodicals; AIDS (Disease) -- Periodicals; 616.9792
• DOI: 10.1016/S2352-3018(22)00163-1
• Languages: English
• ISSNs: 2405-4704

Abstract

Summary: Background: Young children living with HIV have few treatment options. We aimed to assess the efficacy and safety of dolutegravir-based antiretroviral therapy (ART) in children weighing between 3 kg and less than 14 kg. Methods: ODYSSEY is an open-label, randomised, non-inferiority trial (10% margin) comparing dolutegravir-based ART with standard of care and comprises two cohorts (children weighing ≥14 kg and <14 kg). Children weighing less than 14 kg starting first-line or second-line ART were enrolled in seven HIV treatment centres in South Africa, Uganda, and Zimbabwe. Randomisation, which was computer generated by the trial statistician, was stratified by first-line or second-line ART and three weight bands. Dispersible 5 mg dolutegravir was dosed according to WHO weight bands. The primary outcome was the Kaplan-Meier estimated proportion of children with virological or clinical failure by 96 weeks, defined as: confirmed viral load of at least 400 copies per mL after week 36; absence of virological suppression by 24 weeks followed by a switch to second-line or third-line ART; all-cause death; or a new or recurrent WHO stage 4 or severe WHO stage 3 event. The primary outcome was assessed by intention to treat in all randomly assigned participants. A primary Bayesian analysis of the difference in the proportion of children meeting the primary outcome between treatment groups incorporated evidence from the higher weight cohort (≥14 kg) in a prior distribution. A frequentist analysis was also done of the lower weight cohort (<14 kg) alone. Safety analyses are presented for all randomly assigned children in this study (<14 kg cohort). ODYSSEY is registered with ClinicalTrials.gov, NCT02259127 . Findings: Between July 5, 2018, and Aug 26, 2019, 85 children weighing less than 14 kg were randomly assigned to receive dolutegravir (n=42) or standard of care (n=43; 32 [74%] receiving protease inhibitor-based ART). Median age was 1·4 years (IQR 0·6–2·0) and median weight 8·1 kg (5·4–10·0). 72 (85%) children started first-line ART and 13 (15%) started second-line ART. Median follow-up was 124 weeks (112–137). By 96 weeks, treatment failure occurred in 12 children in the dolutegravir group (Kaplan-Meier estimated proportion 31%) versus 21 (48%) in the standard-of-care group. The Bayesian estimated difference in treatment failure (dolutegravir minus standard of care) was –10% (95% CI –19% to –2%; p=0·020), demonstrating superiority of dolutegravir. The frequentist estimated difference was –18% (–36% to 2%; p=0·057). 15 serious adverse events were reported in 11 (26%) children in the dolutegravir group, including two deaths, and 19 were reported in 11 (26%) children in the standard-of-care group, including four deaths (hazard ratio [HR] 1·08 [95% CI 0·47–2·49]; p=0·86). 36 adverse events of grade 3 or higher were reported in 19 (45%) children in the dolutegravir group, versus 34 events in 21 (49%) children in the standard-of-care group (HR 0·93 [0·50–1·74]; p=0·83). No events were considered related to dolutegravir. Interpretation: Dolutegravir-based ART was superior to standard of care (mainly protease inhibitor-based) with a lower risk of treatment failure in infants and young children, providing support for global dispersible dolutegravir roll-out for younger children and allowing alignment of adult and paediatric treatment. Funding: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.