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1. Voluntariness of consent in paediatric HIV clinical trials: a mixed-methods, cross-sectional study of participants in the CHAPAS-4 and ODYSSEY trials in Uganda

Author

Imelda K Tamwesigire, Francis Bajunirwe, Annabelle South, Diana Gibb, Anna Turkova, Deborah Ford, Abbas Lugemwa, Victor Musiime, and Shafic Makumbi

Subjects
Medicine
Abstract

Objectives To examine the voluntariness of consent in paediatric HIV clinical trials and the associated factors.Design Mixed-methods, cross-sectional study combining a quantitative survey conducted concurrently with indepth interviews.Setting and participants From January 2021 to April 2021, we interviewed parents of children on first-line or second-line Anti-retroviral therapy (ART) in two ongoing paediatric HIV clinical trials [CHAPAS-4 (ISRCTN22964075) and ODYSSEY (ISRCTN91737921)] at the Joint Clinical Research Centre Mbarara, Uganda.Outcome measures The outcome measures were the proportion of parents with voluntary consent, factors affecting voluntariness and the sources of external influence. Parents rated the voluntariness of their consent on a voluntariness ladder. Indepth interviews described participants’ lived experiences and were aimed at adding context.Results All 151 parents randomly sampled for the survey participated (84% female, median age 40 years). Most (67%) gave a fully voluntary decision, with a score of 10 on the voluntariness ladder, whereas 8% scored 9, 9% scored 8, 6% scored 7, 8% scored 6 and 2.7% scored 4. Trust in medical researchers (adjusted OR 9.90, 95% CI 1.01 to 97.20, p=0.049) and male sex of the parent (adjusted OR 3.66, 95% CI 1.00 to 13.38, p=0.05) were positively associated with voluntariness of consent. Prior research experience (adjusted OR 0.31, 95% CI 0.12 to 0.78, p=0.014) and consulting (adjusted OR 0.25. 95% CI 0.10 to 0.60, p=0.002) were negatively associated with voluntariness. Consultation and advice came from referring health workers (36%), spouses (29%), other family members (27%), friends (15%) and researchers (7%). The indepth interviews (n=14) identified the health condition of the child, advice from referring health workers and the opportunity to access better care as factors affecting the voluntariness of consent.Conclusions This study demonstrated a high voluntariness of consent, which was enhanced among male parents and by parents’ trust in medical researchers. Prior research experience of the child and advice from health workers and spouses were negatively associated with the voluntariness of parents’ consent. Female parents and parents of children with prior research experience may benefit from additional interventions to support voluntary participation.

Published
2024
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2. Efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of HIV infection (NADIA): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial

Author

Nicholas I Paton, Joseph Musaazi, Cissy Kityo, Stephen Walimbwa, Anne Hoppe, Apolo Balyegisawa, Jesca Asienzo, Arvind Kaimal, Grace Mirembe, Abbas Lugemwa, Gilbert Ategeka, Margaret Borok, Henry Mugerwa, Abraham Siika, Eva Laker A Odongpiny, Barbara Castelnuovo, Agnes Kiragga, Andrew Kambugu, Daniel Kiiza, John Kisembo, John Nsubuga, Max Okwero, Rhona Muyise, Claire Nasaazi, Dridah L. Nakiboneka, Josephine Namusanje, Theresa Najjuuko, Timothy Masaba, Timothy Serumaga, Adolf Alinaitwe, Allan Arinda, Angela Rweyora, Mary Goretti Kangah, Mariam Kasozi, Phionah Tukumushabe, Rogers Akunda, Shafic Makumbi, Sharif Musumba, Sula Myalo, John Ahuura, Annet Mary Namusisi, Daniel Kibirige, Francis Kiweewa, Habert Mabonga, Joseph Wandege, Josephine Nakakeeto, Sharon Namubiru, Winfred Nansalire, Abraham Mosigisi Siika, Charles Meja Kwobah, Chris Sande Mboya, Martha Mokeira Bisieri Mokaya, Mercy Jelagat Karoney, Priscilla Chepkorir Cheruiyot, Salinah Cherutich, Simon Wachira Njuguna, Viola Cherotich Kirui, Ennie Chidziva, Godfrey Musoro, James Hakim, Joyline Bhiri, Misheck Phiri, Shepherd Mudzingwa, Tadios Manyanga, Anchilla Mary Banegura, Betty Agwang, Brian Isaaya, Constantine Tumwine, Eva Laker A. Odongpiny, Nicholas Paton, Peter Senkungu, Yvonne Kamara, Mathius Amperiize, Elizabeth Allen, Charles Opondo, Perry Mohammed, Willemijn van Rein-van der Horst, Yvon Van Delft, Fafa Addo Boateng, Doreen Namara, Pontiano Kaleebu, Sylvia Ojoo, Tapiwanashe Bwakura, Milly Katana, Francois Venter, Sam Phiri, and Sarah Walker

Subjects
Ritonavir, Anti-HIV Agents, Pyridones, Epidemiology, Immunology, HIV Infections, Viral Load, Piperazines, Infectious Diseases, Lamivudine, Virology, Oxazines, HIV-1, Humans, RNA, Drug Therapy, Combination, Prospective Studies, Tenofovir, Heterocyclic Compounds, 3-Ring, Zidovudine, Darunavir
Abstract

WHO guidelines recommend dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) for second-line HIV therapy, with NRTI switching from first-line tenofovir to zidovudine. We aimed to examine whether dolutegravir is non-inferior to darunavir, the best-in-class protease inhibitor drug, and whether maintaining tenofovir in second-line therapy is non-inferior to switching to zidovudine.In this prospective, multicentre, open-label, factorial, randomised, non-inferiority trial (NADIA), participants with confirmed HIV first-line treatment failure (HIV-1 RNA ≥1000 copies per mL) were recruited at seven clinical sites in Kenya, Uganda, and Zimbabwe. Following a 2 × 2 factorial design and stratified by site and screening HIV-1 RNA concentration, participants were randomly assigned (1:1:1:1) to receive a 96-week regimen containing either dolutegravir (50 mg once daily) or ritonavir-boosted darunavir (800 mg of darunavir plus 100 mg of ritonavir once daily) in combination with either tenofovir (300 mg once daily) plus lamivudine (300 mg once daily) or zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily). The NRTI drugs allocated by randomisation were administered orally in fixed-dose combination pills; other drugs were administered orally as separate pills. The previously reported primary outcome was the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 48 weeks. Here, we report the main secondary outcome: the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 96 weeks (non-inferiority margin 12%). We analysed this outcome and safety outcomes in the intention-to-treat population, which excluded only those who were randomly assigned in error and withdrawn before receiving trial drugs. This study was registered at ClinicalTrials.gov, NCT03988452, and is complete.Between July 30 and Dec 18, 2019, we screened 783 patients and enrolled 465. One participant was randomly assigned in error and immediately withdrawn. The remaining 464 participants were randomly assigned to receive either dolutegravir (n=235) or ritonavir-boosted darunavir (n=229) and to receive lamivudine plus either tenofovir (n=233) or zidovudine (n=231). At week 96, 211 (90%) of 235 participants in the dolutegravir group and 199 (87%) of 229 participants in the darunavir group had HIV-1 RNA less than 400 copies per mL (percentage point difference 2·9, 95% CI -3·0 to 8·7), indicating non-inferiority. Nine (4%) participants (all in the dolutegravir group) developed dolutegravir resistance; no participants developed darunavir resistance (p=0·0023). In the other randomised comparison, 214 (92%) of 233 patients in the tenofovir group and 196 (85%) of 231 patients in the zidovudine group had HIV-1 RNA less than 400 copies per mL (percentage point difference 7·0, 95% CI 1·2 to 12·8), showing non-inferiority and indicating the superiority of tenofovir (p=0·019). The proportions of participants with any grade 3-4 adverse event were similar between the dolutegravir (26 [11%]) and darunavir (28 [12%]) groups and between the tenofovir (22 [9%]) and zidovudine (32 [14%]) groups. There were no deaths related to study medication.Dolutegravir-based and darunavir-based regimens maintain good viral suppression during 96 weeks; dolutegravir is non-inferior to darunavir but is at greater risk of resistance in second-line therapy. Tenofovir should be continued in second-line therapy, rather than being switched to zidovudine.Janssen.

Published
2022
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3. Dolutegravir as First- or Second-Line Treatment for HIV-1 Infection in Children

Author

Anna, Turkova, Ellen, White, Hilda A, Mujuru, Adeodata R, Kekitiinwa, Cissy M, Kityo, Avy, Violari, Abbas, Lugemwa, Tim R, Cressey, Philippa, Musoke, Ebrahim, Variava, Mark F, Cotton, Moherndran, Archary, Thanyawee, Puthanakit, Osee, Behuhuma, Robin, Kobbe, Steven B, Welch, Mutsa, Bwakura-Dangarembizi, Pauline, Amuge, Elizabeth, Kaudha, Linda, Barlow-Mosha, Shafic, Makumbi, Nastassja, Ramsagar, Chaiwat, Ngampiyaskul, Godfrey, Musoro, Lorna, Atwine, Afaaf, Liberty, Victor, Musiime, Dickson, Bbuye, Grace M, Ahimbisibwe, Suwalai, Chalermpantmetagul, Shabinah, Ali, Tatiana, Sarfati, Ben, Wynne, Clare, Shakeshaft, Angela, Colbers, Nigel, Klein, Sarah, Bernays, Yacine, Saïdi, Alexandra, Coelho, Tiziana, Grossele, Alexandra, Compagnucci, Carlo, Giaquinto, Pablo, Rojo, Deborah, Ford, Diana M, Gibb, and Anna, Goodman

Subjects
Oral, Cyclopropanes, Male, Adolescent, Pyridones, Administration, Oral, HIV Infections, 3-Ring, Article, Piperazines, Drug Therapy, Heterocyclic Compounds, Oxazines, Humans, HIV Integrase Inhibitors, Child, Preschool, Alkynes, Anti-Retroviral Agents, Benzoxazines, Child, Preschool, Cholesterol, Drug Therapy, Combination, Female, HIV Protease Inhibitors, Heterocyclic Compounds, 3-Ring, Viral Load, HIV-1, General Medicine, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Administration, Combination
Abstract

Item does not contain fulltext BACKGROUND: Children with human immunodeficiency virus type 1 (HIV-1) infection have limited options for effective antiretroviral treatment (ART). METHODS: We conducted an open-label, randomized, noninferiority trial comparing three-drug ART based on the HIV integrase inhibitor dolutegravir with standard care (non-dolutegravir-based ART) in children and adolescents starting first- or second-line ART. The primary end point was the proportion of participants with virologic or clinical treatment failure by 96 weeks, as estimated by the Kaplan-Meier method. Safety was assessed. RESULTS: From September 2016 through June 2018, a total of 707 children and adolescents who weighed at least 14 kg were randomly assigned to receive dolutegravir-based ART (350 participants) or standard care (357). The median age was 12.2 years (range, 2.9 to 18.0), the median weight was 30.7 kg (range, 14.0 to 85.0), and 49% of the participants were girls. By design, 311 participants (44%) started first-line ART (with 92% of those in the standard-care group receiving efavirenz-based ART), and 396 (56%) started second-line ART (with 98% of those in the standard-care group receiving boosted protease inhibitor-based ART). The median follow-up was 142 weeks. By 96 weeks, 47 participants in the dolutegravir group and 75 in the standard-care group had treatment failure (estimated probability, 0.14 vs. 0.22; difference, -0.08; 95% confidence interval, -0.14 to -0.03; P = 0.004). Treatment effects were similar with first- and second-line therapies (P = 0.16 for heterogeneity). A total of 35 participants in the dolutegravir group and 40 in the standard-care group had at least one serious adverse event (P = 0.53), and 73 and 86, respectively, had at least one adverse event of grade 3 or higher (P = 0.24). At least one ART-modifying adverse event occurred in 5 participants in the dolutegravir group and in 17 in the standard-care group (P = 0.01). CONCLUSIONS: In this trial involving children and adolescents with HIV-1 infection who were starting first- or second-line treatment, dolutegravir-based ART was superior to standard care. (Funded by ViiV Healthcare; ODYSSEY ClinicalTrials.gov number, NCT02259127; EUDRACT number, 2014-002632-14; and ISRCTN number, ISRCTN91737921.).

Published
2021
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4. 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

Author

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

Subjects
Adult, Epidemiology, Pyridones, Anti-HIV Agents, Immunology, HIV Infections, 3-Ring, Piperazines, Heterocyclic Compounds, Virology, Oxazines, Humans, Protease Inhibitors, Child, Preschool, Infant, Newborn, Infant, Bayes Theorem, Viral Load, Newborn, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Infectious Diseases, Child, Preschool, Heterocyclic Compounds, 3-Ring, Treatment Outcome
Abstract

Contains fulltext : 283099.pdf (Publisher’s version ) (Open Access) 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

Published
2022

5. Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Author

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

Subjects
Male, Adolescent, Pyridones, Epidemiology, Immunology, Infant, HIV Infections, 3-Ring, Piperazines, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Infectious Diseases, Child, Child, Preschool, Female, Heterocyclic Compounds, 3-Ring, Humans, Oxazines, Rifampin, Uganda, HIV-1, Tuberculosis, Heterocyclic Compounds, Virology, Preschool
Abstract

Contains fulltext : 282959.pdf (Publisher’s version ) (Open Access) BACKGROUND: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. METHODS: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to

Published
2022

6. Simplified dolutegravir dosing for children with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trial

Author

Annet Nanduudu, James Hakim, Deborah Ford, Angela Colbers, Odyssey trial team, Abbas Lugemwa, Carlo Giaquinto, Adeodata Kekitiinwa, David M. Burger, Diana M. Gibb, Pauline D.J. Bollen, Pablo Rojo, Cecilia L. Moore, Godfrey Musoro, Pauline Amuge, Hilda Mujuru, Anna Turkova, Anna Parker, Elisabeth Kaudha, and Shafic Makumbi

Subjects
0301 basic medicine, Adult, Male, Zimbabwe, Pediatrics, medicine.medical_specialty, Adolescent, Epidemiology, Pyridones, Immunology, Human immunodeficiency virus (HIV), HIV Infections, medicine.disease_cause, Article, Piperazines, law.invention, Food and drug administration, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Randomized controlled trial, Pharmacokinetics, law, Virology, Oxazines, medicine, Humans, In patient, Uganda, 030212 general & internal medicine, Dosing, HIV Integrase Inhibitors, Child, Dose-Response Relationship, Drug, business.industry, Body Weight, 030112 virology, Infectious Diseases, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], chemistry, Dolutegravir, Female, Once daily, business, Heterocyclic Compounds, 3-Ring, Tablets
Abstract

Summary Background Paediatric dolutegravir doses approved by stringent regulatory authorities (SRAs) for children weighing 20 kg to less than 40 kg until recently required 25 mg and 10 mg film-coated tablets. These tablets are not readily available in low-resource settings where the burden of HIV is highest. We did nested pharmacokinetic substudies in patients enrolled in the ODYSSEY-trial to evaluate simplified dosing in children with HIV. Methods We did pharmacokinetic and safety substudies within the open-label, multicentre, randomised ODYSSEY trial (NCT02259127) of children with HIV starting treatment in four research centres in Uganda and Zimbabwe. Eligible children were randomised to dolutegravir in ODYSSEY and weighed 20 kg to less than 40 kg. In children weighing 20 kg to less than 25 kg, we assessed dolutegravir's pharmacokinetics in children given once daily 25 mg film-coated tablets (approved by the SRAs at the time of the study) in part one of the study, and 50 mg film-coated tablets (adult dose) or 30 mg dispersible tablets in part two of the study. In children weighing 25 kg to less than 40 kg, we also assessed dolutegravir pharmacokinetics within-subject on film-coated tablet doses of 25 mg or 35 mg once daily, which were approved by the SRAs for the children's weight band; then switched to 50 mg film-coated tablets once daily. Steady-state 24 h dolutegravir plasma concentration-time pharmacokinetic profiling was done in all enrolled children at baseline and 1, 2, 3, 4, 6, and 24 h after observed dolutegravir intake. Target dolutegravir trough concentrations (Ctrough) were based on reference adult pharmacokinetic data and safety was evaluated in all children in the corresponding weight bands who consented to pharmacokinetic studies and received the studied doses. Findings Between Sept 22, 2016, and May 31, 2018, we enrolled 62 black-African children aged from 6 years to younger than 18 years (84 pharmacokinetic-profiles). In children weighing 20 kg to less than 25 kg taking 25 mg film-coated tablets, the geometric mean (GM) Ctrough (coefficient of variation) was 0·32 mg/L (94%), which was 61% lower than the GM Ctrough of 0·83 mg/L (26%) in fasted adults on dolutegravir 50 mg once-daily; in children weighing 25 kg to less than 30 kg taking 25 mg film-coated tablets, the GM Ctrough was 0·39 mg/L (48%), which was 54% lower than the GM Ctrough in fasted adults; and in those 30 kg to less than 40 kg taking 35 mg film-coated tablets the GM Ctrough was 0·46 mg/L (63%), which was 45% lower than the GM Ctrough in fasted adults. On 50 mg film-coated tablets or 30 mg dispersible tablets, Ctrough was close to the adult reference (with similar estimates on the two formulations in children in the 20 to

Published
2020

7. ODYSSEY clinical trial design: a randomised global study to evaluate the efficacy and safety of dolutegravir-based antiretroviral therapy in HIV-positive children, with nested pharmacokinetic sub-studies to evaluate pragmatic WHO-weight-band based dolutegravir dosing

Author

Clare Shakeshaft, Carlo Giaquinto, Tim R. Cressey, Adeodata Kekitiinwa, David M. Burger, Pauline Amuge, Pablo Rojo, Cecilia L. Moore, Osee Behuhuma, Yacine Saϊdi, Linda Barlow-Mosha, James Hakim, Alexandra Compagnucci, Lorna Atwine, Diana M. Gibb, Ebrahim Variava, Hilda Mujuru, Mark F. Cotton, Victor Musiime, Moherndran Archary, Deborah Ford, Cissy Kityo, Thanyawee Puthanakit, Anna Turkova, Avy Violari, Abbas Lugemwa, Medical Research Council Clinical Trials Unit (MRC CTU), University College of London [London] (UCL), University of Zimbabwe (UZ), Baylor College of Medicine Children's Foundation [Kampala, Uganda] (BCMCF), Joint Clinical Research Centre, MUJHU Research Collaboration [Kampala, Uganda] (MUJHURC), Chiang Mai University (CMU), Harvard T.H. Chan School of Public Health, University of Liverpool, Perinatal HIV Research Unit [Johannesburg, South Africa] (PHRU), University of the Witwatersrand [Johannesburg] (WITS), Klerksdorp Tshepong Hospital Complex [Matlosana, South Africa] (KTHC), Family Center for Research with Ubuntu [Cape Town, South Africa] (FCRU), Durban International Clinical Research Site [Durban, South Africa] (DICRS), Essais Thérapeutiques et Maladies Infectieuses, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chulalongkorn University [Bangkok], Africa Health Research Institute [Hlabisa, South Africa] (AHRI), Hlabisa Hospital [Hlabisa, South Africa] (HH), Radboud University Medical Center [Nijmegen], Università degli Studi di Padova = University of Padua (Unipd), Hospital Universitario 12 de Octubre [Madrid], ODYSSEY Trial Team: Shabinah Ali, Abdel Babiker, Chiara Borg, Anne-Marie Borges Da Silva, Joanna Calvert, Deborah Ford, Joshua Gasa, Diana M Gibb, Nasir Jamil, Sarah Lensen, Emma Little, Fatima Mohamed, Samuel Montero, Cecilia L Moore, Rachel Oguntimehin, Anna Parker, Reena Patel, Tasmin Phillips, Tatiana Sarfati, Karen Scott, Clare Shakeshaft, Moira Spyer, Margaret Thomason, Anna Turkova, Rebecca Turner, Nadine Van Looy, Ellen White, Kaya Widuch, Helen Wilkes, Ben Wynne, Carlo Giaquinto, Tiziana Grossele, Daniel Gomez-Pena, Davide Bilardi, Giulio Vecchia, Alexandra Compagnucci, Yacine Saidi, Yoann Riault, Alexandra Coelho, Laura Picault, Christelle Kouakam, Tim R Cressey, Suwalai Chalermpantmetagul, Dujrudee Chinwong, Gonzague Jourdain, Rukchanok Peongjakta, Pra-Ornsuda Sukrakanchana, Wasna Sirirungsi, Janet Seeley, Sarah Bernays, Magda Conway, Nigel Klein, Eleni Nastouli, Anita De Rossi, Maria Angeles Munoz Fernandez, David Burger, Pauline Bollen, Angela Colbers, Hylke Waalewijn, Cissy M Kityo, Victor Musiime, Elizabeth Kaudha, Annet Nanduudu, Emmanuel Mujyambere, Paul Ocitti Labeja, Charity Nankunda, Juliet Ategeka, Peter Erim, Collin Makanga, Esther Nambi, Abbas Lugemwa, Lorna Atwine, Edridah Keminyeto, Deogratiuos Tukwasibwe, Shafic Makumbi, Emily Ninsiima, Mercy Tukamushaba, Rogers Ankunda, Ian Natuhurira, Miriam Kasozi, Baker Rubinga, Adeodata R Kekitiinwa, Pauline Amuge, Dickson Bbuye, Justine Nalubwama, Winnie Akobye, Muzamil Nsibuka Kisekka, Anthony Kirabira, Gloria Ninsiima, Sylvia Namanda, Gerald Agaba, Immaculate Nagawa, Annet Nalugo, Florence Namuli, Rose Kadhuba, Rachael Namuddu, Lameck Kiyimba, Angella Baita, Eunice Atim, Olivia Kobusingye, Clementine Namajja, Africanus Byaruhanga, Rogers Besigye, Herbert Murungi, Geoffrey Onen, Philippa Musoke, Linda Barlow-Mosha, Grace Ahimbisibwe, Rose Namwanje, Monica Etima, Mark Ssenyonga, Robert Serunjogi, Hajira Kataike, Richard Isabirye, David Balamusani, Monica Nolan, Mark F Cotton, Anita Janese van Rensburg, Marlize Smuts, Catherine Andrea, Sumaya Dadan Sonja Pieterse, Vinesh Jaeven, Candice Makola, George Fourie, Kurt Smith, Els Dobbels, Peter Zuidewind, Hesti Van Huyssteen, Mornay Isaacs, Georgina Nentsa, Thabis Ncgaba, Candice MacDonald, Mandisa Mtshagi, Maria Bester, Wilma Orange, Ronelle Arendze, Mark Mulder, George Fourie, Avy Violari, Nastassja Ramsagar, Afaaf Liberty, Ruth Mathiba, Lindiwe Maseko, Nakata Kekane, Busi Khumlo, Mirriam Khunene, Noshalaza Sbisi, Jackie Brown, Ryphina Madonsela, Nokuthula Mbadaliga, Zaakirah Essack, Reshma Lakha, Aasia Vadee, Derusha Frank, Nazim Akoojee, Maletsatsi Monametsi, Gladness Machache, Yolandie Fourie, Anusha Nanan-Kanjee, Juan Erasmus, Angelous Mamiane, Tseleng Daniel, Fatima Mayat, Nomfundo Maduna, Patsy Baliram, Chaiwat Ngampiyasakul, Pisut Greetanukroh, Wanna Chamjamrat, Praechadaporn Khannak, Pornchai Techakunakorn, Thitiwat Thapwai, Patcharee Puangmalai, Ampai Maneekaew, Pradthana Ounchanum, Yupawan Thaweesombat, Areerat Kongponoi, Jutarat Thewsoongnoen, Suparat Kanjanavanit, Pacharaporn Yingyong, Thida Namwong, Rangwit Junkaew, Ussanee Srirompotong, Patamawadee Sudsaard, Siripun Nuanbuddee, Sookpanee Wimonklang, Sathaporn Na-Rajsima, Suchart Thongpaen, Pattira Runarassamee, Watchara Meethaisong, Arttasid Udomvised, Ebrahim Variava, Modiehi Rakgokong, Dihedile Scheppers, Tumelo Moloantoa, Abdul Hamid Kaka, Tshepiso Masienyane, Akshmi Ori, Kgosimang Mmolawa, Pattamukkil Abraham, Moherndran Archary, Rejoice Mosia, Sajeeda Mawlana, Rosie Mngqibisa, Rashina Nundlal, Elishka Singh, Penelope Madlala, Allemah Naidoo, Sphiwee Cebekhulu, Petronelle Casey, Collin Pillay, Subashinie Sidhoo, Minenhle Chikowore, Lungile Nyantsa, Melisha Nunkoo, Terence Nair, Enbavani Pillay, Sheleika Singh, Sheroma Rajkumar, Osee Behuhuma, Olivier Koole, Kristien Bird, Nomzamo Buthelezi, Mumsy Mthethwa, James Hakim, Hilda Mujuru, Kusum Nathoo, Mutsa Bwakura-Dangarembizi, Ennie Chidziva, Shepherd Mudzingwa, Themelihle Bafana, Colin Warambwa, Godfrey Musoro, Gloria Tinago, Shirley Mutsai, Columbus Moyo, Ruth Nhema, Misheck Nkalo Phiri, Stuart Chitongo, Joshua Choga, Joyline Bhiri, Wilber Ishemunyoro, Makhosonke Ndlovu, Thanyawee Puthanakit, Naruporn Kasipong, Sararut Chanthaburanun, Kesdao Nanthapisal, Thidarat Jupimai, Thornthun Noppakaorattanamanee, Torsak Bunupuradah, Wipaporn Natalie Songtaweesin, Chutima Saisaengjan, Stephan Schultze-Straber, Christoph Konigs, Robin Kobbe, Felicia Mantkowski, Steve Welch, Jacqui Daglish, Laura Thrasyvoulou, Delane Singadia, Sophie Foxall, Judith Acero, Gosia Pasko-Szcech, Jacquie Flynn, Gareth Tudor-Williams, Farhana Abdulla, Srini Bandi, Jin Li, Sean O'Riordan, Dominique Barker, Richard Vowden, Colin Ball Eniola Nsirim, Kathleen McClughlin, India Garcia, Pablo Rojo Conejo, Cristina Epalza, Luis Prieto Tato, Maite Fernandez, Luis Escosa Garcia, Maria José Mellado Peña, Talia Sainz Costa, Claudia Fortuny Guasch, Antoni Noguera Julian, Carolina Estepa, Elena Bruno, Alba Murciano Cabeza, Maria Angeles Muñoz Fernandez, Paula Palau, Laura Marques, Carla Teixeira, Alexandre Fernandes, Rosita Nunes, Helena Nascimento, Andreia Padrao, Joana Tuna, Helena Ramos, Ana Constança Mendes, Helena Pinheiro, Ana Cristina Matos, Flavia Kyomuhendo, Sarah Nakalanzi, Cynthia Mukisa Williams, Ntombenhle Ngcobo, Deborah Pako, Jacky Crisp, Benedictor Dube, Precious Chandiwana, Winnie Gozhora, Ian Weller, Elaine Abrams, Tsitsi Apollo, Polly Clayden, Valériane Leroy, Anton Pozniak, Jane Crawley, Rodolphe Thiébaut, Helen McIlleron, Alasdair Bamford, Hermione Lyall, Andrew Prendergast, Felicity Fitzgerald, Anna Goodman, Malbec, Odile, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Radboud University Medical Centre [Nijmegen, The Netherlands], and Universita degli Studi di Padova

Subjects
0301 basic medicine, Male, Pediatrics, [SDV]Life Sciences [q-bio], HIV Infections, Basket trial, Dolutegravir, Efficacy, HIV, Paediatric, Pharmacokinetic, Randomized control trial, Safety, Adolescent, Body Weight, Child, Child, Preschool, Cohort Studies, Drug Dosage Calculations, Europe, Female, HIV Integrase Inhibitors, HIV-1, Heterocyclic Compounds, 3-Ring, Humans, Oxazines, Piperazines, Pyridones, RNA, Viral, South Africa, Thailand, Treatment Outcome, Uganda, Viral Load, World Health Organization, Zimbabwe, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, Heterocyclic Compounds, law, Clinical endpoint, Medicine, Viral, 030212 general & internal medicine, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, Viral load, Cohort study, Research Article, medicine.medical_specialty, 030106 microbiology, 3-Ring, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, lcsh:RC109-216, Dosing, Preschool, Pregnancy, business.industry, Clinical study design, medicine.disease, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], chemistry, RNA, business
Abstract

Background Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children Methods ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children Results Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9–18.0]. 82 (12%) children weighed 14 to Conclusions By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children. Trial registration NCT, NCT02259127, registered 7th October 2014; EUDRACT, 2014–002632-14, registered 18th June 2014 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES); ISRCTN, ISRCTN91737921, registered 4th October 2014.

Published
2021
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