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1. Effect of dolutegravir on folate, vitamin B12 and mean corpuscular volume levels among children and adolescents with HIV: a sub‐study of the ODYSSEY randomized controlled trial

Author

Linda Namutebi Barlow‐Mosha, Grace Miriam Ahimbisibwe, Elizabeth Chappell, Pauline Mary Amuge, Annet Nanduudu, Elizabeth Kaudha, Timothy Amukele, David Balamusani, Bosco Kafufu, Audrey Nimwesiga, Hajira Kataike, Rosemary Namwanje, Gladys Kasangaki, Alice Mulindwa, Gerald Agaba Muzorah, Dickson Bbuye, Victor Musiime, Emmanuel Mujyambere, Mark Ssenyonga, Disan Mulima, Raymonds Crespo Kyambadde, Josephine Namusanje, Richard Isabirye, Mariam Nabalamba, Barbara Musoke Nakirya, Cissy Kityo, Adeodata R. Kekitiinwa, Carlo Giaquinto, Andrew Copp, Diana M. Gibb, Deborah Ford, Philippa Musoke, Anna Turkova, and the ODYSSEY trial team

Subjects
adolescents, children, dolutegravir, folate, HIV, vitamin B12, Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Introduction Dolutegravir‐based antiretroviral therapy (ART) is the preferred antiretroviral treatment for children and adolescents living with HIV. A large surveillance study in Botswana previously raised concerns about an association between pre‐conception dolutegravir and neural tube defects. Before these concerns were subsequently resolved, we set up a sub‐study to look at the effect of dolutegravir on levels of folate and vitamin B12 in children and adolescents within the randomized ODYSSEY trial, as folate and vitamin B12 are known to play a crucial role in neural tube development. Methods We conducted the sub‐study among Ugandan ODYSSEY participants and compared folate and vitamin B12 between children randomized to dolutegravir‐based ART (DTG) and non‐dolutegravir‐based standard‐of‐care treatment (SOC). Plasma folate was measured at enrolment and week 4 on stored samples; in addition, plasma and red blood cell (RBC) folate and vitamin B12 were assayed at week ≥96 in prospectively collected samples. RBC mean corpuscular volume (MCV) was measured 24‐weekly in all ODYSSEY participants. Samples analysed in the sub‐study were collected between September 2016 and October 2020. Results A total of 229 children aged ≥6 years were included in the sub‐study with median age at trial enrolment of 12.3 (interquartile range [IQR] 9.0, 14.7) years, and CD4 count of 501 (IQR 228, 695); 112 (49%) children were male. Most participants (225/229, 98%) had plasma folate results at enrolment and 214 (93%) children had results available for RBC folate, vitamin B12 and plasma folate at week ≥96. MCV results were analysed on 679 children aged ≥6 years enrolled in ODYSSEY. At week 4, mean plasma folate was significantly higher in the dolutegravir arm than in SOC (difference [DTG‐SOC] 1.6 ng/ml, 95% CI 0.8, 2.3; p

Published
2023
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2. 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

Author

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, 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, 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, and N. Sibanda

Subjects
HIV, Children, Adolescents, Randomised, Paediatrics, Dual therapy, Medicine (General), R5-920
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

Published
2023
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3. Borrowing information across patient subgroups in clinical trials, with application to a paediatric trial

Author

Rebecca M. Turner, Anna Turkova, Cecilia L. Moore, Alasdair Bamford, Moherndran Archary, Linda N. Barlow-Mosha, Mark F. Cotton, Tim R. Cressey, Elizabeth Kaudha, Abbas Lugemwa, Hermione Lyall, Hilda A. Mujuru, Veronica Mulenga, Victor Musiime, Pablo Rojo, Gareth Tudor-Williams, Steven B. Welch, Diana M. Gibb, Deborah Ford, Ian R. White, and and the ODYSSEY Trial Team

Subjects
Paediatric trials, Subgroups, Small samples, Bayesian analysis, Borrowing information, Medicine (General), R5-920
Abstract

Abstract Background Clinical trial investigators may need to evaluate treatment effects in a specific subgroup (or subgroups) of participants in addition to reporting results of the entire study population. Such subgroups lack power to detect a treatment effect, but there may be strong justification for borrowing information from a larger patient group within the same trial, while allowing for differences between populations. Our aim was to develop methods for eliciting expert opinions about differences in treatment effect between patient populations, and to incorporate these opinions into a Bayesian analysis. Methods We used an interaction parameter to model the relationship between underlying treatment effects in two subgroups. Elicitation was used to obtain clinical opinions on the likely values of the interaction parameter, since this parameter is poorly informed by the data. Feedback was provided to experts to communicate how uncertainty about the interaction parameter corresponds with relative weights allocated to subgroups in the Bayesian analysis. The impact on the planned analysis was then determined. Results The methods were applied to an ongoing non-inferiority trial designed to compare antiretroviral therapy regimens in 707 children living with HIV and weighing ≥ 14 kg, with an additional group of 85 younger children weighing

Published
2022
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4. Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents and young adults (BREATHER): Extended follow-up results of a randomised, open-label, non-inferiority trial.

Author

Anna Turkova, Cecilia L Moore, Karina Butler, Alexandra Compagnucci, Yacine Saïdi, Victor Musiime, Annet Nanduudu, Elizabeth Kaudha, Tim R Cressey, Suwalai Chalermpantmetagul, Karen Scott, Lynda Harper, Samuel Montero, Yoann Riault, Torsak Bunupuradah, Alla Volokha, Patricia M Flynn, Rosa Bologna, Jose T Ramos Amador, Steven B Welch, Eleni Nastouli, Nigel Klein, Carlo Giaquinto, Deborah Ford, Abdel Babiker, Diana M Gibb, and BREATHER (PENTA 16) trial Group

Subjects
Medicine, Science
Abstract

BackgroundWeekends off antiretroviral therapy (ART) may help engage HIV-1-infected young people facing lifelong treatment. BREATHER showed short cycle therapy (SCT; 5 days on, 2 days off ART) was non-inferior to continuous therapy (CT) over 48 weeks. Planned follow-up was extended to 144 weeks, maintaining original randomisation.MethodsBREATHER was an open-label, non-inferiority trial. Participants aged 8-24yrs with virological suppression on efavirenz-based first-line ART were randomised 1:1, stratified by age and African/non-African sites, to remain on CT or change to SCT. The Kaplan-Meier method was used to estimate the proportion of participants with viral rebound (confirmed VL≥50 copies/mL) under intent-to-treat at 48 weeks (primary outcome), and in extended follow-up at 96, 144, and 192 weeks. SCT participants returned to CT following viral rebound, 3 VL blips or discontinuation of efavirenz.FindingsOf 199 participants (99 SCT, 100 CT), 97 per arm consented to extended follow-up. Median follow-up was 185.3 weeks (IQR 160.9-216.1). 69 (70%) SCT participants remained on SCT at last follow-up. 105 (53%) were male, baseline median age 14 years (IQR 12-18), median CD4 count 735 cells/μL (IQR 576-968). 16 SCT and 16 CT participants had confirmed VL≥50 copies/mL by the end of extended follow-up (HR 1.00, 95% CI 0.50-2.00). Estimated difference in percentage with viral rebound (SCT minus CT) by week 144 was 1.9% (90% CI -6.6-10.4; p = 0.72) and was similar in a per-protocol analysis. There were no significant differences between arms in proportions of participants with grade 3/4 adverse events (18 SCT vs 16 CT participants; p = 0.71) or ART-related adverse events (10 vs 12; p = 0.82). 20 versus 8 serious adverse events (SAEs) were reported in 16 SCT versus 4 CT participants, respectively (p = 0.005 comparing proportions between groups; incidence rate ratio 2.49, 95%CI 0.71-8.66, p = 0.15). 75% of SAEs (15 SCT, 6 CT) were hospitalisations for a wide range of conditions. 3 SCT and 6 CT participants switched to second-line ART following viral failure (p = 0.50).ConclusionsSustainable non-inferiority of virological suppression in young people was shown for SCT versus CT over median 3.6 years. Standard-dose efavirenz-based SCT is a viable option for virologically suppressed HIV-1 infected young people on first-line ART with 3-monthly VL monitoring.Trial registrationEudraCT 2009-012947-40 ISRCTN 97755073 ClinicalTrials.gov NCT01641016.

Published
2018
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5. Neuropsychiatric Manifestations and Sleep Disturbances in Children and Adolescents Randomised to Dolutegravir-Based Antiretroviral Therapy vs Standard-of-Care in the Odyssey Trial

Author

Anna Turkova, Ellen White, Adeodata R. Kekitiinwa, Vivian Mumbiro, Elizabeth Kaudha, Afaaf Liberty, Grace Miriam Ahimbisibwe, Tumelo Moloantoa, Ussanee Srirompotong, Nozibusiso Rejoice Mosia, Thanyawee Puthanakit, Robin Kobbe, Clàudia Fortuny, Hajira Kataike, Dickson Bbuye, Sathaporn Na-Rajsima, Alexandra Coelho, Abbas Lugemwa, Mutsa F. Bwakura-Dangarembizi, Nigel Klein, Hilda Mujuru, Cissy Kityo, Mark F. Cotton, Rashida Abbas Ferrand, Carlo Giaquinto, Pablo Rojo Conejo, Avy Violari, Diana M. Gibb, Deborah Ford, and ODYSSEY Trial Team

Published
2023
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6. 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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7. Borrowing information across patient subgroups in clinical trials, with application to a paediatric trial

Author

Rebecca M, Turner, Anna, Turkova, Cecilia L, Moore, Alasdair, Bamford, Moherndran, Archary, Linda N, Barlow-Mosha, Mark F, Cotton, Tim R, Cressey, Elizabeth, Kaudha, Abbas, Lugemwa, Hermione, Lyall, Hilda A, Mujuru, Veronica, Mulenga, Victor, Musiime, Pablo, Rojo, Gareth, Tudor-Williams, Steven B, Welch, Diana M, Gibb, Deborah, Ford, and Ian R, White

Subjects
DESIGNS, the ODYSSEY Trial Team, Paediatric trials, Epidemiology, Bayesian analysis, Health Informatics, Borrowing information, Small samples, 1117 Public Health and Health Services, ELICITATION, BELIEFS, General & Internal Medicine, Humans, Child, Expert Testimony, Clinical Trials as Topic, Science & Technology, Subgroups, Uncertainty, EXTRAPOLATION, Bayes Theorem, Health Care Sciences & Services, PRIORS, UMBRELLA, Sample Size, Life Sciences & Biomedicine
Abstract

Background Clinical trial investigators may need to evaluate treatment effects in a specific subgroup (or subgroups) of participants in addition to reporting results of the entire study population. Such subgroups lack power to detect a treatment effect, but there may be strong justification for borrowing information from a larger patient group within the same trial, while allowing for differences between populations. Our aim was to develop methods for eliciting expert opinions about differences in treatment effect between patient populations, and to incorporate these opinions into a Bayesian analysis. Methods We used an interaction parameter to model the relationship between underlying treatment effects in two subgroups. Elicitation was used to obtain clinical opinions on the likely values of the interaction parameter, since this parameter is poorly informed by the data. Feedback was provided to experts to communicate how uncertainty about the interaction parameter corresponds with relative weights allocated to subgroups in the Bayesian analysis. The impact on the planned analysis was then determined. Results The methods were applied to an ongoing non-inferiority trial designed to compare antiretroviral therapy regimens in 707 children living with HIV and weighing ≥ 14 kg, with an additional group of 85 younger children weighing Conclusions Borrowing information from a larger subgroup or subgroups can facilitate estimation of treatment effects in small subgroups within a clinical trial, leading to improved power and precision. Informative prior distributions for interaction parameters are required to inform the degree of borrowing and can be informed by expert opinion. We demonstrated accessible methods for obtaining opinions.

Published
2022

8. 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

9. 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

10. Long-term virological outcomes, failure and acquired resistance in a large cohort of Ugandan children

Author

M Boele van Hensbroek, R Nakanjako, Peter Mugyenyi, K C E Sigaloff, Minke H. W. Huibers, Job C. J. Calis, Silvia Bertagnolio, T. F. Rinke de Wit, Sheila Balinda, Elizabeth Kaudha, Ragna S. Boerma, Cissy Kityo, Amsterdam Reproduction & Development (AR&D), Internal medicine, APH - Quality of Care, Graduate School, AII - Infectious diseases, APH - Global Health, Paediatric Intensive Care, Paediatric Infectious Diseases / Rheumatology / Immunology, Global Health, General Paediatrics, and APH - Personalized Medicine

Subjects
0301 basic medicine, Microbiology (medical), Male, medicine.medical_specialty, Anti-HIV Agents, 030106 microbiology, Black People, HIV Infections, Drug resistance, 03 medical and health sciences, 0302 clinical medicine, Acquired resistance, Internal medicine, Early start, Drug Resistance, Viral, medicine, Humans, Pharmacology (medical), Uganda, 030212 general & internal medicine, Treatment Failure, Prospective cohort study, Pharmacology, business.industry, Viral Load, Virological failure, Large cohort, Regimen, Infectious Diseases, Child, Preschool, HIV-1, Female, business, Viral load
Abstract

Objectives To evaluate long-term virological failure (VF) and drug resistance among HIV-infected Ugandan children on first-line ART. Methods In a multicentre prospective cohort study, viral load (VL) and drug resistance mutations (DRMs) were investigated at baseline and 6 monthly intervals in children (age ≤ 12 years). VF (two consecutive VLs >1000 copies/mL or death after 6 months of ART) was defined as early VF (0–24 months of ART) or late VF (25–48 months of ART). An active regimen was defined as partially active if the genotypic susceptibility score (GSS) was Results Between 2010 and 2011, 316 children were enrolled. Viral suppression was achieved in 75.8%, 71.5%, 72.6% and 69.2% at 12, 24, 36 and 48 months. VF occurred in 111/286 (38.8%), of which 67.6% was early and 32.4% late VF. Early VF was associated with a partially active regimen at baseline (OR 6.0, 95% CI 1.9–18.5), poor adherence (OR 3.1, 95% CI 1.3–7.4) and immunodeficiency (OR 3.3, 95% CI 1.1–10.2). Late VF was associated with age >3 years (OR 2.5, 95% CI 1.0–6.6) and WHO stage 3/4 (OR 4.2, 95% CI 1.4–13.4). Acquired DRMs were detected in 27.0% before 24 months, versus 14.4% after 24 months (P Conclusions VF rates were high, occurred predominantly in the first 24 months and appeared to increase again in year four. Risk factors and patterns of early VF/DRMs were different from those of late VF/DRMs. Virological control may improve by close monitoring and prompt switching to second-line therapy in the first 24 months. Late VF may be prevented by early start of ART.

Published
2019
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11. Pretreatment HIV drug resistance results in virological failure and accumulation of additional resistance mutations in Ugandan children

Author

Elizabeth Kaudha, Victor Musiime, Rita Nakanjako, Kim C. E. Sigaloff, Job C. J. Calis, Sheila Balinda, Cissy Kityo, Peter Mugyenyi, Ragna S. Boerma, T. Sonia Boender, Tobias F. Rinke de Wit, Internal medicine, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), APH - Personalized Medicine, AII - Infectious diseases, Graduate School, ARD - Amsterdam Reproduction and Development, Other departments, Global Health, APH - Global Health, Paediatric Intensive Care, AII - Amsterdam institute for Infection and Immunity, and Infectious diseases

Subjects
0301 basic medicine, Microbiology (medical), Male, medicine.medical_specialty, Genotype, Anti-HIV Agents, Black People, HIV Infections, Drug resistance, Logistic regression, 03 medical and health sciences, Internal medicine, Drug Resistance, Viral, Medicine, Effective treatment, Humans, Pharmacology (medical), Uganda, Treatment Failure, Child, Original Research, Pharmacology, business.industry, Viral Load, 030112 virology, Virological failure, Virology, Regimen, Infectious Diseases, Treatment Outcome, Who guidelines, Child, Preschool, Mutation, HIV-1, Female, business, Viral load, HIV drug resistance
Abstract

Background: Pretreatment HIV drug resistance (PDR) can impair virological response to ART, jeopardizing effective treatment for children. Methods: Children aged ≤12 years initiated first-line ART in Uganda during 2010-11. Baseline and 6 monthly viral load (VL) and genotypic resistance testing if VL > 1000 copies/mL was done. The 2015 IAS-USA mutation list and Stanford algorithm were used to score drug resistance mutations (DRMs) and susceptibility. Virological failure (VF) was defined as two consecutive VLs > 1000 copies/mL or death after 6months of ART. Factors associated with failure and acquired drug resistance (ADR) were assessed in a logistic regression analysis. Results: Among 317 children enrolled, median age was 4.9 years and 91.5% received NNRTI-based regimens. PDR was detected in 47/278 (16.9%) children, of whom 22 (7.9%) had resistance against their first-line regimen and were therefore on a partially active regimen. After 24months of follow-up, 92/287 (32.1%) had experienced VF. Children with PDR had a higher risk of VF (OR 15.25, P < 0.001) and ADR (OR 3.58, P=0.01). Conclusions: Almost one-third of children experienced VF within 24months of NNRTI-based first-line treatment. PDR was the strongest predictor of VF and ADR, and therefore presents a major threat in children. There is a need for ART regimens that maximize effectiveness of first-line therapy for long-term treatment success in the presence of PDR or incorporation of routine VL testing to detect VF and change treatment in time, in order to prevent clinical deterioration and accumulation of additional drug resistance. Children ≤3 years should be initiated on a PI-based regimen as per WHO guidelines.

Published
2017
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12. Accumulation of HIV-1 drug resistance after continued virological failure on first-line ART in adults and children in sub-Saharan Africa

Author

Kim Steegen, Kim C. E. Sigaloff, T. Sonia Boender, Mariette E. Botes, Pascale Ondoa, Tobias F. Rinke de Wit, Maureen Wellington, Raph L. Hamers, Immaculate Nankya, Margaret Siwale, Ragna S. Boerma, Job C. J. Calis, Alani S Akanmu, Cissy Kityo, Elizabeth Kaudha, Other departments, Graduate School, Global Health, Infectious diseases, AII - Amsterdam institute for Infection and Immunity, Paediatric Intensive Care, and Internal medicine

Subjects
0301 basic medicine, Microbiology (medical), Drug, Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, Anti-HIV Agents, media_common.quotation_subject, 030106 microbiology, HIV Infections, Drug resistance, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Antiretroviral Therapy, Highly Active, Genotype, Drug Resistance, Viral, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Treatment Failure, Young adult, Child, Africa South of the Sahara, media_common, Retrospective Studies, Pharmacology, business.industry, Retrospective cohort study, Viral Load, Resistance mutation, Reverse transcriptase, Infectious Diseases, Child, Preschool, Mutation, HIV-1, Reverse Transcriptase Inhibitors, Female, business, Viral load
Abstract

Objectives Limited availability of viral load (VL) monitoring in HIV treatment programmes in sub-Saharan Africa can delay switching to second-line ART, leading to the accumulation of drug resistance mutations (DRMs). The objective of this study was to evaluate the accumulation of resistance to reverse transcriptase inhibitors after continued virological failure on first-line ART, among adults and children in sub-Saharan Africa. Methods HIV-1-positive adults and children on an NNRTI-based first-line ART were included. Retrospective VL and, if VL ≥1000 copies/mL, pol genotypic testing was performed. Among participants with continued virological failure (≥2 VL ≥1000 copies/mL), drug resistance was evaluated. Results At first virological failure, DRM(s) were detected in 87% of participants: K103N (38.7%), G190A (21.8%), Y181C (20.2%), V106M (8.4%), K101E (8.4%), any E138 (7.6%) and V108I (7.6%) associated with NNRTIs, and M184V (69.7%), any thymidine analogue mutation (9.2%), K65R (5.9%) and K70R (5.0%) associated with NRTIs. New DRMs accumulated with an average rate of 1.45 (SD 2.07) DRM per year; 0.62 (SD 1.11) NNRTI DRMs and 0.84 (SD 1.38) NRTI DRMs per year, respectively. The predicted susceptibility declined significantly after continued virological failure for all reverse transcriptase inhibitors (all P Conclusions Patterns of drug resistance after virological failure on first-line ART are similar in adults and children in sub-Saharan Africa. Improved VL monitoring to prevent accumulation of mutations, and new drug classes to construct fully active regimens, are required.

Published
2017
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13. Antiretroviral Drug Resistance Profiles and Response to Second-Line Therapy Among HIV Type 1-Infected Ugandan Children

Author

Immaculate Nankya, Joshua Kayiwa, Grace Mirembe, Robert Colebunders, Francis Ssali, Peter Mugyenyi, Elizabeth Kaudha, Cissy Kityo, Hilda Kizito, Victor Musiime, and Matthew Odera

Subjects
Male, HAART, HIV Infections, Drug resistance, Lopinavir, Reverse transcriptase inhibitors, Nucleoside, Uganda, Child, Children, Reverse-transcriptase inhibitor, Antiretrovirals, Africa, East, virus diseases, Viral Load, Resistance mutation, AIDS, Treatment Outcome, Infectious Diseases, Anti-Retroviral Agents, Child, Preschool, Female, Second-line drugs, Viral load, Mutations, Compliance, medicine.drug, medicine.medical_specialty, Adolescent, Genotype, Immunology, Mutation, Missense, Viral diseases, Viral Proteins, Young Adult, Acquired immunodeficiency syndrome (AIDS), Virology, Internal medicine, Drug Resistance, Viral, medicine, Humans, Ritonavir, Height, business.industry, Body Weight, Weight, medicine.disease, CD4 Lymphocyte Count, Regimen, HIV-1, Human medicine, business
Abstract

We sought to determine the pattern of resistance-associated mutations (RAMs) among HIV-1-infected children failing first-line antiretroviral therapy (ART) and ascertain their response to second-line regimens in 48 weeks of follow-up. The design involved a cohort study within an HIV care program. We studied records of 142 children on ART with virological failure to first-line ART and switched to second-line ART with prior genotypic resistance testing. The pattern of RAMs was determined in frequency runs and the factors associated with accumulation of >= 3 thymidine analogue mutations (TAMs) and K103N were determined using multivariate logistic models. Changes in weight, height, CD4, and viral load at weeks 24 and 48 after switch to second-line therapy were determined using descriptive statistics. The children were mean age 10.9+/-4.6 years and 55.6% were male. The commonest nucleoside reverse transcriptase inhibitor (NRTI) RAM was M184V in 129/142 (90.8%) children. TAMs, >= 3 TAMs, 69 insertion complex, K65R/N, and Q151M were observed in 43.0%, 10.6%, 18.3%, 2.8%, and 2.1% of the children, respectively. The commonest nonnucleoside reverse transcriptase inhibitor (NNRTI) RAM was K103N in 72/142 (50.7%) children. The starting ART regimen was associated with accumulation of both >= 3 TAMs (p = 0.046) and K103N (p < 0.0001), while a history of poor adherence was associated with K103N accumulation (p = 0.0388). After 24 weeks and 48 weeks of follow-up on lopinavir-ritonavir based second-line ART, 86/108 (79.6%) and 84.5% (87/103) of the children had viral loads < 400 copies/ml, respectively. The mean CD4 absolute count increased by 173 cells/mu l and 267cells/mu l at weeks 24 and 48, respectively. Increments were also observed in mean weight (1.6 kg and 4.3 kg) and height (1.8 cm and 5.8 cm) at weeks 24 and 48, respectively. Multiple RAMs were observed among HIV-1-infected children with virological failure on first-line ART with M184V and K103N most frequent. The children responded favorably to boosted PI-based second-line ART.

Published
2013
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14. Short communication: high rates of thymidine analogue mutations and dual-class resistance among HIV-infected Ugandan children failing first-line antiretroviral therapy

Author

Immaculate Nankya, Peter Mugyenyi, Kim C. E. Sigaloff, J. Dekker, Lillian Katumba Nakatudde, Elizabeth Kaudha, Cissy Kityo, Joshua Kayiwa, Christine Matama, Job C. J. Calis, Raph L. Hamers, Andrew Mukuye, Tobias F. Rinke de Wit, Victor Musiime, Internal medicine, Global Health, AII - Amsterdam institute for Infection and Immunity, Paediatric Intensive Care, and Infectious diseases

Subjects
Male, medicine.medical_specialty, Genotype, Anti-HIV Agents, Molecular Sequence Data, Immunology, HIV Infections, Drug resistance, Virus, Drug Resistance, Multiple, Viral, Virology, Internal medicine, Drug Resistance, Viral, medicine, Humans, Uganda, Treatment Failure, Child, High rate, Reverse-transcriptase inhibitor, business.industry, HIV, virus diseases, Viral Load, Resistance mutation, Antiretroviral therapy, Confidence interval, Cross-Sectional Studies, Infectious Diseases, Amino Acid Substitution, Child, Preschool, Female, business, HIV drug resistance, Thymidine, medicine.drug
Abstract

HIV-infected children are at high risk of acquiring drug-resistant viruses, which is of particular concern in settings where antiretroviral drug options are limited. We aimed to assess resistance patterns and predict viral drug susceptibility among children with first-line antiretroviral therapy (ART) failure in Uganda. A cross-sectional analysis of children switching ART regimens due to first-line failure was performed at three clinical sites in Uganda. HIV-RNA determination and genotypic resistance testing on all specimens with HIV-RNA >1,000 copies/ml were performed. Major drug resistance mutations were scored using the 2011 International Antiviral Society-USA list. The Stanford algorithm was used to predict drug susceptibility. At the time of switch, 44 genotypic resistance tests were available for 50 children. All children harbored virus with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance [95% confidence interval (CI) 92-100%] and NRTI resistance was present in 98% (95% CI 88-100%). Forty-six percent (95% CI 30-61%) of children harbored ≥2 thymidine analog mutations. M184V was identified as the only NRTI mutation in 27% (95% CI 15-43%). HIV susceptibility to NRTIs, with the exception of tenofovir, was reduced in ≥60% of children. Ugandan children experiencing first-line ART failure in our study harbored high rates of dual-class and accumulated HIV drug resistance. Methods to prevent treatment failure, including adequate pediatric formulations and alternative second-line treatment options, are urgently needed.

Published
2013
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15. Second-line HIV Treatment in Ugandan Children: Favorable Outcomes and No Protease Inhibitor Resistance

Author

Peter Mugyenyi, Joshua Kayiwa, Lilian Nakatudde, Victor Musiime, Ragna S. Boerma, Job C. J. Calis, Mary Kiconco, Michael Boele van Hensbroek, T. Sonia Boender, Immaculate Nankya, Cissy Kityo, Elizabeth Kaudha, Andrew Mukuye, Kim C. E. Sigaloff, Tobias F. Rinke de Wit, Psychiatry, Pediatrics, APH - Global Health, APH - Quality of Care, Internal medicine, AII - Infectious diseases, Graduate School, Amsterdam Reproduction & Development (AR&D), APH - Personalized Medicine, Global Health, Other departments, Paediatric Infectious Diseases / Rheumatology / Immunology, Infectious diseases, and Paediatric Intensive Care

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, Black People, HIV Infections, Drug resistance, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Second line, Internal medicine, Drug Resistance, Viral, Genotype, Prevalence, Antiretroviral treatment, Humans, Medicine, Uganda, Protease inhibitor (pharmacology), Treatment Failure, 030212 general & internal medicine, Child, business.industry, HIV Protease Inhibitors, Viral Load, 030112 virology, Treatment Outcome, Infectious Diseases, Anti-Retroviral Agents, Child, Preschool, Mutation, Pediatrics, Perinatology and Child Health, HIV-1, Female, Underweight, medicine.symptom, business, Viral load, HIV drug resistance
Abstract

BACKGROUND: Data on pediatric second-line antiretroviral treatment (ART) outcomes are scarce, but essential to evaluate second-line and design third-line regimens.METHODS: Children ≤12 years switching to second-line ART containing a protease inhibitor (PI) in Uganda were followed for 24 months. Viral load (VL) was determined at switch to second-line and every 6 months thereafter; genotypic resistance testing was done if VL ≥ 1000 cps/ml.RESULTS: 60 children were included in the analysis; all had ≥1 drug resistance mutations at switch. Twelve children (20.0%) experienced treatment failure; no PI mutations were detected. Sub-optimal adherence and underweight were associated with treatment failure.CONCLUSIONS: No PI mutations occurred in children failing second-line ART, which is reassuring as pediatric third-line is not routinely available in these settings. Poor adherence rather than HIV drug resistance is likely to be the main mechanism for treatment failure and should receive close attention in children on second-line ART.

Published
2016
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16. 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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