PRESENTED AT IAS 2021 – the 11th IAS Conference on HIV Science - PowerPoint Presentation

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PRESENTED AT IAS 2021 – the 11th IAS Conference on HIV Science|18-21 JULY 2021Weight gain in children and adolescents on dolutegravir vs standard of care in the ODYSSEY trial1 MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London, United Kingdom; 2 Joint Clinical Research Centre (JCRC), Kampala, Uganda; 3 University of Zimbabwe, Harare, Zimbabwe; 4 Perinatal HIV Research Unit, University of the Witwarsrand, Johannesburg, South Africa; 5 Baylor College of Medicine, Uganda ;6 Joint Clinical Research Centre (JCRC), Mbarara, Uganda; 7 Makerere University-Johns Hopkins University (MU-JHU) Research Collaboration, Kampala, Uganda; 8 Prapokklao Hospital, Chanthaburi Province, Thailand; 9 Family Center for Research with Ubuntu, Department of Paediatrics & Child Health, Stellenbosch University, Tygerberg, South Africa; 10 HIVNAT, Thai Red Cross AIDS Research Center, Bangkok, Thailand; 11 Enhancing Care Foundation: King Edward VIII Hospital; 12Africa Health Research Institute (AHRI), Kwazulu-Natal, South Africa; 13 INSERM/ANRS SC10-US19, Essais thérapeutiques et maladies Infectieuses, Villejuif, France; 14 Department of Paediatrics, Heartlands Hospital, University Hospitals Birmingham, UK; 15 PHPT/IRD Research Unit, Faculty of Associated Medical Sciences, Chiang Mai University, Thailand 16 Pediatric Infectious Diseases Unit, Hospital 12 de Octubre, Madrid, Spain; 17 University of Padova, Department of Women and Child Health, Padova, ItalyAnna Turkova, Cissy Kityo, Hilda A Mujuru, Ebrahim Variava, Adeodata Kekitiinwa, Abbas Lugemwa, Linda Barlow-Mosha, Chaiwat Ngampiyaskul, Peter Zuidewind, Thanyawee Puthanakit, Rosie Mngqbisa, Ngundu Osee Behuhuma, Hajira Kataike, Godfrey Musoro, Annet Nandudu, Pauline Amuge, Shafic Makumbi, Siva Danaviah, Shabinah Ali, Ben Wynne, Yoann Riault, Steve Welch, Tim R Cressey, Avy Violari, Alexandra Compagnucci, James Hakim , Pablo Rojo, Carlo Giaquinto, Diana M Gibb, Deborah Ford, the ODYSSEY trial team correspondence to a.turkova@ucl.ac.ukA-IAS2021-01311BackgroundMethodsConclusionsDolutegravir is associated with excessive weight gain in adults. ADVANCE trial reported 10kg weight gain on DTG+TAF/FTC and 6kg on DTG+TDF/FTC over 144 weeks.[1]There are limited and conflicting data on DTG-associated weight gain in observational studies in children. A study in the UK CHIPS cohort (n=300) showed no difference in change of BMI-for-age at 12 months after switch to DTG vs PI-based ART in virologically suppressed children.[2]ODYSSEY is a randomised multi-country trial evaluating dolutegravir + 2NRTIs (DTG) versus standard-of-care (SOC) in children starting first-line or second-line ARTThe main trial enrolled children ≥14kg between September 2016 and June 2018We compared weight, height, BMI and BMI-for-age Z-scores (BAZ) between treatment arms using normal regression models adjusting for first-/second-line, randomisation stratification factors and baseline measurements The difference in treatment effect on BAZ in the DTG and SOC arms was assessed by first- and second treatment lines, sex, age and NRTI backbone (non-TDF vs TDF)Proportions becoming newly overweight (BAZ>1-≤2) or newly obese (BAZ>2) are describedChildren grew better after starting DTG compared to non-DTG ARTDifferences between arms in weight, height and BMI were small and stabilizedDifferences between arms were similar by: first- or second-line, sex, age and NRTI backbone (non-TDF / TDF)Few became newly overweight or obese in either armDTG-based ART was not associated with excessive weight gain in children and adolescentsResults707 children were randomised (sub Saharan Africa 88%, Thailand 9%, Europe 4%)311 started first-line (92% efavirenz-based in SOC); 396 second-line (72% lopinavir/ritonavir, 25% atazanavir/ritonavir in SOC)65% initiated ABC+3TC, 23% TDF+XTC, 11% ZDV+3TC At baseline, median age was 12.2 years (IQR 9.1, 14.9; range 2.9-18.0) 49% were femaleMedian follow-up 142 weeks (IQR 124, 159)ResultsTreatment effects did not differ significantly between children not on TDF and those on TDF (heterogeneity p=0.65) BMI: change from baselinew96DTG-SOC 0.3 (95%CI 0.0,0.6) p=0.03 BMI-for-age: change from baselinew96DTG-SOC 0.12 (95%CI -0.01,0.24) p=0.06Mean change from baseline , kg/m2 (95% CI)Mean change from baseline, Z-score (95% CI)There was no difference in treatment effects by age group (heterogeneity p=0.78) Treatment effects did not differ significantly between boys and girls (heterogeneity p=0.37)Change in BMI-for-age: by sexChange in BMI-for-age: by baseline age groupBMI-for-age: no TDF (N=543)BMI-for-age: TDF (N= 164)w96DTG-SOC 0.06 (95%CI -0.19, 0.32)w96DTG-SOC 0.13 (95%CI -0.01, 0.27)Mean change from baseline, (95% CI)Change in BMI-for-age: by TDF at baselineNew overweight and obesityBMI-for-age: <12 years (N=343) Mean change from baseline, (95% CI)BMI-for-age: ≥12 years (N=364)w96DTG-SOC 0.13 (95%CI -0.04, 0.31)w96DTG-SOC 0.10 (95%CI -0.07, 0.27)Mean change from baseline, (95% CI)BMI-for-age: males (N=362)BMI-for-age: females (N=345) w96DTG-SOC 0.06(95%CI -0.12, 0.23)w96DTG-SOC 0.17 (95%CI -0.00, 0.33)Mean change from baseline (95% CI)Change in weight and heightSmall additional gains from baseline in BMI and BMI-for-age in DTG vs. SOCOver 96 weeks mean additional gain in BMI in DTG vs SOC was 0.3 kg/m2, and in BAZ 0.12 SDThe gap between arms did not increase with time ODYSSEY trial schemaChange in body mass index (BMI) and BMI-for-agePopulation at baseline (n=707)MedianIQRRangeWeight, kg31(24, 43)[14 to 85]Height, cm138(125, 153)[89 to 182]BMI, kg/m2 16.3(14.9, 18.5) [9.8, 34.5]BMI-for-age, Z-score*-0.6(-1.4, 0.0)[-7.8, 2.8]At baseline11% had severe thinness/thinness (BMI-for-age <-2 SD)5% were overweight (BMI-for-age >1SD to ≤2SD)1% obese (BMI-for-age >2SD)Weight, Height and BMI at baseline*using UK WHO Term Reference 2009A retrospective study in Eswatini (n=460) showed that switch to DTG in virologically suppressed adolescents was associated with an increase in the rate of BMI gain. [3] A small study in the US adolescents (n=51) has also shown a greater rate of BMI and BMI-for-age increase following switch to INSTI [4]We present the first randomised data in children and adolescents.<18 years old, Starting 1st line or switching to 2nd lineN = 707 ODYSSEY A: First-line ART N=311ODYSSEY B: Second-line ARTN=396Follow-up: until last patient reaches 96 weeksPrimary endpoint: virological or clinical failureDTG N=154SOCN=157DTG N=196SOC N=200Randomisation 1:1Stratified by3rd agent in SOC, NRTI backbone andavailability of resistance testingRandomisation 1:1Stratified by3rd agent in SOC, NRTI backbone andavailability of resistance testingWeight: change from baselineMean change from baseline, kg (95% CI)w96DTG-SOC 1kg (95%CI 0.3,1.7) p=0.004Height: change from baselinew96DTG-SOC 0.8cm (95%CI 0.2, 1.4) p=0.007Mean change from baseline, cm (95% CI)Small additional gains from baseline in weight and height in DTG vs. SOCAt 96 weeks mean additional gain in DTG vs SOC in weight was 1kg, and in height 0.8cmThe differences occurred early and stabilisedReferencesHindley. CROI 2021. Abs 117Crichton et al. HIV Pediatrics 20193. Thivalapill et al. CID 20204. Dirajlal-Fargo et al. CROI 2020Overall, 25 (4%) were newly overweight or obese at 96 weeks: 14 (4%) in the DTG arm & 11 (3%) in SOC (p=0.55)Characteristics of those newly overweight or obese:Median age at enrolment: 13.0 years (IQR 10.3, 15.4)15/311 (5%) on first-line vs 10/396 (3%) on second-line ART 15/345 (4%) females vs 10/362 (3%) males10/167 (6%) on TDF vs 15/540 (3%) not on TDF