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Virological failures and genotypic resistance in children and adolescents randomised to dolutegravir-based ART vs. standard-of-care in the ODYSSEY trial

Title
Virological failures and genotypic resistance in children and adolescents randomised to dolutegravir-based ART vs. standard-of-care in the ODYSSEY trial
Presenter
Cissy Kityo
Authors
C. Kityo * (1), E. White (2), A. Turkova (2), H.A Mujuru (3), I. Nankya (4), B. Wynne (2), S. Ali (2), A. Kekitiinwa (5), A. Lugemwa (6), E. Kaudha (1), A. Liberty (7), H. Cassim (7), M. Archary (8), M. Cotton (9), L. Barlow-Mosha (10), T.R Cressey (11), C. Ngampiyasakul (12), U. Srirompotong (13), O. Behuhuma (14), Y. Saidi (15), A. Bamford (16), R. Kobbe (17), P. Rojo (18), C. Giaquinto (19), D. Gibb (2), D. Ford (2)
Institutions
(1) Joint Clinical Research Centre, Kampala, Uganda, (2) MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London, United Kingdom, (3) University of Zimbabwe, Harare, Zimbabwe, (4) Center for AIDS Research Uganda Laboratories, Joint Clinical Research Centre, Kampala, Uganda, (5) Baylor College of Medicine, Baylor, Uganda, (6) Joint Clinical Research Centre, Mbarara, Uganda, (7) Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa, (8) Department of Paediatrics and Children Health, King Edward VIII Hospital, University of KwaZulu-Natal, Durban, South Africa, (9) Family Center for Research with Ubuntu, Department of Paediatrics & Child Health, Stellenbosch University, Tygerberg, South Africa, (10) Makerere University-Johns Hopkins University (MU-JHU) Research Collaboration, Kampala, Uganda, (11) PHPT/IRD Research Unit, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand, (12) Prapokklao Hospital, Chantaburi, Thailand, (13) Khon Kaen Hospital, Khon Kaen, Thailand, (14) Africa Health Research Institute (AHRI), Kwazulu-Natal, South Africa, (15) INSERM/ANRS SC10-US19, Essais thérapeutiques et maladies Infectieuses, Villejuif, France, (16) Department of Paediatric Infectious Diseases, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom, (17) First Department of Medicine, Division of Infectious Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, (18) Pediatric Infectious Diseases Unit, Hospital 12 de Octubre, Madrid, Spain, (19) University of Padova, Department of Women and Child Health, Padova, Italy

BACKGROUND: ODYSSEY demonstrated superiority of dolutegravir (DTG) based ART versus standard-of-care (SOC) in children '¥14kg starting first- and second-line. We describe virological and drug resistance outcomes by 96 weeks.
METHODS: Virological failure (VF) was defined as confirmed viral load (VL)'¥400c/mL after week 36 or lack of virological response by week 24 with ART switch. Participants with VF were retrospectively tested for post-failure resistance; the corresponding baseline sample was sequenced if '¥1 major IAS mutation was identified.
RESULTS: 311 children started first-line ART (154 DTG, 157 SOC [92% efavirenz]) and 396 started second-line (196 DTG, 200 SOC [72% lopinavir/r, 25% atazanavir/r]). On first-line, 11(7%) DTG vs. 30(19%) SOC experienced VF by 96 weeks, and on second-line, 31(16%) DTG vs. 40(20%) SOC.
First line ART: No participants on DTG had a major IAS drug resistance mutation post-failure. In SOC 18(62%) participants had at least one NRTI, 27(93%) NNRTI and none had PI mutations (Table). Of 13 with resistance post-failure and a baseline resistance test, all developed at least one new NRTI mutation and 18(95%) developed new NNRTI resistance.
Second line ART: Similar proportions in both arms had at least one major mutation post-failure (DTG 22(79%), SOC 35(90%)). In the DTG arm, 4 developed INSTI resistance (3/4 were on twice-daily zidovudine/lamivudine) and 1 had a new PI resistance mutation, not identified at baseline. In SOC, 3 participants developed new NNRTI resistance and 1 new PI resistance (Table).

Table: Genotypic resistance in the ODYSSEY trial

First-line ARTSecond-line ART

DTGSOC
DTGSOC
Participants with resistance post-failure ƪ
NRTI
NNRTI
PI
INSTI*		0/11 (0%)
0/11 (0%)
0/11 (0%)
0/10 (0%)
18/29 (62%)
27/29 (93%)
0/29 (0%)
--- 		p<0.001
p<0.001
---
---		20/28 (71%)
21/28 (75%)
2/28 (7%)
4/22 (18%)		28/39 (72%)
35/39 (90%)
2/39 (5%)
---
p=0.97
p=0.18
p=1.00
---
Participants with emergent resistance, of those with resistance post-failure ƪƪ
NRTI
NNRTI
PI
INSTI*		---
---
---
---		13/13 (100%)
18/19 (95%)
---
---		---
---
---
---		0/16 (0%)
0/18 (0%)
1/2 (50%)
4/4 (100%)		3/23 (13%)
3/26 (12%)
1/1 (100%)
---		p=0.26
p=0.26
p=1.00
---
ƪPost-failure resistance up to week 96, using the latest sample with VL'¥1000c/mL after failure and prior to treatment change. Major IAS drug resistance mutations defined according to 2019 update of the IAS drug resistance mutations. Percentage with resistance post-failure, of those with virological failure by week 96 and post-failure resistance test available for drug-class (integrase gene not sequenced for SOC arm).
ƪƪPercentage with emergent resistance (at least one new IAS mutation detected post-failure compared to baseline sample), of those with resistance post-failure and baseline resistance test available for drug-class.
*4 participants with emergent INSTI resistance: 2 Q148R/K, 1 G118R, 1 G118R+R263K,

CONCLUSIONS: ODYSSEY demonstrated that DTG has a high genetic resistance barrier and prevents emergent resistance to NRTIs in children. We identified no post-failure resistance to any drug class among children initiating first-line DTG, significantly less than first-line SOC. Among those on second-line DTG, there was no new NRTI resistance, however 4 children developed new INSTI resistance, highlighting the need for ongoing adherence support among children starting second-line ART.