Authors: C. Kityo, E. White, A. Turkova, H.A Mujuru, I. Nankya, B. Wynne, S. Ali, A. Kekitiinwa, A. Lugemwa, E. Kaudha, A. Liberty, H. Cassim, M. Archary, M. Cotton, L. Barlow-Mosha, T.R Cressey, C. Ngampiyasakul, U. Srirompotong, O. Behuhuma, Y. Saidi, A. Bamford, R. Kobbe, P. Rojo, C. Giaquinto, D. Gibb, D. Ford
Published in: IAS 2021
Abstract
Background: ODYSSEY demonstrated superiority of dolutegravir (DTG) based ART versus standard-of-care (SOC) in children ≥14kg starting first- or second-line. We evaluate drug resistance by 96 weeks.
Methods: Virological failure (VF) was defined as confirmed viral load (VL)≥400c/mL after week 36 or lack of virological response at week 24 with ART switch. Children with VF were tested for post-failure resistance (major IAS mutation); if resistance was identified, a baseline sample was sequenced. The proportion with emergent resistance post-failure was estimated in those exposed to each drug class in ODYSSEY.
Results: 311 children started first-line ART (154 DTG,157 SOC[92% efavirenz]) and 396 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: no new DTG or NRTI resistance on first-line DTG versus estimated 62% and 88% children with new NRTI and NNRTI resistance respectively among failures in SOC (Table). Second-line: no new resistance to NRTIs on DTG vs estimated 9% among failures in SOC. One child (estimated 3%) with VF on PIs had new PI resistance and two children (100%on NNRTIs had new NNRTI resistance. 4(18%) with VF on DTG had INSTI mutations.
Conclusion: ODYSSEY demonstrated that DTG has a high genetic resistance barrier and prevents emergent resistance to NRTIs in children. We identified no post-failure resistance on first-line DTG, significantly less than first-line SOC. 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.
Table: Genotypic resistance in the ODYSSEY trial
| First-line | Second-line | |||||||||
| DTG | SOC | DTG vs. SOC | DTG | SOC | DTG vs. SOC | |||||
Children with resistance post-failureƪ
| ||||||||||
| NRTI | 0/11 | 0% | 18/29 | 62% | p<0.001 | 20/28 | 71% | 28/39 | 72% | P=0.97 |
| NNRTI | 0/11 | 0% | 27/29 | 93% | p<0.001 | 21/28 | 75% | 35/39 | 90% | p=0.18 |
| PI | 0/11 | 0% | 0/29 | 0% | 2/28 | 7% | 2/39 | 5% | p=1.00 | |
| INSTI | 0/10 | 0% | – | – | 4/22 | 18% | – | – | ||
Children and estimated proportion with emergent resistance post-failure~
| ||||||||||
| NRTI | 0 | 0% | 13 | 62% | 0 | 0% | 3 | 9% | ||
| NNRTI | – | – | 18 | 88% | – | – | 2 | 100% | ||
| PI | – | – | – | – | – | – | 1 | 3% | ||
| INSTI | 0 | 0% | – | – | 4 | 18% | – | – | ||
ƪPost-failure resistance up to week 96, using the latest sample with VL≥1000c/mL after VF and prior to ART switch. % with resistance post-failure, of those with post-failure resistance test available ~Among those with VF and exposed to drug-class, estimated assuming same proportion of new resistance in those with and without available baseline test | ||||||||||