Virological failures and genotypic resistance in children and adolescents randomised to dolutegravir-based ART vs. standard-of-care in the ODYSSEY trial
Authors: E White, A Turkova, HA Mujuru, I Nankya, B Wynne, S Ali, A Kekitiinwa, A Lugemwa, E Kaudha, A Liberty, H Cassim, M Archary, M Cotton, L Barlow-Mosha, TR Cressey, C Ngampiyasakul, U Srirompotong, O Behuhuma, Y Saidi, A Bamford, R Kobbe, P Rojo, C Giaquinto, DM Gibb, D Ford on behalf of the ODYSSEY trial team
Published in: International Workshop on HIV pediatrics
Background: ODYSSEY, a multi-country randomised trial, demonstrated superior treatment efficacy for dolutegravir (DTG) plus two NRTIs versus standard-ofcare (SOC) in children ≥14kg (median age 12 years [range:3-18]) starting first- and second-line ART. 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 up to week 96, using the latest sample with VL≥1000c/mL after failure and prior to treatment change; 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]). NRTI backbones were ABC/3TC (80% first-line, 54% second-line), TDF/XTC (19%, 26%), ZDV/3TC (1%, 19%), and ABC/TDF (0%, 0.8%). On firstline, 11(7%) DTG vs. 30(19%) SOC experienced VF by 96 weeks, and on second-line, 31(16%) DTG vs. 40(20%) SOC. Samples were tested for all 112 failures: median time from VF to resistance test was 24[IQR:12-47] weeks. 47(42%) had post-failure resistance test at week 96, 60(54%) were tested earlier (16 due to treatment change, 44 no later sample available with VL≥1000c/mL or later sample failed to amplify); the remaining 5(4%) failed to amplify on all samples. On first-line, post-failure resistance tests were available as follows: reverse transcriptase (RT)/protease (PR) (11 DTG, 29 SOC), integrase (IN) (10 DTG); on second-line: RT/PR (28 DTG, 39 SOC), IN (22 DTG). First line ART: No participants on first-line DTG had a major IAS drug resistance mutation post-failure (0/11 NRTI/NNRTI/PI; 0/10 INSTI). On SOC, 18/29(62%) participants had NRTI resistance post-failure (DTG vs. SOC p<0.001), 27/29(93%) NNRTI resistance (p<0.001) and 0/29 PI resistance. Of 13 with NRTI resistance post-failure and a baseline resistance test, all developed at least one new NRTI mutation; 18/19(95%) developed new NNRTI resistance. Second line ART: 20/28(71%) DTG vs. 28/39(72%) SOC had at least one NRTI mutation post-failure; 21/28(75%) vs. 35/39(90%) had NNRTI resistance; and 2/28(7%) vs. 2/39(5%) had PI resistance. Among DTG vs. SOC participants with a major resistance mutation post-failure and baseline result, 0/16 DTG vs. 3/23 SOC (p=0.26) developed new NRTI resistance, 0/18 vs. 3/26 (p=0.26) new NNRTI resistance and 1/2 vs. 1/1 new PI resistance. On DTG, 4/22(18%) on second-line developed INSTI resistance (2 Q148R/K, 1 G118R, 1 G118R+R263K); 3/4 were on ZDV/3TC.
Conclusion: ODYSSEY demonstrated that DTG has a high genetic resistance barrier in children, preventing emergent resistance to NRTIs. We identified no postfailure resistance to any drug class amongst 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. These results support using DTG-containing regimens for children starting firstline or second-line ART, but ongoing adherence support is required for children on second-line.
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