Dolutegravir in the long term in children and adolescents: frequent virological failure but rare acquired genotypic resistance

Abstract

Objectives Although widely recommended, data about dolutegravir efficacy in HIV‐1‐infected children/adolescents are scarce, limited to short‐term follow‐up and mainly extrapolated from studies in adults with good adherence to treatment. This study aimed to provide long‐term data about the risk of virological failure (VF) and acquired genotypic resistance in children and adolescents receiving dolutegravir. Methods This retrospective monocentric study included 134 paediatric patients who received a dolutegravir‐based regimen for ≥ 12 months in 2014–2020. Virological failure was defined as not achieving a plasma viral load (pVL) < 50 copies/mL within 3 months of dolutegravir initiation or as experiencing virological rebound ≥ 50 copies/mL. Results Most of the subjects were antiretroviral therapy‐experienced (90.3%), naïve from integrase inhibitors (90.3%) and displayed virological suppression at baseline (63.4%). Their median (interquartile range, IQR) age was 12.0 (8.0–15.8) years. Genotypic susceptibility score of the new regimen was ≥ 2 in 96% of cases. Median (IQR) follow‐up was 34 (22–50) months. Virological failure occurred in 43 people (32.1%), more frequently where the baseline pVL was ≥ 50 copies/mL (67.4% vs. 22.0%, P < 0.01). M184V/I mutations in the reverse transcriptase gene were newly detected in three people with VF. Resistance to dolutegravir (mutations G118R and E138A in the integrase gene) emerged in one adolescent (0.7% of subjects, 2.3% of those with VF). Conclusions Whereas VF is relatively common on dolutegravir in the paediatric population, regimens associating dolutegravir with more than one fully active drug were associated with a low rate of emergent drug resistance. This result strengthens the recommendation of dolutegravir as part of preferred combinations in children/adolescents.

Bictegravir/emtricitabine/tenofovir alafenamide in paediatrics: Real‐life experience from a French cohort (2019–2023)

“…Furthermore, the fact that subjects with VF had longer duration of follow‐up than those with sustained viral suppression (43 vs. 36 months, P = 0.047) suggests that, in paediatrics, the longer the patient's follow‐up, the higher the risk of observing virological rebound. We observed a higher risk of VF in subjects initiating BIC/FTC/TAF with pVL >50 copies/mL on ART than in those with suppressed baseline viraemia, as previously evidenced in children/adolescents initiating dolutegravir‐based ART [14]. This result suggests that, at least in some children/adolescents, major adherence issues persist after switching ART and these cannot be definitely counterbalanced by the good efficacy and tolerance profile of BIC/FTC/TAF.…”

“…In our cohort, much higher rates of VF were observed (38% of subjects, 26% of those with viral suppression at baseline). Similar rates of VF were observed in children and adolescents receiving a dolutegravir-based combination in previous real-life cohorts [13,14], illustrating that maintaining high adherence to treatment in the long term remains challenging in paediatrics. Furthermore, the fact that subjects with VF had longer duration of follow-up than those with sustained viral suppression (43 vs. 36 months, P = 0.047) suggests that, in paediatrics, the longer the patient's follow-up, the higher the risk of observing virological rebound.…”

Treatment Emergent Dolutegravir Resistance Mutations in Individuals Naïve to HIV-1 Integrase Inhibitors: A Rapid Scoping Review

“…Following the review of their titles and abstracts, 232 publications were submitted for full-text review. Following full-text review, 36 publications were found to have reports of INSTI-naïve PLWH who developed one or more INSTI-associated DRMs while receiving DTG [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ], and 21 publications contained in vitro susceptibility results performed using the PhenoSense assay [ 32 , 33 , 35 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , ...…”

Virologic Outcomes and ARV Switch Profiles 2 Years After National Rollout of Dolutegravir to Children Less Than 15 Years in Southern Mozambique

“…13,27 Although drug resistance testing and robust adherence measures were beyond our evaluation scope, poor adherence, with the possibility of some INSTI resistance, was the likely driver of treatment failure. 28,29 There has been concern that NRTI resistance associated with prior failing ART regimens may result in functional monotherapy with DTG in ART-experienced, virally unsuppressed individuals who switch to DTG and maintain the NRTI backbone of the failing regimen, potentially resulting in DTG failure and development of INSTI resistance. 30,31 However, meaningful differences in VLS between children who maintained or switched NRTI backbones at the time of the DTG switch were not observed in our study.…”