INTRODUCTION

Achieving good adherence to treatment and viral suppression in the long term remains challenging in paediatric and young adult patients living with HIV. Overall, virological failure (VF) rates in this group are more than double those in adults, even in high-resource countries [1, 2], leading to a high risk of acquired genotypic resistance in paediatric patients [3].

Dolutegravir is a powerful, easy-to-take, well-tolerated integrase inhibitor (INI), which has been placed as preferred choice for paediatric and adolescent antiretroviral therapy (ART) worldwide [4]. However, data on the efficacy of dolutegravir in these populations remain scarce, often limited by short-term follow-up [5-10], and have mainly been extrapolated from adult trials in which the majority of participants were ≥ 30 years of age and had a high level of treatment adherence [11-13]. Thus, we aimed to provide data on the long-term follow-up and the emergence of resistance to dolutegravir in the paediatric population, which is of particular interest in settings where antiretroviral options are limited.

METHODS

This retrospective, non-interventional study included all HIV-1-infected patients who were followed in the French paediatric Necker hospital and received a dolutegravir-based regimen during at least 12 months between January 2014 and November 2020. Dolutegravir dosing was 25 mg for weight < 30 kg and 50 mg thereafter.

This research was conducted in accordance with the Declaration of Helsinki and national and institutional standards. Parents/guardians provided informed consent for the anonymous use of their children's clinical and biological data for biomedical research (as well as adolescents aged >18 years old at the time of the study). This study was reviewed and approved by the Necker Hospital Institutional Review Board (registration number in the APHP registry: 20201127163505).

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. Follow-up was censored at the time of death, discontinuing medical care in our centre, switching to a dolutegravir-free regimen or at November 2020.

All genotypic resistance tests performed since birth were analysed. Resistance to nucleoside reverse transcriptase inhibitor (NRTI), non-NRTI (NNRTI), protease inhibitor (PI) and INI was defined according to the 2019 ANRS HIV-1 genotypic resistance interpretation algorithm v.30 (www.hivfrenchresistance.org). We estimated genotypic susceptibility score (GSS) from the list of isolated resistance-associated mutations (RAMs), as previously described [14]. In INI-naïve patients with failure to amplify the integrase gene, the virus was considered fully susceptible to dolutegravir.

Chi-squared tests or Fisher's exact tests were used to compare discrete variables, and the Wilcoxon rank-sum test was used to compare continuous variables between patients with suppressed viraemia and patients with VF on dolutegravir. SAS statistical software (v.9.4; SAS Institute, Cary, NC, USA) was used for analyses.

RESULTS

Overall, 134 patients were included at a median (interquartile range, IQR) age of 12.0 (8.0–15.8) years. Their characteristics are shown in Table 1. Most of them were ART-experienced (90.3%) but INI-naïve (90.3%). Among patients with one or more genotypic resistance test performed since birth (85.1%), most of them (64.0%) had a history of RAMs in the reverse transcriptase gene, mainly M184V/I mutations (36.8%), thymidine analogue mutations (14.0%) and/or mutations associated with resistance to nevirapine and/or efavirenz (31.6%) (Table S1). At baseline, 85 subjects displayed virological suppression on ART (63.4% of all patients, 70.2% of those receiving ART).

During a median (IQR) follow-up since dolutegravir initiation of 34 (22–50) months, 43/134 (32.1%) subjects experienced VF: 7/13 (53.8%) in patients receiving first-line ART, and 36/121 (29.8%) in those with ART-exposure prior to dolutegravir initiation. Virological failure consisted of one to three episodes of pVL > 50 copies/mL on dolutegravir, with a median (IQR) cumulative duration of viraemia of 11 (6–25) months and a median (IQR) pVL zenith of 3.8 (2.7–4.9) log₁₀copies/mL. The pVL zenith was ≥ 400 copies/mL and ≥ 1000 copies/mL in 31/43 (72.1%) and 26/43 (60.5%) subjects with VF, respectively. Virological failure occurred more frequently in patients with baseline pVL ≥ 50 copies/mL than in those with suppressed viraemia at dolutegravir initiation (67.4% vs 22.0%, P < 0.01). The risk of VF was not associated with the GSS of the antiretroviral regimen (P = 0.38). With reinforced measures to improve adherence (multifaceted approaches adapted to each subject/family: education of the subject and family about the critical role of adherence, identification and treatment of depression or other mental health issues in the child/adolescent and the caregivers, increased frequency of visits/contacts, medication diaries, home-based nursing intervention, peer support group therapy for adolescents), 16/43 subjects with VF (37.2%) reached pVL < 50 copies/mL again (without ART change) at the last visit.

During VF, M184V/I mutations in the reverse transcriptase gene were newly detected in three patients (7.0% of subjects with VF; 13.6% of those without history of M184V/I mutations prior to dolutegravir initiation). Two of them resuppressed viraemia at their last visit while maintaining the same regimen (Table 2). Acquisition of RAMs in the integrase gene was observed in one adolescent (0.7% of subjects, 2.3% of those experiencing VF): the mutations T66A, L74 M, G118R and E138A were observed 35 months after the VF began.

DISCUSSION

To the best of our knowledge, this is the largest published study on the efficacy of dolutegravir in the paediatric population and, more importantly, the report with the longest follow-up. This is of special interest because dolutegravir is recommended worldwide as part of preferred regimens in children and adolescents [4], but data about its efficacy are mainly extrapolated from adult studies where subjects have high adherence to treatment. Thus, providing data about its long-term efficacy and evaluating the risk of acquired drug resistance in paediatrics are of special importance, especially in settings with limited access to regular virological monitoring and with limited antiretroviral options in the case of acquired drug resistance.

Previous studies/cohorts described rates of VF on dolutegravir varying from 16% to 65% in children/adolescents [5-10]. Some factors may explain these differences, e.g. the age of the subjects. Indeed, if the risk of non-optimal virological control on ART is higher in patients infected perinatally than in those infected during adulthood with similar duration of treatment, the highest proportion of VF concerns perinatally infected adolescents and young adults (13–24 years) [2]. This may help to explain why the adolescents enrolled in the IMPAACT P1093 study (median age = 15 years) had higher risk of VF than observed in our study (65% vs. 32%, respectively [7]). The duration of follow-up may also explain the difference. Indeed, because adherence issues are varying among time during childhood and adolescence, the longer the patient's follow-up, the greater the risk of observing virological rebound. This could have explained the better efficacy profile described in some studies with shorter follow-up (≤ 12 months) than ours [10]. The virological status at baseline is another possible explanation. Indeed, we observed a higher risk of VF in subjects initiating dolutegravir with pVL > 50 copies/mL (mostly on ART) than in those with suppressed baseline viraemia, as previously described [6-10]. This result and the fact that VF was not associated with the GSS of the newly introduced regimen suggest 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 dolutegravir-based combinations. However, as previously reported [5, 6, 8], reinforced measures to sustain adherence can be efficient to improve virological control; at their last visit, one-third of our patients with VF controlled their viraemia again without changing ART.

Pharmacokinetics sub-studies of the randomized ODYSSEY trial recently suggested that adult dolutegravir 50 mg film-coated tablets given once daily provide appropriate pharmacokinetic profiles in children weighing ≥ 20 kg [15]. In our retrospective study, where subjects initiated dolutegravir before the revision of dolutegravir paediatric dosing guidelines, low dolutegravir plasma levels may have contributed to VF in some patients weighing 20–30 kg (and receiving 25 mg dolutegravir once daily).

Among patients without known history of M184V/I mutation, 13.6% of those experiencing VF acquired M184V/I mutations. However, such an event did not hamper the efficacy of the ART regimen; thanks to intervention to improve treatment adherence, two-thirds of adolescents with newly detected M184V/I mutations reached pVL < 50 copies/mL at their last visit without ART change. This finding is consistent with the results of the DAWNING trial, showing that the presence of a M184V/I mutation in adults failing a first-line NNRTI-based regimen does not hamper the efficacy of a regimen combining dolutegravir plus two NRTIs, even when lamivudine or emtricitabine was used [16,17].

Evaluating the risk of emergent INI resistance is of special importance in children and adolescents, who require life-long ART and have limited antiretroviral options in many settings. A recent review of dolutegravir resistance studies (mostly performed in adults) found that 0.7% of ART-experienced, INI-naïve people with one or more fully active dolutegravir's companion drugs, experienced VF and emergent INI resistance [18]. A similarly low rate of acquired dolutegravir resistance (0.7% of subjects, 2.3% of those experiencing VF) was observed in our paediatric cohort, despite a higher rate of VF than in most adult trials/studies and a long cumulative duration of viraemia on dolutegravir in children/adolescents with VF (median 11 months). However, this low risk of acquired INI resistance in children/adolescents could be significantly higher in the case of impaired efficacy of the background drugs associated with dolutegravir. Indeed, the risk of VF plus INI resistance has been shown to be higher in adults with active viral replication while receiving functional dolutegravir monotherapy [18]. Thus, in children/adolescents failing an NNRTI- or PI-containing regimen, switch to dolutegravir-based ART should be discussed early, before accumulation of RAMs against future dolutegravir's companion drugs. This rule is of special importance in low- and middle-income countries with limited access to both genotypic resistance testing and antiretroviral options.

CONCLUSIONS

Whereas VF is relatively common in the paediatric population on dolutegravir, regimens associating dolutegravir with one or more fully active companion drug(s) were associated with overall low rates of emergent drug resistance during ‘real-world’ use. This result strengthens the worldwide recommendation of dolutegravir as part of the preferred combinations in children/adolescents and the need for sustained adherence support in the paediatric population.

CONFLICT OF INTEREST

Conflict of interest: PF received research grants (to his institution) from the French National Agency for AIDS Research (ANRS) and honoraria and travel grants from ViiV Healthcare, Bristol-Myers Squibb, Janssen Cilag, Gilead Sciences and MSD France for participation in advisory boards, educational programmes and conferences. VA-F received grants (to her institution) from the ANRS and the MSD AVENIR foundation, and honoraria and travel grants from ViiV Healthcare, Gilead Sciences and Janssen Cilag for participation in educational programmes and conferences. Other authors: none to declare.

AUTHOR CONTRIBUTIONS

PF conceived the study and drafted the manuscript; SB, VA-F and FV provided contribution to the analysis of the data and the revision of the manuscript. All authors approved the final version and agreed to be accountable for all aspects of the work.