Effectiveness and safety of dolutegravir and raltegravir for treating children and adolescents living with HIV: a systematic review

Abstract

Introduction: Globally about 1.7 million children were living with HIV in 2020. Two integrase strand transfer inhibitors, dolutegravir and raltegravir, are increasingly used in children. We conducted a systematic review to assess the effectiveness and safety of dolutegravir and raltegravir in children and adolescents living with HIV, aged 0-19 years.

Methods: Sources included MEDLINE, Embase, the Cochrane Library, clinical trial registries, abstracts from key conferences and reference list searching. Observational studies and clinical trials published January 2009-March 2021 were eligible. Outcomes included efficacy/effectiveness (CD4 counts and viral load) and/or safety outcomes (mortality, grade 3/4 adverse events and treatment discontinuation) through 6 months or more post-treatment initiation. Risk of bias was assessed using previously published tools appropriate for the study design. Narrative syntheses were conducted.

Results and discussion: In total, 3626 abstracts and 371 papers were screened. Eleven studies, including 2330 children/adolescents, reported data on dolutegravir: one randomized controlled trial (RCT; low risk of bias), one single-arm trial (unclear risk of bias) and nine cohort studies (three low risk of bias, two unclear risk and four high risk). Ten studies, including 649 children/adolescents receiving raltegravir, were identified: one RCT (low risk of bias), one single-arm trial (low risk of bias) and eight cohort studies (four low risk of bias, three unclear risk and one high risk). Viral suppression levels in children/adolescents at 12 months were high (>70%) in most studies assessing dolutegravir (mostly second- or subsequent-line, or mixed treatment lines), and varied from 42% (5/12) to 83% (44/53) at 12 months in studies assessing raltegravir (mostly second- or subsequent-line). Across all studies assessing dolutegravir or raltegravir, grade 3/4 adverse events (clinical and/or laboratory) were reported in 0-50% of subjects, few resulted in discontinuation, few were drug related and no deaths were attributed to either drug.

Conclusions: These reassuring findings suggest that dolutegravir and raltegravir are effective and safe as preferred regimens in children and adolescents living with HIV. With the rollout of dolutegravir in paediatric populations already underway, it is critical that data are collected on safety and effectiveness in infants, children and adolescents, including on longer-term outcomes, such as weight and metabolic changes.

Keywords: HIV; children; drug-related side effects and adverse reactions; integrase inhibitors; systematic review; treatment outcome.

Figure 1

PRISMA flow diagram illustrating the number of included and excluded studies at each stage of the review. Note: The search strategies included terms for darunavir, lopinavir and tenofovir alafenamide (as well as dolutegravir and raltegravir); however, during full paper review, studies were categorized by the treatment of interest and only studies assessing dolutegravir and raltegravir are included here. ^* Of the 220 publications excluded because they assessed an intervention other than dolutegravir or raltegravir, two articles reported data on tenofovir alafenamide and 32 reported data on darunavir or lopinavir (solid formulations). † Of the 14 publications excluded because they assessed an intervention other than dolutegravir or raltegravir, six articles reported data on darunavir or lopinavir (solid formulations).

Figure 2

Summary of risk of bias assessment stratified by study design and treatment: (a) randomized controlled trials, (b) single‐arm trials and (c) observational studies. Green shading indicates low risk of bias, yellow shading indicates unclear risk, orange shading indicates high risk and grey indicates that the question was not applicable for that study. Note: For the assessment of single‐arm trials, none of the interventions were at group level, so Question 12 of the risk of bias tool was not applicable for all studies and is not presented here. List of assessment questions is provided in Table 2. Abbreviations: D, domain; Qu, question.

Figure 3

Proportion of infants, children and adolescents achieving viral suppression of <50 copies/ml (open symbols), or <400 copies/ml, <1000 copies/ml or viral suppression at an unspecified threshold if <50 copies/ml was not reported (shaded symbols) after treatment with (a) dolutegravir or (b) raltegravir over time. Results are stratified by age (colour of symbol), line of therapy (shape of symbol) and study size (size of symbol). Connecting lines link data follow‐up points from the same study population. Data from an individual study may be presented at more than one timepoint; however, at a given timepoint, data from a group of subjects are only presented once (overall data were prioritized over sub‐group data). For randomized controlled trials and single‐arm studies, the timepoint represents the duration of follow‐up; for observational studies, the timepoint represents the median follow‐up time of the study. A table showing the viral load data used to create the scatterplot is included in File S2 (Table S2).

Figure 4

Proportion of subjects exposed to dolutegravir or raltegravir with reported safety outcomes, ordered by study, sub‐population (age or weight group) and timepoint (median follow‐up time for observational studies and ODYSSEY pharmacokinetic sub‐study; duration of follow‐up for other studies). Multiple rows for the same study correspond to different sub‐populations and/or timepoints (further details are provided in File S2, Table S6); subjects or events may, therefore, appear in more than one row. Numbers in coloured cells correspond to the number of subjects who experienced events. Where data are reported for grade 3/4 clinical adverse events and for grade 3/4 laboratory adverse events but not for all grade 3/4 adverse events, this is because overlap between clinical and laboratory events was unclear or not reported. ^* Subjects in the ODYSSEY pharmacokinetic sub‐study were also included in the main trial; results are presented for the sub‐study where additional outcomes were reported to those presented for the main trial; † follow‐up duration was “up to 43 weeks”; ‡ all children were on raltegravir, ritonavir‐boosted darunavir and etravirine; ǁ 13 of the 16 children were on raltegravir, 10 of whom also received darunavir. Abbreviations: 1, first‐line; 2+, second‐ or subsequent‐line; A, adolescents; AE, adverse event; C, children; CHIPS, Collaborative HIV Paediatric Study (United Kingdom and Ireland); CoRISPe, Cohort of the Spanish Paediatric HIV Network; discont., discontinuation; DRV, darunavir; DTG, dolutegravir; Gr 3/4 AE, grade 3 or 4 adverse event; I, infants; IeDEA, International epidemiology Databases to Evaluate AIDS; IMPAACT, International Maternal Pediatric Adolescent AIDS Clinical Trials; mix, mixed or unspecified line of treatment; PK, pharmacokinetics; RAL, raltegravir arm; SoC, standard of care arm.