Effect of transitioning virally suppressed children and adolescents with HIV to dolutegravir-based antiretroviral therapy: emulated target trials in a large cohort in South Africa

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Abstract Background Global HIV programmes are transitioning virally suppressed children and adolescents with HIV (CAWH) from prior regimens to dolutegravir-based antiretroviral therapy (ART). However, the supporting evidence largely stems from randomised trials in viraemic CAWH. The effect of transition for virally suppressed CAWH is unknown. Methods We used observational, de-identified data from 724 clinics in KwaZulu-Natal, South Africa. We sequentially emulated three distinct target trials to estimate the effect of transitioning to dolutegravir-based ART in three paediatric populations: i) ages 8-17 years taking efavirenz-based ART, ii) 8-17 years taking ritonavir-boosted lopinavir (LPV/r)-based ART, and iii) 0-7 years taking LPV/r-based ART, all with a last viral load <1,000 copies/mL. The risk difference (RD) of death or viraemia>1,000 copies/mL through 12 and 24 months was estimated using an inverse probability weighting approach. Findings From January 2020 to August 2024, 37,145 CAWH contributed 454,081 person-trials. In CAWH initially taking efavirenz, the standardised 12-month risk of death or viraemia was 11·9% with continued efavirenz and 6·7% with transition to dolutegravir (RD -5·2 [95% CI -5·8 to -4·6]). In older CAWH initially taking LPV/r, these risks were 17·8% and 9·5%, respectively (RD -8·3 [-10·0 to -6·8]). In younger children, the respective risks were 15·8% and 6·7% (RD -9·0% [-12·7 to -5·4]). Where available, 24-month endpoints showed slightly greater RDs. Interpretation This large-scale, causal analysis highlights improvements in viral suppression and strongly supports ongoing transition to dolutegravir-based ART for virally suppressed CAWH. Funding Gates Foundation, National Institute for Health and Care Research, Swiss National Science Foundation Research in context Evidence before this study We searched PubMed on 23 June 2026 for randomised controlled trials or trial emulations comparing dolutegravir (DTG)-based antiretroviral therapy (ART) with non-DTG-based ART among children and adolescents with HIV (CAWH). The search string is shown in Table S1. Two major trials, ODYSSEY and CHAPAS-4, compared DTG-based with non-DTG-based ART regimens among CAWH with viraemia (i.e. newly starting first-line ART or switching to second-line ART after treatment failure with a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen). Both trials showed better treatment outcomes with DTG-based ART, informing the ongoing programmatic rollout of DTG-based ART for CAWH. In practice, the majority of CAWH eligible for DTG will be virally suppressed on a non-DTG regimen, a group which was not included in ODYSSEY and CHAPAS-4. To date, there is a lack of empirical evidence demonstrating outcomes after paediatric transition to DTG in case of viral suppression. On the one hand, unnecessary ART modification may disrupt adherence; on the other hand, DTG-based ART may be favourable considering the complexity and unpalatability of some prior standard of care regimens. Therefore, there is a need to evaluate the causal effect of transitioning to DTG-based ART in case of viral suppression, specifically among CAWH as a priority group for improving treatment outcomes. Added value of this study Here, we compared treatment outcomes among three distinct paediatric groups in the South African HIV programme who became eligible to transition to DTG-based ART at different time points: older CAWH initially taking efavirenz (EFV)-based ART, older CAWH initially taking ritonavir-boosted lopinavir (LPV/r)-based ART, and young children initially taking LPV/r-based ART. To our knowledge, this study of 38,041 CAWH is the largest clinical cohort of CAWH receiving DTG and presents the first estimate on the effect of transitioning to DTG-based ART among CAWH with viral suppression. Across all groups, the standardised cumulative risk of death or viraemia was lowered by switching to ART containing DTG compared with remaining on the former standard of care, with risk differences (RDs) ranging from -5·2% to -9·0% at 12 months and increasing over follow-up time. Implications of all the available evidence We observed substantial improvements in treatment outcomes with transition to DTG. These findings strongly support the continued transition to DTG-based ART among virally suppressed CAWH.

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