Protecting the Promise of Dolutegravir for Children living with HIV

The scale-up of dolutegravir (DTG)-based antiretroviral therapy (ART) has transformed HIV programmes worldwide.In adults and children, DTG has delivered high rates of viral suppression and generally low levels of drug resistance compared with earlier non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens [1,2].Yet beneath this success lies a quieter risk: a small but important group of children in resource-limited settings (RLS) who face a combination of biological and structural vulnerabilities that could allow DTG resistance to emerge and spread if we are not vigilant. A Fragile Success: The Evidence on Paediatric DTG ResistanceThe evidence for DTG's efficacy in children is strong.The ODYSSEY trial showed that DTG-based ART was superior or non-inferior to standard-of-care regimens in first-and second-line settings, with virologic failure occurring less often [3,4].By week 96, only a small proportion of children in the DTG arm developed integrase strand transfer inhibitor (INSTI) resistance, even though virological failure occurred more often.Most children who failed DTG did so without resistance, highlighting the high genetic barrier to viral resistance.Other paediatric studies echo this pattern.In the IMPAACT P1093 study, which enrolled heavily treatment-experienced children and adolescents, DTG remained active for many participants despite complex resistance profiles, although INSTI resistance emerged in a subset with prolonged failure [5].National surveys using remnant viral load (VL) samples in Uganda similarly found low levels of DTG resistance among children failing first-line DTG-based ART, primarily developing in those with prior NNRTI exposure [6].While DTG has changed the practice of HIV medicine worldwide, it is neither magic nor infallible.Case reports provide a granular view of its use in practice, describing adolescents and infants who developed multiclass resistance including high-level DTG resistance in the context of high baseline viral load, existing NRTI resistance, and suboptimal drug exposure [7,8].These rare examples show that even drugs with high genetic barriers can be overcome when patient-level and system-level vulnerabilities converge.