In the REALITY trial, adults and children with CD4 <100 cells/mm3 were recruited mostly as outpatients (i.e. started off as high risk) but over half had a serious adverse event and 13% died in first 48 weeks after initiation of ART.8 In another trial, nearly a quarter of adults initially recruited as high risk ambulatory outpatients starting ART with low CD4 cell count were subsequently admitted to hospital within six months.28 It is therefore important to develop strategies that address both groups of patients with AHD and recognise that patients transition between groups. The gene discussed is CD4; the disease is mitochondrial DNA depletion syndrome 4a.