02 Aug, 2022
Background: Neural tube defects (NTDs) are known to be associated with maternal folate and vitamin B12 deficiency, and initial surveillance studies suggested an increased risk of NTDs among infants conceived by women taking dolutegravir (DTG). We, therefore, compared folate and vitamin B12 levels among HIV-infected children aged 6-<18 years starting first- or second-line DTG-based antiretroviral treatment (ART) versus Standard of Care (SOC) at 3 Ugandan sites in the ODYSSEY trial.
Methods: Plasma folate was measured on stored samples at baseline and 4 weeks. Red blood cell (RBC) folate and vitamin B12 levels were measured using samples collected prospectively at ≥96 weeks. Samples were analysed in one laboratory using Elecys assays. Normal regression was used to compare change in plasma folate from baseline to 4 weeks (adjusted for baseline) and cross-sectional RBC folate and vitamin B12 between randomised arms, adjusting for site, sample date, first-/ second-line ART and randomisation stratification factors
Results: 229 children ≥6 years were randomised; 51% female, median(IQR) age was 12.3 years (9.0,14.7), CD4 501cells/mm3 (228,795); 67% started second-line ART; 114 started DTG, 115 started SOC (40% lopinavir/ritonavir-, 37% efavarinez-, 23% atazanavir/ritonavir-based ART). By 4 weeks, mean plasma folate was higher in DTG arm versus SOC (difference (DTG-SOC) 1.6 ng/mL; 95%CI 0.8, 2.3; p<0.01). At week ≥96, mean RBC folate was higher in the DTG arm vs SOC (difference 73 ng/mL; 95%CI 3, 143; p=0.04). Plasma and RBC folate levels varied by site, but there was no evidence for heterogeneity of treatment effects (Table). Vitamin B12 levels were similar between arms (p=0.42).
Conclusions: We found no evidence that DTG-based ART was associated with decreased levels of plasma folate or RBC folate; levels were higher than on NNRTI-/PI-based ART though the mechanism is unclear. Vitamin B12 levels were similar in both arms. These results suggest any increased risk of NTDs in infants conceived on DTG is unlikely to be due to DTG causing decreased folate and vitamin B12 levels.