Effect of dolutegravir on folate, vitamin B12 and mean corpuscular volume levels among children and adolescents with HIV: a sub‐study of the ODYSSEY randomized controlled trial

Abstract Introduction Dolutegravir‐based antiretroviral therapy (ART) is the preferred antiretroviral treatment for children and adolescents living with HIV. A large surveillance study in Botswana previously raised concerns about an association between pre‐conception dolutegravir and neural tube defects. Before these concerns were subsequently resolved, we set up a sub‐study to look at the effect of dolutegravir on levels of folate and vitamin B12 in children and adolescents within the randomized ODYSSEY trial, as folate and vitamin B12 are known to play a crucial role in neural tube development. Methods We conducted the sub‐study among Ugandan ODYSSEY participants and compared folate and vitamin B12 between children randomized to dolutegravir‐based ART (DTG) and non‐dolutegravir‐based standard‐of‐care treatment (SOC). Plasma folate was measured at enrolment and week 4 on stored samples; in addition, plasma and red blood cell (RBC) folate and vitamin B12 were assayed at week ≥96 in prospectively collected samples. RBC mean corpuscular volume (MCV) was measured 24‐weekly in all ODYSSEY participants. Samples analysed in the sub‐study were collected between September 2016 and October 2020. Results A total of 229 children aged ≥6 years were included in the sub‐study with median age at trial enrolment of 12.3 (interquartile range [IQR] 9.0, 14.7) years, and CD4 count of 501 (IQR 228, 695); 112 (49%) children were male. Most participants (225/229, 98%) had plasma folate results at enrolment and 214 (93%) children had results available for RBC folate, vitamin B12 and plasma folate at week ≥96. MCV results were analysed on 679 children aged ≥6 years enrolled in ODYSSEY. At week 4, mean plasma folate was significantly higher in the dolutegravir arm than in SOC (difference [DTG‐SOC] 1.6 ng/ml, 95% CI 0.8, 2.3; p