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.

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<0.001), and this difference persisted to week ≥96 (2.7 ng/ml, 95% CI 1.7, 3.7; p<0.001). Mean RBC folate at ≥96 weeks was also higher in the DTG arm (difference 73 ng/ml, 95% CI 3, 143; p = 0.041). There was no difference in the treatment arms for vitamin B12 levels at ≥96 weeks or change in MCV through trial follow-up. CONCLUSIONS: Plasma and RBC folate levels were higher in children and adolescents receiving dolutegravir-based ART than on other ART regimens. Further studies are needed to clarify the mechanisms of these interactions and the clinical implications of increased blood folate levels.

Adherence to antiretroviral therapy in HIV-positive adolescents in Uganda assessed by multiple methods: a prospective cohort study.

BACKGROUND: The effectiveness of traditional adherence measurements used in adolescent populations is difficult to assess. Antiretroviral (ARV) adherence research among adolescents living with HIV in resource-constrained countries is particularly challenging and little evidence is available. OBJECTIVES: The primary objective of this study was to determine the feasibility of a large-scale, long-term study using electronic adherence monitoring in Uganda. The secondary objective was to compare accuracy of pill count (PC) and self-report (SR) adherence with electronic medication vials (eCAPs™). METHODS: Adolescents receiving ARV therapy at the Joint Clinical Research Centre in Kampala, Uganda, were recruited. ARVs were dispensed in eCAPs™ for 1 year. Person-pill-days (PPDs) [1 day where adherence was measured for one medication in one patient] were calculated and a weighted paired t-test was used to compare the levels of adherence among subjects for three different adherence measurement methods. RESULTS: Fifteen patients were included: 40% were female, mean age was 14 years, mean baseline CD4+ cell count was 244 cells/µL, and average treatment duration was 9 months at study entry. Overall, 4721 PPDs were observed. Some eCAPs™ required replacement during the study resulting in some data loss. Consent rate was high (94%) but was slow due to age limit cut-points. Overall adherence for SR was 99%, PC was 97% and eCAP™ was 88% (p<0.05 for all comparisons). 93%, 67% and 23% of patients had an adherence of greater than 95% as measured by SR, PC and eCAP™ methods, respectively. CONCLUSIONS: A large-scale adherence study in Uganda would be feasible using a more robust electronic monitoring system. Adherence measurements produced by PCs and self-reporting methods appear to overestimate adherence measured electronically.