Effect of dolutegravir on folate and vitamin B12 status among HIV-infected children and adolescents in the ODYSSEY trial

Title

Effect of dolutegravir on folate and vitamin B12 status among HIV-infected children and adolescents in the ODYSSEY trial

Presenter

Linda Barlow-Mosha

Authors

L. Barlow-Mosha * (1), G. Ahimbisibwe (1), E. Chappell (2), P.M. Amuge (3), A. Nanduudu (4), E. Kaudha (4), T. Amukele (5), D. Balamusani (6), B. Kafufu (6), A. Nimwesiga (6), C. Kityo (4), A.R Kekitiinwa (3), R. Namwanje (1), G. Kasangaki (1), A. Mulindwa (4), G.A. Muzorah (3), D. Bbuye (3), M. Nolan (1), C. Giaquinto (7), D.M Gibb (2), D. Ford (2), P. Musoke (1,8), A. Turkova (2), The ODYSSEY Trial Team.

Institutions

(1) Makerere University-Johns Hopkins University (MU-JHU) Research Collaboration, Kampala, Uganda, (2) MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London, United Kingdom, (3) Baylor College of Medicine Children's Foundation-Uganda, Kampala, Uganda, (4) Joint Clinical Research Centre, Kampala, Uganda, (5) Johns Hopkins University, Department of Pathology, Baltimore, United States, (6) Infectious Diseases Institute Core Laboratory, Kampala, Uganda, (7) University of Padova, Department of Women and Child Health, Padova, Italy, (8) Makerere University College of Health Sciences, Department of Paediatrics and Child Health, Kampala, Uganda

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).

Table. Difference in change in plasma folate from baseline to week 4, and cross-sectional red blood cell folate and serum vitamin B12 at '¥96 weeks in DTG-arm compared to SOC-arm
Measure DTG arm SOC arm Adjusted difference
(DTG-SOC)* Arm x site interaction**
n mean SE n mean SE mean 95% CI p p
Change in plasma folate from baseline to week 4, ng/ml 110 0.4 0.3 107 -1.1 0.3 1.6 0.8, 2.3 <0.01 0.66
RBC folate at week '¥96, ng/ml 109 822 29 105 808 28 73 3.0, 143 0.04 0.82
Vitamin B12 at week '¥96, pg/ml 109 478 21 105 504 26 -26 -91, 39 0.42 0.57
*Adjusted for site, date of sample, first- vs. second-line, availability of routine resistance testing, NRTI backbone, and baseline value (for change in plasma folate only); **Test for heterogeneity of treatment effect by site.
Presenting mean change in plasma folate from a baseline of 6.1 ng/ml.

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.

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Table. Difference in change in plasma folate from baseline to week 4, and cross-sectional red blood cell folate and serum vitamin B12 at '¥96 weeks in DTG-arm compared to SOC-arm
Measure	DTG arm			SOC arm			Adjusted difference (DTG-SOC)*			Arm x site interaction**
Measure	n	mean	SE	n	mean	SE	mean	95% CI	p	p
Change in plasma folate from baseline to week 4, ng/ml	110	0.4	0.3	107	-1.1	0.3	1.6	0.8, 2.3	<0.01	0.66
RBC folate at week '¥96, ng/ml	109	822	29	105	808	28	73	3.0, 143	0.04	0.82
Vitamin B12 at week '¥96, pg/ml	109	478	21	105	504	26	-26	-91, 39	0.42	0.57
Adjusted for site, date of sample, first- vs. second-line, availability of routine resistance testing, NRTI backbone, and baseline value (for change in plasma folate only); *Test for heterogeneity of treatment effect by site. Presenting mean change in plasma folate from a baseline of 6.1 ng/ml.