Efficacy of Vitamin D for the Prevention of Pulmonary Tuberculosis and Mortality in HIV: A Randomised, Double-Blind, Placebo-Controlled Trial

Background: Observational data suggests that low vitamin D status is associated with an increased incidence of pulmonary tuberculosis (TB) and mortality among people living with HIV; however, the efficacy of vitamin D supplementation remains unknown. Methods: We conducted a randomized, double-blind, placebo-controlled trial of vitamin D3 supplementation among 4,000 HIV-infected adults initiating antiretroviral therapy (ART) with low 25-hydroxyvitamin D (25(OH)D) levels in Dar es Salaam, Tanzania. The vitamin D group received weekly 50,000 IU vitamin D3 supplements for the first month of ART followed by daily 2,000 IU vitamin D3 supplements. The placebo arm received a matching weekly and daily placebo regimen. Findings: A total of 415 deaths were recorded and there was no overall effect of vitamin D3 supplementation on the risk of mortality (hazard ratio (HR): 1·04; 95% CI: 0·85-1·25; p=0·73). However, vitamin D3 supplementation appeared to reduce the risk of death by 41% (0-65%) among participants with baseline pulmonary TB and by 48% (95% CI: 11-69%) among those with WHO HIV Stage IV disease at the time of ART initiation. There was no effect on the overall incidence of pulmonary TB (HR: 0·78; 95% CI: 0·54-1·13; p=0·19), although vitamin D3 was found to reduce the incidence of sputum smear-positive pulmonary TB (HR: 0·54; 95% CI: 0·31-0·92; p=0·03). The vitamin D3 regimen increased serum 25(OH)D (p<0·001) and did not increase the risk of hypercalcemia (p=1·00) as compared to placebo. Interpretation: Vitamin D3 supplementation may improve survival for the subset HIV-infected adults initiating ART with pulmonary TB disease or advanced HIV disease and reduce the incidence of sputum smear positive pulmonary TB. Trial Registration: ClinicalTrials.gov, NCT01798680. Funding Statement: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Declaration of Interests: The authors stated: "None to declare." Ethics Approval Statement: The trial protocol was approved by the Harvard T. H. Chan School of Public Health Institutional Review Board, the Tanzanian National Health Research Ethics Sub Committee (NatHREC), and the Tanzania Food and Drug Authority (TFDA) and was overseen by an independent data and safety monitoring board.