High-dose vitamin D3 during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial

Abstract

Background Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolites induce antimycobacterial immunity in vitro. Clinical trials investigating the effect of adjunctive vitamin D on sputum culture conversion are lacking. Methods We conducted a multi-centre randomised controlled trial of adjunctive vitamin D in adults with sputum smear-positive pulmonary tuberculosis in London, UK. 146 participants were allocated to receive 2.5 mg vitamin D3 or placebo at baseline and at 2, 4 and 6 weeks after starting standard tuberculosis treatment. The primary endpoint of the trial was time from initiation of antimicrobial therapy to sputum culture conversion. Participants were genotyped for TaqI and FokI polymorphisms of the vitamin D receptor (VDR), and interaction analyses were conducted to determine the influence of VDR genotype on response to vitamin D. This trial is registered with ClinicalTrials.gov (NCT00419068). Findings 126 participants were included in the primary efficacy analysis (62 allocated to intervention, 64 allocated to placebo). Median time to sputum culture conversion was 36.0 days in the intervention arm and 43.5 days in the placebo arm (adjusted HR 1.39; 95% CI 0.90-2.16, P=0.14). TaqI genotype modified the effect of vitamin D supplementation on time to sputum culture conversion (Pinteraction=0.03), with enhanced response seen only in participants with the tt genotype (HR 8.09, 95% CI 1.36-48.01, P=0.02). FokI genotype did not modify the effect of vitamin D supplementation (Pinteraction=0.85). Mean serum 25-hydroxyvitamin D at 8 weeks was 101.4 nmol/L vs. 22.8 nmol/L in intervention vs. placebo arms (95% CI for difference 68.6-88.2 nmol/L, P<0.001). Interpretation Administration of four doses of 2.5 mg vitamin D3 elevated serum 25-hydroxyvitamin D concentrations in patients receiving intensive phase treatment for pulmonary tuberculosis and reduced time to sputum culture conversion in participants with the tt genotype of the TaqI VDR polymorphism.