Elsevier

The Lancet

Volume 377, Issue 9761, 15–21 January 2011, Pages 242-250
The Lancet

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

https://doi.org/10.1016/S0140-6736(10)61889-2Get rights and content

Summary

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 absent.

Methods

We undertook a multicentre randomised controlled trial of adjunctive vitamin D in adults with sputum smear-positive pulmonary tuberculosis in London, UK. 146 patients were allocated to receive 2·5 mg vitamin D3 or placebo at baseline and 14, 28, and 42 days after starting standard tuberculosis treatment. The primary endpoint was time from initiation of antimicrobial treatment to sputum culture conversion. Patients were genotyped for TaqI and FokI polymorphisms of the vitamin D receptor, and interaction analyses were done to assess the influence of the vitamin D receptor genotype on response to vitamin D3. This trial is registered with ClinicalTrials.gov number NCT00419068.

Findings

126 patients were included in the primary efficacy analysis (62 assigned to intervention, 64 assigned to placebo). Median time to sputum culture conversion was 36·0 days in the intervention group and 43·5 days in the placebo group (adjusted hazard ratio 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 patients with the tt genotype (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 concentration at 56 days was 101·4 nmol/L in the intervention group and 22·8 nmol/L in the placebo group (95% CI for difference 68·6–88·2; p<0·0001).

Interpretation

Administration of four doses of 2·5 mg vitamin D3 increased serum 25-hydroxyvitamin D concentrations in patients receiving intensive-phase treatment for pulmonary tuberculosis. Vitamin D did not significantly affect time to sputum culture conversion in the whole study population, but it did significantly hasten sputum culture conversion in participants with the tt genotype of the TaqI vitamin D receptor polymorphism.

Funding

British Lung Foundation.

Introduction

WHO estimates that there were 9·4 million cases of tuberculosis and 1·8 million deaths from the disease globally in 2008.1 Augmentation of immune responses to Mycobacterium tuberculosis could shorten the course of antimicrobial treatment in drug-sensitive tuberculosis or improve outcome in drug-resistant disease.2 Calcitriol, the active metabolite of vitamin D, induces antimycobacterial activity in vitro.3 This metabolite modulates the host response to mycobacterial infection by induction of reactive nitrogen and oxygen intermediates,4, 5 suppression of matrix metalloproteinase enzymes implicated in the pathogenesis of pulmonary cavitation,6 and induction of the antimicrobial peptide cathelicidin,7, 8 which induces autophagy.9 Calcitriol modulates immune responses by binding vitamin D receptors expressed by antigen-presenting cells and activated lymphocytes to regulate transcription of genes responsive to vitamin D. The human vitamin D receptor is polymorphic; carriage of the t allele of the TaqI vitamin D receptor polymorphism is associated with an increase in calcitriol-induced phagocytosis of Mycobacterium tuberculosis in vitro10 and more rapid sputum culture conversion in patients with pulmonary tuberculosis.11 By contrast, carriage of the f allele of the FokI vitamin D receptor polymorphism is associated with a reduction in transcriptional activity,12 reduction of calcitriol-induced phagocytosis,10 and slower sputum culture conversion in pulmonary tuberculosis.11

Several case series have reported that daily doses of 625 μg to 2·5 mg vitamin D improve patients' response to antimicrobial treatment for pulmonary tuberculosis.13 Randomised controlled trials investigating doses of up to 125 μg/day vitamin D or equivalent in active tuberculosis have shown no clinical benefit,14, 15, 16, 17 but a trial investigating a higher dose regimen (250 μg/day) reported reduced time to sputum smear conversion in the intervention group.18 However, sputum smear conversion has limited value as a biomarker of treatment response in pulmonary tuberculosis because microscopy is less sensitive and less specific than culture for the detection of viable M tuberculosis bacilli in sputum.19 Consequently, multivariable analysis shows that sputum culture conversion, but not sputum smear conversion, is independently related to risk of long-term treatment failure or relapse.20 We therefore undertook a clinical trial to investigate the effect of high-dose vitamin D3 on time to sputum culture conversion in patients receiving intensive-phase antimicrobial treatment for pulmonary tuberculosis; subgroup analyses were done to investigate whether the effect of adjunctive vitamin D on time to sputum culture conversion was modified by TaqI or FokI vitamin D receptor genotypes.

Section snippets

Patients

Patients were recruited from ten National Health Service Trusts in London, UK. Those with newly diagnosed pulmonary tuberculosis and acid-fast bacilli visible on sputum smear microscopy were assessed for eligibility. Full eligibility criteria are listed in webappendix p 1. Main exclusion criteria were age less than 18 years and serum corrected calcium concentration more than 2·65 mmol/L. The study was approved by the East London and The City Research Ethics Committee (ref 06/Q0605/83), and

Results

We assessed 464 patients for eligibility between Jan 25, 2007, and July 3, 2009—214 were ineligible, 104 were eligible but declined randomisation, and 146 were randomised. Reasons for ineligibility are presented in the webappendix p 5. Of the 146 randomised patients, eight were infected with non-tuberculous mycobacteria, three had negative baseline cultures, and nine had no follow-up sputum culture data. Thus, 126 patients formed the intention-to-treat population. Median age did not differ

Discussion

Administration of four doses of 2·5 mg vitamin D3 did not affect time to sputum culture conversion in the whole study population, but it did significantly hasten sputum culture conversion in patients with the tt genotype of the TaqI vitamin D receptor polymorphism. A large increase in mean serum 25-hydroxyvitamin D concentration was measured in patients in the intervention group.

Our study has several strengths. Patients in the intervention group received a preparation with verified vitamin D3

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