Abstract
Background Randomised controlled trials of adjunctive vitamin D in pulmonary tuberculosis (TB) treatment have yielded conflicting results. Individual participant data meta-analysis could identify factors explaining this variation.
Methods We meta-analysed individual participant data from randomised controlled trials of vitamin D in patients receiving antimicrobial therapy for pulmonary TB. Primary outcome was time to sputum culture conversion. Secondary outcomes were time to sputum smear conversion, mean 8-week weight and incidence of adverse events. Pre-specified subgroup analyses were done according to baseline vitamin D status, age, sex, drug susceptibility, HIV status, extent of disease and vitamin D receptor genotype.
Results Individual participant data were obtained for 1850 participants in eight studies. Vitamin D did not influence time to sputum culture conversion overall (adjusted HR 1.06, 95% CI 0.91–1.23), but it did accelerate sputum culture conversion in participants with multidrug-resistant pulmonary TB (adjusted HR 13.44, 95% CI 2.96–60.90); no such effect was seen in those whose isolate was sensitive to rifampicin and/or isoniazid (adjusted HR 1.02, 95% CI 0.88–1.19; p-value for interaction=0.02). Vitamin D accelerated sputum smear conversion overall (adjusted HR 1.15, 95% CI 1.01–1.31), but did not influence other secondary outcomes.
Conclusions Vitamin D did not influence time to sputum culture conversion overall, but it accelerated sputum culture conversion in patients with multidrug-resistant pulmonary TB.
Abstract
A meta-analysis of individual participant data from clinical trials reports that adjunctive vitamin D accelerates sputum culture conversion in patients with multidrug-resistant tuberculosis, but not in those with drug-sensitive disease http://ow.ly/f2oN30n2OxJ
Footnotes
This article has supplementary material available from erj.ersjournals.com
This study is registered at PROSPERO with identifier number CRD42015020288.
Transparency declaration: A.R. Martineau is the manuscript's guarantor, and he affirms that the manuscript is an honest, accurate and transparent account of the study being reported. The study was conducted as pre-specified in the protocol, except for the following aspects. Subgroup analysis of the primary outcome by vitamin D dose (<4000 versus ≥4000 IU·day−1 or equivalent) was not performed, since studies investigating doses of <4000 IU·day−1 or equivalent [14, 15] did not evaluate time to sputum culture conversion. Subgroup analysis of the primary outcome by type of vitamin D administered (D2 versus D3) was not performed, since vitamin D2 was not administered in any included study: all investigated vitamin D3. A pre-specified sensitivity analysis excluding studies deemed at high risk of bias was not conducted, since no included trial fell into this category. In response to reviewers’ requests we did two exploratory adjustments of the subgroup analysis evaluating effects of vitamin D in patients with versus without MDR-TB in addition to the pre-specified adjustments for age, sex and clustering of participants within trials: one included additional adjustment for baseline vitamin D status (25(OH)D <25 versus ≥25 nmol·L−1) and the other included additional adjustment for presence versus absence of cavitation on baseline chest radiograph.
Author contributions: A.R. Martineau initiated the project and wrote the study protocol. D.A. Jolliffe and A.R. Martineau assessed eligibility of studies for inclusion. D.A. Jolliffe, A.R. Martineau, R. Raqib and M.A. Haq performed risk of bias assessments. D. Ganmaa, C. Wejse, R. Raqib, N. Salahuddin, P.K. Daley, A.P. Ralph, T.R. Ziegler and A.R. Martineau were all directly involved in the acquisition and supply of individual participant data for the work. D.A. Jolliffe designed and executed statistical analyses, with input from A.R. Martineau. A.R. Martineau and D.A. Jolliffe wrote the first draft of the report. All authors revised it critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions relating to the accuracy or integrity of any part of the work were appropriately investigated and resolved.
Conflict of interest: D.A. Jolliffe has nothing to disclose.
Conflict of interest: D. Ganmaa has nothing to disclose.
Conflict of interest: C. Wejse has nothing to disclose.
Conflict of interest: R. Raqib has nothing to disclose.
Conflict of interest: M.A. Haq has nothing to disclose.
Conflict of interest: N. Salahuddin has nothing to disclose.
Conflict of interest: P.K. Daley has nothing to disclose.
Conflict of interest: A.P. Ralph reports grants from Australian National Health and Medical Research Council, during the conduct of the study; one of the trials included in this meta-analysis was funded by the Australian National Health and Medical Research Council.
Conflict of interest: T.R. Ziegler has nothing to disclose.
Conflict of interest: A.R. Martineau has nothing to disclose.
Support statement: A.R. Martineau and D.A. Jolliffe are supported by the Higher Education Funding Council for England (HEFCE).
- Received October 19, 2018.
- Accepted December 12, 2018.
- Copyright ©ERS 2019
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