Evolution of evidence on vitamin D supplementation in tuberculosis: A comprehensive umbrella review of nine systematic reviews.

BACKGROUND

Vitamin D supplementation as adjunctive therapy in tuberculosis has generated multiple systematic reviews with variable conclusions. The proliferation of syntheses in this field requires comprehensive evaluation to determine the temporal evolution of evidence and its translation into clinical recommendations.

OBJECTIVE

To synthesize systematic reviews on vitamin D supplementation in tuberculosis, evaluate the temporal evolution of conclusions, examine heterogeneity in clinical outcomes, and determine the quality of available evidence for clinical practice.

METHODS

An umbrella review was conducted in accordance with PRIOR guidance for overviews of reviews, searching MEDLINE, Embase, Web of Science, and Scopus. Systematic reviews examining vitamin D as adjunctive therapy in tuberculosis were included. Methodological quality was assessed using AMSTAR-2 and ROBIS, and evidence certainty was evaluated with GRADE adapted for umbrella reviews. Overlap among primary randomized trials was quantified using a citation matrix and the corrected covered area (CCA).

RESULTS

Nine systematic reviews (2009-2022) were identified, encompassing 300-2991 participants. A citation matrix identified 16 unique primary RCTs and 64 trial occurrences across nine reviews, corresponding to very high overlap (CCA = 37.5%). Meta-analytic findings consistently demonstrated null effects for primary outcomes: culture conversion RR 1.04-1.05, time to conversion HR 1.04-1.15, and mortality without significant differences. Subgroup analyses revealed potential effects in VDR TaqI tt genotype (HR 8.09, 95% CI 1.36-48.01) and multidrug-resistant tuberculosis (RR 2.40, 95% CI 1.11-5.18), although these findings were based on small sample sizes. Safety profiles were favorable with hypercalcemia <2%.

CONCLUSIONS

Current evidence from overlapping systematic reviews does not support routine vitamin D supplementation as adjunctive therapy to improve tuberculosis treatment outcomes in unselected populations. Signals in VDR TaqI tt genotype carriers and multidrug-resistant tuberculosis remain hypothesis-generating and require prospective validation before clinical translation.