Vitamin D nutrient to treat TB begs the prevention question

In The Lancet, Adrian Martineau and colleagues report a randomised multicentre trial of vitamin D3 (colecalciferol) as adjunctive therapy for active tuberculosis, This study, and fi ve other ongoing trials, were all designed to show faster recovery from active infection with Mycobacterium tuberculosis. Martineau and colleagues showed that the addition of vitamin D3 shortened the time to sputum clearance by 1 week, from 43·5 to 36·0 days, but the decrease did not reach conventional statistical signifi cance. For patients possessing the tt genotype of the TaqI vitamin D receptor polymorphism, vitamin D3 produced a remarkable acceleration in clearance of mycobacilli from sputum. For the other subgroups with active disease in all the trials, the conclusion must await a future meta-analysis. However, no one is addressing whether activation of latent tuberculosis might have been prevented if vitamin D nutritional status had not been so low in these patients. A decade ago, two of the authors of Martineau and colleagues’ paper reported interactions between TaqI genotypes, vitamin D nutritional status, and susceptibility to tuberculosis. It seems that nothing, in this context, has changed for patients with tuberculosis, because their serum 25-hydroxyvitamin D concen trations are still well below the threshold for rickets (25 nmol/L). Nutritional guidelines and public health policies in the UK have failed to prevent such dismal levels of 25-hydroxyvitamin D occurring. Consistently, patients with tuberculosis have lower 25-hydroxyvitamin D concentrations than does the control population. In Canada and the USA, new dietary recommendations for vitamin D have recently been published by the Institute of Medicine. The report summarised the evidence about vitamin D and tuberculosis but concluded that: “In the absence of verifi able dose–response data from RCTs [randomised controlled trials] a conclusion about asthma, autoimmune, or infectious diseases as indicators for DRI [daily recommended intake] development cannot be reached.” The report says that before implementing dietary guidance that might prevent disease, policy makers not only demand evidence from controlled clinical trials but also want those trials to investigate several doses. ClinicalTrials.gov does not include any trial whose outcome is prevention of tuberculosis activation. However, the doses of vitamin D used by Martineau and colleagues are in a range that could be applied to prevention, because the doses align with physio logical replacement. Although the doses of vitamin D3 used (2·5 mg at 0, 14, 28, and 42 days) sound high in a dietary context, the average serum 25-hydroxyvitamin D at the end of the 56 days was 101·4 nmol/L, which is not even halfway up the range of 25-hydroxyvitamin D attainable by exposing skin to sunshine. This modest 25-hydroxyvitamin D response in relation to dose is because the eff ective half-life of vitamin D is at least 56 days. Therefore the dose was not administered long enough to produce the full eff ect of that dose. Martineau and colleagues’ and the similar ongoing trials are essentially addressing the question of whether physiological blood levels of the nutrient can function therapeutically. No matter what the eventual outcome of the tuberculosis meta-analysis might be, the results will continue to beg the question: why had patients with tuberculosis not been maintained at the higher 25-hydroxyvitamin D concentrations before the infection became active? The problem is that the sort of research that stands a realistic chance of getting funded is fundamentally diff erent from that demanded by those who establish policy, such as the nutrient intakes pertinent to public health and disease prevention. Tuberculosis gives an Published Online January 6, 2011 DOI:10.1016/S01406736(10)62300-8

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