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Vitamin D and tuberculosis: more effective in prevention than treatment?

IT IS NOW THIRTY YEARS since the possible connection between vitamin D deficiency and susceptibility to tuberculosis was first put forward.1 The hypothesis was based on three observations. First, very high incidence rates of tuberculosis had been observed in recent migrants to the United Kingdom from South Asia: notably, extra-pulmonary disease accounted for 50% of cases among South Asians compared to just 15% of cases in Whites. This pattern of disease echoed that seen in human immunodeficiency virus (HIV) infected patients, suggesting that an ‘acquired immunodeficiency of migration’ might be operating. Second, it was known that vitamin D deficiency was highly prevalent among South Asians living in the UK, and that serum 25-hydroxyvitamin D (25[OH]D) concentrations dropped rapidly after migration to this relatively sunless region. Third, evidence had started to emerge that vitamin D metabolites induced antimycobacterial activity in mononuclear phagocytes. In this issue of the Journal, Sloan et al. report findings of a cohort study from Malawi investigating the relationship between baseline vitamin D status and response to anti-tuberculosis treatment in 169 patients with smear-positive pulmonary disease, of whom 58% were HIV-infected. As might be expected in this sunny setting, the prevalence of vitamin D deficiency was relatively low: 28% of participants had serum 25[OH]D concentrations ,50 nmol/l compared with 92% in London.2 No association between baseline vitamin D status and treatment response was seen. This finding contrasts with that of analagous studies conducted in settings where profound vitamin D deficiency is more prevalent,3 but is in keeping with results of randomised controlled trials of adjunctive vitamin D therapy, which have not shown significant acceleration of sputum culture conversion4 despite demonstration of enhanced resolution of inflammatory markers.5 Several similar trials are due to report shortly, but a consensus seems to be emerging that adjunctive vitamin D is not going to emerge as a candidate for treatment shortening: in drug-susceptible disease, at least, quadruple therapy appears to mask the benefits of immunomodulation by vitamin D that was seen in the pre-antibiotic era. Where next for the vitamin D and tuberculosis story? With respect to adjunctive therapy, individual patient data meta-analysis of the burgeoning number of trials in this field may reveal sub-groups in which adjunctive therapy may confer clinical benefit, such as those with profound vitamin D deficiency, multidrug-resistant disease or particular genotypes of vitamin D receptor. This project is now underway. More detailed studies are also needed to clarify the effects of Mycobacterium tuberculosis and anti-tuberculosis treatment on vitamin D metabolism, and to determine whether vitamin D deficiency might predispose to extra-pulmonary dissemination. The original question regarding tuberculosis prevention is currently being addressed in Phase 3 trials – one testing the effectiveness of vitamin D in preventing pulmonary tuberculosis among 4000 HIVinfected adults in Tanzania, and another testing the ability of vitamin D to prevent acquisition of latent M. tuberculosis infection among 8200 schoolchildren in Mongolia. To our knowledge, trials of vitamin D to prevent active disease in non-HIV-infected adults are currently lacking, and this represents a significant research need. But it is to be hoped that by the time the original hypothesis reaches its fortieth birthday we will have some answers to the prevention question from adequately powered clinical trials.