Vitamin D in the treatment and prevention of tuberculosis

Tuberculosis (TB) is a global emergency: a third of the world population is estimated to be latently infected with Mycobacterium tuberculosis (MTB), of whom approximately 10% will develop reactivation disease in their lifetime [1]. The number of new cases of active TB worldwide continues to rise: latest estimates report 8.8 million new cases and 1.6 million deaths per year [2]. Current efforts to control the disease focus on antibiotic therapy of both active and latent disease. This is effective in drug-sensitive disease, but treatment is prolonged and incomplete adherence contributes to the emergence of drug resistance. The development of an immunomodulatory agent that enhances response to standard anti-tuberculous therapy could greatly improve TB control worldwide.

The potential for vitamin D to enhance immunity to TB infection was realized as long ago as 1849, when Chapman reviewed the use of cod-liver oil in TB, concluding that it was ‘probably the only remedial agent by which the vital powers may be enabled to struggle successfully against that malady’ [3]. Following the structural identification and synthesis of vitamin D from yeast, Charpy pioneered the use of pharma-cological doses of vitamin D (in intermittent oral boluses of 600,000 IU) in the treatment of cutaneous TB [4]. Similar doses of vitamin D were used to treat pulmonary TB in the pre-antibiotic era, although this practice was never evaluated with randomized controlled trials [5]. More recently, Davies observed that people migrating to Britain from countries with a high incidence of latent MTB infection experience rates of active TB that exceeded rates in their countries of origin, and that this increased risk coincided with the development of vitamin D deficiency, probably arising as a result of decreased sun exposure [6]. He suggested that vitamin D deficiency may predispose to reactivation of latent TB infection in this setting, a hypo-thesis supported by the observation that vitamin D deficiency is associated with susceptibility to active TB [7] and that vitamin D supplementation enhances antimycobacterial immunity in TB contacts [8].

Vitamin D does not possess anti-microbial activity but its active metabolite, calcitriol, induces antimycobacterial activity in vitro in macrophages, the cells that control growth of MTB [9]. Calcitriol modulates immune responses by ligating membrane vitamin D receptors (VDR) to induce rapid effects, or nuclear VDR to induce genomic effects [10]. Experiments using selective agonists and antagonists of these two receptors indicate that ligation of nuclear VDR is both necessary and suffici-ent for induction of antimycobacterial immunity by calcitriol in vitro[11]. Calcitriol induces expression of the antimicrobial peptide cathelicidin [12], which restricts the growth of MTB in vitro[13,14], and induction of this gene has recently been shown to be required for calcitriol-induced antimycobacterial immunity [15]. MTB infection also induces macrophage expression of 1-α hydroxylase [13], the enzyme that synthesizes calcitriol from 25-hydroxyvitamin D (25[OH]D; the principle circulating metabolite of vitamin D). Since extrarenal 1-α hydroxylase follows first-order kinetics, the rate at which it synthesizes calcitriol depends on the availability of the 25(OH)D substrate [16]. Orally ingested vitamin D is freely converted to 25(OH)D; this provides the rationale for administering parent vitamin D to induce antimycobacterial responses at the site of disease.

The administration of intermittent bolus doses of vitamin D is well tolerated and produces sustained elevations in serum 25(OH)D at a low cost [17]. These properties make vitamin D an attractive potential adjunct to standard anti-microbial therapy for active TB, with the potential to decrease infectiousness, shorten treatment in drug-sensitive disease or improve outcome in drug-resistant disease. Several case series report that adjunctive vitamin D enhances the response to antimicrobial therapy for pulmonary TB [5], and two clinical trials evaluating this practice have been reported to date. The first reported that 1000 IU vitamin D administered daily had no statistically significant effect on response to treatment in 24 children with active TB [18]; the second reported that 10,000 IU vitamin D administered daily to 67 adult patients with pulmonary TB during the initial 6 weeks of therapy reduced time to sputum smear conversion [19]. Microscopy is a relatively insensitive technique for the detection of viable MTB in sputum, and sputum smear conversion is not a recognized correlate of risk of post-treatment relapse [20]. Therefore, further Phase II trials are needed to evaluate whether adjunctive vitamin D enhances response to standard anti-tuberculous therapy; these should adopt a primary outcome measure recognized to correlate with risk of post-treatment relapse, such as sputum culture conversion [21]. Since standard quadruple antibiotic therapy is effective at inducing sputum culture conversion in drug-sensitive disease, it may be that efficacy of adjunctive vitamin D in TB treatment will be demonstrated more clearly in patients suffering from multidrug-resistant disease.

Further work is also required to establish the optimum dose of vitamin D that should be administered in such studies. Case series reporting the use of vitamin D in the treatment of cutaneous TB stated that ‘the size of the dose, so long as it was massive, did not matter’ [22], and doses reported to be effective as an adjunct to antimicrobial therapy for pulmon-ary disease generally exceeded 40,000 IU/day [5]. Kimball has recently reported that administration of progressively increasing weekly doses of up to 280,000 IU were well tolerated and did not induce hypercalcemia in patients with multiple sclerosis [23]. Hypersensitivity to vitamin D has been reported in TB patients [24]; therefore, Phase I studies investigating the safety of doses of at least 40,000 IU/day need to be conducted. However, given that a dose of 10,000 IU/day has been reported to be well tolerated by TB patients [19], it does not seem unreasonable to proceed with Phase II studies investigating equivalent dosing regimens in the interim [101]. Whatever the dose investigated, response to adjunctive vitamin D may well vary according to the baseline vitamin D status, or to polymorphisms in the vitamin D metabolic and signaling pathways. Trials will need to be conducted in different settings to investigate these possibilities, and analyses will need to take such potential determinants of response into account.

A second potential clinical application for vitamin D in MTB infection is as an intervention to prevent reactivation of latent disease. Since the short-term risk of reactivation disease is relatively low (<5% risk in the year following acquisition of latent MTB infection), clinical trials powered to detect the effect of vitamin D supplementation on incidence of active TB will need to be very large. Assuming a 5% 1-year risk of active TB in the control group, for example, a total of 13,492 individuals would need to be randomized to detect a 20% difference in TB incidence between groups at 1 year, with 80% power at the 5% significance level [25]. In order to maximize the chance of detecting an effect, studies would need to be conducted in vitamin D-deficient populations with a very high baseline TB incidence and potential for long-term follow-up. Potential study populations for such a trial include prisoners and mine workers in countries with a high TB burden. As for the trials discussed previously, the efficacy of different dosing regimens would also need to be investigated. We have shown that very profound deficiency (25[OH]D < 10 nmol/l) is associated with susceptibility to active disease [7], raising the possibility that even modest vitamin D supplementation might be of protective benefit. However, the emerging consensus is that 75 nmol/l represents the optimum serum 25(OH)D concentration for a range of physio-logical functions [26], and this may be a more appropriate target concentration for participants in the intervention arm of such a study.

In conclusion, the conduct of clinical trials to investigate potential clinical applications of administration of vitamin D in TB infection presents significant methodological challenges, and much remains to be done in terms of optimizing both interventions and outcome measures. The potential impact of positive results arising from these studies is huge, however, and justifies the considerable resources that will be required to evaluate this novel strategy to combat the scourge of TB.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.