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2.3.1 Justification and evidence
Undernutrition is a common consequence of TB disease, due to TB-related changes in macronutrient and micronutrient status (98). Micronutrients (vitamins and minerals) are required for metabolic processes. Low serum concentrations of micronutrients (e.g. vitamins A, E and D; and the minerals iron, zinc and selenium) have been reported from cohorts of patients starting treatment for TB disease (99, 100). Macronutrients and micronutrients work together to contribute to tissue regeneration and cellular integrity.
2.3.1.1 Single micronutrients
The systematic review for PICO Question 2 identified 33 RCTs (36 publications) that provided data on the effect of single micronutrients (vitamin A, vitamin D, selenium or zinc) compared with no micronutrients or placebo, for people with TB (52, 100-134). The overall certainty of evidence for each micronutrient intervention was rated as low. The provision of vitamin B6 (pyridoxine) alongside isoniazid-based treatment of TB infection and disease is already recommended and is an established practice for individuals at risk of peripheral neuropathy, including people living with HIV and people with undernutrition (46, 135). Vitamin B6 was therefore not included in this systematic review.
Recommendation 7:
Vitamin D for people with TB in research settings
Vitamin D supplementation: Evidence from two trials suggests that vitamin D supplementation may result in an increase in TB cure (2 trials, n=570, RR 1.25 [95% CI: 1.09, 1.43], low certainty evidence) (108, 128). The data from these two trials came from two different populations and used different approaches to participant selection and vitamin D administration. Participants (n=500) from one trial in Egypt came from a population with a high prevalence of vitamin D deficiency but their serum vitamin D levels were not measured (108). Participants (n=70) from the other trial in China had recorded vitamin D deficiency (128). The vitamin D dosing in the two studies also differed.
The evidence is very uncertain on the effect of vitamin D supplementation, compared with placebo or no vitamin D, for adverse events (4 trials, n=1246, RR 0.70 [95% CI: 0.50, 0.99], very low certainty evidence) (104, 108, 124, 127), serious adverse events (4 trials, n=1577, RR 1.06 [95% CI: 0.38, 2.95], very low certainty evidence) (52, 106, 116, 122), change in BMI (4 trials, n=1088, MD 0.09 [95% CI: –0.37, 0.55], very low certainty evidence) (106, 120, 126), and change in serum vitamin D (4 trials, n=663, standardized MD 4.10 [95% CI: 2.64, 5.56], very low certainty evidence) (101, 106, 111, 129). There was probably no difference in the risk of death during TB treatment between the intervention arm and the control arm (7 trials, n=2455, RR 1.20 [95% CI: 0.78,1.84], moderate certainty evidence) (52, 104, 106, 116, 120, 127, 133).
The GDG noted the increase in TB cure and that the balance of desirable effects probably outweighed the undesirable effects. GDG members therefore agreed on a conditional recommendation in favour of the intervention. It was highlighted, however, that the data on TB cure were based on two trials that were rated low certainty evidence owing to a high risk of bias. The GDG noted that dosing differed between the two trials, and that one trial included participants with vitamin D deficiency only, whereas the other did not measure participants’ serum vitamin D levels. There was no significant impact on other critical or important TB treatment outcomes. The GDG therefore agreed that vitamin D supplementation may be provided as part of TB treatment within the context of rigorous research, to answer outstanding questions such as dosage, the nutrient status of the target population and the impact of vitamin D on other TB treatment outcomes.
Other single micronutrients: The review found no association between vitamin A or zinc supplementation and the risk of death or TB treatment completion compared with the control group (114, 115, 118, 130); there was also no association between zinc supplementation and TB cure or change in BMI (113, 118). There were no data on the association of selenium with TB treatment outcomes, change in weight or BMI (109). However, supplementation of vitamin A, selenium and zinc were each associated with increased serum levels of the respective micronutrients (107, 109, 115, 118, 131). The certainty of evidence ranged from very low to moderate. Details of these outcomes are given in the GRADE summary of findings tables in Web Annex B.
The GDG observed that the data did not demonstrate any desirable effect of vitamin A, selenium and zinc on the critical and important TB treatment outcomes, or on any other critical outcomes other than micronutrient serum levels. After considering benefits, harms, resource implications, feasibility, acceptability and equity, the GDG agreed that an increase in micronutrient levels alone would not be sufficient to support a recommendation for or against the provision of these micronutrients to people with TB; therefore, they judged that no recommendations should be made.
2.3.1.2 Multiple micronutrients
The systematic review for PICO Question 2 identified 18 publications (17 trials) assessing the effect of multiple micronutrient supplements, defined as a single administration of two or more micronutrients, compared with no micronutrients or placebo in people with TB, on the outcomes rated as critical (22, 98, 100, 102, 103, 107, 110, 112, 114, 115, 118, 119, 121, 125, 126, 134, 136, 137). The overall certainty of evidence was moderate.
The systematic review found that the provision of multiple micronutrients probably shows no difference in the critical outcomes of TB cure, treatment completion, mortality or change in weight or body mass (see Web Annex B). These findings were also consistent among studies that included only children (22, 100, 115). In addition, no associated difference was found for death, TB treatment completion, and change in weight or body mass among people living with HIV (see Web Annex B) (119, 121, 137). Multiple micronutrient supplements may result in an increased risk of blurred vision (1 trial, n=373, RR 2.77 [95% CI: 1.11, 6.92], low certainty evidence) (126), and probably increased serum levels of copper at 6 months (1 trial, n=403, standardized MD 1.81 [95% CI: 1.57, 2.04], moderate certainty evidence) (115).
Multiple micronutrient supplements may result in a slight reduction in time to sputum culture conversion at 2 months (2 trials, n=385, MD –0.54 weeks [95% CI: –0.95, –0.13], low certainty evidence) (114, 118). An important finding was that multiple micronutrients may result in a reduction in relapse among people living with HIV not on antiretroviral therapy (ART) (1 trial, n=241, RR 0.37 [95% CI: 0.15, 0.92], low certainty evidence). However, this evidence was not deemed to be sufficient to support any recommendation, given that ART is now recommended for all people living with HIV, regardless of CD4 cell count (137).
After reviewing the data, and considering the desirable effects, harms, resource implications, feasibility and acceptability, the GDG agreed that the balance of desirable over undesirable effects did not favour the provision of multiple micronutrients as a nutritional intervention for people with TB, unless those micronutrients are otherwise indicated.
The GDG therefore agreed that the recommendation outlined in the 2013 guidelines on nutritional care and support for patients with TB (11) – “A daily multiple micronutrient supplement at 1× recommended nutrient intake should be provided in situations where fortified or supplementary foods should have been provided in accordance with standard management of moderate undernutrition” – should no longer apply as a standalone intervention to improve TB treatment outcomes.
In addition, it was agreed that the recommendations for pregnant and postpartum women outlined in the guidelines on nutritional care and support for patients with TB (11) should be retired. This decision was based on the fact that there were no data identified in the review that related specifically to pregnant and postpartum women with TB. Thus, for pregnant and postpartum women with TB, countries should refer to the updated guidelines on single and multiple micronutrient supplementation for the general population of pregnant and postpartum women (35, 37, 138-140).
2.3.2 Subgroup considerations
In general, micronutrient supplementation is not recommended by WHO unless there is evidence of micronutrient deficiency or clear evidence to show a positive impact on a given condition compared with any undesirable effects. Hence, the only population for which WHO recommends vitamin D supplementation, outside the context of rigorous research, is very low birth weight infants aged below 6 months (141). Vitamin D supplementation is not recommended for pregnant women unless they have documented vitamin D deficiency (35, 139). A GDG that reviewed the evidence on vitamin D supplementation during pregnancy in 2019 concluded that there was insufficient evidence to assess the balance of desirable and undesirable effects of such supplementation during pregnancy (139).
2.3.3 Implementation considerations
An intervention that is recommended only in the context of rigorous research indicates that there are important uncertainties about the intervention. In such instances, implementation should take the form of research that aims to address unanswered questions and uncertainties related both to the efficacy or effectiveness and the safety of the intervention, and to its acceptability and feasibility (37). In addition to clinical trials, rigorous research includes implementation research using high-quality methods appropriate to the specific research questions (138). Proposed research questions related to the use of vitamin D during TB treatment are listed in Chapter 4 (Research gaps).
As part of counselling, all people with TB should be encouraged and supported to be adequately nourished, which is best achieved through consumption of a healthy, balanced diet that contains the nutrients they require, including vitamin D, calcium and other micronutrients. People with TB should also be advised that sunlight is the most important source of vitamin D. Programmes may consider the inclusion of foods (e.g. oil or margarine) fortified with vitamin D as part of nutritional interventions provided to people with TB, particularly in settings with a high prevalence of vitamin D deficiency, according to the related WHO guidance (142-144). In some countries with a high prevalence of vitamin D deficiency in the population, fortified foods may already be made available as part of a national public health strategy (145, 146).
As part of updating national guidelines on TB and undernutrition, programmes will need to revise their guidance relating to micronutrients for people with TB. They will need to update health education materials to include clear messaging on the importance of a healthy balanced diet. Pregnant women with TB should receive nutritional care as per WHO guidelines for pregnant women who do not have TB (35, 37, 138-140).