Tuberculosis

Vitamin D Supplements for Prevention of Tuberculosis Infection and Disease

Participants

Screening, Randomization, and Follow-up.

QFT denotes QuantiFERON-TB Gold In-Tube assay.

Baseline Characteristics of the Participants.

From September 2015 through March 2017, a total of 11,475 children were invited to participate in the trial. Of these children, 9814 underwent QFT testing. Among the 8851 children who had a negative QFT result, 4418 were randomly assigned to receive vitamin D3 and 4433 to receive placebo (Figure 1). The mean age of the children was 9.4 years, 49.3% were female, and 80.1% had a bacille Calmette Guérin vaccination scar. The mean serum 25(OH)D level was 11.9 ng per milliliter (30 nmol per liter); 95.6% of children had a 25(OH)D level below 20 ng per milliliter, and 31.8% had a 25(OH)D level below 10 ng per milliliter (25 nmol per liter). The characteristics of the children were balanced between the two groups (Table 1).

Mean Serum 25-Hydroxyvitamin D (25[OH]D) Level According to Time and Trial Group.

Levels of 25(OH)D were higher at the end of the trial in the group that received vitamin D supplementation than in the placebo group (mean between-group difference, 20.3 ng per milliliter; 95% CI, 19.9 to 20.6). To convert the 25(OH)D values to nanomoles per liter, multiply by 2.496. ? bars indicate the standard deviation. The plus minus values are means ±SD. The values in parentheses are the numbers of children.

The median follow-up was 3.0 years (interquartile range, 2.9 to 3.1) in both groups, and the median number of doses of vitamin D or placebo that were administered was 152 (interquartile range, 138 to 158). Valid QFT results at the end of the trial were obtained for 8117 participants (91.7% of the children who underwent randomization) who were included in the analysis of the primary outcome; a total of 8819 children had at least one follow-up visit and had data included in the analyses of the incidence of active tuberculosis and the incidence of acute respiratory infection. Follow-up 25(OH)D levels were available for all children who had available QFT results at the end of the trial; the mean 25(OH)D level at 3 years was higher in the vitamin D group than in the placebo group (31.0 vs. 10.7 ng per milliliter [75 nmol per liter vs. 25 nmol per liter]; difference, 20.3 ng per milliliter [50 nmol per liter]; 95% confidence interval [CI] for difference, 19.9 to 20.6) (Figure 2). At the end of the trial, 89.8% of children in the vitamin D group and 5.6% in the placebo group had a 25(OH)D level of 20 ng or higher per milliliter.

Primary and Secondary Outcomes

Respiratory Infection.

At the 3-year follow-up, conversion to a positive QFT result, as defined by an interferon-γ level that was at or above the threshold value of 0.35 IU per milliliter (the primary outcome), occurred in 281 children. The percentage of children with a positive QFT result was similar in the two groups: 3.6% (147 of 4074 children) in the vitamin D group and 3.3% (134 of 4043) in the placebo group (adjusted risk ratio, 1.10; 95% CI, 0.87 to 1.38; P=0.42) (Table 2). In the overall trial population, no significant between-group difference was observed in the proportion of children who had QFT conversion according to an interferon-γ level that was at or above the threshold value of 4.0 IU per milliliter (adjusted risk ratio, 0.67; 95% CI, 0.39 to 1.12). We found no evidence to suggest that assignment to the vitamin D group rather than to the placebo group had an effect on the mean antigen-stimulated interferon-γ level in QFT supernatants, either in the overall population (adjusted mean difference between groups, −0.01 IU; 95% CI, −0.04 to 0.02) or in the subgroup of children with a baseline 25(OH)D level below 10 ng per milliliter (adjusted mean difference between groups, −0.04 IU; 95% CI, −0.09 to 0.02) (Table S1 in the Supplementary Appendix).

Post Hoc Analysis

Subgroup analysis revealed no evidence to suggest heterogeneity of treatment effect for the outcome of QFT conversion according to an interferon-γ level at or above the threshold value of 0.35 IU per milliliter in children with a baseline 25(OH)D level of less than 10 ng per milliliter as compared with children with a level of 10 ng or higher per milliliter. However, subgroup analysis of QFT conversion at the threshold value of 4.0 IU per milliliter raised the possibility that in children with a baseline 25(OH)D level below 10 ng per milliliter, the risk of QFT conversion at this higher cutoff was lower among children assigned to receive vitamin D than among those assigned to placebo (adjusted risk ratio, 0.41; 95% CI, 0.17 to 0.99); this result was not seen in children with a baseline 25(OH)D level of 10 ng or higher per milliliter (adjusted risk ratio, 0.90; 95% CI, 0.46 to 1.77) (Table 2). The results of this subgroup analysis should be interpreted with caution, given that there was no adjustment for multiple comparisons and the analysis was performed post hoc.

Tuberculosis Disease

Tuberculosis disease was diagnosed by local doctors in 46 children during the trial. These events were evenly distributed between the two groups: among children who had at least one follow-up visit at which they were assessed for tuberculosis disease, 21 of 4401 (0.5%) children in the vitamin D group and 25 of 4418 (0.6%) children in the placebo group received a diagnosis of tuberculosis (adjusted risk ratio, 0.87; 95% CI, 0.49 to 1.55). A total of 26 of these children were classified as having confirmed or probable tuberculosis disease by the trial end-point committee and were also evenly distributed between groups (13 of 4401 children in the vitamin D group and 13 of 4418 children in the placebo group; adjusted risk ratio, 1.05; 95% CI, 0.49 to 2.27). Subgroup analysis revealed no heterogeneity of treatment effect for either outcome in children with a baseline 25(OH)D level of less than 10 ng per milliliter or in children with a level of 10 ng or higher per milliliter (Table 2).

Acute Respiratory Infection

Among children who had at least one follow-up visit at which they were assessed for acute respiratory infection, 63 children had at least one hospitalization for treatment of acute respiratory infection (29 of 4401 children in the vitamin D group and 34 of 4418 in the placebo group; adjusted risk ratio, 0.86; 95% CI, 0.52 to 1.40). No between-group difference was seen in the proportion of children who had at least one episode of symptoms of acute respiratory infection (adjusted risk ratio, 1.00; 95% CI, 0.98 to 1.02) or who were receiving at least one course of antibiotics for treatment of acute respiratory infection (adjusted risk ratio, 0.99; 95% CI, 0.93 to 1.05). No effect of the intervention was seen when the proportions of children who reported upper or lower acute respiratory infection were analyzed separately (Table S2). Subgroup analyses revealed no heterogeneity of treatment effect for acute respiratory infection outcomes in children with a baseline 25(OH)D level below 10 ng per milliliter or in those with a level of 10 ng or higher per milliliter (Table 2).

Sensitivity Analyses

With respect to all the outcomes described above, the results were materially unchanged when inverse probability weighting was used to correct for any potential bias due to missing data. Additional information is provided in Table S3.

Adverse Events

Adverse Events.

A total of 10 children (4 in the vitamin D group and 6 in the placebo group) died during the trial, and 324 (142 in the vitamin D group and 182 in the placebo group) had one or more nonfatal serious adverse events (Table 3 and Table S4). None of these events were judged to be related to vitamin D or placebo. Symptomatic hypercalcemia developed in 1 child in the vitamin D group who had a corrected serum calcium level of 2.70 mmol per liter (10.8 mg per deciliter). The hypercalcemia manifested with nausea and epigastric discomfort; vitamin D was discontinued, and the hypercalcemia and symptoms resolved. Three children had a serum 25(OH)D level that was higher than 80 ng per milliliter at the 3-year follow-up (87.6 ng per milliliter [219 nmol per liter], 93.6 ng per milliliter [234 nmol per liter], and 95.7 ng per milliliter [239 nmol per liter]); none of the children had symptoms. A total of 15 nonfatal adverse events led to discontinuation of the trial regimen (in 10 children in the vitamin D group and 5 in the placebo group).


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