Daily adjunctive therapy with vitamin D3 and phenylbutyrate supports clinical recovery from pulmonary tuberculosis: a randomized controlled trial in Ethiopia

Abstract

Objective: Immunotherapy using vitamin D (vitD3 ) and phenylbutyrate (PBA) may support standard drug regimens used to treat infectious diseases. We investigated if vitD3 + PBA enhanced clinical recovery from pulmonary tuberculosis (TB).

Methods: A randomized controlled trial was conducted in Addis Ababa, Ethiopia. Patients with smear-positive or smear-negative TB received daily oral supplementation with 5000 IU vitD3 and 2 × 500 mg PBA or placebo for 16 weeks, together with 6-month chemotherapy. Primary end-point: reduction of a clinical composite TB score at week 8 compared with baseline using modified intention-to-treat (mITT, n = 348) and per-protocol (n = 296) analyses. Secondary end-points: primary and modified TB scores (week 0, 4, 8, 16, 24), sputum conversion, radiological findings and plasma 25(OH)D3 concentrations.

Results: Most subjects had low baseline plasma 25(OH)D3 levels that increased gradually in the vitD3 + PBA group compared with placebo (P < 0.0001) from week 0 to 16 (mean 34.7 vs. 127.4 nmol L-1 ). In the adjusted mITT analysis, the primary TB score was significantly reduced in the intervention group at week 8 (-0.52, 95% CI -0.93, -0.10; P = 0.015) while the modified TB score was reduced at week 8 (-0.58, 95% CI -1.02, -0.14; P = 0.01) and 16 (-0.34, 95% CI -0.64, -0.03; P = 0.03). VitD3 + PBA had no effect on longitudinal sputum-smear conversion (P = 0.98). Clinical adverse events were more common in the placebo group (24.3%) compared with the vitD3 + PBA group (12.6%).

Conclusion: Daily supplementation with vitD3 + PBA may ameliorate clinical TB symptoms and disease-specific complications, while the intervention had no effect on bacterial clearance in sputum.

Trial registration: ClinicalTrials.gov NCT01698476.

Keywords: clinical trial; host defence; phenylbutyrate; tuberculosis; vitamin D.

Conflict of interest statement

Conflict of interest statement

No conflict of interest to declare.

© 2018 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

Figures

Fig. 1

Trial profile. Consort flow diagram of patients with suspected pulmonary TB, from screening to analysis. Patients ineligible for randomization included HIV infection (n=418), relocation after diagnosis (n=17), age 5 days into TB chemotherapy (n=2), pregnancy (n=2) and mental health problems (n=1). Diseases other than TB included pulmonary fibrosis (n=14), cancer (n=2), and pulmonary thromboembolism (n=2) while other concomitant diseases included HIV infection (n=2), liver disease (n=3) and renal disease (n=3). Discontinued intervention included patients with liver toxicity (n=3), adherence failure (n=5) and cancer (n=1). Lost to follow up included patients who withdraw their consent (n=30), moved from study area (n=12), or were imprisoned (n=1). Patients who dropped out from the placebo treatment at week 0: n=11, week 4: n=9, week 8: n=5 and week 16: n=2. Patients who dropped out the vitD3+PBA treatment at week 0: n=14, week 4: n=5, week 8: n=5 and week 16: n=1.

Fig. 2

Primary efficacy analyses. (a) The primary clinical TB score was assessed at baseline and at weeks 4, 8, 16, and 24 after initiation of anti-TB chemotherapy. Adjunct vitD3+PBA treatment was provided during the first 16 weeks of standard care. The efficacy analysis included comparison of the vitD3+PBA and placebo treatment between week 0 and week 8. Crude data from the mITT cohort are presented as the mean and 95% CI. The blue line (circles) represents placebo while the red line (triangles) represents vitD3+PBA treatment. The horizontal bar indicate the estimated difference (given a linear reduction of the TB score) in weeks that it would take to reduce the primary TB score in the placebo group to a level comparable to the TB score in the vitD3+PBA group assessed at the end of adjunct treatment at week 16. (b) Forrest plot showing the odds ratio of the individual diseases symptoms included in the primary efficacy analysis. The estimate and 95% CI at week 8 are shown.

Fig. 3

Sputum-smear conversion analyses. (a) Longitudinal analysis of time to sputum-smear conversion after initiation of anti-TB chemotherapy in patients who were sputum-microscopy positive at enrolment. Crude data are presented in a Kaplan-Meier curve. The blue line represents placebo while the red line represents vitD3+PBA treatment. The hazard ratio (HR) and 95% CI is shown. (b) AFB-grading among sputum-smear positive TB patients at baseline compared to week 4 and 8 after initiation of anti-TB chemotherapy. AFB-positivity (+) was graded using microscopy as no AFB (negative), scanty (0–1), +1, +2, or +3 AFB. Data are shown in a bar graph with a colour scale from 0 (red) to 3+ (blue) AFB. The numbers and proportion of AFB+ TB patients in the placebo vs vitD3+PBA group at week 4 and 8 are also indicated in the graph. Patients with a negative sputum-smear result at baseline were excluded from the conversion analysis. (c) Sputum-culture conversion among both Mtb-culture positive and negative TB patients at baseline compared to week 8 after initiation of anti-TB chemotherapy. Bar graph showing negative Mtb-culture (red) vs positive Mtb-culture (blue).

Fig. 3

Sputum-smear conversion analyses. (a) Longitudinal analysis of time to sputum-smear conversion after initiation of anti-TB chemotherapy in patients who were sputum-microscopy positive at enrolment. Crude data are presented in a Kaplan-Meier curve. The blue line represents placebo while the red line represents vitD3+PBA treatment. The hazard ratio (HR) and 95% CI is shown. (b) AFB-grading among sputum-smear positive TB patients at baseline compared to week 4 and 8 after initiation of anti-TB chemotherapy. AFB-positivity (+) was graded using microscopy as no AFB (negative), scanty (0–1), +1, +2, or +3 AFB. Data are shown in a bar graph with a colour scale from 0 (red) to 3+ (blue) AFB. The numbers and proportion of AFB+ TB patients in the placebo vs vitD3+PBA group at week 4 and 8 are also indicated in the graph. Patients with a negative sputum-smear result at baseline were excluded from the conversion analysis. (c) Sputum-culture conversion among both Mtb-culture positive and negative TB patients at baseline compared to week 8 after initiation of anti-TB chemotherapy. Bar graph showing negative Mtb-culture (red) vs positive Mtb-culture (blue).

Fig. 4

VitD3 analysis. Plasma levels of 25(OH)D3 in the placebo compared to the vitD3+PBA group at baseline and at weeks 4, 8, and 16 after initiation of anti-TB chemotherapy. Data are shown in a scatter dot plot with blue symbols for placebo and red symbols for vitD3+PBA treatment. The solid line indicates the median, and the dashed lines mark the thresholds for vitD3 deficiency and insufficiency.

Fig. 5

Subgroup analyses. Longitudinal assessment of (a) the primary or (b) the modified TB score in TB patients with 25(OH)D3 levels ≤50 nmol/l and a TB score>5 at baseline. The primary clinical TB score and the modified TB score were assessed at baseline and at weeks 4, 8, 16, and 24. Crude data from this cohort are presented as the mean and 95% CI. The blue line (circles) represents placebo while the red line (triangles) represents vitD3+PBA treatment. (c) Forrest plot showing the odds ratio of the individual diseases symptoms included in the primary TB score for TB patients with 25(OH)D3 levels ≤50 nmol/l and a TB score>5 at baseline. The estimate and 95% CI at week 8 are shown.