Significant Effects of Oral Phenylbutyrate and Vitamin D3 Adjunctive Therapy in Pulmonary Tuberculosis: A Randomized Controlled Trial

PLoS One. 2015 Sep 22;10(9):e0138340. doi: 10.1371/journal.pone.0138340. eCollection 2015.

Abstract

Background: Development of new tuberculosis (TB) drugs and alternative treatment strategies are urgently required to control the global spread of TB. Previous results have shown that vitamin D3 (vitD3) and 4-phenyl butyrate (PBA) are potent inducers of the host defense peptide LL-37 that possess anti-mycobacterial effects.

Objective: To examine if oral adjunctive therapy with 5,000IU vitD3 or 2x500 mg PBA or PBA+vitD3 to standard chemotherapy would lead to enhanced recovery in sputum smear-positive pulmonary TB patients.

Methods: Adult TB patients (n = 288) were enrolled in a randomized, double-blind, placebo-controlled trial conducted in Bangladesh. Primary endpoints included proportions of patients with a negative sputum culture at week 4 and reduction in clinical symptoms at week 8. Clinical assessments and sputum smear microscopy were performed weekly up to week 4, fortnightly up to week 12 and at week 24; TB culture was performed at week 0, 4 and 8; concentrations of LL-37 in cells, 25-hydroxyvitamin D3 (25(OH)D3) in plasma and ex vivo bactericidal function of monocyte-derived macrophages (MDM) were determined at week 0, 4, 8, 12 and additionally at week 24 for plasma 25(OH)D3.

Results: At week 4, 71% (46/65) of the patients in the PBA+vitD3-group (p = 0.001) and 61.3% (38/62) in the vitD3-group (p = 0.032) were culture negative compared to 42.2% (27/64) in the placebo-group. The odds of sputum culture being negative at week 4 was 3.42 times higher in the PBA+vitD3-group (p = 0.001) and 2.2 times higher in vitD3-group (p = 0.032) compared to placebo. The concentration of LL-37 in MDM was significantly higher in the PBA-group compared to placebo at week 12 (p = 0.034). Decline in intracellular Mtb growth in MDM was earlier in the PBA-group compared to placebo (log rank 11.38, p = 0.01).

Conclusion: Adjunct therapy with PBA+vitD3 or vitD3 or PBA to standard short-course therapy demonstrated beneficial effects towards clinical recovery and holds potential for host-directed-therapy in the treatment of TB.

Trial registration: clinicaltrials.gov NCT01580007.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Antimicrobial Cationic Peptides / genetics
  • Antimicrobial Cationic Peptides / metabolism
  • Antitubercular Agents / therapeutic use
  • C-Reactive Protein / analysis
  • Calcifediol / blood
  • Calcium / blood
  • Cholecalciferol / therapeutic use*
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Humans
  • Leukocytes, Mononuclear / metabolism
  • Logistic Models
  • Macrophages / cytology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Phenylbutyrates / therapeutic use*
  • Placebo Effect
  • RNA, Messenger / metabolism
  • Sputum / microbiology
  • Treatment Outcome
  • Tuberculosis, Pulmonary / drug therapy*
  • Tuberculosis, Pulmonary / microbiology
  • Tuberculosis, Pulmonary / pathology

Substances

  • Antimicrobial Cationic Peptides
  • Antitubercular Agents
  • Phenylbutyrates
  • RNA, Messenger
  • CAP18 lipopolysaccharide-binding protein
  • Cholecalciferol
  • 4-phenylbutyric acid
  • C-Reactive Protein
  • Calcifediol
  • Calcium

Associated data

  • ClinicalTrials.gov/NCT01580007

Grant support

This study was supported by the International Centre for Diarrheal Disease Research, Bangladesh (icddr,b), Sida (Sida Agreement support; Grant 384, SWE-2008-065) and Swedish Strategic Foundation (SSF, Grant No. RBd08-0014) and the Swedish Heart-Lung Foundation (Grant No. 2013-0366). No funding bodies had any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.