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

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 D(3) (vitD(3)) 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 vitD(3) or 2x500 mg PBA or PBA+vitD(3) 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 D(3) (25(OH)D(3)) 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)D(3). RESULTS: At week 4, 71% (46/65) of the patients in the PBA+vitD(3)-group (p = 0.001) and 61.3% (38/62) in the vitD(3)-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+vitD(3)-group (p = 0.001) and 2.2 times higher in vitD(3)-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+vitD(3) or vitD(3) 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