Table 1.
Evidence supporting HDTs for TB.
| HDT mechanism | Examples of potential HDTs agents | Evidence on host effect | Reference |
|---|---|---|---|
| Reducing excessive tissue damaging inflammation | Ibuprofen (NSAIDs)a | Inhibits prostaglandin production by inhibiting cyclooxygenase. Reduces lung pathology and Mycobacterium tuberculosis burden in mouse models | Vilaplana et al. (135) |
| Zileuton (leukotriene synthesis inhibitors)a | Inhibits lipoxygenase activity, blocking leukotriene production, and increasing PGE2 levels. Prevents type I IFN-driven acute mortality of M. tuberculosis-infected mice | Mayer-Barber et al. (136) | |
| Tofacitinib (tyrosine kinases inhibitors)a | JAK blocker with anti-inflammatory properties (JAK/STAT pathway is downstream the activation of most cytokine receptors), shortens the time required to lung sterility in a chronic TB mouse model | Maiga et al. (137) | |
| Adalimumab (anti-TNFα)b | Life-threatening pulmonary TB attributable to the recovery of TNF-dependent inflammation caused by withdrawal of adalimumab. Lung inflammation worsened despite clearance of viable M. tuberculosis from sputum and lung tissue by antimicrobial therapy. Clinical improvement did not occur until adalimumab treatment was resumed | Wallis et al. (138) | |
| Prednisolone (glucocorticoids)d | Modulate extreme immunopathological reactions and improved mortality for TB pericarditis and meningitis. Possible benefit in pulmonary TB. Adjunctive treatment with corticosteroids may improve the clinical outcome and may accelerate sputum smear conversion from HIV coinfected patients | Evans (139); Critchley et al. (140); Bilaçeroğlu et al. (141); Mayanja-Kizza et al. (142) | |
| Modulating innate and adaptive immune responses | Simvastatin (statins)a | Inhibits the 3-hydroxy-3-methylglutaryl coenzyme reductase, reducing the cholesterol levels within phagosomal membranes, which promotes phagosomal maturation and autophagy. Reduces bacterial burden in human PBMCs and MDMs. Improves histopathologic findings, with reduced lung M. tuberculosis burdens in experimental murine infection | Parihar et al. (143) |
| Carbamazepine (anticonvulsants)a | Sodium-channel blocker, capable of enhancing autophagic killing of intracellular M. tuberculosis in macrophages through cellular myoinositol depletion. In mice infected with a highly virulent MDR strain, carbamazepine treatment reduced bacterial burden, improved lung pathology, and stimulated adaptive immunity | Schiebler et al. (144) | |
| Metformin (biguanides, antidiabetic drugs)c | Interrupts the mitochondrial respiratory chain, increases production of mitochondrial reactive oxygen species, and facilitates phagosome–lysosome fusion, leading to enhanced killing of intracellular M. tuberculosis. In the mouse model, T cell responses and the efficacy of conventional TB drugs are improved, with resultant reduced lung pathology. In two separate human cohorts, metformin associates with decreased TB severity and improved clinical outcome in active TB and is associated with enhanced M. tuberculosis-specific T cell immune response in LTBI | Singhal et al. (145) | |
| Vitamin D3d | Induces the gene expression of beta-defensin 2 and human cathelicidin LL-37 that are able to suppress the growth of M. tuberculosis and modulate antimicrobial responses. Adjunct therapy with vitamin D3 enhanced intracellular mycobacterial killing in macrophages, increased sputum culture conversion, and reduced clinical symptoms in TB patients | Mily et al. (146); Rahman et al. (147) | |
| Immune checkpoint inhibition | Nivolumab and pembrolizumab (anti-PD-1)a | PD-L1 gene expression is elevated in patients with active TB disease. Human gene expression of PD-1 and PD-L1 in whole-blood decrease during successful TB treatment. Infections with live M. tuberculosis upregulated PD-L1 expression on monocytes. In vitro PD-1 blocking rescued M. tuberculosis-specific IFN-γ-producing T cells from undergoing apoptosis. PD-1 blockade potentiates the specific degranulation of CD8+ T cells | Singh et al. (148); Jurado et al. (149); Hassan et al. (150) |
| Immune activation, cytokine therapy | Recombinant human IFN-γb | IFN-γ administration in a patient with MSMD caused by IL-12Rβ1 deficiency provided a noticeable clinical effect, with no additional adverse effects | Alangari et al. (151) |
| Cell-based therapy | Autologous BM-MSCsd | BM-MSCs have immunomodulatory properties that can reduce damaging inflammation, induce tissue regeneration, and restore productive immune responses. Single-dose autologous BM-MSC is a safe adjunct therapy for patients with MDR or XDR-TB in combination with standard drug regimens and reconstituted anti-M. tuberculosis T cell responses in a phase 1 trial | Skrahin et al. (152) |
| Antimicrobial-potentiating effect | Verapamil (calcium-channel blockers)a | Blocks efflux pump, resulting in higher intracellular antimycobacterial drug levels and enhanced drug activity. Accelerates both the bactericidal and the sterilizing activities of the regimen in a mouse model. Adjunctive use of verapamil decreases the MIC of bedaquiline in the wild-type strain M. tuberculosis H37Rv and also in drug-susceptible and drug-resistant clinical isolates. Potentiates the activity of bedaquiline against M. tuberculosis in an in vivo mouse model. Permits lower doses of bedaquiline and thereby reduce its dose-related toxicities | Gupta et al. (153) |
BM-MSCs, bone marrow-derived mesenchymal stromal cells; MDMs, monocyte-derived macrophages; MDR, multidrug resistant; MIC, minimum inhibitory concentration; PBMCs, peripheral blood mononuclear cells; NSAIDs, non-steroidal anti-inflammatory drugs; XDR, extensively drug resistant; TB, tuberculosis; LTBI, latent TB infection; HDT, host-directed therapy; IFN, interferon; MSMD, Mendelian susceptibility to mycobacterial disease; IL, interleukin; TNF, tumor necrosis factor; PGE2, prostaglandin E2; HIV, human immunodeficiency virus.
Following are the types of studies.
aPreclinical.
bCase reports.
cObservational studies.
dRandomized trials.