Though many drugs re-purposed as HDTs have known safety profiles, they must be evaluated in the context of individuals with TB, given that factors such as malnutrition, co-infection with HIV and inflammation tend to alter drug metabolism (32, 33).

The concomitant use of HDT with anti-TB therapy needs to be evaluated. For instance, mild risk of hepatotoxicity of some drugs could be potentiated when used along with anti-mycobacterial drugs. Additionally, it is important to evaluate drug-drug interactions with antiretroviral therapy, as co-infection with TB-HIV is common and of particular concern (26).

People living with HIV (PWH) and those with other types of immunosuppression, children, and individuals with resistant TB may have different immune responses to TB and thus could respond differently to HDTs (34). Similarly, ethnic differences in TB immune response may also be reflected in different responses to HDTs (35). It is critical that clinical studies include ethnically diverse and clinically relevant populations.

While most studies focus on pulmonary TB, extra-pulmonary TB has a high prevalence in some areas, particularly in countries with a high burden of TB (36) with worse outcomes when compared with pulmonary TB (37–39). For instance, having tuberculous meningitis or disseminated TB is associated with lower cure rates and higher mortality rates (37–39).

There may be an ideal time for use during disease course depending on how the host immune response is modulated, and administration in the wrong time frame may be deleterious (31, 40).

Earlier sterilization and control of inflammation may result in shorter antimycobacterial treatment durations leading to improved patient adherence and increased likelihood of cure (41).

Aspirin is a drug based on acetylsalicylic acid that performs antiplatelet (42), anti-inflammatory (43), and analgesic (44) functions and is a potential adjuvant in the treatment of TB (45, 46).

The anti-inflammatory role of aspirin has been increasingly studied for modulating neutrophil-mediated inflammatory responses. The effect of low-dose aspirin seems to enhance control of bacillary load and improve survival in the late stages of TB in C3HeB/FeJ murine model (45). A study in C3HeB/FeJ mice found that low-dose aspirin had an anti-inflammatory effect in the later stage of active TB by reducing excess, non-productive inflammation, while enhancing Th1-cell responses for the elimination of bacilli (47). In BALB/c mice, aspirin administration enhanced the effect of pyrazinamide and resulted in additional clearance of viable mycobacteria in the lungs and spleen during the initial phase of TB treatment (48). However, the combination of aspirin and Isoniazid-like treatment of murine pulmonary TB was associated with increased mycobacterial load in the spleen and lungs (48). Together, these findings highlight the urgent need for additional clinical studies to assess the impact of timing in disease course and the efficacy of concomitant aspirin use with different anti-TB drug combinations.

In addition to the anti-inflammatory effects, the antiplatelet role of aspirin may also be beneficial in TB treatment given that TB promotes a basal state of hypercoagulability that favors thromboembolic events (49) and platelets have been directly associated with pro-inflammatory status (50). A cohort study of pulmonary TB patients from Taiwan found that low doses of aspirin were associated with decreased morbidity and increased survival of patients on anti-TB regimen, without increasing the risk of bleeding (46). Similarly, a phase two CT in HIV-unexposed adults with tuberculous meningitis found that 1,000 mg of aspirin reduced 3-month mortality rates for this group of patients (51). A hypercoagulation state is present in tuberculous meningitis, leading to vascular complications (49). Using aspirin in this scenario has previously been shown to reduce the incidence of strokes and mortality at 3 months (52).

The results of these preliminary studies are underpowered and require additional robust CTs to prompt a change in current treatment guidelines. Nevertheless, they suggest that aspirin may aid TB treatment in all cases or in subgroups, in those with pulmonary TB or tuberculous meningitis. Importantly, the use of aspirin would be easily implemented given the low cost, high availability and limited side effect profile.

The ClinicalTrials.gov database lists one ongoing multi-center, phase IIB, placebo controlled, randomized CT that aims to evaluate the efficacy and safety of aspirin and ibuprofen as adjunct drugs in TB treatment, as detailed in Table 1.

Ibuprofen is a non-steroidal anti-inflammatory drug that inhibits both COX1 and COX2 cyclooxygenases. It is widely used and has an excellent safety profile, even in children (76). In a mouse model mimicking active TB in humans, the use of ibuprofen reduced bacillary load and affected lung area, leading to increased survival (77). These effects are mainly attributed to inhibition of the synthesis of PGE2, which inhibits phagocytosis, bacterial killing, production of nitrite (76) and T-helper 1 cytokines, and production of tumor necrosis factor α (TNF-α) (78). Another study in a murine model noted that ibuprofen enhanced the bactericidal effect of pyrazinamide during TB treatment (48). As noted above, this approach is currently under investigation in a phase II multi-center placebo-controlled trial (Table 1).

N-acetylcysteine (NAC) is a potent antioxidant widely used as a mucolytic agent in chronic obstructive pulmonary disease (COPD) and cystic fibrosis (79). The role of NAC in TB therapy remains under study. To date, prior studies have indicated that NAC might reduce host oxidative responses (80), reduce pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α (81) and have direct antimycobacterial properties (81, 82).

A study conducted in Brazil compared oxidative stress status in plasma of patients with pulmonary TB, latent TB infection, and healthy uninfected individuals (82). Pulmonary TB patients exhibited higher levels of oxidation products and a reduction of antioxidants compared with latent TB cases or uninfected controls. Cultures were exposed to different doses of NAC and the authors found decreased oxidative stress in treated macrophages and reduced mycobacterial growth when exposed to a high concentration of NAC (82). The capacity of NAC to control Mtb infection was further tested in vivo in a mouse (C57BL/6) model, resulting in a significant reduction of mycobacterial loads in the lungs (82).

In a phase II randomized CT that evaluated the adjuvant use of NAC in hospitalized individuals with TB-HIV (RIPENACTB study) (80), NAC-treated patients exhibited a significant increase in glutathione levels and total antioxidant status along with lowered levels of lipid peroxidation, a toxic process of oxidative stress response. In this study, the adjuvant use of NAC was not unsafe (80). Similarly, another randomized CT in those with newly diagnosed pulmonary TB in India reported a significant increase in glutathione peroxidase levels in patients receiving NAC and conventional anti-TB therapy compared to placebo group (patients under TB therapy only). Patients receiving NAC-based adjunctive therapy exhibited significant reduction of radiological lung infiltration, faster sputum conversion and more regulated immunological response, when compared to the group without NAC. A substantial body weight gain and improved antioxidant status was noted in the intervention group suggesting a potential promising role for NAC as adjuvant anti-TB therapy (83). Moreover, NAC may play a role in preventing hepatotoxicity of anti-TB usual therapy. An Iranian randomized CT (84) evaluated the effect of adjuvant NAC in those undergoing four drug anti-TB therapy compared with those without NAC therapy. Liver enzyme levels including aspartate aminotransferase, alanine aminotransferase and bilirubin were significantly lower following 1 and 2 weeks of NAC treatment. In this study NAC co-administration appeared to reduce the risk of hepatotoxicity commonly associated with anti-TB therapy.

N-acetylcysteine is a low-cost drug that seems to be safe for use in pulmonary TB treatment. Nevertheless, its effectiveness is still to be proven. One CT is currently in progress to clarify this question (Table 1).

Vitamin D (VITD) participates in the reabsorption of calcium from the bone and intestine and has a fundamental role in bone constitution and remodeling (85). It also acts as an immunomodulatory hormone and influences other processes including central nervous system function and cardiovascular health (86, 87).

In the presence of Mtb, VITD plays an essential role in activated macrophages and monocytes in response to antigen exposure by enhancing levels of 1,25(OH) 2D in monocyte/macrophages from normal human hosts (88). The increased levels of 1,25(OH) 2D induces the expression of cathelicidin, an antimicrobial protein responsible for killing infectious agents like Mtb (89). Some studies have reported that VITD can down-regulate the expression of mTOR protein, thus inducing autophagy (90). Importantly, VITD deficiency has been associated with susceptibility to TB infection in a comparative cross-sectional study that identified a high prevalence of VITD deficiency among newly diagnosed TB patients and in their household contacts (91). To date, 10 completed studies and four ongoing related to VITD and pulmonary TB were identified in the ClinicalTrials.gov records (Table 1).

The use of VITD as adjunctive therapy has had conflicting results regarding improvement of sputum conversion. Faster sputum conversion rates were found in TB patients receiving adjunctive VITD supplementation in a randomized placebo-controlled CT in Indonesia (92) and China (93). Another CT from Bangladesh demonstrated enhanced intracellular killing of Mtb in macrophages ex vivo in combination with increased sputum culture conversion at week 4 and at week 8 compared to the placebo group (94). This effect, however, was unable to be replicated in a number of CTs of VITD supplementation in TB disease (93, 95–97). Two CTs with MDR/RR-TB patients in Georgia (95) and Mongolia (96) identified higher sputum culture conversion with high dose of VITD use, suggesting a possible role in this subset of patients with MDR/RR TB. Another randomized controlled trial found that daily VITD administration in TB infected patients led to enhanced clinical recovery, particularly those with lower levels of VITD and an elevated TB score at enrollment (97).

Although lower levels of VITD are commonly observed in individuals with pulmonary TB, clinical and bacteriological results from randomized controlled trials of adjunctive VITD supplementation have demonstrated limited clinical benefits. A meta-analysis found that there is no evidence to support the adjuvant use of VITD. Most studies are limited by small sample sizes and include only HIV-uninfected adults with pulmonary TB (98). Additional larger studies are needed to investigate the effects of VITD and other micronutrients in specific TB treatment subgroups that have worse prognosis, immunosupression, MDR/RR-TB and individuals with diabetes.

Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading collagen and other structural proteins (99). When highly expressed, as in inflammatory conditions, they contribute to tissue damage (100). TB leads to upregulation of MMPs and an imbalance between MMPs and tissue inhibitors of metalloproteinases (TIMPs) (101, 102). This imbalance is associated with TB severity and extent of TB lesions, as well as formation of lung cavitation (103), which in turn is associated with high bacillary burden, delayed sputum culture conversion, emergence of drug resistance, and higher transmission of Mtb (104). MMPs also play a role in the formation of granulomas (105) and are responsible for the breakdown of the blood brain barrier, leading to poor outcomes in cases of central nervous system TB (106–108). In this context, inhibitors of MMPs may be a particularly effective HDT for TB. Doxycycline is the only FDA−approved MMP inhibitor (102). It is originally used as a bacteriostatic antibiotic of the tetracycline class. It is also an inhibitor of MMP1 and MMP9 (102) which may be responsible for reducing pulmonary cavity volume and loss of granuloma size (109). Doxycycline has been shown to inhibit mycobacterial growth in animal and in vitro models (110, 111). A pilot phase 2 CT (Doxy-TB) (109), comparing doxycycline plus standard TB therapy to placebo plus standard TB therapy has been concluded with results pending (Table 1). Doxycycline is a licensed, safe and affordable drug, with significant potential to improve TB outcomes (112). Future CTs are needed with larger sample sizes and different TB clinical forms besides pulmonary TB, such as central nervous system TB.

Vitamin A deficiency is a serious and widespread public health problem (113). It is more common during infection and can increase the severity of infectious diseases and the risk of death (113).

A recently systematic review/meta-analysis found that supplementation with vitamin A associated with earlier sputum conversion, decreased abnormalities in chest radiography, and improved lung function in patients undergoing TB treatment (114). A randomized controlled trial with a 2 × 2 factorial design in Qingdao, China determined that adjunctive supplementation with vitamin A did not improve time to smear conversion in pulmonary TB patients (93). Conversely, a double-blind, placebo-controlled study in patients with newly diagnosed TB found that vitamin A supplementation was associated with earlier sputum smear conversion (115). Furthermore, a randomized placebo-controlled, double-blind, two-by-two factorial trial evaluated the use of multivitamin/mineral supplementation with vitamin A and found a significant decrease in mortality during treatment of sputum-positive TB patients co-infected with HIV (116).

Three CTs registered with ClinicalTrials.gov with the status of completed were identified for Vitamin A supplementation in TB treatment (Table 1). The CT NCT00057434 conducted in Malawi did not identify a survival benefit with micronutrient supplementation with vitamin A in adults with HIV and pulmonary TB (69). Another CT (NCT00311298) found that multi-vitamin/mineral supplementation (Vitamin A) and zinc decrease mortality during treatment in patients with HIV and pulmonary TB (116). The remaining CT (NCT00801606) observed that micronutrient supplementation (Vitamin A) during treatment is associated with weight gain in children with TB though did not impact the clearance of lesions by chest X-ray (117).

These studies highlight conflicting results, though significantly lack evaluation of impact on clinical relevant outcomes (cure/death/recurrence). Larger trials with clinical important outcomes are needed to better evaluate the adjuvant use of vitamin A in TB treatment.

Mycobacterium tuberculosis has been shown to thrive in cholesterol rich environments, as cholesterol can improve both survival and growth of the pathogen in a host cell. Mtb uses cholesterol in the macrophage membrane to bind and enter the cell (118). Subsequently, after the infection, macrophage accumulates lipid bodies forming foamy cells that utilize cholesterol as the main source of nutrition for bacteria. The lipid bodies have also been associated with Mtb growth restriction, drug resistance and delayed phagosome maturation due to enhanced IL-10 induction (119).

Statins are the most used cholesterol reducing drugs. They are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme reductase (HMG-CoA), with both cholesterol lowering and anti-inflammatory and immunomodulatory functions and offer the most promising candidates for adjuvant HDT against TB (15, 120). The mechanism of action of statins against TB continue to be studied though research to date has identified the following: restrict the generation of foamy cells that otherwise support Mtb persistence by decreasing cholesterol biosynthesis (121); promote phagosome maturation and autophagy (122); increase percentages of Natural killer T (NKT) cells within cultures and expression of co-stimulatory molecules on monocytes, with higher secretion of IL-1b and IL-12p70 (123, 124); inhibit TGF-β (125, 126). Animal studies have found that simvastatin therapy in Mtb-infected mice reduces dissemination of Mtb from the lungs (122), promotes killing of intracellular Mtb by macrophages and enhances the bactericidal activity of isoniazid (119) and rifampin (127). A study in mice evaluated the treatment-shortening potential of therapy with statins plus anti-TB drugs and found a reduced time required to eradicate TB infection with no increased risk of relapse (128).

Some retrospective studies in Taiwan and South Korea have evaluated the role of statin use in preventing TB finding that chronic statin users had a lower risk of developing TB, compared to non-statin users (120, 129). Though intriguing, these study findings unfortunately have not been reproduced in different populations distinct from those with COPD and diabetes and lack adjustment for important confounding factors (130–134). A meta-analysis of data from nine of these cohort studies concluded that statin use was associated with reduced incidence of active TB (135). To our knowledge no retrospective studies have evaluated the impact of statins during TB treatment on clinical outcomes.

Four ongoing CTs of statins in TB may offer further clarity (Table 1): StAT-TB, a phase 2B dose finding study using pravastatin (NCT03882177); ATORTUB, using atorvastatin (NCT04721795); ROSETTA, using rosuvastatin (NCT04504851), and StatinTB (NCT04147286), a proof-of-concept phase II study testing the use of atorvastatin in reducing lung inflammation after TB treatment.

Given the pre-clinical studies results and the number of ongoing CTs, statins may represent one of the most promising drugs in the pipeline for HDT. If proven beneficial in clinical studies, its use in clinical practice can be easily implemented, considering its low cost and wide availability though likely will need additional safety testing given the possibility of hepatoxicity.

Metformin is the first-line therapy in those with type 2 diabetes (136) and is a safe and widely used medication. Results from multiple studies suggest that concurrent use of metformin for TB may be beneficial even in non-diabetic individuals (137).

How metformin acts against TB remains unclear. Pre-clinical studies have found that it facilitates phagosome-lysosome fusion and promotes expression of 5′ adenosine monophosphate-activated protein kinase (AMPK) (14), an enzyme usually activated during metabolic stress that controls energy homeostasis (138). As such, metformin may promote increased production of reactive oxygen species (ROS) and subsequent killing of intracellular Mtb (14).

A study performed by Singhal et al. in TB infected mice revealed that metformin reduced intracellular growth of Mtb, enhanced the efficacy of anti-TB drugs, and reduced lung damage and inflammation (139). This study served as a proof-of-concept demonstrating that metformin may be an option as adjunctive therapy of TB. Another study evaluating the sterilizing role of metformin found no differences in Mtb burden in the metformin adjuvant group versus TB treatment alone (140). Some possible reasons for the divergent results are the different model mouses and the different TB drugs used in both studies. Singhal et al. used a single anti-TB drug (isoniazid or ethambutol), whereas Duta NK et al. employed four drugs, which may have masked a possible role of metformin in sterilization. The inclusion of rifampin may also have altered the pharmacokinetics of metformin (140). Alternatively, it may be that metformin acts in an immunomodulatory role that is more clinically relevant than sterilization. Another study with mice found that metformin enhanced the effectiveness of Mtb-specific CD8 + T cell responses in local and systemic sites during infection, with increased decreased mortality and anti-mycobacterial properties and decreased inflammatory cytokine production such as TNF (141). Furthermore, Bohme J. et al. found that metformin enhances the immunogenicity and protective efficacy of BCG in mice (142).

Prior retrospective studies in patients with type 2 diabetes and TB suggest that metformin use was beneficial during TB treatment with reduced risk of cavitary TB (139), more rapid sputum conversion (143), lower mortality despite significantly higher glycated hemoglobin values (139, 144) and lower risk of recurrence (145) when compared to the use of other diabetes treatment regimens during TB treatment.

Considering the evidence above, the drug safety profile, wide availability, and low cost, there remains an important role for CTs to evaluate the effectiveness of metformin as TB adjunctive therapy. Currently, ClinicalTrials.gov reports two CTs investigating Metformin use in individuals with pulmonary TB that are currently recruiting participants in Thailand and South Africa (Table 1).