Emerging drugs and alternative possibilities in the treatment of tuberculosis

ABSTRACT

Introduction: Tuberculosis (TB) remains a global health problem. Drug resistance, treatment duration, complexity, and adverse drug reactions associated with anti-TB regimens are associated with treatment failure, prolonged infectiousness and relapse. With the current set of anti-TB drugs the goal to end TB has not been met. New drugs and new treatment regimens are needed to eradicate TB.

Areas covered: Literature was explored to select publications on drugs currently in phase II and phase III trials. These include new chemical entities, immunotherapy, established drugs in new treatment regimens and vaccines for the prophylaxis of TB.

Expert opinion: Well designed trials, with detailed pharmacokinetic/pharmacodynamic analysis, in which information on drug exposure and drug susceptibility of the entire anti-TB regimen is included, in combination with long-term follow-up will provide relevant data to optimize TB treatment.

The new multi arm multistage trial design could be used to test new combinations of compounds, immunotherapy and therapeutic vaccines. This new approach will both reduce the number of patients exposed to inferior treatment and the financial burden. Moreover, it will speed up drug evaluation.

Considering the investments involved in development of new drugs it is worthwhile to thoroughly investigate existing, non-TB drugs in new regimens.

KEYWORDS:

• Tuberculosis
• immunotherapy
• vaccines
• phase II/III

1. Background

Tuberculosis (TB) is an infectious disease, caused by Mycobacterium tuberculosis (Mtb).[1] Once considered a disease of the past generally affecting poor people, nowadays TB is accepted as a threat for the entire community. TB is the leading cause of infectious disease related deaths worldwide.[2] In the year 2014, around 9.6 million people developed TB and 1.5 million people died from this disease, 390,000 of whom were HIV positive.[2] In addition, it is estimated that around one-third of the world’s total population is latently infected, 5–10% of whom will develop active disease.[3] The problem is further exacerbated by the emergence and spread of multidrug-resistant Mtb strains. Multidrug-resistant tuberculosis (MDR-TB) is characterized by resistance to at least the two most potent first-line anti-TB drugs isoniazid and rifampicin. Extensively drug-resistant tuberculosis (XDR-TB) is a form of MDR-TB in which the causative TB strain is in addition resistant to a fluoroquinolone and at least one of the three second-line injectable anti-TB drugs (Table 1).[4–9] Globally, over 480,000 MDR-TB cases are diagnosed each year. The incidence amounts to 3.3% in newly diagnosed cases and 20% in previously treated cases. Moreover, treatment success rate is only 50%.[2] Despite the global average of 3.3% for incidence MDR-TB in new TB cases, in some high incidence settings (e.g. countries of the former Soviet Union), not <20–30% of new cases represent MDR-TB.[2,8] Furthermore, 9.7% of patients with MDR-TB develop XDR-TB.[2]

Table 1. World Health Organization (WHO) classification of anti-TB drugs (4, 16).

Treatment	Group	Drug
First-line	Group 1: Oral drugs	Isoniazid (H)
		Rifampicin (R)
		Ethambutol (E)
		Pyrazinamide (Z)
		Rifabutin (Rfb)
		Rifapentine (Rpt)
Second-line	Group 2: Injectable or parenteral agents	Streptomycin (S)
		Kanamycin (Km)
		Amikacin (Am)
		Capreomycin (Cm)
	Group 3: Fluoroquinolones	Levofloxacin (Lfx)
		Moxifloxacin (Mfx)
		Gatifloxacin (Gfx)
	Group 4: Oral bacteriostatic agents	Ethionamide (Eto)
		Prothionamide (Pto)
		Cycloserine (Cs)
		Terizidone (Trd)
		p-Aminosalicylic acid (PAS)
		p-Aminosalicylatesodium (PAS-Na)
Third-line	Group 5: Anti-TB drugs with limited data on efficacy and/or long-term safety in the treatment of drug-resistant TB	Bedaquiline (Bdq)
		Delamanid (Dlm)
		Linezolid (Lzd)
		Clofazimine (Cfz)
		Amoxicillin/clavulanate (Amx/Clv)
		Imipenem/cilastatin (Ipm/Cln)
		Meropenem (Mpm)
		High-dose isoniazid (high-dose H)
		Thioacetazone (T)
		Clarithromycin (Clr)

2. Medical need for new drugs

The period between 1950 and 1960 was marked by the discovery and development of the most effective four-drug treatment regimen to cure drug-susceptible tuberculosis (DS-TB). This included isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E).[10] In particular, the introduction of rifampicin, in 1960, was considered a major breakthrough because it reduced the treatment duration from 18 months to 9 months. Re-introduction of low dose pyrazinamide enabled the formation of the current ‘short-term’ treatment regimen of 6 months.[11] Between 1960 and 2000 there was little activity in the development of more advanced anti-TB drug treatment regimens; despite the fact that fluoroquinolones were introduced in treatment regimens of MDR-TB cases. With the high cure rate of 86% for DS-TB, the new challenge lies in the improvement of MDR-TB/XDR-TB treatment as this is not sufficiently developed to achieve a reasonable cure rate and causes a high number of human catastrophes. In many geographic areas, if MDR-TB can be diagnosed, the standard MDR-TB treatment regimen of the World Health Organization (WHO) might not even be available. Cure rates of MDR-TB are limited to 50%.[2,10] Therefore, major improvements in diagnosis and treatment are needed.

There are several problems associated with the current treatment regimens for TB. First, for DS-TB the lengthy treatment duration (6–8 months), the complexity and adverse drug reactions associated with anti-TB regimen result in high rates of non-adherence. This leads to treatment failures, prolonged infectiousness, resistance, relapses and even chronic cases.[11,12] Second, the available treatment regimens for MDR-TB and XDR-TB are much more expensive, toxic and less effective than for DS-TB.[10] Often, treatment approaches for MDR-TB and XDR-TB are not evidence-based. The treatment duration of MDR-TB/XDR-TB is unacceptably long (18–24 months) and drugs are often unavailable in many developing countries.[10] Third, concurrent use of anti-HIV drugs have created huge management problems because of non-adherence, overlapping toxicity profiles, drug–drug interactions and risk of immune reconstitution syndrome in HIV-TB patients.[12,13] Fourth, current prophylactic therapy for latent TB with isoniazid risks non-adherence.[11] Last but not least, reliable susceptibility testing for first- and second-line drugs is often lacking. Therefore, the choice of the treatment regimen is not based on knowledge, but on best practice. The introduction of the GeneXpert enables the fast diagnosis of rifampicin resistance, but not resistance against second-line drugs.[2,14] Therefore, the adjustment of treatment may not always represent the best option.

Ideally, new chemotherapeutic agents should be able to overcome the mentioned problems associated with current treatment regimens. They should ideally reduce treatment duration, be effective in MDR-TB and XDR-TB treatment, utilize alternative mechanisms of action in Mtb, penetrate all tissues where Mtb resides in humans, have lower toxicity profiles, synchronize better with antiretroviral therapy (ART) and be active against latent TB bacilli.[11–13,15]

From the year 2000 onwards, joint efforts of scientists, funding bodies, the WHO’s Stop TB Department, and other organizations are contributing to break the stalemate in new anti-TB drug development.[10] A range of new compounds are now in the pipeline including repurposed and readily available drugs (e.g. thioridazin, fluoroquinolones, linezolid, meropenem-clavulanate), re-engineered drugs and new compounds (preclinical and clinical phase of development). Furthermore, two new drugs; bedaquiline and delamanid have been approved by Food and Drug Administration (FDA) in the USA and the European Medicines Agency (EMA) and are now available on the market to treat MDR-TB.[12]

3. Existing treatment

The current WHO treatment regimen for new TB cases include a 2 month HRZE regimen in the intensive phase, followed by a 4 month HR regimen in the continuation phase. Ethambutol is recommended during intensive phase of treatment for patients with non-cavitary TB, smear negative pulmonary TB, or extra pulmonary, HIV negative patients. In TB meningitis, ethambutol is replaced by streptomycin (S), because of the better penetration of streptomycin into the cerebrospinal fluid in the presence of inflamed meninges. In the absence of in vitro isoniazid drug susceptibility testing results, ethambutol is added to HR in the continuation phase to prevent the acquisition of drug resistance against isoniazid.[16] In countries where the probability of MDR-TB is low to medium, previously treated patients (at least 30 days of previous anti-TB treatment as a cut-off) waiting for the results of drug susceptibility testing, receive an empiric regimen that includes HRZES for 2 months followed by HRZE for 1 month (intensive phase) and HRE for 5 months (continuation phase). In high incidence MDR-TB settings, empirical MDR-TB regimen is prescribed consisting of a minimum of four drugs that are certain to be effective including a first-line oral agent, an effective aminoglycoside or polypeptide, a fluoroquinolone and one or more drugs from group 4 and if necessary group 5. This certainty in the selection of treatment is of course based on the availability of reliable drug susceptibility tests. Treatment is continued for at least 18 months after culture conversion.[8,15,17]

The programmatic management of MDR-TB consists of at least four second-line anti-TB drugs for effective treatment during an intensive phase of 8 months, and a continuation phase lasting for 12–18 months. This regimen includes a fluoroquinolone, a parenteral agent, ethionamide (or prothionamide) and cycloserine. In addition, it is recommended to add pyrazinamide to the entire therapeutic regimen. Also, use of at least two of the group five drugs is recommended when necessary.[4,14,18] To treat MDR-TB patients it is essential to determine which second-line anti-TB drugs are administered with what frequency within a specified area. Some second-line anti-TB drugs are used less in a given area and therefore might be more effective in drug-resistant TB treatment regimens, while other widely used agents might have an increased risk of ineffectiveness.[18] However, the golden standard remains the selection of an individualized treatment regimen based on molecular testing to assure that an effective drugs will be given. A point-of-care test (POCT) should provide a rapid, sensitive and specific result to enable early initiation of treatment.[19] Therefore, simple POCTs would be very useful, particularly if data on drug levels and bacterial genetic resistance marker are also available.

The WHO list of first-, second- and third-line anti-TB drugs is shown in Table 1. All the first-line anti-TB drugs, except for streptomycin, are in group 1. Streptomycin has been classified with the other injectable agents in group 2. All the drugs, except for streptomycin, in the groups 2–4 are second-line, or reserve drugs.

4. Market review

TB was declared as a public health emergency in 1993.[11] To fight efficiently against this worldwide epidemic, the WHO introduced the Directly Observed Treatment, Short course strategy (DOTS) which has now become an essential and internationally recommended TB control program. DOTS strategy is founded on five major components: (i) political commitment with increased and sustained financing, (ii) high quality microscopy for case detection, (iii) uninterrupted supply of short-course chemotherapy drugs, (iv) directly observed chemotherapy regimen use and (v) systemic monitoring and evaluation and impact measurement. The DOTS strategy focuses on the treatment of new DS-TB cases with standardized regimen of first-line drugs, under which the treatment success rate is about 90% and treatment costs are <10$ per patient.[20,21] Despite this effort and success in decreasing the TB incidence, TB and especially drug resistant strains remain a problem.[2]

In the year 1997, the global drug resistance survey conducted by the WHO reported MDR-TB for the first time. As a response to the alarming results, the WHO and partner organizations developed the ‘DOTS Plus strategy’ in 1999, for the programmatic management of MDR-TB.[20,22] The DOTS-Plus strategy is built upon five elements of DOTS and takes into account another three main components i.e. diagnosis based on culture, individual drug susceptibility testing of Mtb isolates and use of first- and second-line drugs in the treatment of MDR-TB.[20,22] To increase access to second-line drugs and prevent acquisition of drug resistance, the WHO and Stop TB partnership have been supporting low- and middle-income countries to procure drugs at highly concessionary prices (60–90% reductions) through the Green Light Committee (GLC) initiative.[20,22,23] The GLC initiative is composed of the GLC Committee, the WHO/GLC Secretariat, the Global Drug Facility, and other partner organizations. In particular, the Global Drug Facility, in collaboration with the Global Drug Fund and major pharmaceutical companies assist in the procurement of quality assured anti-TB drugs to the GLC approved sites through grants or direct procurement.[24]

From 2000 to 2011, GLC approved 138 projects in 90 countries with 30,000 patients treatments supplied by Global Drug Fund in 2012, compared with 19,605 patients in 2011.[22,25] However, the GLC projects covered only a small fraction of the 480,000 MDR-TB cases registered. Moreover, because in many geographic areas laboratory facilities are lacking, the number of MDR-TB cases presumably is an under-representation of the actual situation. The vast majority of diagnosed MDR-TB cases is treated by non-GLC approved national programs.[26] In non-GLC approved sites, second-line drugs are often purchased through the local market, where the quality of drugs may not be assured and management programs may not be controlled. For example, a Indian generic manufacturing company has been supplying the generic version of linezolid at lower prices to the regulatory and non-regulated markets in the Middle East, Thailand and Bangladesh.[27] It is however clear that the global health apparatus for addressing, managing and treating MDR-TB is still inadequate and slow to respond to the transformation from MDR-TB to XDR-TB.

5. Current research goals

Recently, the WHO launched the ‘End TB strategy’ as a new post-2015 Global TB strategy with a long-term vision to achieve a TB free world.[8] This strategy aims not only to control TB, but to eliminate it as a public health problem by 2035. The ‘End TB strategy’ targets to reduce TB deaths by 95%, cut new cases by 90% in the period between 2015 and 2035, and ensure no family is burdened with catastrophic expenses because of TB.[28,29] Interim milestones are set for 2020, 2025 and 2030. Furthermore, the new strategy supports universal access to high quality MDR-TB diagnosis and treatment.[8] However, with a decline rate of just 1.5% in new TB cases from 2000 to 2013 and the emergence of MDR-TB and XDR-TB strains, the target attainment by 2035 looks ambitious.[30] It is clear that without better, faster-acting and affordable drugs, TB is not going to disappear any time soon.

The ‘End TB strategy’ has set up three pillars, research and development being the foundation.[29] The new strategy strongly focuses on strengthening the volume and capacity of TB research on a global scale, investment in better TB diagnostics, new drugs and treatment regimens, and development of effective and safe vaccines. This would be the only low-cost and effective way of TB elimination.[28] Since its inception in 2000, the TB Alliance has been making significant progress in the search for new TB regimens. New drugs are developed in consortia with public and private stakeholders, including pharmaceutical companies, universities and other research laboratories around the world.[31] Moreover, private initiatives such as the Bill and Melinda Gates Foundation have been supporting innovative research in TB biomarkers to facilitate a fast and easy-to-perform TB diagnosis.

6. Scientific rationale

Current targets in treatment of DS-TB are inhibition of cell wall synthesis of Mtb (isoniazid and ethambutol), disruption of plasma membranes and energy metabolism (pyrazinamide) and inhibition of RNA synthesis (rifamycins).[11] The multi-drug resistant form of TB is treated with a combination of thionamides and cycloserine which inhibit cell wall synthesis, fluoroquinolones which inhibit DNA gyrase, PAS which inhibits synthesis of DNA precursors and cyclic peptides and aminoglycosides that inhibit protein synthesis.[32] In XDR-TB there are also resistance mechanisms in the causative Mtb against at least a fluoroquinolone and one aminoglycoside. Therefore, the drugs that can be effective in this stadium of the disease are limited. New drugs and new bacterial targets are needed to treat these serious forms of TB. Currently, there are new anti-TB drugs under development that inhibit cell wall synthesis (SQ-109, betalactams), inhibit both cell wall synthesis and cell respiration (nitroimidazoles), inhibit ATP synthase (diarylquinolines), inhibit protein synthesis (macrolides, oxazolidinones) and for some new drugs the mechanism of action has not been fully elucidated yet.[11]

There are different alternative treatment strategies that are investigated in combination with the already marketed and widely used anti-TB drugs. For instance, shortening of treatment with standard anti-TB drugs, but a higher dose of rifampicin, rifapentine and moxifloxacin is investigated to improve treatment outcomes and adherence.

Another new development in the treatment of TB is immune response modulating by for example glucocorticoids, vaccines, pascolizumab and interferon gamma.

Not only new targets in the treatment of TB are important in eradicating the disease, also prophylaxis of TB with an effective vaccine is important to reduce the development and transmission of the disease. The relatively ineffective Bacille Calmette–Guérin (BCG) vaccine however is the only licensed vaccine for prophylaxis of TB at the moment. BCG vaccine has documented efficacy against TB meningitis and miliary disseminated disease in children (86% on average).[33] However, it does not prevent primary infection, nor reactivation of latent TB.[33] Therefore, the WHO ‘Stop TB Strategy’ endorses the importance of the development of new vaccines to be able to eliminate TB by 2050.[33] Two strategies are being pursued in TB vaccine development for the prevention of transmission and development of TB. The first strategy is the development of a new vaccine to replace the BCG vaccine. The other strategy is the development of a vaccine that should be combined with the BCG vaccine to enhance BCG activity.[34]

7. Competitive environment

7.1. Search strategy

To select the products and treatment strategies currently under investigation in a phase II/III trial, we searched clinicaltrials.gov with the search term tuberculosis and selected phase II and phase III studies from the period of January 2005 to September 2015. We excluded trials for other therapeutic indications, diagnostic products for TB, vitamins, minerals, herbal medicines and dietary supplements.

We also searched the Pubmed database for search terms (TB or tuberculosis) and drug and [clinical trial, phase II or clinical trial, phase III (publication type)] from January 2005 to September 2015, and confined the search to articles in English.

Furthermore, the website from the Working Group on New TB Drugs [35] and the TB Alliance [36] were searched for new drugs.

7.2. Products in phase II/III

7.2.1. New chemical entities

After a few decades without new drugs emerging from the pipeline, recently several new drugs have been approved to treat TB (Table 2). One of these new drugs, bedaquiline (TMC207), is an anti-TB drug with a new mode of action. Bedaquiline is a diarylquinoline which targets mycobacterial ATP synthase. It in fact inhibits the proton pump of the critical enzyme ATP synthase through binding to the oligomeric and proteolipic subunits.[37] Inhibition of ATP synthase results in mycobacterial cell death. The new mode of action, the fact that it has been decades as a new anti-TB drug has emerged from the pipeline, and the accelerated approval procedure, underlines the potential of this new anti-TB drug. However, unexplained excess deaths were observed in the bedaquiline arm of these trials. The FDA approved bedaquiline for the treatment of MDR-TB with a black box warning concerning these observed excess deaths.[38] The WHO developed an implementation strategy for the introduction of bedaquiline at country level. This plan described stepwise approach for a safe implementation of bedaquiline. One of the key points is to implement the introduction of bedaquiline in pilot sites, because of the need for close supervision and monitoring. Afterwards, the experience of these pilot sites can be used to upscale the implementation of bedaquiline to a national level after collection of suitable evidence about the feasibility and effectiveness of adding the drug to MDR-TB treatment regimens.[39]

Table 2. New chemical entities for the treatment of TB under investigation in phase II or III trials.

Compound	Structure	Indication	Stage of development	Mechanism of action
Nitroimidazole				Inhibit the synthesis of cell wall components methoxy-mycolic and keto-mycolic acid
Delamanid (OPC-67683, Deltyba)	C25H25F3N4O6	Treatment	II/III
Metronidazole	C6H9N3O3	Treatment	II
Pretomanid (PA-824)	C14H12F3N3O5	Treatment	II/IIB
Diarylquinoline				Inhibits the proton pump of the critical enzyme ATP synthase
Bedaquiline (TMC207)	C32H31BrN2O2	Treatment	II/III
Adamantanoylindoles				Decreases incorporation of mycolic acids into the cell wall
SQ109	C22H38N2	Treatment	II/III
Fluoroquinolones				DNA-gyrase and topoisomerase IV inhibitor
Gatifloxacin	C19H22FN3O4	Treatment	II/III
Levofloxacin	C18H20FN3O4	Treatment	II/III
Beta-lactams				Inhibition of cell wall biosynthesis
Faropenem	C12H15NO5S	Treatment	II
Ertapenem	C22H25N3O7S	Treatment	II
Oxazolidinones				Protein synthesis inhibitor through binding to 23S RNA in the 50S ribosomal subunit
AZD5847 AstraZeneca	C21H21F2N3O7	Treatment	II
Linezolid Pfizer	C16H20FN3O4	Treatment	II
Sutezolid (PNU-100480) Sequella	C16H20FN3O3S	Treatment	II
Other
Micronutrients	Micronutrients: vitamin A 5000 IU, vitamin B1 20 mg, vitamin B2 20 mg, vitamin B6 25 mg, vitamin B12 50 microg, folic acid 0.8 mg, niacin 40 mg, vitamin C 200 mg, vitamin E 60 mg, vitamin D3 5 µg/200 IU, selenium 0.2 mg, copper 5 mg, and zinc 30 mg	Treatment (secondary)	II	Improve treatment outcome by enhancing nutritional status

The other new chemical entity that has been registered is the dihydro-imidazooxazole, or nitroimidazole, delamanid. Although the working mechanism of this drug is not fully elucidated, delamanid may inhibit the synthesis of methoxy-mycolic and keto-mycolic acid through a radical intermediate.[40] Both methoxy-mycolic and keto-mycolic acid are crucial components of the cell wall of the mycobacteria.[41] As a pro-drug, delamanid requires activation, possibly through mycobacterial F420 coenzyme system.[41] Similarly, the nitroimidazole pretomanid (PA-284) from the same group of drugs as metronidazole and recently registered delamanid, has a similar mode of action. Metronidazole itself is also been studied in a phase II trial.[42]

Besides these new chemical entities that have been recently approved, there are several other new and repurposed anti-TB drugs being studied in phase II and III research at the moment. Examples include the adamantanoylindole SQ109 and the oxazolidinones AZD-5847, linezolid and sutezolid (PNU-100480) (Table 2). The oxazolidinone linezolid is registered for the treatment of infections because of methicillin resistant Staphylococcus species and vancomycin resistant Enterococcus species. Linezolid is used off-label in the treatment of MDR-TB as a recommendation in the WHO guidelines for the programmatic management of MDR-TB.[18] However, at the moment several phase II and III studies are under evaluation (Table 2). For instance, a phase II dose ranging study is carried out to select the optimal dose of linezolid in DS-TB patients, besides the MDR-TB/XDR-TB for which linezolid is currently being used. The oxazolidinone linezolid inhibits protein synthesis through binding to 23S RNA in the 50S ribosomal subunit of the mycobacteria. Furthermore, chloramphenicol, macrolides and lincosamides bind to this site, but the lack of cross-resistance between the oxazolidinones and these antibiotics supports evidence for a new mechanism of action.[43–45] Linezolid-resistant Mtb strains seem to be rare. In only four of 210 multidrug-resistant Mtb strains linezolid resistance was observed.[46]

AZD-5847 is one of the new compounds that currently being studied in a phase II, randomized, open label trial. AZD-5847 is an oxazolidinone, with a corresponding expected mechanism that is similar to linezolid. The sutezolid (PNU-100480) is a third oxazolidinone with a similar working mechanism. Differences between the oxazolidinone drugs may be expected in relative efficacy against mycobacteria for the specific drug, in pharmacokinetics, and in adverse events that may occur during administration. As the use of the promising linezolid might be limited because of its toxicity, a similar drug with a more favorable adverse effects profile would be highly welcome.

SQ109 is one of the two new drugs, together with bedaquiline, with a new, unique mechanism in targeting mycobacteria. SQ109 decreases incorporation of mycolic acids into the cell wall.[47] Finally, the fluoroquinolones, such as moxifloxacin, already have an important place in treatment of MDR-TB. There are several studies being carried out with structure analogs of these fluoroquinolones, such as gatifloxacin and levofloxacin (Table 2). Both are already in the WHO MDR-TB Guideline (WHO 2011), but, as is the case for many MDR-TB drugs, more research is needed in order to optimize treatment.

The betalactams faropenem and ertapenem are being studied in phase II trials. The high efficacy of meropenem suggests these drugs may be promising future candidates in anti-TB treatment regimens.[48] Not only drugs, but also the effect of improving patient’s nutritional status on treatment outcome by administering micronutrients is being studied in phase II, although one might say that this should be part of standard care.

7.2.2. Immunotherapy

Table 3 describes immune-modulating compounds in development for treatment of TB.

Table 3. Immunotherapy. Immune-modulating compounds in development for the treatment of TB in phase II or III trials.

Compound	Group	Indication	Stage of development	Mechanism of action
Prednisolone	Glucocorticoid	Tuberculous pericarditis	III	Glucocorticoid therapy may decrease the risk of death by reducing cardiac tamponade and pericardial constriction by attenuating inflammatory response
Interferon gamma	Dimerized soluble cytokine	Treatment (adjuvant)	II	Reduce inflammatory cytokines at the site of disease, improve clearance of Mtb from the sputum and improve constitutional symptoms
Pascolizumab	Humanized monoclonal antibody	Treatment (adjuvant)	II	An anti-IL-4 monoclonal antibody, a key cytokine in the immune response to TB, might be of value as an adjunct to standard treatment
V5	Vaccine	DS-TB, MDR-TB, HIV-TB	II	Immunomodulating preparation derived from the blood of hepatitis B and C donors, oral tablet
V7	Vaccine	DS-TB and MDR-TB	III	Heat-killed Mycobacterium vaccae formulated as an oral pill
Mycobacterium w (Immuvac)	Vaccine	Pulmonary TB	III	Immunomodulator for intradermal injection

TB: tuberculosis; DS-TB: drug-susceptible tuberculosis; MDR-TB: multi-drug resistant tuberculosis; HIV-TB: co-infection of HIV and tuberculosis; Mtb: Mycobacterium tuberculosis.

Current treatment regimens for pulmonary TB require at least 6 months of therapy. Immune adjuvant therapy with nebulized or subcutaneously administered recombinant interferon-c1b (rIFN-cb) may reduce pulmonary inflammation and reduce the period of infectivity by promoting earlier sputum clearance.[49] In a randomized, controlled clinical trial, the addition of nebulized rIFN-cb to DOTS resulted in reduced bronchoalveolar lavage (BAL) cytokines, more rapid clearance of Mtb from sputum, less severe symptoms and reduced inflammatory macrophage-neutrophil alveolitis. In patients with cavitary TB, nebulized rIFN-cb may have a role in adjunctive immune stimulation.[49]

There are conflicting recommendations in international guidelines regarding the role of adjunctive glucocorticoid therapy in patients with tuberculous pericarditis. Glucocorticoid therapy may decrease the risk of death by reducing cardiac tamponade and pericardial constriction, but it also increases the risk of cancer in HIV infected patients.[50,51] In the trial on the management of pericarditis the efficacy and safety of adjunctive prednisolone and Mycobacterium indicus pranii is evaluated in patients in Africa who had tuberculous pericarditis. Repeated doses of intradermal heat-killed M. indicus pranii immunotherapy may reduce inflammation associated with TB and increase the CD4 + T-cell count in persons infected with HIV.[52–54]

Adjunctive therapy with prednisolone for 6 weeks and treatment by M. indicus pranii for 3 months did not have a significant effect on the combined outcome of death from all causes, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis.[55] Both therapies were also associated with an increased risk of HIV-associated cancer. However, the use of adjunctive glucocorticoids reduced the incidences of pericardial constriction and hospitalization.[55]

There is furthermore a study ongoing with pascolizumab, evaluating the safety and efficacy of blocking interleukin-4 in patients receiving standard combination therapy for pulmonary TB. IL-4 is a key cytokine in the immune response to TB that may impair the clearance of mycobacteria. Pascolizumab, an anti-IL-4 monoclonal antibody, might be of value as an adjunct to standard treatment.[56]

In the TB vaccine development pipeline there are also vaccines developed for use in the treatment of TB, in combination with anti-TB chemotherapy. Immunitor V-5 (V5) is an oral bivalent vaccine consisting of heat-inactivated hepatitis C virus (HCV) antigens from pooled blood of hepatitis B virus (HBV)- and HCV-infected patients.[57] The clinical benefit of V5 versus placebo in combination with anti-TB therapy was investigated in 55 TB patients (including MDR-TB and HIV-TB) in a phase II trial. V5 was well tolerated and clinical symptoms improved among all patients treated with V5.[58] V5 can shorten TB treatment as shown in a phase II trial with newly diagnosed, relapsed and MDR-TB patients.[59]

V7 is an oral formulation of Mycobacterium vaccae. In a phase II trial, it was shown safe and had the potential to improve efficacy of standard treatment as determined by sputum smear conversion compared with placebo and shorten treatment duration of TB in DS-TB, DR-TB and MDR-TB.[60] In another phase II trial there was no statistically significant difference in outcome in patients treated with V7 compared with the placebo, possibly because of the small sample size.[60] A phase III study with V7 in DS-TB, MDR-TB and HIV-TB is currently ongoing.[61]

Mycobacterium w is commercially available under the brand name of ‘Immuvac’ injection and approved for use as immune modulator against Mycobacterium leprae in patients with leprosy. A phase III study investigating the efficacy and safety of Mycobacterium w as immune modulator in 300 newly diagnosed pulmonary TB patients in India was completed in 2011,[62] but the results are not published yet.

7.2.3. New treatment regimens

Over the last decade, several phase II or III trials have been performed with drugs which have been used in TB treatment in order to ameliorate treatment success, or to shorten standard therapy (Table 4). Several large phase III studies have been performed to investigate the possibilities of shortening standard treatment in DS-TB.[63–65] The poor patient adherence for the long TB treatment regimens may increase the risk of drug resistance. The development of short-term treatment regimen could contribute to reduce drug resistance, adverse events and in total lower costs.[66] Shortening standard treatment from 6 to 4 months, in adults with non-cavitary DS-TB and culture conversion after 2 months, resulted in a higher relapse rate.[63]

Table 4. new regimens with (established) anti-TB drugs investigated in phase II or III trials.

Regimen	Indication	Phase	Ref
Shortening therapy 2 months HRZE + 2 months HR vs. 2 months HRZE + 4 months HR (standard)	DS-TB	III	[56]
Moxifloxacin 2 months HRZM vs. 2 months HRZE (standard)	DS-TB	II	[63]
Moxifloxacin 4 months HRZM vs. 4 months MRZE vs. 2 months HRZE + 4 months HR (standard)	DS-TB	III	[57]
Rifapentine 2 months HZE + RP 10 mg/kg vs. 2 months HZE + RP 15 mg/kg vs. 2 months HZE + RP 20 mg/kg vs. 2 months HRZE (standard)	DS-TB	II	[62]
Moxifloxacin/Rifapentine 2 months MRZE + 2 months 2 weekly M 400 mg RP 900 mg vs. 2 months MRZE + 4 months weekly M 400 mg RP 1200 mg vs. 2 months HRZE + 4 months HR (standard)	DS-TB	III	[58]
Rifampicin/ Moxifloxacin 2 weeks R 450 mg HZE vs. 2 weeks R 450 mg MHZ vs. 2 weeks R 450 mg M 800 mg HZ vs. 2 weeks R 600 mg i.v. HZE vs. 2 weeks R 600 mg i.v. MHZ vs. 2 weeks R 600 mg i.v. M 800 mg HZ	TB-meningitis	II	[59]
Rifampicin 2 weeks R 10 mg/kg + 1 week HZE vs. 2 weeks R 20 mg/kg + 1 week HZE vs. 2 weeks R 25 mg/kg + 1 week HZE vs. 2 weeks R 30 mg/kg + 1 week HZE vs. 2 weeks R 35 mg/kg + 1 week HZE	DS-TB	II	[60]
Isoniazid H 10 mg/kg vs. H 20 mg/kg vs. Placebo	Pre-exposure prophylaxis	II/III	[64]
Isoniazid/Ethambutol 6 months H 300 mg E 800 mg vs. 36 months H 300 mg	Preventive therapy	III	[65]
Isoniazid/Rifampicin 9 months 2 weekly H 900 mg vs. 4 months R 600 mg	Latent-TB	III	^−

All medication was orally ingested and in the following doses unless otherwise specified. H: isoniazid 5 mg/kg daily; R: rifampicin 10 mg/kg daily; Z: pyrazinamide 25 mg/kg daily; E: ethambutol 15 mg/kg daily; M: moxifloxacin 400 mg daily; RP: rifapentine; i.v.: intravenously; TB: tuberculosis; DS-TB: drug susceptible tuberculosis.

Evidence emerges that higher doses of rifampicin are needed in the treatment of TB.[67–69] Current rifampicin dosing is believed to be at the low end of the dose response curve. In the distant past, the recommended dose was selected on basis of its effectivity at the lowest cost and lowered by fear of adverse effects.[68] In a phase II trial in tuberculous meningitis, rifampicin 600 mg intravenously was compared with 450 mg orally in the first 2 weeks of treatment. Furthermore, moxifloxacin 400 mg was compared with 800 mg. The higher dose of rifampicin and moxifloxacin, both normal and high dose, were found to be safe. In another phase II trial, higher doses of rifampicin up to 35 mg/kg were found to be safe and well tolerated for 2 weeks.[68]

Rifapentine is a cyclopentyl ringsubstituted rifamycin. Compared with rifampicin, rifapentine has a longer half-life and lower minimum inhibitory concentration (MIC) against Mtb.[70] A phase II dose-ranging study showed that rifapentine doses of up to 20 mg/kg once daily was well tolerated and safe during the first 2 months of intensive treatment.[70]

Moxifloxacin is a fluoroquinolone that has potent in vitro activity against Mtb. Early studies of moxifloxacin in murine models of TB showed that the drug had good bactericidal activity and could be an important additive to isoniazid.[71] The added effect of moxifloxacin is its improvement of sterilization of infected sites. Based on experience with pyrazinamide, it was suggested that this improvement might lead to shortening of treatment duration.[71] Moxifloxacin indeed shortened culture conversion in the initial phase of TB treatment.[71] However, in a phase III trial in which either isoniazid or ethambutol were substituted by moxifloxacin in a 4-month regimen, both regimens were inferior to 6 months standard treatment.[64]

Jindani et al. investigated two different regimens with moxifloxacin and rifapentine. They concluded that the 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as standard treatment. However, the 4-month regimen with twice weekly dosing of moxifloxacin and rifapentine had a significantly higher relapse rate than the control regimen.[65] Based on the results of these two large phase III trials, moxifloxacin has not proven to be able to reduce treatment duration until now.

In a phase II/III trial in HIV-infected and HIV-uninfected children, the efficacy of pre-exposure prophylaxis of isoniazid was investigated. Isoniazid 10 and 20 mg/kg daily for 96 weeks was compared with placebo. All children received BCG-vaccination against TB within 30 days of birth.[72] Isoniazid prophylaxis as compared with placebo was safe, but ineffective as pre-exposure prophylaxis against TB in HIV-infected and HIV-uninfected children.[72] An open-label phase III trial investigated the equivalence of a 6-months regimen with isoniazid and ethambutol and a 36-months regimen with isoniazid preventive therapy in HIV-infected patients. Both regimens were similarly effective in preventing TB, when compared with historical incidence rates. However, there was a trend to lower TB incidence with the 36-months isoniazid regimen. Furthermore, no increase in isoniazid resistance was observed compared with the rate in HIV-infected patients.[73] An open-label phase III trial compared 9-months isoniazid with 4-months rifampicin regarding toxicity and completion in an internalized population with latent TB infection. Rifampicin resulted in fewer elevated liver function tests and less toxicity.[74]

7.2.4. Vaccines

Currently, various vaccines for the prevention of TB are tested in phase II or III trials (Table 5). Because there is no clinical parameter that can reliably predict anti-TB treatment response, sputum smear and culture status after 2 months of anti-TB medication are the most commonly used indicators in these studies to measure therapeutic response [75–77] .

Table 5. Vaccines for the prevention of TB investigated in phase II or III trials.

Compound	Vaccine type	Indication	Stage of development	Mechanism of action
RUTI	BCG booster	Latent TB	II	RUTI is a polyantigenic liposomal vaccine made of detoxified, fragmented M. tuberculosis cells (FCMtb), for the prevention of active TB in subjects with latent TB for subcutaneous administration
M72/AS01 (GSK 692342)	BCG booster	TB prevention, HIV-TB	II	Recombinant fusion protein with an adjuvant systems (AS01) containing the immunostimulants 3-O-desacyl-4 -monophosphoryl lipid A (MPL) and Quillaja saponaria fraction 1 (QS21), combined with liposomes for intramuscular injection
Mtb72 F/AS02	BCG booster	TB prevention	II	Recombinant fusion protein with an adjuvant system (AS02) is an oil-in-water emulsion containing the immunostimulants MPL and QS21. It is a preparation for intramuscular injection
AERAS-402	BCG booster	TB prevention	II	AERAS-402 is a replication-deficient serotype 35 adenovirus containing DNA that expresses a fusion protein of three Mtb antigens: 85A, 85B and TB10.4 for intramuscular injection
AERAS-404 (H4:IC31)	BCG booster	TB prevention	II	H4 antigen is a fusion protein created from two Mtb antigens: antigen Ag85B and TB10.4 for intramuscular injection
AERAS-456	BCG booster	Latent TB	II	AERAS-456 (H56:IC31) contains a fusion protein of three mycobacterial antigens (the early secreted antigens Ag85B and ESAT-6, and the latency antigen Rv2660c) formulated in the Th1-stimulating IC31 adjuvant for intramuscular injection
MVA85A/ AERAS-485	BCG booster	TB prevention	II	MVA85A is a recombinant strain of modified Vaccinia Ankara virus expressing the immunodominant Mtb protein, antigen 85A for intradermal injection
ID93 + GLA-SE vaccine	BCG booster	Pulmonary TB		Recombinant subunit vaccine which combines four antigens belonging to families of Mtb proteins associated with virulence (Rv2608, Rv3619, Rv3620) or latency (Rv1813) formulated it in a stable oil-in-water emulsion for intramuscular injection
M. vaccae	BCG replacement	TB prevention		Mycobacterium vaccae for injection
VPM1002	BCG replacement			VMP1002 is a recombinant BCG strain for intradermal administration

BCG: Bacille Calmette–Guérin; TB: tuberculosis; HIV-TB: co-infection of HIV and tuberculosis; Mtb: Mycobacterium tuberculosis.

RUTI is a polyantigenic liposomal vaccine made of detoxified, fragmented Mtb cells for the prevention of active TB in subjects with latent TB.[78] In a phase II placebo controlled trial, RUTI was investigated in HIV-infected and -uninfected subjects with latent TB. The safety profile was acceptable, however, there was a high number of subjects with local reactions as development of nodules and even abscesses. The immunogenicity profile shown in this study suggests that a single dose of the RUTI vaccine could be used in further research.[78]

M72/AS01 (GSK 692342) is derived from the Mtb72 F vaccine, and is a recombinant fusion protein derived from the Mtb proteins Mtb32A and Mtb39A with an adjuvant systems (AS01) containing the immunostimulants 3-O-desacyl-4-monophosphoryl lipid A (MPL) and Quillaja saponaria fraction 1 (QS21), combined with liposomes.[79] In a phase II dose-finding study in purified protein derivative (PPD) positive adults, a dose of 10 µg was selected for further research.[80] This dosage of M72/AS01 was also investigated in HIV-infected adults receiving combination antiretroviral therapy. It was well tolerated and immunogenic in this population.[81] The product was considered safe in adolescents living in a TB endemic region.[82] There is a large study ongoing with M72/AS01, evaluating the efficacy of two doses of the vaccine in healthy volunteers living in TB endemic countries compared with placebo.[83]

Earlier there was another formulation developed of Mtb72 in an oil-in-water emulsion (Mtb72/AS02) which was investigated in Mycobacterium-primed adults. It was well tolerated and induced immune response.[84] However, M72/AS01 turned out to induce significantly higher T-cell response compared with Mtb72/AS02.[79]

AERAS-402 is a replication-deficient serotype 35 adenovirus containing DNA that expresses a fusion protein of three Mtb antigens: 85A, 85B and TB10.4 after intramuscular injection. Two doses of AERAS-402 were well tolerated, safe and induced an immune response in HIV patients.[85] In BCG-vaccinated infants treated with AERAS-402 the vaccine had an acceptable safety profile, but the response rate was lower than seen in adults.[86]

AERAS-404 (H4:IC31) has been developed as a BCG booster vaccine. H4 is a fusion protein created from two mycobacterial antigens: antigen Ag85B and TB10.4.[87] IC31 is a combination of a leucine-rich peptide and a synthetic oligonucleotide.[88] A dosage of 15 µg of AERAS-404 was considered safe and induced T-cell response in a phase I study in South African adults.[89] It’s safety and efficacy is currently under investigation in a phase II trial in healthy adolescents.[90] Safety is also investigated in infants.[91]

AERAS-456 contains a fusion protein of three mycobacterial antigens (the early secreted antigens Ag85B and ESAT-6, and the latency antigen Rv2660c) formulated in the Th1-stimulating IC31 adjuvant for intramuscular injection. It’s safety is currently investigated in a phase II trial in healthy adults with and without latent TB infection.[92]

ID93 + GLA-SE is a recombinant subunit vaccine which combines four antigens belonging to families of Mtb proteins associated with virulence (Rv2608, Rv3619, Rv3620) or latency (Rv1813) formulated in a stable oil-in-water emulsion for intramuscular injection.[93] The safety and immunogenicity of different dosage combinations of ID93 + GLA-SE vaccine administered as an intramuscular injection is currently investigated in a phase II trial in adults with pulmonary TB.[94]

MVA85A is a recombinant strain of modified Vaccinia Ankara virus expressing the immunodominant Mtb protein, antigen 85A. It was designed to enhance the protective efficacy of BCG against TB.[95] MVA85A was safe and induced T-cell response in infants treated in a dose finding study with MVA85A.[96] The safety and efficacy of MVA85A was later investigated in children previously vaccinated with BCG. MVA85A was well tolerated, however, it did not protect significantly against TB.[97] In a phase II trial, the vaccine was tested in HIV patients. Although it was well tolerated, again it was not effective against TB.[98] Currently, a phase I trial has started investigating the safety and immunogenicity of MVA85A aerosol versus intramuscular injection.

Mycobacterium vaccae has been approved as an immunotherapeutic agent for adjuvant therapy of TB in China.[99] A phase III trial investigating the efficacy of M. vaccae versus placebo in a high risk group is ongoing to add new indications (prevention of TB) for application of M. vaccae.[100]

VMP1002 is a recombinant BCG strain. The safety and immunogenicity of this vaccine compared with BCG was investigated in a phase II trial with newborn infants in South Africa. The study was completed in 2012, no results have been published till today.[101]

8. Potential development issues

Development issues that are encountered in the development of new drugs for the treatment of TB can be variable. One of the issues in developing a new drug is the financial costs, which are approximately $300–500 million. The turnover and commercial return for new drugs is insufficient for pharmaceutical companies to cover the high costs that are associated with the selection of a new chemical entity, (pre)clinical testing, marketing and distribution of a new drug. Because the majority of TB patients live in low-income countries, the feasible pricing of the new drugs will not be high enough for pharmaceutical companies to make the development of a new TB drug commercially interesting.[102] Governments or other organization could intervene and could stimulate pharmaceutical companies to develop new drugs for example by financial compensation or adjustment of patent duration. Another hesitation for pharmaceutical companies when developing a new anti-infective drug for TB, is that they might be limited to further investigate the potential effect of this drug for other indications to enlarge their turnover because of public health interests.[103] When the incidence of TB decreases, cash flow for pharmaceutical companies is likely to diminish when TB incidence becomes (very) low. However, to totally eradicate TB from this world, a high financial contribution is needed until TB is totally vanished.

To discover new drugs for the treatment of TB, new research strategies are now pursued to select new entities by genome-derived targeted approaches (target-to-drug instead of drug-to-target approach) or phenotypic screening of the whole bacterial cell.[104,105] A problem encountered in the target-to-drug approach is that promising compounds may inhibit a purified enzyme, but lack efficacy against the Mycobacterium as a whole.[104] Development issues that are encountered in the phenotypic screening of the whole cell strategy are that the mechanism of action of a promising drug is not always known and selected compounds may have non-specific mechanisms of action, or induce cytotoxic effects.[105] For example, the failure of moxifloxacin in clinical trials. Studies in mice showed that standard treatment regimen including moxifloxacin had greater bactericidial activity than the standard treatment regimen without moxifloxacin. Based on this observation, it was thought that adding moxifloxacin to treatment regimens could produce cure without relapse after a shorter treatment duration.[106,107] However, the study of Gillespie et al. shows that the murine model may have overpredicted the sterilizing potency of moxifloxacin, because the shorter moxifloxacin treatment regimens worked insufficiently.[64] Furthermore, moxifloxacin may not reach adequate concentrations in critical niches where the Mtb reside.[108]

Challenges that are encountered in the development of vaccines are for example adverse events as seen in studies with RUTI and immunogenicity as observed in the development of MVA85A.[78,97,98] The immune response of the mice, most commonly used in the available and feasible animal models, differs materially from that of humans. In the past years, although a lot of products are under investigation in phase II/III trials, no new prophylactic vaccines have emerged from the development pipeline.

When a new drug is developed, investigating the effective treatment regimen is very important. The Critical Path to New TB Regimens (CPTR), an initiative from several pharmaceutical companies and non-governmental organizations, enables testing of multiple regimens with new anti-TB drugs at the same time and this shortens the timelines for drug development significantly. A challenge in combining different drugs are the pharmacokinetic (drug–drug interactions) and toxicity profiles.[105]

For the older anti-TB drugs, investigating combinations with new drugs can be promising to improve efficacy and shorten treatment duration. Funds are needed to allow for new, well-designed trials. Furthermore, international cooperation is important to investigate these treatment regimens in larger patient populations.

9. Conclusion

Tuberculosis remains a serious health care problem; especially the increase in MDR-TB is worrisome. Fortunately, the field of drug development has never been as active as today. Studies to optimize the dose and treatment duration of currently licensed drugs show successful preliminary results. Repurposed drugs may be a quick win if proven successful in phase II and III studies. More importantly, new drugs are being licensed for TB treatment. Because of medical need they are released on the market in an early stage. Hopefully these drugs appear to be a valuable asset to the current armamentarium of the TB physician. TB treatment may truly change when dormant bacilli can be targeted by either new drugs or by a boosted immune response. The combination of therapeutic vaccines, immunotherapy and new drugs may contribute to shortening the treatment regimen. The dream of every TB researcher is that a treatment regimen will be developed that reduces TB treatment to the level of a community acquired pneumonia which can be cured within 2 weeks with well tolerated drugs. Also prevention of TB transmission with an effective vaccine will hopefully be possible in the future. However, products from this discipline have been disappointing in the last decade.

In the next 5–10 years, lots of data from various phase II and phase III trials will become available which will hopefully result in optimization of current TB treatment.

10. Expert opinion

Currently much effort is put in optimization of available TB treatment regimens. Data from pharmacokinetic and pharmacodynamic in vitro and in vivo models have provided new information on the dose- response to anti-TB drugs. In addition, new theoretical approaches to describe the susceptibility of pathogens to drugs have been established. Besides the minimal inhibitory concentration, the minimal bactericidal concentration and mutant prevention concentration have entered the field of pharmacokinetics and pharmacodynamics (PK/PD). It is important to realize that concentrations to prevent development of drug resistance are higher than concentration to kill susceptible pathogens.[109] Decades of too low dosing of for instance rifampicin have fueled the MDR-TB epidemic.[68] However, current knowledge on PK/PD is unfortunately not included in phase III clinical trials. To include PK/PD in phase III studies requires intensive PK sampling, drug susceptibility testing of Mtb, frequent culturing of patient’s samples to evaluate clinical and microbiological response and long-term follow-up.[110] This is an expensive and burdensome strategy but the only option to fully understand the effect of treatment. Often only limited PK sampling in a subset of patients is currently performed, drug susceptibility testing is only performed at baseline and at best after a few months of treatment. In addition, because of the lack of molecular testing, re-infection can often not be distinguished from treatment failure in high endemic settings. In an ideal study, a real life patient population treated in a regular setting would be included in clinical studies. This would make translation into daily practice very easy. Likely, this will not happen in the near future, but adding a detailed PK/PD analysis to the study on efficacy of drugs will provide the opportunity to better analyze treatment results of individual patient.[111]

In addition to all new drugs emerging, new trial designs have been developed. The classical approach is to test each drug individually in phase II and subsequently in phase III studies. It would take decades to complete evaluation of a complete new regimen for TB treatment in the conventional way. New adaptive trial design will be helpful to reduce the number of unsuccessful studies. The new multi arm multistage (MAMS) trial design will compare several regimens or treatment arms simultaneously.[112] At different stages of the trial, interim analysis are performed and compared with standard treatment. Treatment arms that do not meet specified criteria are stopped. This helps to reduce expensive trial costs, reduce the number of patients exposed to inferior treatment and more importantly will speed up drug evaluation. In these trials, new combinations of compounds, immunotherapy and therapeutic vaccines should be tested.

This new approach to evaluate the combination of new products or alternative treatment strategies requires intensive collaboration between different parties. These initiatives benefit from experience of the different participants and create a synergistic study environment. This is especially needed for an infectious disease, as TB, for which resources for development are scarce. Innovative trial designs may be an important strategy to overcome these problems.[11]

Considering the investments involved in the development of new drugs, we think that it is worthwhile to thoroughly investigate old drugs in new regimens. Prerequisites for such investigations are that actual MICs and information on both drug exposure and treatment outcome is available and investigated. Such trials should be powered to detect differences in relapse rate, acquired drug resistance or toxicity.

Hopefully the current developments in new compounds, improved trial design and multi-party collaborations will result in accelerated progress in optimization of TB treatment.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.