Review
Tuberculosis—advances in development of new drugs, treatment regimens, host-directed therapies, and biomarkers

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Summary

Tuberculosis is the leading infectious cause of death worldwide, with 9·6 million cases and 1·5 million deaths reported in 2014. WHO estimates 480 000 cases of these were multidrug resistant (MDR). Less than half of patients who entered into treatment for MDR tuberculosis successfully completed that treatment, mainly due to high mortality and loss to follow-up. These in turn illustrate weaknesses in current treatment regimens and national tuberculosis programmes, coupled with operational treatment challenges. In this Review we provide an update on recent developments in the tuberculosis drug-development pipeline (including new and repurposed antimicrobials and host-directed drugs) as they are applied to new regimens to shorten and improve outcomes of tuberculosis treatment. Several new or repurposed antimicrobial drugs are in advanced trial stages for MDR tuberculosis, and two new antimicrobial drug candidates are in early-stage trials. Several trials to reduce the duration of therapy in MDR and drug-susceptible tuberculosis are ongoing. A wide range of candidate host-directed therapies are being developed to accelerate eradication of infection, prevent new drug resistance, and prevent permanent lung injury. As these drugs have been approved for other clinical indications, they are now ready for repurposing for tuberculosis in phase 2 clinical trials. We assess risks associated with evaluation of new treatment regimens, and highlight opportunities to advance tuberculosis research generally through regulatory innovation in MDR tuberculosis. Progress in tuberculosis-specific biomarkers (including culture conversion, PET and CT imaging, and gene expression profiles) can support this innovation. Several global initiatives now provide unique opportunities to tackle the tuberculosis epidemic through collaborative partnerships between high-income countries and middle-income and low-income countries for clinical trials training and research, allowing funders to coordinate several national and regional programmes for greatest overall effect.

Introduction

WHO estimated that in 2014, 9·6 million people (5·4 million men, 3·2 million women, and 1 million children) fell ill with tuberculosis worldwide.1 The resulting 1·5 million deaths made tuberculosis the leading infectious cause of death globally.1 WHO further estimated 480000 cases (and 190000 deaths) were multidrug resistant (MDR; defined as resistant at a minimum to rifampicin and isoniazid; figure 1), and only a quarter of these cases were reported. An estimated 9·7% of cases of MDR tuberculosis were extensively drug resistant (XDR; defined as MDR plus additional resistance to at least one fluoroquinolone and one second-line injectable drug), and have been reported in 105 countries.1 In 2014, MDR tuberculosis accounted for 3·3% of new tuberculosis cases and 20% of previously treated cases.1 Only half of these patients will successfully complete treatment. Of those patients with outcome data, death (16%), loss to follow-up (16%), and treatment failure (10%) are common1 due to weaknesses in current regimens, national programmes, and operational challenges. MDR tuberculosis thus constitutes a major threat to global public health security. WHO's 2015 annual tuberculosis report1 states that “without new tuberculosis drugs and regimens, it will be very difficult to improve treatment outcomes in the near future”, adding “intensified research and development is one of the three pillars of WHO's Post-2015 Global Tuberculosis Strategy, and will play a crucial role in accelerating the reductions in tuberculosis incidence and mortality required to reach global tuberculosis targets by 2035”.

Many unmet medical needs exist for all forms of tuberculosis (panel). In this Review we describe how these needs can be addressed by recent developments in new and repurposed antimicrobial drugs and host-directed therapies, advances in biomarkers, strategies for regimen development, and opportunities afforded by regulatory innovation.

Section snippets

New and repurposed antimicrobial drugs

Regimens comprising entirely new drugs would be an important therapeutic advance, because they would reduce the present requirement for drug-susceptibility testing, thus simplifying patient care. The current tuberculosis antimicrobial drug pipeline shows eight drugs in phase 2–3 trials (figure 2). Two new drugs (bedaquiline and delamanid) are in confirmatory phase 3 trials, having received accelerated approvals for MDR tuberculosis based on phase 2 data in 2012, and 2014, respectively. However,

Host-directed therapeutics to eradicate infection and prevent lung damage

Scientific interest has recently increased in targeting of host factors to identify new treatments for MDR tuberculosis. Host-directed therapies (HDTs)—including new and repurposed drugs, biologics, and cellular therapies—have been proposed to shorten treatment duration, prevent resistance, and reduce lung injury, by promoting autophagy, antimicrobial peptide production, other macrophage effector mechanisms, and inhibiting mechanisms causing lung inflammation and matrix destruction.45, 46, 47

Advances in tuberculosis biomarkers

Biomarkers are measurable characteristics that can form the basis of surrogate endpoints, thereby accelerating drug development.73 However, progress in tuberculosis biomarkers has been slow.74, 75, 76 In 2015, a blueprint identified important research steps for advances in this area and emphasised collaboration and harmonisation of efforts.77 Four areas of particular interest for new tuberculosis regimens are sputum-culture status, PET, whole-blood bactericidal activity, and gene expression

Shortening of treatment in drug-susceptible tuberculosis

Relapse (the epigenetic persistence and subsequent reactivation of drug-susceptible but phenotypically tolerant, non-replicating bacilli) is the most common adverse clinical outcome in patients with drug-sensitive tuberculosis. The risk of relapse increases as the duration of treatment is reduced.80 Identification of shorter regimens that do not unacceptably increase the relapse risk has been a major research focus.

Efforts to shorten treatment have so far been diverse. Some trials have

Improvement of outcomes in patients with MDR tuberculosis

By contrast with drug-susceptible tuberculosis, poor outcomes in MDR tuberculosis more often are representative of treatment failure rather than relapse.101 Treatment failure precludes patient relapse.102 Relapses are less common in MDR tuberculosis than drug-sensitive tuberculosis, even after accounting for this competing endpoint.103 However, relapse will likely become more important in MDR tuberculosis trials as more effective regimens are studied and shorter treatment durations are judged.

Innovative strategies for new drugs, regimens, and research capacity in MDR tuberculosis

These previously stated observations illustrate the challenges faced by tuberculosis drug developers. In drug-sensitive tuberculosis, researchers must contend with a 6-month regimen that is relatively well tolerated and efficacious in trial conditions, even though it has been difficult to implement in real-world settings and yet more difficult to improve. In MDR tuberculosis, researchers must contend with control regimens requiring up to 3 years of treatment and follow-up, consisting of drugs

Search strategy and selection criteria

We restricted our searches to reports published after Jan 1, 1996, in English. We did several searches of PubMed using the search term “tuberculosis” plus “clinical trials”, “biomarkers”, and “drug development”, and individual searches for each of the drugs Q203, SQ109, TBA-354, bedaquiline, delamanid, levofloxacin, moxifloxacin, pretomanid, pyrazinamide, rifapentine, rifampicin, and sutezolid (PNU-100480), and compounds identified by the Stop TB Partnership Working Group for New TB Drugs

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