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

Abstract

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.

Gene Expression Signatures in Tuberculosis Have Greater Overlap with Autoimmune Diseases Than with Infectious Diseases

“…Tuberculosis (TB) continues to be depressingly persistent as a global pandemic, killing more than any other infectious agent (1), and the mechanisms underlying pulmonary pathology remain elusive (2). Diverse clinical phenomena and experimental observations recently led us to hypothesize that an infectioninitiated autoimmune phenomenon is part of the pathological process (3), and others have since noted this association (4,5).…”

“…Chronic obstructive pulmonary disease (COPD) exacerbations are critical events that lead to poor health status (1), lung function decline (2), and mortality (3). However, treatment options for acute exacerbations remain limited.…”

CD1b-restricted GEM T cell responses are modulated byMycobacterium tuberculosismycolic acid meromycolate chains

“…Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major human pandemic and is responsible for more deaths than any other infectious disease (1). The only licensed vaccine, Bacille Calmette-Guérin (BCG), provides very limited protection against adult TB that leads to transmission (2), and therefore new strategies to control the disease are needed.…”

The Alternative Sigma Factors SigE and SigB Are Involved in Tolerance and Persistence to Antitubercular Drugs

“…Moreover, the recent selection and spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) mutants of Mycobacterium tuberculosis will threaten our ability to treat this disease in the near future (1). Even though the treatment of resistant M. tuberculosis strains has recently been facilitated by the approval of two new drugs, there is still the need to discover new molecules whose mechanisms of action could reduce treatment length, increase patient compliance, and lead to a reduction of mutant selection (2).…”