NIH Reviews Status of TB Diagnosis and Treatment

Resistant strains hinder drug development

March 24 marks the day in 1882 when German microbiologist Robert Koch announced he had discovered Mycobacterium tuberculosis (Mtb), the bacterium that causes TB. Today, more than a century later, TB remains one of the world’s deadliest diseases, according to a new report from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The agency’s statement was issued in conjunction with World Tuberculosis Day 2016.

Quoting data from the World Health Organization (WHO), the NIAID reported that, in 2014, TB sickened 9.6 million people across the globe and killed 1.5 million people, mainly in developing countries. TB is also a leading cause of death in people with human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome (AIDS): In 2015, one in three deaths among HIV-infected individuals worldwide was due to TB.

Although most cases of TB are curable, certain forms of the bacterium that causes the disease are becoming resistant to the drugs designed to kill them, the NIAID said. Patient adherence to therapy was already difficult, as most TB regimens require taking medications daily for six months to two years. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB has caused significant setbacks in the effort to effectively treat and cure patients, the NIAID reported. According to the WHO, among 480,000 total cases of MDR-TB in 2014, 190,000 people (40%) died.

A key goal in TB drug discovery is to shorten the duration of standard treatment regimens for the disease. In an NIAID-supported trial, investigators are testing a higher dose of first-line rifampin over a shortened treatment period. In addition, NIAID researchers are collaborating with international investigators on studies of novel TB treatments. For example, the NIAID and its collaborators conducted a trial in more than 1,000 MDR-TB and XDR-TB patients in South Korea and China that demonstrated the efficacy of linezolid for the treatment of XDR-TB.

New diagnostic tools are in development to detect early Mtb infection more accurately and to identify and track drug-resistant strains. Many countries still diagnose TB by examining sputum samples under a microscope to detect TB bacteria; this approach can take a day to complete and cannot diagnose drug-resistant strains, the NIAID said. The agency contributed to the development of the GeneXpert diagnostic test, which can detect TB and MDR-TB within two hours. The test is now used in numerous countries, and the NIAID-supported TB Clinical Diagnostic Research Consortium––a group of researchers in the United States, South Africa, Uganda, Brazil, and South Korea—is working to expand the capability of the test to accurately detect XDR-TB. The NIAID is also funding a large-scale project at the Genomic Center for Infectious Diseases at the Broad Institute to sequence the genomes of drug-resistant strains of Mtb. These data will aid the development of TB diagnostics and rapid drug-susceptibility tests for MDR-TB and XDR-TB.

The WHO has estimated that approximately one-third of the world’s population is latently infected with Mtb, meaning that they do not show the symptoms of TB disease. A person with latent TB infection has a 5% to 10% risk of developing active, transmissible TB during his or her lifetime. The NIAID’s Tuberculosis Research Units program has helped to identify biomarkers that define the various stages of infection and is conducting animal and human studies to examine why most people with latent TB infection do not develop disease.

Safe and effective vaccines are critical to the effort to control TB globally, the NIAID said. The Bacille Calmette-Guérin (BCG) vaccine developed in 1921 is the only vaccine available for use against TB. It provides some protection against severe forms of TB in children; however, it does not reliably protect adults. New vaccines to replace BCG or to boost the immunity conferred by BCG are needed to protect against TB infection, disease, and disease recurrence, according to the NIAID. The agency is supporting research on candidate TB vaccines, including an investigational aerosol vaccine that induced immune responses in rhesus macaques and protected them against pulmonary infection with Mtb.

At least one-third of the 37 million people with HIV infection worldwide are latently infected with Mtb and are 26 times more likely to develop active TB disease than are those without HIV, according to WHO data. A 10-nation study conducted by the NIAID-funded AIDS Clinical Trial Group (ACTG) recently demonstrated that isoniazid was as effective as a standard four-drug empiric TB treatment regimen for preventing TB and reducing mortality in adults with advanced HIV/AIDS in high-risk regions. Another ACTG trial is testing a regimen containing bedaquiline and delamanid to treat patients with MDR-TB. TB also accelerates the progression of HIV infection to AIDS, making it the leading cause of death associated with HIV infection globally, the NIAID noted.

Source: NIH; March 24, 2016.