Long before the emergence of AIDS, SARS, and a host of other headline-grabbing infections, there was tuberculosis (TB). While the disease may have largely receded from the minds of many of those living in developed countries, this ancient scourge infects fully one third of the world's population and kills 2 million people each year, not including the 20% of HIV-infected individuals who die with active TB.
But no country is immune, as travel and immigration have brought the disease to all corners of the globe. Surveillance data show that 14 871 individuals with active TB disease live in the United States, less than half of whom are native-born (MMWR Morb Mortal Wkly Rep. 2004;53;209-214).
To complicate matters, the emergence of multidrug-resistant TB (MDR-TB) strains of Mycobacterium tuberculosis and coinfection with HIV are making it even more difficult to treat many patients today. Recently, however, more effort has been devoted to TB research because the economic and health benefits of tackling the disease outweigh the costs of ignoring the problem.
TB THEN AND NOW
Better therapies are urgently needed. While effective drugs exist that can cure most cases of the disease, more than 30 years have elapsed since rifampin (rifampicin), the most recently developed drug, became available. Mortality due to TB is increasing for the first time in more than 40 years.
"TB is one of the earliest organisms we identified as causing disease, and it has outwitted us for years," said Maria Freire, PhD, who heads the nonprofit Global Alliance for TB Drug Development, in New York City.
Part of the problem with current drug regimens is that the drugs must be taken over a 6- to 9-month period. Because achieving compliance can be difficult without close monitoring of patients, the World Health Organization (WHO) introduced today's standard TB therapy: directly observed treatment, short-course (DOTS). The number of individuals around the world needed to implement this system is enormous, noted Freire.
Despite its success, however, DOTS may have fostered complacency about TB, said Marilyne Bonnet, MD, of the nonprofit Médecins Sans Frontières (MSF), in Geneva, Switzerland.
"WHO promoted DOTS as the unique and fantastic strategy to control TB all over the world," she said. This may have created a perception that "for TB, we already had a strategy, so maybe there was less priority for the development of new diagnostic tools or new drugs," she added.
"We're putting the emphasis on DOTS because that's what you can do today," said Christopher Dye, DPhil, of WHO's Communicable Diseases, in Geneva. But the WHO is trying to diversify, said Dye, and is joining forces with other agencies, nonprofit organizations, and pharmaceutical companies.
OBSTACLES TO CONTROL
Complicating efforts is the emergence of MDR-TB, especially in countries that were part of the former Soviet Union. Resistant strains tend to emerge when patients taking standard drugs fail to complete the 6- to 9-month regimen needed for cure. Treating MDR-TB infection becomes vastly more difficult because standard drugs are ineffective against it.
"We're talking about 12 to 24 months of treatment, a much lower success rate, intravenous drugs, and unbelievably expensive drugs," explained Melvin Spigelman, MD, Director of Research and Development at the Global Alliance for TB Drug Development. This makes the need for newer, more effective agents even more urgent, he said.
Detecting the infection, which exists in a latent form and does not cause noticeable symptoms for years, is another obstacle to TB control effects, especially in developing countries.
"We haven't got a good field test yet that we can use for the majority of people with TB, because a lot of them live in very resource-poor settings," said MSF's Rowan Gillies, MBBS. Sputum microscopy is often used to diagnose TB, but more practical tests, such as serological tests and nucleic acid amplification, are being developed by companies and institutions such as the recently formed Foundation for Innovative New Diagnostics, a nonprofit governed by public health experts, business leaders, scientists, and patient representatives.
The WHO has set a goal to detect 70% of all TB and treat 85% of detected cases by 2005. In most parts of the world, treatment is close to the 85% goal. "But we're only currently at about 37% detection," said Dye. "In many peoples' minds, the number one obstacle to effective TB control is case detection."
INVIGORATED DRUG RESEARCH
Scientists are hoping that having the complete genome sequence of the best characterized strain of M tuberculosis in hand will help advance efforts to develop better diagnostic tests, drugs, and vaccines (Nature. 1998;393:537-544). Many research groups are working to identify key genes and proteins of the bacterium that might serve as potential therapeutic drug targets (Expert Opin Ther Targets. 2004;8:79-93). Some of the most promising targets include those that are important for the bacterium's metabolism—there are more than 250 genes involved in lipid metabolism alone. Others might be those that influence immunogenicity; along these lines, scientists are working on various ways to alter antigen presentation and boost host immune responses (Nat Rev Microbiol. 2003;1:97-105).
While clues from the genome have invigorated TB research, experts are not predicting that new agents will start gushing forth from the drug development pipeline. For one thing, scientists have had a difficult time fully understanding properties of the M tuberculosis's life cycle and metabolism; its complex biology allows the bacterium to persist in a dormant stage within host cells for years. In addition, there has been a lack of commercial interest in developing drugs for infectious diseases found predominantly in developing countries.
"I think people are coming to the conclusion that the private sector, left to its own devices, will never come up with good drugs, diagnostics, or vaccines for the developing world, because there aren't the market incentives," said Dye.
To overcome this, a number of public-private partnerships have formed to provide an economic incentive. "There's money to be made, and it is clear that there are ways to come up with new drugs through multilateral partnerships," said Ken Castro, MD, Director of the Division of TB Elimination at the Centers for Disease Control and Prevention, in Atlanta, Ga.
The Global Alliance for TB Drug Development is one such partnership that is attempting to accelerate the discovery and development of new medications. The organization is overseeing preclinical tests of a number of drug candidates, including nitroimidazopyrans and fluoroquinolones. The nitroimidazopyran PA-824 acts quickly, disrupts bacterial fatty acid and protein synthesis, and can kill both active and latent forms of TB. The fluoroquinolone moxifloxacin (currently marketed by Bayer Corporation for other bacterial infections) is now in phase 2 clinical trials for TB. It may also hold promise for MDR-TB (Am J Respir Crit Care Med. 2004;169:421-426).
But Gillies said that more drug candidates need to be entering the TB drug pipeline to increase the likelihood of a successful therapy reaching the clinic. "It's a good start, but drug development is a very difficult thing, and a number of drugs obviously won't work," he said. "You have to come at it from a lot of different angles, with a lot of urgency and cash."
VACCINE DEVELOPMENT
As valuable as new drugs could be, "vaccination is the ultimate control method for TB," said Dye. The current vaccine, bacille Calmette-Guérin (BCG), was developed in the early 1900s, and while it helps protect against childhood forms of TB, it provides variable protection in adults. WHO recommends BCG vaccination of neonates in countries with high rates of TB; the CDC advises its use in pediatric patients residing in settings where TB transmission is high and in healthcare workers who may be exposed to resistant TB strains.
Hundreds of new TB vaccine candidates are under study by academic centers across the United States, from the Harvard School of Public Health, in Boston, Mass, to Colorado State University, in Fort Collins, to the University of California, Los Angeles. Pharmaceutical companies and international institutions are also part of the endeavor.
Also, as with drug development, public-private partnerships are paving the way for vaccine research. The Bill and Melinda Gates Foundation recently awarded an $82.9 million grant to the Aeras Global TB Vaccine Foundation, in Bethesda, Md, to develop and test new TB vaccines. The grant will partner Aeras with academic institutions, governments, and companies in the United States and Europe, as well as in South Africa and other developing countries.
Candidate vaccine types include subunit vaccines, consisting of immunogenic mycobacterial components; DNA vaccines; live, attenuated mycobacteria; and live, attenuated nonmycobacterial vectors, such as Salmonella or vaccinia virus (Bull World Health Organ. 2002;80:483-488).
Aeras is collaborating with several basic researchers to design new candidate vaccines, with the goal of licensing and manufacturing at least one new and effective TB vaccine for worldwide distribution at a reasonable cost within the next decade, said Jerry Sadoff, MD, Aeras president and CEO. One approach is to develop a recombinant BCG bacterium that overexpresses a key TB antigen, thereby making the vaccine more immunogenic (Infect Immun. 2003;71:1672-1679). A second is to put genes from other bacteria, such as Listeria monocytogenes, into BCG. This might improve the vaccine because M tuberculosis hides and replicates within host cell vacuoles, while bacteria such as L monocytogenes survive in the cytoplasm. The insertion of a gene from L monocytogenes into BCG has been shown to result in better antigen presentation and increased T-cell immune responses (Proc Natl Acad Sci U S A. 1998;95:5299-5304).
Officials hope one or more of these will be successful. "If we have that magic bullet, then we can come up with a vaccination campaign—and then, end of story," said Castro.