Global initiatives to fight tuberculosis are beginning to bring results, despite a continued lack of funds.
In developed countries, tuberculosis (TB) faded from public consciousness in the late 20th century, the result of vaccines and treatments that made the disease appear conquered. In recent years, however, TB has gained visibility once again, due in no small part to an alarming development: the increasing prevalence of deadly multi-drug resistant (MDR-TB) and extensively drug resistant (XDR-TB) tuberculosis strains.
Although multi-drug resistant strains are not new, recent studies have highlighted that the problem is much more serious than previously thought. Not only are these powerful strains of TB increasingly common and widespread-- XDR-TB has been detected in nearly 50 countries--they spread more easily than experts realized. According to Dr. Gail Cassell, Vice President for Scientific Affairs and Distinguished Research Scholar for Infectious Diseases at Eli Lilly, 60-70% of XDR-TB cases can be treated with existing drugs, but up to 40% cannot.
"To treat these strains we not only need a single new antibiotic, we need a combination of three or four new antibiotics, tomorrow," Cassell told Healthcare Briefing.
MDR-TB is defined by its resistance to first line drugs isoniazid and rifampicin, while XDR-TB resists those drugs as well as fluoroquinolone and at least one of three second-line drugs (kanamycin, amikacin, or capreomycin). These strains, some of which do not respond to any available medicines, arose in part from mismanagement of TB treatments. TB treatment courses are cumbersome and long, which decreases chances that patients (especially in resource poor settings) will complete them properly or at all.
A study published in The Journal of Infectious Diseases in 2007 challenges conventional wisdom that individual patient treatment failure is the main cause of TB drug resistance, however. Researchers at Shanghai Medical College, in partnership with other institutions including the University of California (Davis) School of Medicine, used molecular genotyping methods to analyze patient data from a five-year period. They found that "In Shanghai, the vast majority of drug resistance during therapy was not due to poor response to the initial treatment regimen or to an inadequate treatment regimen but rather to ongoing transmission of drug-resistant strains of M. tuberculosis."
"Previously it was thought that most strains of drug resistant TB [arose] because patients failed to take their drugs...but that's not what the current data suggests," Cassell said.
The discovery highlighted the urgency of developing new and improved diagnostic tools that identify MDR-TB strains rapidly, as well as the need for new classes of drugs to fight the disease.
Small steps toward funding TB research
Developing these tools has been difficult given dismal funding for TB research. Research and development has stalled since the 1960s, mainly due a lack of funding. The public sector is the largest funder of TB research, followed by philanthropic institutions, since pharmaceutical companies have little financial incentive to invest in tuberculosis research. Perhaps due to the fact that TB treatments have been administered for generations, the disease receives scant investment compared to other diseases, such as HIV/AIDS.
"Estimates of R&D funding for TB relative to HIV/AIDS vary depending on methodology, but even conservative estimates indicate TB funding is only about 5% of HIV/AIDS funding, considering the public sector," Dr. Ann Ginsberg, Head of Clinical Development at the TB Alliance, told Healthcare Briefing. "If one also takes private sector investments into account, the relative figure for TB drops dramatically."
Although estimated funding gaps total nearly US$400m per year, the 90 countries that bear the bulk of TB cases have experienced a small upsurge in funding over the past few years, according to information from the World Health Organization (WHO). In 2008, funding for TB control--which includes research programs, health system strengthening and other measures--reached US$3.3bn across those countries, more than three times the amount available in 2002. Although the investments remain insufficient, changes in how public and private sector actors develop drugs has helped kick-start a new wave of TB drug research and development.
Front-loading the clinical pipeline
To fight MDR and XDR-TB, pre-clinical and clinical drug pipelines must be as robust as possible to increase the chance of novel candidates being developed. A rise in public-private partnerships (PPPs), particularly product development partnerships (PDPs) such as the Global Alliance for TB Drug Development (TB Alliance), have accelerated work on both early and late stage research and drug development for TB.
"The PDPs....have really helped stimulate the field because we help to lower the barriers for the pharmaceutical companies to get involved; they see us as partners with specific TB expertise, and funding," Ann Ginsberg of the TB Alliance said. The private sector is "more likely to work on the discovery end if they know there will be somebody on the other end to help with the clinical trials."
Using this model, the TB Alliance has developed the largest TB drug pipeline in history. Their most advanced candidate, Moxifloxacin, is currently in Phase III trials in partnership with the drug's developer, Bayer. The trials, which began in early 2008 at several sites in Africa, seek to determine whether or not the drug, a fluoroquinolone, could be used in combination with others to reduce the regular course of TB treatment from six to four months. A reduction in treatment time would improve the chances that patients would complete their therapy, and complete it correctly. Unlike rifampicin, Moxifloxacin also avoids interactions with anti-retroviral therapies used by AIDS patients. Depending on the results, the TB Alliance may conduct additional trials to determine whether the drug can be used for forms of MDR-TB.
On the other end of the spectrum, the Lilly TB Drug Discovery Initiative (TB Initiative), a public-private partnership formed in 2007 by Eli Lilly and Company, The Infectious Disease Research Institute (IDRI) and the National Institute of Allergy and Infectious Diseases (NIAID), plans to identify targets and compounds that can be developed into new drugs to fill the (currently thin) early stage pipeline. Specialists from a range of fields will screen "new, validated targets" against Eli Lilly's chemical library of more than 500,000 compounds and several hundred compounds from Merck & Co.
In October 2008, the TB Initiative announced its first compound acquisitions. CPZEN-45, donated by Tokyo's Microbial Chemistry Research Foundation (MCRF), has already shown efficacy in MDR and XDR-TB infected mice, indicating that the antibiotic uses a novel mechanism of action. In addition, UK biotech company Summit submitted a novel class of compounds that are active against MDR strains. Researchers must conduct additional toxicology studies before either compound can be considered a clinical candidate.
Cutting down diagnosis time
The WHO estimates that less than five percent of MDR-TB cases are diagnosed, and only a portion of those are being treated. Conventional culture and drug susceptibility testing (DST) tools used to diagnose MDR-TB take up to three months, during which patients may spread the strains to others and/or develop resistance to other drugs in their current regimen. Many die before knowing they have it.
Although diagnostic tool developments receive very little funding compared with drug development research, more than a dozen new methods or approaches to TB diagnosis are currently in the pipeline. Perhaps the greatest achievement in TB diagnostics from the past several years is the development of line probe assays that can identify rifampacin and isoniazid resistance in less than two days.
In studies conducted by the South African Medical Research Council (SAMRC), the Foundation for Innovative New Diagnostics (FIND), and the National Health Laboratory Service (NHLS), researchers found that line probe assays are highly sensitive and can be introduced in high-volume public health laboratories, though specialized training and laboratory facilities are needed. Furthermore, the use of line probe assays in routine diagnostic algorithms could reduce lab costs by 30-50% compared to DST.
As a result of these and other studies, the WHO changed its official policies regarding TB diagnosis last year, calling for the use of line probe assays worldwide. To achieve this, the organization partnered with UNITAID, FIND, and the Stop TB Partnership to bring equipment and training for line probe assays to 16 countries over three years.
The introduction of line probe assays, and the development of early- and advanced-stage drug candidates, have provided hope that we may yet conquer TB, a disease has been ignored for far too long. Nonetheless, a great deal of investment of time and money is needed in order to control a disease that kills more than 1.5m people every year.