What is TB?
Tuberculosis (TB) is a bacterial disease that most commonly affects the lungs (pulmonary TB). In otherwise healthy individuals, most infections are latent and therefore asymptomatic. About 5% of people infected with TB will develop active disease within the first year after exposure and an additional 5% are likely to develop active TB from latent infection over the course of their lifetime. In immunocompromised patients, such as those with HIV, the risk of developing active TB from an infection increases to ~10% per year.
Global Burden
TB is a worldwide health problem. 27% of the global population – about 1.9 billion people currently have latent TB. Interestingly, 80% of the global burden is borne by only 22 countries. In fact, India and China bear one-third of the total TB burden.1 The World Health Organization (WHO) estimated that 1.4 million people died from tuberculosis in 2010.2 An estimated 12% of incident cases occurred in patients who were HIV positive.
| WHO Region |
Incidence TB (in thousands)1 |
| Africa |
2,800 |
| Americas |
270 |
| Eastern Mediterranean |
660 |
| Europe |
420 |
| Southeast Asia |
3,300 |
| Western Pacific |
3,300 |
| Total: |
10,750 |
Drug resistance and the growing global presence of drug resistant tuberculosis are alarming. Approximately 3% of cases are multidrug resistant (MDR – defined as resistant to both rifampin and isoniazid).
| WHO Region |
Incidence MDR-TB (in thousands)1 |
| Africa |
69 |
| Americas |
8.2 |
| Eastern Mediterranean |
24 |
| Europe |
81 |
| Southeast Asia |
130 |
| Western Pacific |
120 |
| Total: |
432.2 |
The four countries with the highest incidence of MDR-TB were:
- China: 100,000 cases
- India: 99,000 cases
- The Russian Federation: 38,000 cases
- South Africa: 13,000 cases
In 2010, the estimated incidence increased to 650,000 cases of MDR-TB.2 The WHO reported that as of July 2010 58 countries reported as least one case of extensively drug-resistant TB (XDR-TB, defined as MDR + resistant to at least a fluoroquinolone and .an aminoglycoside).
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Causative Agent and Transmission
Micrograph of M. tuberculosis under a
magnification of over 15000X
(photo: CDC/Janice Carr/Ray Butler)
Tuberculosis is caused by the acid-fast Gram-positive bacterium Mycobacterium tuberculosis. The bacteria are most commonly spread by aerosol; when a person with active pulmonary disease exhales, coughs, sneezes, or even talks, tiny droplets containing bacteria are produced that can be inhaled by others. Inhalation of these droplets can result in infection.
Pathogenesis
Tuberculosis infection usually results in either asymptomatic disease, known as latent TB, or active pulmonary infection, known as active TB. In approximately 90% of infections, the M. tuberculosis bacteria invade macrophages in the host lung but are rapidly encapsulated in a granuloma in the lungs formed by the host’s immune response. The bacteria remain alive and are able to replicate within the granuloma but do not cause symptoms. This stage of disease is referred to as the latent stage. Because the bacteria are sequestered, latent TB is not transmissible.
People living with HIV and infected with TB are 21-34 times more likely to develop active disease compared to those without HIV.7 When children present with TB it is more disseminated with greater incidence of extra-pulmonary TB.8
In about 5% of new infections and in an additional 5% of the infected patient population over time, M. tuberculosis escapes the control of the immune system or granuloma and replicates within the lungs or other tissues of the body. Active replication of M. tuberculosis in the lungs leads to symptomatic or active pulmonary disease. Symptoms include a cough lasting more than two weeks, coughing up blood, fatigue, fever, chills, night sweats, weight loss, or appetite loss. Lung damage is primarily attributed to the host immune response mounted against the bacteria.
Control Strategy
The WHO has developed an integrated strategy for TB control called the Stop TB Strategy. This initiative has six core components, including:
- Expanding and enhancing access to directly observed treatment, short course (DOTS; standard of care for TB treatment)
- Addressing TB/HIV co-infection issues, MDR-TB, and the needs of vulnerable populations
- Strengthening health systems with a focus on primary care
- Engaging all providers to promote the standard of care for TB
- Empowering TB patients and communities
- Promoting and enabling research for new drugs, vaccines, and diagnostics as well as operational studies of current tools
The goal of the Stop TB Strategy is to significantly decrease the burden of TB by 2015 and ultimately eliminate TB as a public health concern by 2050. Funding for TB control efforts is estimated to reach nearly US$5 billion by 2011.3
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Existing Products
Drugs
Standard treatment of active TB consists of combination treatment with four drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol, substituting in streptomycin for ethambutol if meningitis is observed) daily for 2 months followed by two drugs (isoniazid and rifampicin) daily for 4 months.4
The WHO recommends that all treatment be provided using the DOTS method. DOTS in an acronym for directly observed therapy short-course and refers to the use of observers, generally community or health care worker volunteers, to observe patients as they take their daily TB medications. The strategy improves patient adherence and reduces the risk of the development of drug resistance. The DOTS program extends beyond its original acronym definition to encompass a greater strategic approach for the treatment of TB including five principles:5
- Political commitment with increased and sustained financing
- Case detection through quality-assured bacteriology
- Standardized treatment with supervision and patient support
- An effective drug supply and management system
- A monitoring and evaluation system, and impact measurement
From 1995-2009, the Stop TB Program was able to successfully treat 41 million cases of tuberculosis, saving approximately 6 million lives.
Latent TB is treated in the developed world using one of four regimes: isoniazid monotherapy for 6 or 9 months, isoniazid and rifapentine for six months or rifamin for four months. Latent TB is not treated in the developing world except in patients with HIV co-infection.9
Rifampicin which is used in TB treatment regimens induces cytochrome P450 and this leads to metabolism and reduction in systemic exposure and effectiveness of HIV protease inhibitors.10
Vaccines
The bacille Calmette-Guérin (BCG) vaccine is the only vaccine available for the prevention of tuberculosis. BCG is a live attenuated vaccine prepared from an attenuated strain of Mycobacterium bovis. M. bovis is a bacterium that is related to human M. tuberculosis but primarily infects cows. In order to attenuate the live bacteria and produce the vaccine, the M. bovis was passaged in special media 230 times by a group of French scientists.
The BCG vaccine has been in use for more than 80 years and is known to protect newborn infants from TB-related meningitis and other systemic TB infections that can result from active disease. The reported vaccine efficacy in preventing primary TB infection, conversion of disease from latent to active forms, or pulmonary TB in adolescents or adults in the long-term is highly variable, with most studies showing little or no efficacy.
Diagnostics
Numerous diagnostic assays are available for TB, but each of the current assays has significant limitations for use in resource poor settings. The most commonly used diagnostics as well as their relative strengths and weaknesses are described below.
| Test |
Strengths |
Weaknesses |
| Sputum smear microscopy (SSM; using acid-fast staining) |
Key component of the DOTS therapy strategy employed by WHO to control TB |
Requires extensive training for low throughput results
Lack of sensitivity: 70% sensitive in TB patients, <50% sensitive in HIV positive TB patients, and cannot detect extrapulmonary or latent TB
Lower limit of detection (10,000 bacteria per mL of sputum) |
| Bacterial culture from sputum |
Gold standard
Can be used to determine drug susceptibility |
3-4 weeks to result
Cannot detect latent TB |
| Tuberculin skin test (Purified Protein Derivative, PPD, or Mantoux Test) |
Can detect latent TB |
Nonspecific
Patients with prior BCG vaccination have false positive
Cannot differentiate between latent and active TB
Does not work in HIV positive patients |
| Cellular assay from blood (Quantiferon-TB Gold, Cellestis Limited, Australia) |
Can detect latent TB even in patients with prior BCG vaccination |
Does not differentiate between latent and active TB |
| Nucleic acid amplification (Primarily used in research, one point of care test Xpert MTB/RIF by Cepheid available outside the US) |
Potential for use at the point of care
Can identify rifampicin-resistant infections without bacterial culture
Xpert MTB/RIF accurately diagnoses TB and MDR-TB in 100 minutes and is 26 countries are now using this system |
Expensive |
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In July 2011, the WHO released a recommendation against the use of rapid serological tests for active TB, calling them "inconsistent and imprecise," potentially leading to "misdiagnosis, mistreatment, and potential harm to public health."6
References
- WHO 2010 TB report.
- WHO 2011/2012 Tuberculosis Global Facts
- WHO Stop TB Factsheet.
- WHO (2010) Treatment of tuberculosis: guidelines – 4th ed.
- WHO (2006) The Stop TB Strategy: Building on and enhancing DOTS to meet the TB-related millennium development goals.
- WHO (2011) WHO warns against the use of inaccurate blood tests for active tuberculosis (News Release).
- WHO 2012 Tuberculosis Factsheet
- WHO Childhood Tuberculosis
- CDC, Treatment Regimens for Latent Tuberculosis Infections
- 10. Koul A. et al. (2011) “The challenge of new drug discovery for tuberculosis.” Nature, 469: 483-490
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Drugs
PIPELINE
ANALYSIS
Drug development for TB is rapidly expanding and improving. Several recent events have helped encourage this process including:1
- 2008-2009: Significant pledges of funding from the U.S. and U.K. governments to support TB drug development through TB Alliance.
- June 2009: First program for parallel development of a novel TB drug for both drug sensitive and MDR-TB launched by TB Alliance and Tibotec for the development of TMC207.
- March 2010: Launch of the Critical Path to TB Drug Regimens (CPTR) Initiative to reduce the time for development of novel TB drugs to <6 years, joint project between the Bill & Melinda Gates Foundation, TB Alliance, and the Critical Path Institute with support from the U.S. Food & Drug Administration (FDA).
- October 2010: The first proof of concept clinical trial (phase II) to evaluate new combination therapies for TB was initiated. This is the first evaluation in over 50 years of entirely novel drug combinations for TB, as opposed to substituting single new products into existing drug combination regimens.
Beyond government, non-profit, and product development partnership participation, TB drug development benefits from significant participation by the pharmaceutical and biotech industries. Companies participating in TB drug development include Anacor Pharmaceuticals, AstraZeneca, Bayer, Eli Lilly, GlaxoSmithKline (GSK), Lupin Pharmaceuticals, Novartis, Pfizer, Otsuka, Sanofi-aventis, Sequella, and Tibotec.
Tuberculosis has the largest and most diverse discovery and pre-clinical stage pipelines of the neglected diseases. Products span multiple drug target classes including, but not limited to:
- Nucleic acid synthesis
- Lipid biosynthesis
- Energy metabolism
- Proteases
- Kinases
- Protein synthesis
Additionally, multiple whole cell screens and projects to identify and develop natural products as inhibitors are underway.
| |
Strengths |
Weaknesses |
Opportunities |
Risks |
| Fluoroquinolones (Nucleic acid synthesis) |
| Most advanced program: Moxifloxicin, Phase III (Additional phase III product currently on hold) |
Known antibiotic
FDA approved for other indications since 1999
Most advanced stage product
Unique mechanism of action, inhibition of DNA gyrase, compared to on market products reducing risk for cross resistance and increasing potential for efficacy in MDR-TB |
Like existing TB products, known risks for liver toxicity or side effects in patients with hepatoinsufficiency |
Combination therapies with existing products and with other new products in development
Potential to shorten treatment course through new combination development
|
Low potential for safety improvement over existing drugs (related molecule, gatifloxicin, is on hold for TB development and is no longer being produced for use in the US for other indications due to adverse events)
There is pre-existing drug resistance due to wide use of this class of antibiotics for non TB indications. |
| Nitroimidazoles |
| Most advanced program: PA-824 and OPC-67683, Phase II (Additional programs in pre-clinical development) |
Unique mechanism of action compared to on market products reducing risk for cross resistance and increasing potential for efficacy in MDR-TB
Related molecules are FDA approved for other indications
Phase II data for PA-824 showed early bactericidal activity at lower drug concentrations than expected
|
Nitroimidazole analogs in use or in development for other diseases are known to have side effects |
Nitroimidazoles are in use or in development for multiple NTDS, so potential for overlap and data sharing among developers
Combination therapies with existing products and with other new products in development
Potential to shorten treatment course through new combination development |
|
| Diarylquinolines (Energy metabolism) |
| Most advanced program: TMC207, Phase II (Additional programs in discovery stage development) |
Unique mechanism of action compared to on market products reducing risk for cross resistance and increasing potential for efficacy in MDR-TB
Concurrent development for both drug sensitive TB and MDR-TB underway
Phase II clinical trial results using TMC207 as add-on to standard treatment for MDR-TB showed faster clearance of bacteria from sputum |
Caused significantly more nausea relative to current standard of care for MDR-TB in a phase II trial but did not result in discontinuation of treatment |
Most advanced product with clinical evidence for efficacy against MDR-TB
Combination therapies with existing products and with other new products in development
Potential to shorten treatment course through new combination development
|
Low potential for safety improvement over existing drugs |
| Oxazolidinones (Protein synthesis) |
| Most advanced program: PNU-100480, Phase II (Additional programs in phase I and discovery stages of development) |
Related to linezolid, an oxazolidinone used for the treatment of other bacterial infections
Unique mechanism of action, 70S ribosome inhibition, compared to on market products for TB reducing risk for cross resistance and increasing potential for efficacy in MDR-TB |
The related oxazolidinone, linezolid, has been reported to have serious neurologic, ophthalmologic, and hematologic toxicities associated with inhibition of mitochondrial protein synthesis.
However, phase I data with PNU-100480 suggests the toxicities are within tolerable limits |
Combination therapies with existing products and with other new products in development
Potential to shorten treatment course through new combination development
|
Safety profile in patients with TB, as compared to currently used drugs and other products in clinical development, remains to be determined
Not currently part of novel drug combination trials
|
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Vaccines
PIPELINE
ANALYSIS
For some diseases, full sterilizing immunity is essential to warrant the development and use of a vaccine. For tuberculosis, however, there are a variety of potential vaccination strategies that could have a significant impact on the control of TB. These include:3
- Pre-exposure vaccination (especially valuable if it works in HIV positive patients) to
- Prevent or at least delay TB reactivation from the latent form
- Achieve sterile immunity to M. tuberculosis
- Post-exposure vaccination
- To delay TB reactivation from the latent form (especially in HIV positive patients)
- As a therapeutic vaccine to kill M. tuberculosis (including prevention of latent infections)
Vaccines currently in development primarily focus on pre-exposure prevention of tuberculosis disease, although studies relating to prevention of reactivation of TB are also underway. The majority of studies rely on a heterologous prime-boost approach that uses combinations of vaccines based on different technologies and antigens to provide a more comprehensive immune response to infection. Studies of new vaccines as boosters in individuals with prior childhood BCG vaccination are the cornerstone of this approach.
Vaccination strategies for TB in the future will most likely include:
- New prime-boost studies using improved recombinant BCG vaccines as the “prime” component replacing the current BCG vaccine
- More extensive evaluation of clinical stage vaccines in alternate vaccination strategies (i.e., therapeutic, prevention of reactivation, safety, and efficacy in HIV positive populations)
| |
Strengths |
Weaknesses |
Opportunities |
Risks |
| Inactivated |
Most advanced program: M. vaccae vaccine (Preventive, Boost following BCG prime), Phase III
Additional product in phase II as a therapeutic vaccine |
Based on well accepted strategy for vaccine development |
Traditionally, inactivated whole cell vaccines primarily induce humoral immunity which may be less relevant for TB as it is an intracellular pathogen |
New recombinant BCG strains for improved prime are in development and provide potential for improved immune response in prime-boost combinations
Potential role in novel heterologous primer-boost combinations |
Multiple components of the immune response are important for mediating TB immunity but mechanisms of protection not fully understood
Immune stimulation through vaccination could worsen immune response-related damage |
| Recombinant/purified protein |
Most advanced program: M72 (Preventive, Boost following BCG prime), Phase II
Additional products in phase I development |
Based on well accepted strategy for vaccine development
M72 is being developed by GlaxoSmithKline (GSK) and has access to GSK’s proprietary adjuvants
M72 induces CD4+ T-cell response |
Unlikely to be sufficient for vaccine alone
Traditionally, recombinant protein vaccines primarily induce humoral immunity which may be less relevant for TB as it is an intracellular pathogen |
New recombinant BCG strains for improved prime are in development and provide potential for improved immune response in prime-boost combinations
Potential role in novel heterologous primer-boost combinations |
Multiple components of the immune response are important for mediating TB immunity but mechanisms of protection not fully understood
Immune stimulation through vaccination could worsen immune response-related damage |
| Viral vector |
Most advanced program: AERAS-402/Crucell Ad35 and MVA85A/AERAS-485 (Preventive, Boost following BCG prime), Phase II
Additional product in phase I development
|
AERAS-402/CrucellAd35 induces CD8+ T-cell response whereas MVA85A/AERAS-485 induces polyfunctional CD4+ T-cells, suggesting viral vector strategy can be used to simulate different components of the immune response |
|
New recombinant BCG strains for improved prime are in development and provide potential for improved immune response in prime-boost combinations
Potential to be first approved viral vector vaccine
Potential role in novel heterologous prime-boost combinations |
There are no FDA approved viral vector vaccines on market
Termination of adenovirus-based HIV vaccine trial in 2005 raised safety concerns which may lead to increased regulatory scrutiny
Multiple components of the immune response are important for mediating TB immunity but mechanisms of protection not fully understood
Immune stimulation through vaccination could worsen immune response-related damage |
| Live attenuated |
Most advanced program: AERAS-422 (Preventive, recombinant BCG to replace current BCG strain for priming vaccinations), Phase I
Additional product in discovery stage development |
Potential to replace current BCG for newborn vaccination as well as serve as the new prime for prime-boost vaccination strategies |
Finding populations with no history of BCG vaccination for later stage clinical efficacy studies may be challenging
Risk for causing symptoms in high risk populations (i.e., HIV positive) if attenuation is not sufficient |
Current BCG vaccine is highly variable in quality and efficacy, so improved rBCG has a high probability of replacing the existing vaccine
Potential role in novel heterologous primer-boost combinations |
Efficacy studies in newborns to replace current BCG entirely may be difficult |
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Diagnostics
PIPELINE
ANALYSIS
The potential for successful development of point of care diagnostics for tuberculosis is increasing. Although the Cepheid GeneXpert nucleic acid amplification device is now available outside the U.S., significant price reduction will be necessary before this or other molecular devices can be used effectively in resource poor settings.
Alternative inexpensive rapid diagnostic tests for use at the point of care in resource poor settings have been explored. Point-of-care rapid diagnostic tests are available for HIV, malaria, and a limited number of other diseases for use in resource poor settings. The majority of these tests are immune-based disposable lateral flow devices that are inexpensive and easy to use. An independent evaluation of 19 commercially available TB rapid diagnostic tests conducted by the WHO/TDR demonstrated that these products were far inferior to microscopic evaluation of sputum smears with sensitivity and specificity ranging from 0.97% to 59.7% and 53% to 98.7%, respectively.4 New biomarker innovation is needed before improved lateral flow rapid tests will be feasible.
Additional new tuberculosis diagnostic test development is ongoing through support of the Foundation for Innovative New Diagnostics (FIND) and other multilateral partnerships. Additional information on TB diagnostics in development is available through the Evidence-Based Tuberculosis Diagnosis site.
References
- TB Alliance (2010) 2010 Annual Report: More than ever it’s time for a faster cure.
- Schwalbe NR et al. (2008) “Estimating the market for tuberculosis drugs in industrialized and developing nations.” The International Journal of Tuberculosis and Lung Disease 12: 1173–1181.
- Kaufmann, SHE (2010) “Future vaccination strategies against tuberculosis: thinking outside the box.” Immunity 33: 567-577.
- WHO (2008) Laboratory-based evaluation of 19 commercially available rapid diagnostic tests for tuberculosis (Diagnostics evaluation series, 2).
Get Involved
To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs or contact us at globalhealthprimer@bvgh.org.