Tuberculosis pipeline introduction
Dr. Robert Kochs identification and characterization of Mycobacterium tuberculosis (MTB) as the cause of tuberculosis (TB) in 1882 was fundamental in proving the relationship between microorganisms and disease, which revolutionized the study and treatment of infectious diseases. The first randomized control trialconsidered the gold standard for clinical trialsevaluated streptomycin for the treatment of TB. By the mid-1980s, six-month combination treatment with four drugs could cure 95% of TB cases. However in the 1980s TB research went into hibernation, and despite all of these significant contributions, the scientific community failed to understand or control MTB. The microscopeused by Dr. Koch to discover MTBis still the most commonly used diagnostic tool but detects fewer than 19% of all TB cases worldwide. A new class of TB drugs has not been approved in over 40 years; and some of the most powerful current drugs cannot be used with certain anti-HIV treatments. Calmette-Guérin (BCG), the only licensed vaccine for TB disease, is almost 90 years old and offers little to no protection from pulmonary TB. Decades of neglect by funders, scientists, and political leaders has led to the unacceptable situation today where there are more TB cases than every before. To successfully treat and cure TB disease, we must renew our commitment to use all our resources to accelerate the development of better vaccines, drugs and diagnostic tools.
Mycobacterium tuberculosis is a large, complex bacterium that causes tuberculosis disease in humans and other mammals. TB is a highly contagious disease that spreads from person to person when an infectious person discharges TB bacilli (germs) into the air by coughing, which are then inhaled into the lungs by another individual. Risk of infection increases in crowded environments with poor ventilation, and little to no sunlight or ultraviolet light exposure (Escombe 2009).
Approximately 90% of persons infected with TB are able to contain the bacilli for their entire lives and may never even know that they are infected with TB. Once the TB bacilli enter the lung, the immune system sends cells to contain the bacteria and trap it in immunological prisons called granuloma. When this happens, TB does something that science has yet to fully understandit changes its diet and stops and/or significantly slows down replication. At this point, TB is in latency. Most people latently infected with TB are able to maintain this state for the rest of their lives.
Despite the ease of transmission and the fact that one third of the worlds population2 billion peopleis latently infected with TB, the disease is a disproportionately low priority on the global health agenda, as manifested by the lack of political will, meager funding, and inadequate progress against the disease. The majority of people infected with latent TB infection (LTBI) are able to contain the bacilli from causing symptoms and pose no risk of infecting others. However, annually, approximately 10% of those with LTBI go on to develop active TB disease. In 2008, an estimated 9.4 million people developed active TB disease (WHO 2009). Little is known about what triggers LTBI to progress to active TB disease but once TB is able to break out of its immunological prison, it is considered to have progressed to active TB disease. Children under the age of five, and people who are malnourished and/or immune-compromised are at increased risk of disease progression. In most cases, active TB disease develops in the lungs, but it can also manifest in other parts of the body (extrapulmonary TB)which is much more common in infants, young children and people with HIV.
TB is a preventable and curable disease. Yet it is a killer, especially for pregnant women, children, people with HIV, and others who are malnourished or suffer from immune suppression. In 2008, TB claimed the lives of 1.82 million people, of which 500,000 occurred among people infected with HIV, making it the leading cause of death for people with HIV (WHO 2009).
These data reveal TB control efforts are failing, and that the Millennium Development Goal (MDG) to halt and reverse the incidence of TB by 2015, and eliminate it as a public health threat by 2050 will not be met. In 2008, the case detection rate for all forms of TB was only 61%, and the treatment success rate for reported TB cases in 2007 reached 86%the first time this indicator has met the 85% target set by the World Health Assembly in 1991 (WHO 2009).
Despite the availability of drugs to treat and cure up to 95% of drug-susceptible TB casescontrol efforts are weakened by concurrent HIV in Africa, soaring multidrug-resistant (MDR) TB rates in the former Soviet Union, and weak health systems almost everywhere.
Multi-drug resistant (MDR) and Extensively drug-resistant (XDR) TB
Over the past 62 years, MTB has been exposed to single and multiple chemotherapy regimens, allowing MTB strains to evolve when treatment is inadequate, incomplete, intermittent, or inappropriate. Failure to properly treat drug-susceptible TB leads to the emergence of circulating strains of drug resistant TB. Multidrug-resistant (MDR-TB) and extensively drug-resistant TB (XDR-TB) are two types of drug-resistant TB strains defined by the number and types of drugs the TB bacilli are resistant to. MDR-TB is TB bacteria that are resistant to two of the most powerful first-line drugs, isoniazid and rifampicin. XDR-TB is TB bacteria that are resistant to any of the fluoroquinolone drugs (cipro-, gatiflox-, levo-, moxiflox-, or ofloxacin) and any one of the three second-line injectables (amikacin, capreomycin, or kanamycin), as well as isoniazid and rifampicin. Inadequate health and TB control systems facilitate the creation of drug resistant TB because they fail to properly treat drug-susceptible TB. Treatment for drug-susceptible TB normally involves a 6-8 month treatment regimen using four oral TB drugs, but patients regularly face adherence obstacles due to the high pill burden, drug-to-drug interactions, toxic side effects, drug stock outs and/or length of treatment. Consequently, when treatment is inconsistent, inadequate, or interrupted, the TB bacteria begin to mutate, develop resistance to the anti-TB medication, multiply and make the individual sick again.
Treatment for drug-resistant TB is complex and expensive. Diagnosis of MDR or XDR-TB requires sophisticated diagnostic tools, technicians and laboratory capacity, which are limited or non-existent in resource poor regions that need it most. The World Health Organization (WHO) estimates there were 500,000 new cases of MDR-TB in 2007the highest number of MDR cases ever reportedof which only 30,000 cases were confirmed, and a mere 1% were started on treatment (WHO 2009a).
TB diagnostics, prevention, treatment and care challenges
Sputum smear microscopy, the most commonly used TB diagnostic tool, is over 125 years old. The test involves collecting a sputum sample coughed up from the lungs of a patient suspected of having TB, staining the sample, and identifying the rod-like shaped MTB bacteria under a microscope. Smear-positive TB is a diagnosis confirming the presence of actively replicating TB bacteria in the lungs. Unfortunately, the sputum smear test is not very accurate and at best captures 62% of new smear positive cases (WHO 2009). The smear test functions particularly poor among children and immune-compromised individuals who have low bacterial load in their sputum, and is unable to diagnose TB outside the lungs or drug resistant TB (WHO, 2009). For instance, among people with HIV, smear microscopy detects only ~ 35% of cases (Corbett 2003), resulting in misdiagnosis and delays in accessing life-saving TB treatment.
The HIV pandemic highlights the urgent need to develop an easy to use TB point- of-care diagnostic test that can perform well in health posts that do not have regular access to running water, electricity, or skilled laboratory technicians. This tool would benefit all people with TB that are currently unable to get accurate diagnoses, but will be especially helpful for TB/HIV coinfected persons and children who are at greater risk for disease and death. In low and middle-income settings, where high HIV-related TB is prevalent, new diagnostic tools for use in health posts can be a major step forward in TB control by detecting more cases of HIV-infection related TB, connecting people to TB care more promptly, decreasing TB transmission in the community, and preventing future cases of drug-resistant TB (Dorman 2010).
In sub-Saharan Africa, where up to 70% of people with TB are HIV positive (WHO 2010b), health workers who suspect TB in the absence of a sputum smear positive test are recommended to use a culture test to confirm pulmonary or extrapulmonary TB disease (Getahun 2010). This test involves a lengthy process where sputum or other clinical samples are collected from a TB patient and placed in a solid or liquid media and left to grow until detectable. If TB grows in the media, the person is said to have a positive culture test (i.e. active TB disease). Since MTB multiplies once every 16-20 hours through a process known as binary fission, a clinician must wait 3-4 weeks to confirm drug-susceptible TB and up to 16 weeks for drug resistant TB strains using solid media. In settings where liquid culture is used, bacterial growth can be observed in 8-11 days or two to four weeks for drug-susceptible and drug-resistant TB, respectively.
Relying on a culture test not only requires time, but a well-resourced laboratory with skilled technicians and good biosafety measures to prevent contamination and protect laboratory personnel from infection. In low and middle-income countries, clinicians sometimes rely on one laboratory to culture TB bacteria for the entire country, leading to further delays and weak quality control (WHO 2009). Over the course of 3-4 weeks, a patient without treatment can infect at least three more individuals (Beresford 2010) and be at increased risk of TB morbidity and mortality.
The most widely administered vaccine in the world is the Calmette-Guérin, or BCG, the only vaccine licensed for TB. With over 100 million doses administered per year, it is estimated that the lives of over 40,000 children are saved annually. Unfortunately, BCG causes a potentially fatal reaction in HIV-infected infants and children and is therefore not recommended for use in this population. Considering that infants, children and people with HIV, at any age, are at increased risk for TB disease progression, a new vaccine that is safe and effective for these vulnerable populations is vital to eradicating TB.
First-line TB treatment in people with HIV presents special challenges not seen among HIV-negative persons with TB. Among them are increased length of treatment, increased risk of drug toxicities, and higher pill burden and drug-drug interactions when TB treatment and anti-retroviral (ARV) treatments are taken together (Sterling 2010). Nevertheless, treatment success is possible if patients receive ongoing support and coordinated care, including careful monitoring of clinical outcomes for both TB and HIV.
From a prevention angle, data from clinical trials examining the use of ART before, during and after anti-TB regimens shows that early initiation of antiretroviral treatment (ARV) can greatly reduce the risk of developing active TB disease among people with HIV (Getahun 2007), and improve survival rates for HIV-infected individuals with confirmed active TB disease (Sterling 2010). Along with ARV treatment, a 6-9 month regimen of 300 mg of isoniazid preventative therapy is also recommended by WHO for people with HIV, once active TB disease is ruled out (WHO 2007c).
TB continues to outpace our gravely inadequate current global response efforts. The growing rates of HIV-related TB, MDR and XDR-TB underscore the need for bold leadership to mobilize resources that can address the serious gaps in our TB control efforts. To halt and reverse the incidence of TB by 2050 requires a substantial investment in funds to develop and roll out new TB diagnostic tools, better vaccines, and more tolerable TB treatments for use in resource-constrained settings. This investment is estimated at two billion dollars per year (TAG 2010) to meet research targets around new drugs, vaccines, diagnostics, basic science, applied and operational research. Since TB disproportionately impacts children and people with HIV, these new tools must address research and programmatic challenges to meet the needs of the communities at greatest risk for TB (Chamie 2010). The following chapters discuss in detail the latest developments in TB treatment, vaccines and diagnostics, and outline specific recommendations on how to move the research agenda forward.
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Chamie G, Luetkemeyer A, Charelbois E, Havlir DV. Tuberculosis as part of the natural history of HIV infection in developing countries. Clinical Infectious Diseases: Synergistic Pandemics: Confronting the Global HIV and Tuberculosis Epidemics. 2010 May; 50(3): S245-254.
Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med. 2003; 163; 1009-1021.
Dorman, SE. New Diagnostic Tests for Tuberculosis: Bench, Bedside, and Beyond. Clinical Infectious Diseases: Synergistic Pandemics: Confronting the Global HIV and Tuberculosis Epidemics. 2010 May; 50(3): S173-S177.
Getahun H, Gunneberg C, Granich R, Nunn P. HIV infection associated tuberculosis: The epidemiology and the response. Clinical Infectious Diseases: Synergistic Pandemics: Confronting the Global HIV and Tuberculosis Epidemics. 2010 May; 50(3): S201-S207.
Getahun H, Harrington M, OBrien R, Nunn P. Diagnosis of smear-negative pulmonary tuberculosis in people with HIV infection or AIDS in resource-constrained settings: informing urgent policy changes. Lancet. 2007; 369; 2042-2049.
Sterling TR, Pham PA, Chaisson RE. HIV Infection-Related Tuberculosis: Clinical Manifestations and Treatment. Clinical Infectious Diseases: Synergistic Pandemics: Confronting the Global HIV and Tuberculosis Epidemics. 2010 May; 50(3): S223-S230.
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WHO (a). Global Tuberculosis Control Epidemiology, Strategy, Financing. March 2009.
WHO (b). Joint TB/HIV Interventions. Accessed June 3, 2010 from http://www.who.int/hiv/topics/tb/tuberculosis/en.
WHO (c). Tuberculosis care with TB-HIV co-management: Integrated Management of Adolescent and Adult Illness (IMAI). 2007.