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The documents listed below are historical, archived information. The information contained in these documents, while accurate at the time of release, may not be the most current available.

The Plan

GOAL III: Develop new tools

Develop and assess new tools for the diagnosis, treatment, and prevention of TB.

Improving the application of current tools can enhance TB prevention and control efforts, but achieving the goal of TB elimination will require more. The United States needs to develop and then quickly and appropriately implement new technology to accelerate the decline in TB morbidity and make TB elimination a reality. In the long run, an effective vaccine would have the greatest impact on the ability to control and ultimately eliminate TB. However, new tools are also needed to improve the accuracy and speed of TB diagnosis and the effectiveness of TB treatment. The nation therefore needs to expand its research program, capitalizing on past investments and progress and creating critically needed new tools for diagnosing, treating, and preventing TB.

Objective III-A
Develop a coordinated plan for TB research.

NIH and CDC have the lead in federally funded research on TB. Other agencies involved in TB research include FDA, HRSA, the Veterans Administration (VA), the Occupational Safety and Health Administration (OSHA), the Indian Health Service (IHS), and the Department of Defense (DoD). Despite the involvement of each of these agencies in basic and operational research on TB, the nation lacks a clearly articulated research strategy that addresses each group's responsibilities and contributions. A coordinated research plan is needed to maximize efficiency, ensure attention to highest priority activities, and avoid duplication of efforts. In part to address this need and to move operational research forward, in 2001 the CDC established the Tuberculosis Epidemiologic Studies Consortium (TBESC). TBESC is composed of 22 collaborative research groups, each existing as a formal partnership between an academic institution and a state or metropolitan TB control program.

Activities

  1. Achieve consensus that a coordinated research plan is needed.
  2. Convene a meeting of representatives of interested public sector agencies and private companies to develop a prioritized list of research activities and to assign lead responsibilities for these activities.
  3. Disseminate the research plan.

Objective III-B
Develop new methods to diagnose persons with latent TB infection and to identify infected persons who are at high risk of developing active TB.

Achieving the goal of TB elimination will require increased attention to persons with latent TB infection and those at greatest risk of developing active TB.8, 11 Identifying and treating these persons can prevent the onset of active TB and interrupt the spread of disease. Until recently, skin testing with purified protein derivative (PPD) tuberculin was the only practical way to detect latent TB infection. In the United States, the tuberculin skin test (TST) is used as an initial screening test for both latent infection and active TB; a positive TST indicates an increased risk of subsequently developing, or currently having, active TB.59 Despite its widespread use and a large body of data on its standardization, the TST has several elemental shortcomings that limit its usefulness:

  • Persons infected with nontuberculous (environmental) mycobacteria and those previously vaccinated with BCG (an anti-TB vaccine used in many other countries) can test falsely positive.
  • Many conditions, most notably HIV-associated immunosuppression, can blunt the response to tuberculin and lead to false-negative results.
  • The lack of standardization in administering and reading the test can affect the results.59

A promising advance may address at least one of these limitations. The discovery of the role of T-lymphocytes and gamma-interferon in the immune process has led to the development of a blood test for cell-mediated immune reactivity to M. tuberculosis. An initial assessment of this test suggests that it may be useful in distinguishing persons with positive TST reactions due to BCG vaccination and sensitization by environmental mycobacteria.

In "Comparison of a Whole-blood Interferon Assay with Tuberculin Skin Testing for Detecting Latent Mycobacterium tuberculosis Infection," the authors conclude that the interferon assay was comparable with the TST in its ability to detect latent infection, was less affected by BCG vaccination, was able to discriminate responses due to nontuberculous mycobacteria, and avoided the variability and subjectivity associated with placing and reading TSTs (JAMA 2002;286:1740-1747).

TB control is also hampered by the inability to reliably identify infected persons who are most likely to develop active TB.11 Factors related to the progression from latent infection to active TB include 1) the intensity of the initial exposure, 2) recent rather than remote infection, and 3) medical conditions such as HIV infection that weaken immunity. A better understanding of the immunologic and genetic factors associated with the human response to TB infection is needed to predict which persons with latent infection are at highest risk of progressing to active disease. This information is also needed to guide the development of an optimal TB vaccine. Involving private sector biotechnology and pharmaceutical companies in collaborative endeavors will be increasingly important.

Activities

In coordination with other federal agencies

  1. Continue the development and assessment of cytokine-based assays for the diagnosis of latent TB infection. Continue support for studies of more specific mycobacterial antigens that might enhance diagnostic accuracy.
  2. Provide continued support for the development of specific skin-test antigens to improve the diagnosis of latent TB infection, and conduct studies of the usefulness of purified and specific antigens for TB skin testing. The immunologic response measured by skin testing differs from that assessed by cytokine assays, and it is possible that a combination of skin testing and cytokine assays will be able to better identify persons with latent infection who are at highest risk of progression to active TB.
  3. Through the TBESC, support and expand epidemiologic studies to identify immunologic and genetic markers that are associated with protection against TB and susceptibility to progression from latent infection to active disease.
  4. Develop and refine new molecular, biochemical, and immunologic methods for rapid, accurate, and cost-effective diagnosis of active TB and drug-resistant TB, including technologies for use in low-income countries.

Objective III-C
Assess new drugs to improve TB treatment and prevention.

Until the FDA approval of rifapentine in 1998, it had been more than 25 years since the introduction of a novel compound for the treatment of TB. Despite many calls over the past two decades for the development of new anti-TB drugs, the pharmaceutical industry has, with few exceptions, indicated little interest in undertaking work in this area. One factor impeding this pursuit is the erroneous perception that current drugs are adequate for the control of TB. In fact, new TB drugs are urgently needed to 1) improve current treatment regimens by shortening the duration of treatment and/or offering more widely spaced intermittent treatment; 2) improve the treatment of MDR TB; and 3) provide more effective treatment for latent TB infection.60

Although the current TB treatment regimens are highly effective, they are far from ideal. The main drawback is the prolonged duration of treatment; currently, at least 6 months of treatment is required. Not only is treatment lengthy, but the regimens are complex; the initial part of therapy requires taking four different medications. Although rates of serious adverse reactions are low, therapy can also be associated with unpleasant side effects.

To be effective, treatment must be continued to completion. The prolonged TB drug regimens are associated with high rates of nonadherence and subsequent increased mortality and creation of chronic drug-resistant cases.61 Development of drug resistance is far more likely when treatment is not supervised and when recommended regimens are not used. To ensure that patients take their medicine correctly, DOT is generally advised. New drugs that could be administered in shorter, simpler regimens would have the greatest impact on the TB problem in the near term.

As rates of MDR TB increase in many countries,44, 62 finding alternative drugs to improve the treatment of patients with drug-resistant TB is also a high priority. Patients with MDR TB must be treated with a combination of "second-line" drugs that are not only more expensive but also more toxic and less effective than the standard medications.63

The final impetus for the development of new TB drugs is to improve the treatment of latent infection. Among the approximately 2 billion persons worldwide with latent TB infection, an estimated 100 million to 200 million will develop active disease. In the United States and several other low-incidence countries, isoniazid has been used for the treatment of latent infection in persons at greatest risk of disease progression. Isoniazid has also been shown to be effective in preventing the development of TB in TB-HIV coinfected persons, and WHO has recommended the use of isoniazid in such persons.64 Because isoniazid therapy has significant limitations, however, new drugs to improve the treatment of latent infection are needed to eliminate TB from low-incidence countries.11

Historically, CDC has been the lead U.S. agency for the conduct of clinical trials to evaluate TB treatments. From 1993 to 1994, CDC contracted with investigators at academic medical centers, health departments, and VA hospitals to conduct U.S. Public Health Service (USPHS) Study 22, a randomized trial to evaluate rifapentine. The findings demonstrated the efficacy of once-weekly treatment for selected TB patients and are being used to update TB treatment recommendations being issued jointly by CDC and ATS.

From 1997 to 1998, CDC worked with the same group to establish the TBTC, an investigator-driven program modeled on the NIH-supported Community Program for Clinical Research in AIDS (CPCRA). The TBTC is evaluating rifapentine and other drugs to improve and shorten TB treatment and has embarked on a study of treatment of latent TB infection with a once-weekly, 12-dose regimen of rifapentine and isoniazid.

Globally, several countries with high rates of TB (e.g., Kenya, Uganda, South Africa, India, Brazil) also have considerable capacity to conduct clinical trials. In the past, CDC has supported TB research in several of these countries, and investigators at many sites are interested in collaborating on both treatment and prevention studies. Such studies would greatly facilitate the development of new treatment and prevention drugs that are needed not only in the United States and other industrialized countries but also in high-burden countries where the TB epidemic is most severe.

Activities

  1. Continue and enhance support for the TB Trials Consortium. Provide needed resources to both increase capacity at the research sites and recruit new sites, and collaborate with interested partners (within and outside the United States), so that ongoing and additional studies can be completed expeditiously.
  2. Encourage enhanced private-sector support and public- or private-sector collaboration for the development of new, effective drugs and other therapeutic interventions to improve the treatment of both active TB and latent TB infection.
  3. Work with interested partners to develop and support an international TB trials network.

Objective III-D
Develop a new and effective TB vaccine.

A concerted and sustained national effort to develop an effective new TB vaccine is crucial to eliminating TB from the United States and significantly reducing the global burden of TB. Vaccine development will require the sustained commitment of both private and public sector funds over several decades to support intramural and extramural research. Much of this work will fall within the mission of NIH, but CDC, as well as other federal agencies, have important roles to play.65

The Global Alliance for TB Drug Development is an international nonprofit organization whose vision is the provision of new medicines with equitable access for the improved treatment of TB. Its mission is to accelerate the discovery and/or development of cost-effective, affordable new TB drugs that will shorten or simplify treatment, provide a more effective treatment of multidrug-resistant TB, and improve the treatment of latent TB infection. The Global Alliance seeks to have a new drug that achieves these improvements registered by 2010. The Global Alliance is one of a new breed of public-private partnerships that pursue a social mission by drawing upon best practices, expertise, and resources from both the public and private sectors.

Activities

Assist relevant federal agencies and other national and international partners to

  1. Establish consensus among public and private funding agencies, vaccine manufacturers, and professional organizations that a new TB vaccine is an urgent public health priority. Identify a long-term commitment of private- and public-sector funds to support vaccine research.
  2. Develop a comprehensive vaccine development strategy that builds on the Blueprint for Tuberculosis Vaccine Development.39 The strategy should specify
    • Desirable characteristics of a new vaccine.
    • Action steps for vaccine development.
    • Roles and responsibilities of the public sector, industry, and academia.
    • Projected time line.
    • Estimate of resource needs.
  3. Increase biomedical research to define host factors for TB protection and susceptibility.
    • Expand basic research efforts to define 1) host factors that may protect against both the establishment of infection and the development of TB disease, and 2) the properties of the tubercle bacillus that permit it to survive years after the establishment of infection. Organize studies with hypothesis-generating protocols linking epidemiology, human immune status and response, and other physiological responses to TB infection and disease and the bacteriology of infecting organisms, taking advantage of the best available science, incident cases, contacts, and laboratory facilities.
    • Expand studies to determine the immunologic and genetic markers related to protection and progression from latent infection to active disease.
    • Determine correlates of protection for trial participants to facilitate vaccine trials.
  4. Develop new animal models for assessing vaccine efficacy.
  5. Increase collaborations between the private and public sectors for implementation of clinical vaccine trials.
    • Increase collaboration among CDC, FDA, and NIH5 through regular communications of the Federal TB Task Force.
    • Develop and foster relationships with international organizations (e.g., WHO), funding agencies (e.g., U.S. Agency for International Development [USAID], World Bank, private foundations), and vaccine manufacturers.
    • Convene a working group with representatives from these agencies to develop protocols for fieldtesting of candidate vaccines.
    • Identify vaccine trial sites in the United States and in high-incidence countries, and make immediate preparations for clinical testing. Avoid committing major funding expenditures for vaccine testing sites too far in advance of the availability of minimally suitable vaccine candidates.
    • Increase dialogue among the USPHS, FDA, WHO, USAID, vaccine manufacturers, and other interested parties (e.g., public health and medical communities, private foundations).
    • Seek collaborations domestically and internationally with public and private partners to advance vaccine development. Work with sister agencies and other national and international partners to enhance the activities of established groups that provide guidance and oversight on TB vaccine development.

Objective III-E
Develop and implement a program of research on behavioral factors related to TB treatment and prevention.

Despite the efforts of national, state, and local TB programs, nonadherence with prescribed treatment remains a major barrier to TB elimination.11 An additional weapon in the TB elimination arsenal is research to 1) understand behavioral factors related to TB treatment and prevention in patients and health care providers, and 2) design and implement methods for improving adherence with TB treatment. The IOM charged CDC with developing and implementing a behavioral and social science research agenda to promote this understanding as a needed "new tool" for achieving TB elimination.

The last national effort to assess the state of TB-related behavioral and social research was a conference conducted in 1994.66 The proceedings generated many ideas but produced no structure for planning and directing research. In the interim, much research has been conducted, and many promising practices and effective interventions have been implemented in state and local TB programs. Data and findings reside, however, with individual researchers and program staff. There is also a wealth of untapped but potentially transferable research on other health problems characterized by similar adherence issues. By comprehensively and critically examining these studies, a research agenda can be developed that builds on what works and that addresses current gaps.

Activities

  1. Collect information on current TB-related behavioral research.
    • Review published and unpublished materials to identify effective behavioral initiatives and best practices in the 68 CDC-funded TB control programs.
    • Select promising practices and initiatives, and conduct follow-up interviews to describe and identify the replicable aspects of each.
  2. Convene a meeting of experts to develop a research agenda.
    • Include a range of stakeholders, including researchers, program staff, CBOs, and policy makers.
    • Charge the participants with reviewing the status of behavioral and social science research as it relates to TB control.
    • Structure the meeting to identify existing and needed resources and information, set goals and objectives for a research agenda, and develop a plan of action for conducting behavioral and social science research related to TB control and prevention.
    • Establish working groups to review progress and revise and advance the agenda.

Objective III-F
Rapidly transfer findings from research studies into practice.

Successful implementation of new technologies will require education and training to produce changes in the practices of health care providers.

Activities

  1. Create messages, materials, and programs for health care providers to ensure their understanding and application of new developments in TB prevention and control.
  2. Base the messages, materials, and programs on established communication and behavior-change theories and models.
  3. Develop a communications/media strategy to ensure efficient transfer of new technologies into practice.
 
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