CDC's Response to Ending Neglect
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.
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.
- Achieve consensus that a coordinated research plan is needed.
- 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
- Disseminate the research plan.
Develop new methods to diagnose persons with latent TB infection
and to identify infected persons who are at high risk of developing
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
- 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
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.
In coordination with other federal agencies
- 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
- 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.
- 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.
- 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
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
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.
- 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.
- 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.
- Work with interested partners to develop and support an international
TB trials network.
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
|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.
Assist relevant federal agencies and other national and international
- 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
- 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,
- Projected time line.
- Estimate of resource needs.
- Increase biomedical research to define host factors for TB protection
- 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
- 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.
- Develop new animal models for assessing vaccine efficacy.
- 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
- Convene a working group with representatives from these
agencies to develop protocols for fieldtesting of candidate
- 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.
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.
- 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.
- 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.
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
- Create messages, materials, and programs for health care providers
to ensure their understanding and application of new developments
in TB prevention and control.
- Base the messages, materials, and programs on established communication
and behavior-change theories and models.
- Develop a communications/media strategy to ensure efficient
transfer of new technologies into practice.