Research and Development
The preceding review and analysis suggest at least six areas for economic and epidemiological research and development:
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DOTS expansion. Refinement of existing cost estimates of scaling up DOTS programs to reach and move beyond targets for case detection (70 percent) and cure (85 percent) in the poorest countries—notably in Africa—through more comprehensive planning and budgeting exercises. The analyses should include the costs of developing fully staffed health services, with expanded and renovated infrastructure and improved management capacity where necessary, and the costs of the new initiatives that will be required to improve case detection and cure rates.
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Service delivery. Assessment of the potential for health service restructuring to detect, diagnose, and treat TB patients more efficiently through syndromic management of respiratory diseases at primary health centers and through collaborations between public and private health services, between different parts of the public sector health service, and between TB and HIV/AIDS control programs.
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Complementary strategies. Further investigation of the costs and effectiveness of strategies that are potentially complementary to DOTS, including active case finding and TLTI in high-risk populations, and the management of drug resistance and of patients infected with HIV.
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Impact and targets. Evaluation of the actual and potential effects of the tools (mostly drugs) now being used for TB control. This research requires a better understanding of the ways human population density, age structure, migration, HIV coinfection, and drug resistance affect TB epidemiology. The analyses should check the internal consistency of international targets for the implementation and effect of chemotherapy programs, as defined by the MDGs. The analyses should also make better use of the rich body of routine surveillance data collected by all national TB control programs around the world.
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Risk factors. Assessment of the reductions in TB cases and deaths that could be made by reducing exposure to environmental risk factors, notably indoor and outdoor air pollution, tobacco smoking, and malnutrition. These risk factors affect the establishment of infection, the progression to active disease, and the outcome of treatment.
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New diagnostics, drugs, and vaccines. A sensitive and specific test for active TB that is cheap and simple to use at the first point of contact between patients and health services would be a major advance in diagnosis. Mycobacterial culture, which detects a higher proportion of active TB patients than sputum-smear microscopy, is a prerequisite for screening for drug resistance. However, present culture methods are slow, taking four to six weeks to obtain a result. Technology based on phage amplification and nucleic acid amplification can establish whether cultures are positive in days or hours, but this technology needs to be packaged for use in developing countries (Albert and others 2002, 2004; Johansen and others 2003; Woods 2001). The tuberculin skin test is being superseded in many developed countries by more specific methods for detecting infection (Doherty and others 2002; Pai, Riley, and Colford 2004). A test that can predict who will progress from latent to active disease, as yet hypothetical, would greatly increase the feasibility of treating latent infection.
Among a growing list of new vaccine antigens (Fruth and Young 2004), three of the most promising are now undergoing phase 1 safety trials in humans. One trial has evaluated mycobacterial antigen 85, delivered as a recombinant smallpox vaccine (Goonetilleke and others 2003). Another is testing a live attenuated BCG bacterium (rBCG30) that overexpresses antigen 85B protein and that provides guinea pigs with greater protection than BCG alone (Horwitz and others 2000). A third trial is assessing a fusion protein of two different antigens in adjuvant, referred to as Mtb72f, that is likely to be used as a booster to either BCG or rBCG30 (Reed and others 2003). Compounds that could form the basis of new drugs and new drug regimens include the nitroimidazopyran PA-824. Experiments with a mouse model of TB have shown that PA-824 has bactericidal activity similar to that of isoniazid and sterilizing activity that may rival that of rifampicin and that it is particularly active against dormant bacilli.
Among the most important recent discoveries is a diarylquinoline with a novel mode of action on the ATP synthase of M. tuberculosis that powerfully inhibits both drug-sensitive and drug-resistant strains of bacilli (Andries and others 2004). Alongside these laboratory studies, analytical and operational research are needed to find out what kinds of new tools will give the best returns on investment. Investigations of this kind will contribute to the introduction of new vaccines, drugs, and diagnostics and will inform the work of the Foundation for Innovative New Diagnostics (http://www.finddiagnostics.org), the Global Alliance for TB Drug Development (http://www.tballiance.org), and the AerasGlobal TB Vaccine Foundation (http://www.aeras.org).
