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Originally Published IVD Technology July/August 2005
Commentary
Global efforts to develop IVDs for tropical diseases
Roy R. Mondesire
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Roy R. Mondesire, PhD, is a former scientist in the special program
for research and training in |
The World Health Organization (WHO; Geneva) plays a major role in reducing the worldwide impact of diseases by leading the global effort in surveillance, prevention, control, and research. In each of these areas, the emphasis is on strengthening, reinforcing, and coordinating national and international systems. The special program for research and training in tropical diseases (TDR) is a global scientific collaboration within the communicable diseases cluster at WHO. Cosponsored by the United Nations Children’s Fund, the United Nations Development Program, the World Bank, and WHO, the TDR program helps to fight major diseases that disproportionately affect the world’s poor.
The TDR program consists of six matrix systems. The Science Strategy and Knowledge unit assesses and provides strategic and disease-relevant scientific information that can inform, monitor, and implement the program’s research strategy. It assists with the program’s assessment of research priorities related to tropical diseases. The Implementation Research and Methods unit is focused on research that provides evidence on new and improved methods for disease control and their health impact. Such research can assist national and other control programs with respect to policy and strategy development. Strategic and Discovery Research covers biomedical, strategic, social, economic, and product discovery research for identifying new targets for drugs, diagnostics, and vaccines, as well as socioeconomic issues on countries and diseases.
The Research Capability Strengthening unit is engaged in capacity strengthening that is intended to provide long-term support to institutions and research groups. Program Planning and Management is responsible for overall planning and management of the TDR program’s activities. Product Development and Evaluation works on developing new drugs and IVDs from a regulatory perspective, and undertakes clinical efficacy and safety evaluations of existing products.
The diagnostics division within the Product Development and Evaluation unit works with public and private sectors to promote the development of new, accurate, user-friendly, and affordable point-of-care tests for healthcare settings in developing countries. The division provides expert consultations that are used to assist with the overall diagnostic strategies. The diagnostics division also facilitates the evaluation and standardization of tests in developing regions by establishing specimen and strain banks in various geographic areas. Collectively, these approaches reduce the time required for test development and evaluation. Wider access to high-quality, low-cost tests is ensured when they are included in the WHO bulk-procurement scheme.
Diagnostics Focus on
the Diseases
Most of the diagnostics activity in the TDR program is devoted to 10 diseases, which are grouped into three categories. Category one consists of human African trypanosomiasis (HAT), dengue, and leishmaniasis. These diseases are considered to be emerging and uncontrolled. Category two includes malaria, schistosomiasis, and tuberculosis (TB). For these conditions, while a control strategy is available, the disease burden still persists. Category three comprises chagas disease, leprosy, lymphatic filariasis, and onchocerciasis. For these conditions, control strategies have proven effective, the disease burden is falling, and elimination is planned.
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Table I. Disease focus areas at the special program for research and training in tropical diseases. |
All of these diseases pose risks to not only residents but also travelers in endemic areas (see Table I). Outbreaks have occurred among travelers, and the risks are highest when there is an epidemic in progress. This is particularly true for vector-borne infections. Given the distribution of the diseases, the validation of the relevant diagnostic tests is conducted in geographically diverse settings within the affected developing countries.
Another diagnostics activity in the TDR program is the Sexually Transmitted Disease Initiative. This is an important initiative since more than 20 pathogens can be transmitted through sexual intercourse. Chlamydia, genital herpes, gonorrhea, human papillomavirus, syphilis, trichomoniasis, and HIV represent the most common ones. WHO estimates that more than 340 million new cases of curable sexually transmitted infections occur each year, with the majority occurring in developing countries. Such infections also dramatically increase the risk of HIV transmission. The initiative’s current priorities include developing and evaluating diagnostic tests for chlamydia, gonorrhea, and syphilis.
Diagnostics Challenges
Communicable and noncommunicable diseases are responsible for the deaths of approximately 57 million individuals each year. Infectious and parasitic diseases account for about 35% of these deaths.1 It is disturbing that despite the significance of this problem, there is a paucity of investment in research and development on such diseases. Early diagnosis with adequate and effective treatment is critical to managing such diseases.
Because of the invasiveness and complexity in the life cycles of some pathogens, diagnostic approaches may be more challenging. For example, two stages are recognized in the clinical presentation of HAT: the early hemolymphatic stage and the late encephalitic stage. Early diagnosis of this disease is necessary to preclude the onset of irreversible neurological disorders and prevent transmission. In HAT therapeutics, definitive stage differentiation of the disease is important, since inappropriate treatment of patients with central nervous system involvement will lead to death. Conversely, treating patients for central nervous system involvement during the early stages of the disease may result in severe drug toxicity.
Dengue presents another diagnostics challenge. In diagnosing dengue, numerous immunochemical and molecular approaches have been employed. Because of the dangers associated with dengue hemorrhagic fever, a test with a higher prognostic value for predicting the evolution of the disease into severe fever is required. Moreover, a clear differentiation from other flaviviruses, such as Japanese encephalitis and St. Louis encephalitis, is mandatory for accurate diagnosis. More recently, in attempts to improve diagnosis, measurements of nonstructural dengue proteins have been used in addition to detection of specific IgG or IgM antibodies to various viral components.
TB diagnostics are also not without complexities. Besides the need for higher test sensitivity and specificity, the ability to identify individuals with active TB is important. The smear sputum test identifies active pulmonary TB but not extrapulmonary TB, common among HIV-positive individuals. The clinical diagnosis of TB is further complicated by the fact that opportunistic infections in immunocompromised patients produce symptoms that are similar to TB. Interferon-g assays that are based on cocktails of TB-specific region-of-difference-1 antigens have shown some promise for TB diagnosis. However, few of these approaches have been validated for use in endemic countries with a high prevalence of latent TB, high Bacillus Calmette-Guerin vaccine coverage, and exposure to nontuberculosis mycobacteria.
Diagnostics Methods
For the majority of these diseases, traditional diagnostic methods are used. The specimen type depends on the disease being investigated, and blood, urine, saliva, sputum, or tissue biopsies are usually tested. Several diagnostic methods for antigen and antibody detection have been made commercially available. Such methods are generally based on immunofluorescence, particle or cell agglutination, enzyme-linked immunosorbent assays, chemiluminescence, rapid immunochromatographic techniques, and others.
The use of nucleic acid amplification tests offering sensitivity, specificity, and prognostic value that are higher than traditional diagnostic technologies is increasing. Examples of nucleic acid tests include transcription-mediated amplification, polymerase chain reaction, reverse transcription polymerase chain reaction, nucleic acid sequence–based amplification, strand displacement amplification, and loop-mediated isothermal amplification.
Despite the availability of new and powerful tools in genomics, immunochemistry, and engineering, many commercially available tests for tropical diseases are deficient in a number of ways. For example, most of the test kits lack well-documented performance characteristics. They are relatively expensive, and few have received regulatory approval in the United States or the countries of need. Several IVD manufacturers and investigators have been exploiting progress in protein and nucleic acid microarrays, microfluidics, and various types of biosensors for tropical disease diagnostics. However, manufacturers must address the critical attributes of affordability, robustness, and ease of use that allow such newer methodologies and platforms to be implemented in developing countries.
Collaborative Efforts
More funding is needed to improve health conditions through the use of better diagnostics and treatment in developing countries. For example, confirmation of cure and early detection of drug-resistant organisms will assist in making health systems more effective in disease control. Despite this need, only 10% of the funds that are spent annually on health research are designated for research into 90% of the world’s health problems.2
In order to meet future diagnostics needs, the TDR program collaborates with IVD manufacturers and other institutions. For example, the program awards grants on a competitive basis for the application of new technologies for disease diagnostics. Proposals are encouraged from groups working on routine IVDs and in disciplines such as bioinformatics, functional genomics, and the physical and chemical sciences.
The potential profits to be realized by IVD manufacturers can be substantial. Manufacturers should invest in relevant scientific research and engineering, and keep in mind the needs of the countries where the tests will be used.
Exciting new opportunities have emerged out of the TDR program’s efforts. For example, the program served as an incubator for the Medicines for Malaria Venture (MMV). In 1999, MMV was launched as an independent nonprofit foundation for expanding antimalarial drug discovery and development projects.
Another group emerging from the TDR program is the Foundation for Innovative New Diagnostics (FIND). In 2003, FIND was launched in conjunction with the Bill and Melinda Gates Foundation, and represents an expansion of ongoing efforts to find and develop new diagnostics for neglected infectious diseases. FIND and the TDR program have developed a joint work plan to deliver new and affordable tools for TB to the public sector. The establishment of these organizations to address specific needs is an example of how the TDR program can initiate new activities in partnership with other organizations.
Conclusion
The risk of major epidemics means that surveillance and ongoing control measures must be maintained in developing countries. IVD manufacturers must dedicate appropriate research and development to deliver high-quality diagnostic products to developing countries. Dedicated and sustained global efforts to understand and manage tropical infectious diseases are necessary to prepare for emerging, re-emerging, and new threats to global health.
References
1. “World Health Report 2004,” the World Health Organization Web site (Geneva: [accessed 2 June 2005]); available from Internet: www.who.int/whr/2004/en/index.html.
2. “10/90 Report on Health Research 2003–2004,” Global Forum for Health Research Web site (Geneva: [accessed 2 June 2005]); available from Internet: www.globalforumhealth.org/ site/002__What%20we%20do/005__
Publications/001__10%2090%20reports.
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