Neglected Tropical Diseases: Moving Beyond Mass Drug Treatment To Understanding The Science
- Adel Mahmoud (amahmoud{at}princeton.edu)
Abstract
Neglected tropical diseases (NTDs) represent a major health burden in many developing countries. To date, global efforts to control thirteen parasitic and bacterial infections that affect more than 1.4 billion people have relied on mass drug administration. This singular approach should now be expanded to a more comprehensive suite of tools including coordinated community-based programs, vector control, local training, education, and environmental change. In addition, an intensive basic research agenda is urgently needed to develop effective diagnostic, preventive, and therapeutic interventions to stay one step ahead of the evolutionary adaptation tactics of disease-causing microbes and parasites.
We need different strategies to stay ahead of these evolving microbes and parasites.
Neglected tropical diseases (NTDs) represent a set of conditions whose group label is derived from the paucity of efforts directed to their alleviation. The widespread use of drug therapies for reducing the burden of disease caused by helminths (parasitic worms) was introduced several decades ago.1 Recently, this approach—which treats the entire local at-risk population, not just infected individuals—has been extended to the control of most neglected tropical diseases caused by a heterogeneous group of infectious organisms (Exhibit 1⇓).2 Widespread drug therapy has had a short-term impact on parasite burden in Africa, Asia, and Latin America.3 However, experience to date raises questions about the sustainability of such results. A major concern is that the “top-down” design of these programs often underemphasizes the need to develop locally adapted strategies to achieve acceptability and sustainability.4
List Of Neglected Tropical Diseases (NTDs) With The Highest Burden Of Illness That Are Commonly Targeted In Control Programs Worldwide
Development Of Drug-Therapy Strategies
The role of mass drug administration in controlling infection and disease caused by Schistosomiasis mansoni, a type of parasitic worm, was first proposed in landmark studies in Brazil and Egypt, respectively, by Kurt Kloetzel5 and Abdel Fattah Sherif.6 Both obtained epidemiologic evidence that drug therapies reduced some of the major clinical manifestations caused by this parasite—enlarged liver and spleen. These fundamental findings were extended in the 1970s by taking advantage of newer, more effective, safer, and orally administered antischistosomal drugs. Targeted drug therapy and population-based treatment programs were adopted as major components of schistosomiasis control strategies globally7 and were advocated by multiple agencies, including the World Health Organization (WHO).8
This approach has been expanded recently to a large set of NTDs, even though they represent a very heterogeneous group of infectious agents.2 The targets for current programs in mass drug administration include soil-transmitted helminths, lymphatic filariasis (which causes the painful disfigurement known as elephantiasis), onchocerciasis (river blindness), and trachoma (the world’s leading cause of preventable blindness). But recent investigations suggest that there are limits to this singular drug-therapy approach.
Community communication.
In their recent study in Uganda, Melissa Parker and colleagues demonstrated the challenges facing a national neglected tropical disease control program.4 Uganda was one of the first countries to implement the Schistosomiasis Control Initiative and similar measures to control soil-transmitted helminths. The program faced typical difficulties with distribution and effective delivery of antischistosomal drugs as well as problems convincing adults of the safety and necessity of the therapy.4 The authors concluded that expanding the educational and informational components of the program and establishing a well-articulated communication plan with local populations would have improved the program’s success.
Long-term effects on children.
A second concern was related to the long-term effects on children’s growth and school performance.9,10 In their detailed assessment of the outcome of drug therapy for NTDs in published reports, David Taylor-Robinson and colleagues9 examined data from thirty-four drug trials to treat soil-transmitted helminthes. They found no consistent long-term effect in relation to body-weight gain or cognitive and school performance for school-age children enrolled in most of these studies.
Reinfection and drug resistance.
Reinfection and the emergence of drug-resistant organisms call into question the sustainability of the drug-only approach to neglected tropical diseases.11 Current evidence for detection of varying degrees of resistance (Exhibit 2⇓) questions the advisability of relying on a single-minded, mass treatment approach to controlling NTDs when experience indicates that success may require multiple coordinated strategies.12 The scientific basis for drug-only programs also requires reassessment given the current paucity of our fundamental knowledge of the biology, epidemiology, and molecular organization of these organisms and their interactions with humans and vectors (organisms, most often insects, that transmit infection).
Examples Of Reported Studies On Development Of Varying Degrees Of Resistance To Drug Treatment In Neglected Tropical Diseases (NTDs)
Resetting The Agenda For Neglected Tropical Diseases
Scientific assessment indicates the necessity of resetting strategies for global control of neglected tropical diseases. The primary objective should be to reshape the approach from predominantly drug therapy to comprehensive, multifaceted, and coordinated community-based programs with rigorous and independent evaluation. In the meantime, intensification of the basic research agenda, as advocated by many,13,14 is urgently needed. The only way to discover effective diagnostic, preventive, or therapeutic tools is to stay one step ahead of microbial evolutionary adaptation tactics.
The five essential components of a new neglected tropical diseases agenda are as follows: (1) a comprehensive, multifaceted, community-based program using all available control tools; (2) well-articulated, transparent, and independent monitoring and evaluation; (3) intensification of basic investigation of NTDs; (4) discovery and development of new diagnostic, therapeutic, and preventive approaches; and (5) expanded and qualified human capacity to guide, lead, and implement these strategies at the local level.
Past experience.
Examining the experience during the twentieth century indicates that successful control efforts for infectious diseases were based on multiple approaches.15 From the hookworm campaign in the U.S. Southeast16 to controlling schistosomiasis in some countries,7 it was the comprehensiveness of control programs that resulted in success. While vaccination as a single-based strategy worked in the case of smallpox eradication, additional successes have been difficult. In the case of polio, much progress has been made, but eradication has proved elusive. Furthermore, controlling several infectious diseases through vaccination as is practiced in many countries, effective in the short term, is dependent on maintaining rigorous and regular administration of vaccines to every new age cohort.17
Recent changes.
In recent years, attempts to expand drug-based NTD control programs to include additional approaches have begun, as well as efforts to integrate these programs into a broader agenda for health in developing countries. For example, in a recent editorial, former U.S. Ambassador to the United Nations Thomas Pickering called for a UN General Assembly meeting to identify initiatives to alleviate world poverty by focusing on the combined challenges of disease, hunger, and underdevelopment.18 Overcoming neglected tropical diseases would certainly be part of such a conversation. The often repeated call for “beyond deworming” is an expression of the need to expand further the effort against infectious diseases.19
Examples of comprehensive programs.
The issue is related not only to what resources are available but also to what will work and be sustainable. For example, the Asian Center of International Parasite Control has expanded activities in the Greater Mekong region (Cambodia, Laos, Myanmar, Thailand, Vietnam, and China’s Yunnan Province) to integrate school deworming programs with many development and health improvement projects.20 The aim is to place drug therapy for NTDs within the framework of health-promoting school activities.
The case of insect-transmitted NTDs is another example of the necessity of multiple complementary approaches to control. By applying certain statistical research methods, it was possible to determine that single “one size fits all” approaches were unlikely to succeed at controlling the disfiguring disease lymphatic filariasis.21
The existence of complex system dynamics in filariasis and many vector-transmitted NTDs demonstrates the necessity of including vector control along with mass drug therapy and other measures to achieve sustainability of program goals. It is these kinds of analytical tools of parasite-transmission ecology that must constitute the basis for strategic control imperatives.
Progress in mathematical modeling of the multiple parameters relevant to control is another key development that requires a much more intensified effort involving biologists, mathematicians, and sociologists to articulate what should be the targets of NTD control efforts. Currently, there is no consensus on program goals because of insufficient evidence, and the research in this field is still limited. Eradication or elimination is a desirable long-term strategy. However, the scientific basis for feasibility of such goals needs to be more rigorously established in all cases.
Scientific challenges.
We are still facing major gaps in our fundamental understanding of the infectious agents causing NTDs and their molecular mechanisms of interaction with vectors and hosts. Recent efforts to sequence the genome of several micro- and macroparasites and their insect intermediate hosts hold great promise.22–25 Macroparasites are multicellular organisms that have specific biological features such as a long reproductive cycle, slow rate of acquisition of infection in humans in most endemic areas, and, sometimes, inability to reproduce within the definitive human host.26 Microparasites are unicellular, or smaller, organisms like protozoa, bacteria, and viruses that exhibit fast reproductive rates in definitive and intermediate hosts and that multiply and increase their density in the human host (Exhibit 1⇑).27
Genome-sequencing studies need to be expanded to include a better understanding of virulence and interaction with human and insect vectors. Promising efforts using powerful new technologies in genomics (the study of an organism’s DNA sequence), proteomics (the study of protein structures and functions), and metabolomics (the study of unique chemical fingerprints generated by cellular processes) of human pathogens are under way. For example, recent examination of the metabolomics of falciparum malaria (the most dangerous form of the disease) stages in red blood cells demonstrated several previously unrecognized metabolic pathways of significance for parasite survivability.28 These efforts should expand the scope of research to encompass system and ecological understanding of communities of microbes and their interactions with humans.
A byproduct of these studies will allow molecular identification and characterization of validated targets for drug-therapy interventions.29 Such an effort is likely to provide, for the first time, an opportunity to study mechanisms of drug activity, their possible enhancement, and, more important, how the emergence of drug resistance can be mitigated.
Current drug therapy for most neglected tropical diseases is reliant on only one or two drugs, which exemplifies the vulnerability and risk we are facing without new therapies. Discovery of new drugs against most NTDs will require a better knowledge of biochemical pathways, structural targets, and well-validated proofs of mechanisms. This effort will not be brought to fruition unless new forms of interdisciplinary collaboration between discovery and development are explored, involving partnerships among academe, governments, industry, and private funders.
The other aim of discovery efforts should focus on the development of vaccines against NTDs. It is unlikely that effective and durable control of these infections will be accomplished in the absence of new preventive vaccines and marked improvements in environmental/societal conditions of water, sanitation, and housing.15 An expanded vaccine research and development effort is therefore urgently needed.
Clinical and experimental evidence for inducing effective immunologically based protection against some forms of leishmaniasis30 (a disease caused by a protozoan parasite and transmitted to humans through the bite of certain sand fly species) and hookworms31 (an intestinal parasite and soil-transmitted helminth) have been amply demonstrated. Translating these observations into usable vaccine preparations has been scientifically challenging because of our limited knowledge of human immunology and the molecular organization of these parasites. The effort requires deeper understanding of human immunologic responses to the causative organisms, leading, it is hoped, to new discoveries in vaccine science. The targets for new diagnostic and preventive tools should include the microbial pathogens as well as their intermediate vectors.
Lastly, none of these efforts will bear fruit without a tangible commitment to the development of a sufficiently large and qualified local human capacity to guide and implement these complex strategies at the community level.
The challenge of neglected tropical diseases or of infectious diseases in general is a window on the power and complexity of the evolutionary relationship between humans, their environment, and microorganisms.32 Development of human societies and their ability to control some of these infectious diseases is a complex and multifaceted challenge. We have learned that except for rare exceptions, “magic bullet” solutions are unlikely to be sustainable over time. This is not to say that positive short-term results are not valuable; they can be, as long as they do not delay policymakers’ recognition of the urgent need for more comprehensive approaches. Although this may seem self-evident, the required global and local capacity to undertake such efforts is still lacking, thus leading intervention programs to focus mainly on the technological components of the intervention. Winning the battle against infectious diseases will require more than purely technological solutions. It must include a combined set of scientific, socioeconomic, educational, environmental, and workforce strategies.
Footnotes
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Adel Mahmoud (amahmoud{at}princeton.edu) is a professor in the Department of Molecular Biology and the Woodrow Wilson School, Princeton University, in Princeton, New Jersey. Elias Zerhouni, formerly head of the National Institutes of Health, is a professor in the Department of Radiology and Biomedical Engineering and senior adviser at Johns Hopkins Medicine in Baltimore, Maryland.
