Control of Neglected Tropical Diseases

doi:10.1056/NEJMra064142

Volume 357:1018-1027		September 6, 2007		Number 10

Control of Neglected Tropical Diseases

Peter J. Hotez, M.D., Ph.D., David H. Molyneux, Ph.D., D.Sc., Alan Fenwick, Ph.D., Jacob Kumaresan, M.B., B.S., Dr.P.H., Sonia Ehrlich Sachs, M.D., Jeffrey D. Sachs, Ph.D., and Lorenzo Savioli, M.D.

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The neglected tropical diseases are a group of 13 major disablingconditions that are among the most common chronic infectionsin the world's poorest people. A blueprint for the control orelimination of the seven most prevalent neglected tropical diseases— ascariasis, trichuriasis, hookworm infection, schistosomiasis,lymphatic filariasis, trachoma, and onchocerciasis — hasbeen established by a group of private, public, and internationalorganizations working together with pharmaceutical partnersand national ministries of health. Through the newly establishedGlobal Network for Neglected Tropical Diseases, with updatedguidelines for drug administration issued by the World HealthOrganization (WHO), partnerships are coordinating their activitiesin order to launch a more integrated assault on these conditions.If new resources are made available, as recommended by the Commissionfor Africa, a scaled-up approach to simple interventions couldlead to sustainable decreases in poverty in some of the world'spoorest countries. These decreases would represent a major successstory for the United Nations Millennium Declaration.

"Other Diseases"

The Millennium Declaration, adopted by world leaders at theUnited Nations in September 2000, establishes an ambitious setof eight millennium development goals to eliminate extreme poverty,hunger, and disease by 2015. The sixth goal, "to combat HIV–AIDS[human immunodeficiency virus infection–acquired immunodeficiencysyndrome], malaria, and other diseases," specifically addressesthe health and economic impact of infectious diseases. Thisgoal has led to considerable and welcomed large-scale financialsupport through ambitious initiatives sponsored by the Groupof Eight (G8) governments to fight HIV–AIDS and malaria.These initiatives include the U.S. President's Emergency Planfor AIDS Relief, the U.S. President's Malaria Initiative, andthe Global Fund to Fight AIDS, Tuberculosis, and Malaria.¹^,²^,³^,⁴^,⁵However, programs to combat many of the "other diseases," particularlythe neglected tropical diseases, have not yet benefited fromsuch support.¹^,²^,³^,⁴^,⁵

The 13 parasitic and bacterial infections known as the neglectedtropical diseases include three soil-transmitted helminth infections(ascariasis, hookworm infection, and trichuriasis), lymphaticfilariasis, onchocerciasis, dracunculiasis, schistosomiasis,Chagas' disease, human African trypanosomiasis, leishmaniasis,Buruli ulcer, leprosy, and trachoma.²^,³^,⁴ An expanded list couldinclude dengue fever, the treponematoses, leptospirosis, strongyloidiasis,foodborne trematodiases, neurocysticercosis, and scabies,⁴ aswell as other tropical infections. The parasitic and bacterialdiseases identified as being neglected are among some of themost common infections in the estimated 2.7 billion people wholive on less than $2 per day. These diseases occur primarilyin rural areas and in some poor urban settings of low-incomecountries in sub-Saharan Africa, Asia, and Latin America (Table 1).The neglected tropical diseases lead to long-term disabilityand poverty.²^,³^,⁴^,⁵^,²⁰ The poverty results from disfigurementor other sequelae of long-term illness, impaired childhood growthand development, adverse outcomes of pregnancy, and reducedproductive capacity (Table 2).³^,²¹^,²² These features contrastwith those of emerging acute infections, such avian influenza,Ebola virus infection, and West Nile virus infection.⁵

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Table 1. The Major Neglected Tropical Diseases Ranked by Prevalence.

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Table 2. Major Characteristics of the Most Prevalent Neglected Tropical Diseases.

In aggregate, the neglected tropical diseases cause approximately534,000 deaths annually.⁴ This substantial number of deathsis considerably less than that resulting from lower respiratorytract infections, diarrheal diseases, HIV–AIDS, or malaria.However, if metrics are applied to the disability and povertyassociated with these diseases, the neglected tropical diseasescan be shown to constitute large burdens on the health and economicdevelopment of low-income countries. In terms of disability-adjustedlife-years, the neglected tropical diseases together rank closelywith diarrheal diseases, ischemic heart disease, cerebrovasculardiseases, malaria, and tuberculosis as being among the mostimportant health problems in the developing world (Figure 1).⁴^,⁵In addition, the effect of the neglected tropical diseases onworker productivity causes annual losses of billions of dollars.²⁴^,²⁵^,²⁶^,²⁷

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Figure 1. The 10 Leading Causes of Life-Years Lost to Disability and Premature Death.
The number of years lost to disability and premature death (disability-adjusted life-years) for the 13 major neglected tropical diseases were calculated according to a method we described previously.⁴ The disability-adjusted life-years for the other conditions are based on data from the World Health Organization.²³ The ranking of disease burdens is based on data in Hotez.⁵

Preventive Chemotherapy

Through the expanded use of mass drug administration as wellas targeted treatments, we now have the opportunity to controlor even eliminate some of the most important neglected tropicaldiseases in terms of prevalence and disease burden.¹^,²^,³^,⁴^,⁵^,²⁰^,²⁸^,²⁹^,³⁰^,³¹^,³²^,³³^,³⁴^,³⁵^,³⁶^,³⁷^,³⁸^,³⁹The use of mass drug administration for the control of neglectedtropical diseases, or preventive chemotherapy, was pioneeredin China. In that country, the prolonged and targeted use ofsalt containing diethylcarbamazine resulted in the eliminationof lymphatic filariasis as a public health problem,³⁰ and thewidespread use of praziquantel and other measures (includingsnail control and health education) is leading to the controlof schistosomiasis.³¹ Egypt has also succeeded in reducing theprevalence of lymphatic filariasis and schistosomiasis and theirassociated morbidity.³⁰^,³⁵

Such successes have laid a foundation for the establishmentof international partnerships to control or eliminate theseinfections.¹ A critical step occurred in the late 1980s, whenMerck created the first partnership to control a neglected tropicaldisease; this partnership was formed to deliver donated ivermectinto treat onchocerciasis.³ To date, more than 300 million treatmentshave been provided, initially through the Onchocerciasis ControlProgram and subsequently through the African Programme for OnchocerciasisControl and the Onchocerciasis Elimination Program for the Americas.³²In addition, Pfizer has partnered with the International TrachomaInitiative to donate azithromycin as part of a comprehensiveprogram to eliminate trachoma,³³ and GlaxoSmithKline is workingwith the WHO, Merck, and the Global Alliance to Eliminate LymphaticFilariasis to add donated albendazole to mass-drug-administrationregimens of either diethylcarbamazine or ivermectin.³⁴ Theseefforts have resulted in the near elimination of lymphatic filariasisas a public health problem in Egypt, Samoa, and Zanzibar³⁰^,³⁴^,³⁵and of trachoma as a public health problem in Morocco.³⁶ Similarly,using donated generic formulations of praziquantel from MedPharmand other organizations, the Schistosomiasis Control Initiativeand African health ministries have significantly reduced thedisease burden of urinary and intestinal schistosomiasis inschoolchildren in six countries in East and West Africa,³⁷^,³⁸and the widespread use of albendazole and mebendazole is havingan effect on school performance and the disease burden of soil-transmittedhelminth infections,⁶ especially ascariasis and trichuriasis,among children. Dracunculiasis is on the verge of being eradicated.¹⁸^,⁴⁰^,⁴¹Many of these large-scale programs are being conducted in responseto several World Health Assembly resolutions calling for theglobal control or elimination of the neglected tropical diseaseswith the greatest disease burden as a public health problemby the year 2020 or sooner.⁴²^,⁴³

Integration of Control

Although great progress has been made in several countries,¹^,²^,³^,⁴^,⁵^,²⁰^,³⁰^,³¹^,³²^,³³^,³⁴^,³⁵^,³⁶^,³⁷it is unclear whether existing financial resources and globalpolitical commitments are sufficient to reach the World HealthAssembly's ambitious goals. Instead, it is likely that enhancedefforts will be required to expand global coverage and integratemeasures to control the neglected tropical diseases. These effortswill involve harmonizing and coordinating the activities ofthe partnerships devoted to the control or elimination of theseven most prevalent neglected tropical diseases and linkingthem with national health ministries and the WHO. The rationalefor integrating preventive chemotherapy measures is based onthe observation that there is extensive geographic overlap andcoendemicity among these seven diseases (Figure 2).²^,³^,⁴^,⁵^,²⁰

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Figure 2. Nations with Five, Six, or Seven Neglected Tropical Diseases to Be Targeted for Integrated Preventive Chemotherapy.
Of the 56 nations to be targeted with a rapid-impact package, shown in yellow, 37 are located in the World Health Organization (WHO) African region, 5 in the WHO Region of the Americas, 5 in the WHO Eastern Mediterranean region, 3 in the WHO South-East Asia region, and 6 in the WHO Western Pacific region. Data regarding the occurrence of lymphatic filariasis, onchocerciasis, schistosomiasis, and the three soil-transmitted helminth infections are derived from the WHO.⁴⁴ Data regarding the occurrence of trachoma are derived from the WHO.⁴⁵ The five nations shown in orange — Burkina Faso, Ghana, Mali, Niger, and Uganda — will be targeted for integrated control in national programs through the support of the U.S. Agency for International Development Neglected Tropical Disease Control Program beginning this year. The two nations shown in red — Rwanda and Burundi — will be targeted for integrated control in national programs through the support of Geneva Global beginning this year.

Populations in such regions are infected with several differentparasites and have multiple neglected tropical diseases simultaneously.²^,³^,⁴^,⁵^,²⁰^,⁴⁶Therefore, the delivery of a rapid-impact package of drugs isbeneficial. The rapid-impact package is so named because thedrugs can be quickly deployed by community-based distributors,with rapid reductions in disabilities, improvement in well-being,and, in some cases, interruption of disease transmission. Thispackage includes a combination of four of six drugs: albendazoleor mebendazole, praziquantel, ivermectin or diethylcarbamazine,and azithromycin.² Through coordination of the partnershipsto control neglected tropical disease and the public healthinfrastructures they create, these drugs can be delivered atan estimated cost savings of 26 to 47% as compared with nonintegratedprograms.⁴³ Because four of the six rapid-impact drugs are donated,the projected average total cost is as low as $0.40 to $0.79per person per year in sub-Saharan Africa.²^,⁴³^,⁴⁷ Thus, an entireat-risk population of approximately 500 million could be treatedfor $400 million or less annually. Such estimates are a fractionof the annual costs of treatments with antiretroviral agentsor directly observed multidrug therapy for tuberculosis.² Moreover,the most prevalent neglected tropical diseases, especially hookworminfection and schistosomiasis, are frequently endemic with malariaand HIV–AIDS,⁴^,⁴⁸^,⁴⁹^,⁵⁰^,⁵¹ and they have considerablecoexisting or synergistic effects.⁴⁹^,⁵⁰^,⁵¹ Therefore, preventivechemotherapy could have an important collateral effect.⁴

To catalyze the integration of measures in order to controlneglected tropical diseases, a group of partnerships that arecommitted to combatting the seven most prevalent of these diseasesare cooperating with each other in the Global Network for NeglectedTropical Diseases. This network operates according to WHO treatmentguidelines and algorithms and with vector management and otherenvironmental control measures (Table 3).⁴⁴

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Table 3. General Guidelines for Preventive Chemotherapy for the Seven Most Prevalent Neglected Tropical Diseases.

Integrated control of these diseases at the national level willrequire substantial financial resources to expand coverage ofcommunity-based mass drug administration and targeted treatments.The U.S. Agency for International Development recently announceda 5-year, $100 million award to provide preventive chemotherapyfor 40 million people, and Geneva Global has committed $8.8million for preventive chemotherapy in Rwanda and Burundi (Figure 2).The Bill and Melinda Gates Foundation has awarded $47 millionto address critically important questions regarding operationalresearch for effective integration. However, these awards constitutea fraction of the overall costs required to scale up programsin sub-Saharan Africa and elsewhere. It is estimated that a5-year program to control or eliminate the major neglected tropicaldiseases in sub-Saharan Africa could cost approximately $1 billionto $2 billion. An estimated $2 to $9 per disability-adjustedlife-year (i.e., per life-year lost to disability or prematuredeath) would be averted for deworming,⁵² with up to 47% in costsavings through integration.⁴³ This cost for the coordinatedcontrol or elimination of the seven most prevalent neglectedtropical diseases represents a relatively inexpensive but potentpublic health intervention. It also represents a priority investmentin human capital and a reduction in global poverty.⁵³

The Need for New Tools of Control

Despite its enormous benefits, preventive chemotherapy withthe rapid-impact package will not affect the three neglectedtropical diseases with the highest rates of death — Chagas'disease, human African trypanosomiasis, and visceral leishmaniasis.Strategies to control these diseases are based on surveillance,early diagnosis and treatment, and vector control.¹⁷^,⁵⁴^,⁵⁵ Thesecriteria for effective control present challenges because ofthe lack of appropriate diagnostic tools and safe drugs. Todate, the greatest successes in the control of Chagas' diseaseand human African trypanosomiasis have occurred as a resultof vector control. Vector control has dramatically reduced thetransmission of Chagas' disease in five South American countries.⁵⁴The transmission of human African trypanosomiasis has been reducedthrough the use of simple, impregnated tsetse-fly traps thatsupplement surveillance and diagnostic measures.¹⁷

Although strategies to control and eliminate human African trypanosomiasis,leishmaniasis, and Chagas' disease are available,⁵⁶^,⁵⁷ ultimately,success will almost certainly depend on access to new and cost-effectiveproducts for improved control. However, in the absence of commercialmarkets for drugs for neglected tropical diseases, the pipelineof new drugs for these diseases has virtually dried up duringthe past three decades.⁵⁸ In response to this crisis, partnershipshave been established to address product development for neglectedtropical diseases. These partnerships for product developmentare either exploiting newly completed genome projects for protozoanparasites⁵⁹ in order to identify potential drug targets forhigh-throughput screening or taking more traditional approachesto drug development and clinical testing.⁶⁰ As a result of theseactivities, several new antiprotozoan drugs are under developmentfor Chagas' disease, leishmaniasis, and human African trypanosomiasis,including miltefosine, paromomycin, sitamaquine, imiquimod,a pentamidine analogue known as DB289, and a vinyl sulfone knownas K777, as well as combinations such as nifurtimox–eflornithineand paromomycin combined with antimonial agents.⁵⁵^,⁶⁰^,⁶¹^,⁶²Highly efficacious drugs for the treatment of Buruli ulcer havenot been developed.

Even with regard to the proposed rapid-impact package, challengesremain. These challenges include integrated and rapid mappingof the seven targeted diseases; careful assessment of safety,compatibility, and compliance; integrated monitoring and evaluationthat are compatible with the capacity of the health system,on the one hand, and with scientific need, on the other; cost-effectivenessand cost–benefit studies; and analyses to determine theeffect of integrated control on health systems.⁴^,⁵² In countriessuch as Burkina Faso, Ghana, Niger, Nigeria, Togo, and Uganda,where integrated efforts to control neglected tropical diseasesare under way, additional challenges have included limited accessto drugs such as generic praziquantel (which is not yet donatedon a large scale) and albendazole (which is currently donatedonly for the control of lymphatic filariasis), insufficientor fragmented funding, and a need for increased support fromnongovernmental development organizations. In addition, Africanhealth ministries are beginning to struggle with the implementationof integrated control of neglected tropical diseases in theface of the demands of other disease-control programs, includingG8-funded initiatives for HIV–AIDS, tuberculosis, andmalaria. It is expected that these issues will pose particularchallenges in areas that have experienced conflict and in fragilenation states.

Studies to determine the rates of post-treatment reinfectionand to detect the emergence of anthelmintic drug resistancewill be essential for monitoring and evaluation.⁴^,⁵ The possibilitythat resistance has already emerged is a serious concern, especiallyfor the benzimidazole anthelmintic agents (e.g., albendazoleand mebendazole) and ivermectin,⁶³^,⁶⁴ and without a new generationof tools for disease control and appropriate environmental controlmeasures, the risk of repeating past mistakes remains.³^,⁴^,⁶⁵Therefore, it is important to commit resources to the improvementof available diagnostic tests and surveillance tools, especiallyfor lymphatic filariasis and onchocerciasis,³²^,⁶⁶ and to developand test new, promising anthelmintic drugs such as tribendimidinefor soil-transmitted helminth infections,⁶⁷^,⁶⁸ a new macrofilaricide,and antiwolbachia-based therapies for the elimination of onchocerciasis.¹³Although they are still experimental, medical therapies targetingwolbachia bacterial endosymbionts of filarial parasites offernew approaches to the reduction of parasite reproductive capacityand parasite-induced inflammation.⁶⁹ However, the best prospectfor the sustainable control of the neglected tropical diseasesis the development of vaccines.²¹ Several vaccines against neglectedtropical diseases, including vaccines against hookworm infection,⁶⁸schistosomiasis,⁷⁰ and leishmaniasis,⁷¹ are in phase 1 and phase2 clinical trials by partnerships for product development.⁴^,²¹In principle, it is possible to develop new "antipoverty vaccines"against all of the neglected tropical diseases²¹; these wouldbe used as "vaccine-linked chemotherapy" alongside drugs ina comprehensive treatment and prevention framework.⁷²

Drug and vaccine manufacturers from so-called innovative developingcountries are assisting partnerships in their efforts to developnew products to control neglected tropical diseases. These middle-incomecountries, such as Brazil, China, and India, have the technicaland industrial capacities to produce new drugs, vaccines, anddiagnostic tests.³^,⁷³^,⁷⁴ Enhanced support by the G8 governmentswould accelerate innovation and essential health research forthe developing world.⁷⁵

Public Policy for Integrated Control

The High-Level Forum on the Health Millenium Development Goalshas described partnership activities as best practices for movingforward a global agenda. Tackling neglected tropical diseasesrepresents one of the "quickest wins" in terms of reducing thedisease burden as well as developing new drugs and vaccines.²There are additional opportunities to bundle the control ofneglected tropical diseases with the control of malaria andHIV–AIDS.⁷⁶ Such measures could exploit the geographicoverlap of these conditions⁴⁸ as well as potential synergiesin public health control, with resultant cost savings.⁵⁰^,⁷⁷For example, a recent study showed that the administration ofdrugs for neglected tropical diseases by community distributorsresulted in a ninefold increase in the distribution of antimalariabed nets.⁷⁷

Through partnerships to control the neglected tropical diseasesand the Global Network for Neglected Tropical Diseases, a comprehensiveframework is in place to provide preventive chemotherapy packagesand to develop, test, and distribute a new generation of toolsto control these diseases. This framework is an important modelin disease control and poverty reduction. It also addressesimportant themes related to equity and ethics in developingcountries⁷⁸ and critical elements of humanitarian assistance;these themes could be incorporated into a larger foreign-policyframework.⁵ According to the United Nations Special Rapporteuron the right to the highest attainable standard of health, aneffective and integrated program to control neglected tropicaldiseases strengthens local health systems, fosters communityinvolvement in health, helps to ensure monitoring and accountability,and serves to destigmatize these conditions by dispelling mythsand misconceptions about them through evidence-based informationand education.⁷⁸ The global community is now well positionedto control or eliminate neglected tropical diseases in developingcountries and to link these efforts to programs to combat HIV–AIDSand malaria.

Dr. Hotez reports being director of the Human Hookworm VaccineInitiative, which receives support from the Bill and MelindaGates Foundation; an inventor on an international patent application(PCT/US02/33106) for hookworm vaccine; and president of theSabin Vaccine Institute, which receives support from GenevaGlobal and support for activities unrelated to control of neglectedtropical diseases from Merck, Wyeth, and GlaxoSmithKline. Dr.Molyneux reports being director of the Global Alliance to EliminateLymphatic Filariasis and the Lymphatic Filariasis Support Centre,which receives support from the United Kingdom Department forInternational Development and GlaxoSmithKline, and participatingin the Mectizan Expert Committee/Albendazole Coordination meetings,which receive support from the Mectizan Donation Program supportedby Merck. Dr. Fenwick reports being director of the SchistosomiasisControl Initiative, which receives support from the Bill andMelinda Gates Foundation. All of the authors except Dr. Saviolireport being member partners of the Global Network for NeglectedTropical Diseases, which receives funding from Geneva Global.No other potential conflict of interest relevant to this articlewas reported.

Source Information

From the Sabin Vaccine Institute, and George Washington University, Washington, DC (P.J.H.); Liverpool School of Tropical Medicine Lymphatic Filariasis Support Centre and the Global Alliance to Eliminate Lymphatic Filariasis, Liverpool, United Kingdom (D.H.M.); the Schistosomiasis Control Initiative, Imperial College London, London (A.F.); the International Trachoma Initiative, New York (J.K.); the Earth Institute at Columbia University, New York (S.E.S., J.D.S.); and the Department of Neglected Tropical Diseases, World Health Organization, Geneva (L.S.).

Address reprint requests to Dr. Hotez at the Sabin Vaccine Institute and the Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Ross Hall 736, 2300 Eye St., NW, Washington, DC 20037, or at mtmpjh{at}gwumc.edu.

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Control of Neglected Tropical Diseases
Huppatz C., Durrheim D. N., Molyneux D., Fenwick A., Savioli L.
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N Engl J Med 2007; 357:2407-2408, Dec 6, 2007. Correspondence

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