Neglected Tropical Diseases: Progress Towards Addressing the Chronic Pandemic

Review

Neglected tropical diseases: progress towards addressing the chronic pandemic

David H Molyneux, Lorenzo Savioli, Dirk Engels

The concept of neglected tropical diseases (NTDs) emerged more than a decade ago and has been recognised as a Published Online valid way to categorise diseases that aff ect the poorest individuals. Substantial progress in control and elimination has September 14, 2016 been achieved and policy momentum has been generated through continued bilateral, philanthropic, and non- http://dx.doi.org/10.1016/ S0140-6736(16)30171-4 governmental development organisation (NGDO) support, and donations of drugs from pharmaceutical companies. Department of Parasitology, WHO has defi ned a Roadmap to reach 2020 targets, which was endorsed by member states in a World Health Liverpool School of Tropical Assembly Resolution in 2013. NTDs have been included within the Sustainable Development Goal targets and are a Medicine, Liverpool, UK crucial component of universal health coverage, conceptualised as “leaving no one behind”. WHO reported that more (Prof D H Molyneux DSc); Global than 1 billion people in 88 countries have benefi ted from preventive chemotherapy in 2014. The research agenda has Schistosomiasis Alliance, Chavannes de Bogis, defi ned the need for aff ordable products (diagnostics, drugs and insecticides). However challenges such as insecurity Switzerland (L Savioli MD); and and weak health systems continue to prevail in the poorest countries, inhibiting progress in scaling up and also in Department of Control of achieving Roadmap goals. Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland Introduction Momentum for further investment came in 2015 (D Engels MD) NTDs and the global heath agenda with the inclusion of NTDs within the health targets of Correspondence to: In this Review, we will present progress since the 2010 the Sustainable Development Goals (SDGs)11 when the Prof David H Molyneux, Lancet Series on neglected tropical diseases (NTDs).1–4 Global Fund Board12 agreed to support interventions Department of Parasitology, NTDs have been defi ned as a group of infections strongly that addressed co-infection and co-morbidities and the Liverpool School of Tropical Medicine, Pembroke Place, associated with poverty in tropical and subtropical G7 Heads of State recognised NTDs as a major Liverpool, L3 5QA, UK environments. NTDs are diverse in biological and challenge emphasising the need to support research [email protected] transmission characteristics; they predominantly infect and interventions.13 An agreed SDG target was to populations in low-income and middle-income countries reduce the number of people accessing NTD with limited access to health services.5 During the past interventions by 90% by 2030. However, the burden of decade, the momentum to address NTDs has been driven NTDs is heavy on the poorest people in G20 countries by pledges from pharmaceutical companies to provide (together with Nigeria) and if these countries free medicines (all on the WHO Essential Medicines list implemented NTD programmes then a high proportion and valued in billions of US$), NGDOs’ commitments to of the NTD burden could be resolved.14 assist implementation of programmes in endemic Increased investment for NTDs will improve the countries, bilateral support from the US and UK Govern- wellbeing of vulnerable groups, which together with ments, and an increase in commitment from endemic improvements in water, sanitation, hygiene, and countries.6 However, despite evidence that interventions education, are appropriate links to many of the SDGs. to address NTDs are one of the best health investments, NTDs defi ne poverty in many settings and have been only 0·6% of offi cial development assistance for health is described as litmus tests of progress in poverty provided to NTDs aff ecting more than 1 billion people. alleviation, or are described as markers of poverty.15 This underinvestment refl ects a persistent and continuing inequity in global health fi nancing.7 NTD partnerships: evolution and expansion The London Declaration of 20128 recorded increased from disease-specifi c to a wider context commitments of donated drugs for visceral leishmaniasis, Disease-specific partnerships represent the diversity lymphatic fi lariasis, and schistosomiasis, while earlier of communities involved in NTDs and have made a commitments to provide drugs for fascioliasis, leprosy, major contribution to scaling up of programmes. leishmaniasis, lymphatic fi lariasis, onchocerciasis, NGDO commitment was pioneered by NGDOs that trypanosomiasis, and soil-transmitted helminthiases at supported the delivery of ivermectin for onchocerciasis no cost to endemic countries were reinforced. In 2013, control and multidrug therapy for leprosy elimination the World Health Assembly approved Resolution WHA programmes.16 Since 2010, new partnerships have 66.12, which defi ned strategies for NTDs with clear emerged to coordinate and advocate for particular targets and milestones for 17 NTDs, and endorsed the conditions (table). Disease-specific alliances generate WHO NTD Roadmap goals linking NTDs to universal opportunities for advocacy and increased resources health coverage. NTDs are addressed through fi ve from non-traditional donors, and reflect the need to strategies: preventive chemotherapy, intensifi ed disease facilitate interaction between endemic countries, management, vector control, veterinary public health inter national organisations, non-governmental measures for zoonotic neglected diseases, and through organisations, pharmaceutical donors, philanthropic improved water and sanitation.9,10 foundations, and academia. www.thelancet.com Published online September 14, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30171-4 1 Review ned stategy; ned Research and operational and Research needs Implement defi to liposomal increase access amphotericin B and implement vector control based on documented status of vectorof resistance populations .. Improved diagnostics; oral for both early and latetherapy stage disease; scale-up of use of tiny targets for vector disease incontrol; for acute Uganda, implement of cattle and chemotherapy ofselective application insecticide to cattle Implementation and resourcing of dog vaccination strategy and improved access vaccine to post-exposure Improved diagnostic and therapeutics to treat chronic ofdisease; implementation intradomiciliary vector control Improve availability of vaccine;Improve availability diagnostics; epidemiological situation of dengue Africa;in capacity for case management and vector control (Table continues on next page) continues (Table ned Treatment progress Treatment Reduced incidence reported betweenReduced of reported2011 and 2013; number todeclined from 38 007 in 2011 cases 15 609 in 2013 India, Bangladesh through increased caseand Nepal, drugs andto detection, better access enhanced surveillance; improved defi strategy for vector control now of liposomaland availability doseamphotericin B as single treatment over 2010–15 period to less than 3000 to less over 2010–15 period with 10 000 casesin 2015, compared in 2009; enhanced support for of endemic foci nowsurveillance accurate maps ned by defi Americas—40% reported of all casesAmericas—40% reported from Haiti; progress in selected Africa, countries (Philippines, South with introduction of dog Tanzania) vaccination programmes; Bangladesh reported 50% reduction in rabies withdeaths between 2010 and 2013, of free post- increased availability exposure vaccine 20 endemic countries have achieved to reduce 100% blood screening transfusion risk 96 million cases manifest clinically .. .. 36of reported cases number Reduced 150the of cases in number Reduced 100year; 50–390 million infections per countries 19 in Americas, east Africa, and Asia 21 in Americas Partnerships and alliancesPartnerships Endemic Drugs for Neglected Diseases Initiative (DNDi) .. Pan-African Programme forPan-African Trypanosomiasis Control; Eradication and Drugs for Neglected Diseases Initiative (DNDi); for InitiativeFund Diagnostics (FIND) Global Alliance for Rabies Global Control Global Chagas’ Coalition; Drugs for Neglected Diseases Initiative (DNDi) Dengue Vaccine Dengue Vaccine Initiative; Vaccine Dengue Paediatric Vector Initiative; Innovative Control Consortium (IVCC) c 100% case-detection and treatment, with 000 <1 case per 10 districtpopulation at and sub-district levels .. Elimination in 100% ofElimination in 100% foci Eliminate human rabies dogs transmission by and dog-to-dog transmission in all ected countries in aff Asia South-East WHO’s and Western Pacifi regions Dengue control and surveillance systems established in all ofregions; number 25%cases reduced by (2009–10 baseline) and 50% deaths by c ed WHO Roadmap targets WHO Roadmap year reported; enhance wider patient accessibility; elimination of disease of foci in 80% control and enhanced surveillance should to 50% reductionlead of humanin number 2015deaths by rabies Interrupt transmission via intradomiciliary Americavectors in Latin and transmission via blood transfusion in Latin America, Europe and the western Pacifi Eliminate human rabies transmitted by dog-to-dogdogs and transmission in all endemic areas in Latin America; intensifi control interventions established in 10 high priority countries .. .. 3000–4200 Sustainable vector 9100 2000–3000 cases per 10 300 51 600 .. sources 55 000) sources 55 .. 1·46 26 000 (other 3·32 0·56 0·55 0·83 47·90 152 000 WHO Roadmap ...... Global burden* DALYS (million) DALYS year Deaths per 2015/2017 2020 Latest WHO resolutions, year WHA66.12, 2013 .. WHA60.13, 2007 WHA57.2, WHA57.2, 2004 WHA51.14, 1998 1950 WHA.55.17, WHA.55.17, 2002 18 Visceral Indian sub- continent Leish- maniases Human African trypanosomiasis Chagas’ disease Rabies WHA3.20, Dengue and dengue haemorr- hagic fever All NTDs Protozoa Viruses

2 www.thelancet.com Published online September 14, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30171-4 Review Understand the Understand role of dogs as impediment to eradication; of insecurity;access in areas enhanced surveillance in remaining endemic villages; of cyclopsmaintain control where cases not contained Continue search for improved drugs to treat cutaneous and muco-cutaneous disease; ofimprove if possible access populations to therapy in ict areas; in stable political confl areas, implement reservoir to reducecontrol programmes animal reservoir to Implement pilot projects evaluate strategy; engage sanitation and veterinary, to reduce food safety sectors will requiredisease burden— tools- combination of treatment oxfendazole or to prevent of pigs vaccination or cure porcine cysticercosis; to pig vaccine expected receive regulatory approval in India Research and operational and Research needs (Table continues on next page) continues (Table ed by the by ed ed cases ed rmed case. rmed cation of Dracunculiasis of cation infections can be treated withtreated infections can be WHO International Commission for WHO International the Certifi of guineaEradication (ICCDE) as free disease as no verifi worm these countries since reported from the eradication programme began in 1986 Angola and Democratic Republic of Angola and Democratic Republic to be certifi Congo require 16 countries previously endemic the transmission since of ed free certifi eradication programme began in 1986. 4 countries remain endemic (Chad, Ethiopia, Mali and South Sudan). Kenya and Sudan are in pre- than cation stage following more certifi without a confi years 3 incidence reported throughout area ofthroughout area incidence reported ict in Middle Eastern region confl Taenia praziquanetl but no standard treatment exists for NCC; individual treatment with case praziquantel or or both, antiepilepticalbendazole drugs, or corticosteroids Treatment progress Treatment ..data available, although increased No .. 4: Chad, Ethiopia, Mali, and South Sudan countries Partnership of Partnership endemic Cartercountries, WHO, UNICEF Center, Drugs for Neglected Diseases Initiative (DNDi) .. Partnerships and alliancesPartnerships Endemic ed Global ed Certifi Eradication .. upInterventions scaled in selected countries for taeniasis / solium Taenia cysticercosis control and elimination .. 70% of all cases70% detected and at least 90% of all detected cases treated in the Eastern Mediterranean Region .. WHO Roadmap targets WHO Roadmap No deaths attributed No deaths attributed estimated that 30% epilepsy tocases due neurocysticercosis (NCC) in endemic countries; deaths from epilepsy related to NCC estimated as 6·9% in Cameroon and 0·5% in Mexico .. 0·50 1200; however, 22 human cases reported in 2015 in 4 endemic countries (Chad, 9; Ethiopia, 3; Mali, 5; and South Sudan, 5), down from 126 cases reported in 2014 Global burden* DALYS (millions) DALYS year Deaths per 2015/2017 2020 WHA64.16, 2011 .. Latest WHO resolutions, year Dracu- nculiasis Cysticer- cosis/ Taeniasis Cutaneous .. Helminth (Continued from previous page)

www.thelancet.com Published online September 14, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30171-4 3 Review ned lariasis Loa loa orts to address to orts Implement albendazole year in times per 2 with vectorco-endemic areas control via impregnated bednets; scale-up defi interventions in newly endemic areas; assess impact of onchocerciasis programmes lariasis endemicity and on fi of lymphatic fi impact programmes on soil- transmitted helminthiases; durationdevelop a short on anti- laricide based macrofi wolbachia antibiotics as a doxycycline; substitute for trials;complete triple therapy increase eff morbidity Defi of endemicne extent Defi develop serological andareas; molecular methods for improved diagnosis; increase to praziquantel (or access triclabendazole for withfascioliasis); engage to reduce risk via other sectors health education and improved sanitation Research and operational and Research needs Implement pilot strategy in of high risk areas (Table continues on next page) continues (Table al; cient to cient Continued maintenance ofContinued maintenance of 559 milliontreatments—peak achieved in 2014; 11 countries have programmes;not commenced MDA 23 countries have implemented but not reached 100%limited MDA geographical coverage—insuffi of elimination;target reach 2020 18 countries moved into surveillance Transmission phase following Assessment Surveys; diethylcarbamazine available as donated product since 2013–14 Egypt of fascioliasis; increasedEgypt andtreatments for fascioliasis in Peru Bolivia since 2009; increased treatment programme for Vietnam opisthorchiasis in Laos and ofof areas for clonorchis; mapping Cambodia and initiation endemicity in of treatment programme Treatment progress Treatment distribution since 2010; highglobal disease inof cystic prevalence (5–10%) parts of Latin America, China, Central disease has highAfrica; alveolar Asia, and withTibetan Plateau prevalence in of 16 000 cases; cross-sectorincidence coordination with toauthorities implement known control measures — carcass condemnation; deworming of off to of access dogs and reduction introduction of diagnostic ultrasound; (puncture, of PAIR and promotion aspiration, injection and respiration) surgery strategy ..data available, but no change in Limited 17of cases reported in numbers Reduced In 2014, 73 countries countries Global Alliance to Eliminate Filariasis (GAELF) Lymphatic .. Partnerships and alliancesPartnerships Endemic .. ofed as free 100% of all endemic100% will have beencountries verifi transmission or will have entered post- intervention surveillance 75% of population at75% of infection reachedrisk preventiveby chemotherapy; morbidity controlled in all endemic countries Validated strategy Validated available for echinococcosis/ hydatidosis and upinterventions scaled in selected countries for their control and elimination ective endemic countries willendemic countries the criteria have met to stop interventions the post- and entered intervention surveillance phase .. WHO Roadmap targets WHO Roadmap validate eff strategies where disease is a public health problem (eg, major burden in China) ..of all 81 70% By 2017, 1200to Pilot projects 7000 deaths reported in 2005 GBD but not by study; 7·9 million cases with severe sequelae 1·88 2·78 0·14 DALYS (millions) DALYS year Deaths per 2015/2017 2020 Global burden* WHA50.29, 1997 .. .. Latest WHO resolutions, year lariasis Lymphatic Lymphatic fi Foodborne trematodes Echino- coccosis (Continued from previous page)

4 www.thelancet.com Published online September 14, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30171-4 Review ne laricide based on based laricide ne areas where areas ne Evaluate value of treating of Evaluate value adults if transmission to be interupted; develop drug cacy monitoring at scale; effi orevaluate new products combinations; improve diagnostic tools Develop paediatric praziquantel formulation; ne link between HIV and defi to urogenital schistosomiasis of HIVevaluate risk transmission Research and operational and Research needs durationDevelop a short macrofi anti-wolbachia antibiotics as a doxyclycine; substitute for times implement ivermectin 2 oryear strategy for control per defi Africa; elimination in areas of transmission;low defi transmission has been of implementation arrested by new WHO guidelines (Table continues on next page) continues (Table progress towards; progress of highculties exist in area transmission;of ed as free has increased from 200 million in 2010 ofto 271 million in 2014 (47% estimated 576 million children at risk); of 269 millionin 2014, 138 million to be in pre-school children estimated treated treatment were (globalneed of of 51·4%); in 2016, Indiacoverage through a treated 140 million children school-based deworming programme and in 2014 Egypt day, in a single treated 2 million school-age children week period over a 4 million requiring treatment reached; in million requiring 2014, 61·6 million school age and adult individuals year-olds) (5–14 that treated—20% of needed; drugdonated Praziquantel available as tablets being donated with 250 million donors purchasingavailable in 2016; additional praziquantel levels of endemicity post-control.levels and Mexico now Colombia, Ecuador, verifi todocuments Guatemala has submitted verify transmission; overall,absence of total population112 million/172 million estimated to require treatment (65·3% global coverage) Treatment progress Treatment nationwide elimination in Burundi, Guinea Bissau, Kenya, Malawi,Chad, and Senegal; focal Mali, Niger, elimination in 6 countries (Cameroon, Tanzania, Ethiopia, Nigeria, Sudan, Uganda) has been achieved but in Cameroon diffi withtransmission zones co-endemic Venezuela Loa loa ; Northern focus in while southern focusunder surveillance using cross border Brazil/Venezuela oryear times per ivermectin 4 to doxycycline reduce transmission; new communities found Yanomami infected ..treated of school-age children Number ..of 261 In 2013, 47 million individuals 37 30 countries previously had varying countries STH Coalition managed by STH Children Without Worms Global Schistosomiasis Alliance Partnerships and alliancesPartnerships Endemic Organization for Elimination of the Onchocerciasis in African Americas (OEPA); Onchocerciasis Project for ofAPOC (closed end Control 2015) and now Expanded Special Project for Elimination of Africa NTDs) c and c 75% of preschool-aged and school-aged ofchildren in need treatment are regularly treated in all endemic countries Regional elimination inRegional Americas, Pacifi nationally in selected Africa; 75% countries in of school-aged children treated in all regularly endemic countries Elimination in selected Africa countries in of preventive chemotherapy, including children (preschool-aged and school-aged children) treated in are regularly 100% of endemic countries as a public health problem in eastern Mediterranean, Caribbean and Indonesia and Mekong basin WHO Roadmap targets WHO Roadmap Elimination in Latin Yemen America and 2700of people in need 50% 11 700 Regional elimination attributed 3·31 5·19 0·49 No deaths DALYS (millions) DALYS year Deaths per 2015/2017 2020 Global burden* WHA54.19, 2001 WHA.65.21, 2012 WHA62.1 2009; WHA47.32, 1994 Latest WHO resolutions, year Soil- transmitted helminthiases Schisto- somiasis Oncho- cerciasis (Continued from previous page)

www.thelancet.com Published online September 14, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30171-4 5 Review of care diagnostic of care Implement morbidity management .. Develop polyvalent antivenom not needing cold chain; advocate for greater to snake bite as attention cause of mortality Implement expanded trichiasis surgery Focus on Focus countries with continuing high prevalence Research and operational and Research needs Rapid point

ned as a nition of areas of with 5000 in 2009 0 data. recent years; deﬁ endemicity completed enabling scale up of SAFEup completed enabling scale of individualsstrategy; Number receiving azithromycin increased from to 54·7 million in45 million in 2010 2014, with increased number of districts delivered intrichiasis surgery treated; 43% of districts where it was deﬁ azithromycin treatment strategy qualitymanufacturers and no alternatives available for common Africa snakebite in public health problem with target totarget with public health problem 2015 50% by exceed Treatment progress Treatment reported 2200 new cases in 2014 compared ..overof problem Increased recognition .. mapping Project Trachoma Global ..of Pilot studies show success ..text See countries Global Snake Bite Initiative ..of antivenom stopped by Production International Podoconiosis Initiative (Footwork) International Trachoma International Trachoma GET 2020 Initiative and International Leprosy Elimination Programme Global Buruli Ulcer InitiativeGlobal Buruli 33that report regularly 12/15 countries Partnerships and alliancesPartnerships Endemic .. .. Global eradication .. All countries will haveAll countries UIG and be the achieved free from blinding trachoma as a public- health problem Global elimination ofGlobal elimination the public health problem 70% of cases detected withearly and cured antibiotics in all endemic countries .. 10% of endemic countries were expected to have achieved the UIG by 2016, 40%2013; by of endemic countries this goal and achieved entered post-endemic surveillance .. WHO Roadmap targets WHO Roadmap therapy Oral antibiotic incorporated into treatment control and 5000–6000 96 000 per year000 per 96 .. No deaths attributed attributed attributed cases per year cases per MDA=mass drug administration. UIG=ultimate intervention goal. *Global Burden of Diseases, Injuries, and Risk Factors Study 201 of Diseases, Injuries, and Risk Factors UIG=ultimate intervention goal. *Global Burden drug administration. MDA=mass .. .. 6,8,46,52,53,57 0·33 No deaths 0·006 No deaths Not calculated .. .. DALYS (millions) DALYS year Deaths per 2015/2017 2020 Global burden* .. WHA2.6, 1949 WHA62.1, 2009 2004 1991 Latest WHO resolutions, year Podo- coniosis Snake bite .. Yaws/ endemic trepone- matoses Trachoma Trachoma (avoidable blindness) Buruli ulcer WHA57.1, Leprosy WHA44.9, Non-infectious NTDs (Continued from previous page) Bacteria Data are derived from various sources. Data are research needs treatment progress, and targets, partnerships, endemic countries, the associated global burden, diseases and tropical : Neglected Table

6 www.thelancet.com Published online September 14, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30171-4 Review

Science underpinning the NTD case and anxiety of patients with NTDs as well as caregivers The burden of NTDs has only recently been highlighted as a problem with The Global Burden of Disease study of 201017 attributed signifi cant additional burden.20 some 27 million disability-adjusted life years (DALYs) to NTDs. A 2014 study18 included other conditions not Defi nition of research priorities included within the WHO offi cial NTD list of 17 diseases, Research priorities for NTDs have been published in a and attributed 47·9 million DALYs to all NTDs; another series of reports by WHO and the Special Programme study5 in 2009 estimated the burden for NTDs was for Research and Training in Tropical Diseases, outlining 56 million DALYs. The global annual mortality from priorities for kinetoplastid parasites (trypanosomes and NTDs was reported as around 150 000 deaths per year by leishmanias), helminth infections, zoonoses and viral the Global Burden of Disease study.17 However, this infections (dengue, and other arboviruses).26 A consensus estimate excluded deaths from rabies (55 000 deaths), has been reached that new drugs, insecticides, and snakebite (up to 94 000 deaths), cancers associated with diagnostics are required, which will off er improved and trematode infections (60 000 deaths), and neurological cost-eff ective therapies, vector-control tools, and NTD conditions such as neurocysticercosis-related diagnostics. Attempts to develop vaccines for multi- epilepsy (60 000 deaths)—these deaths are also included cellular parasites are yet to develop a product for large- in other categories. These fi gures suggest the total scale use. However, progress to address the expanding annual mortality from NTDs is actually around 350 000. dengue threat has been made with the development of a In 2010, WHO reported that schistosomiasis mortality vaccine for dengue (Dengvaxia, Sanofi Pasteur, Lyon, alone could be as high as 280 000 per year in Africa—a France). Dengvaxia has been licenced in Mexico for use 20-fold diff erence from the offi cial GBD data.19 Morbidity in highly endemic areas, after results of safety and from permanent blindness, debilitating skin disease, effi cacy studies in clinical trials showed reduced disability and disfi gurement with long term psychological incidence of hospitalisation in vaccinated children and social and economic consequences will elevate the aged 2–16 years old in three clinical trials involving total DALY burden but are not included in Global Burden 35 000 children.27 of Disease metrics.20 Research to improve delivery of existing products and evaluate effi cacy of existing therapeutics will be necessary, NTD comorbidities: HIV, epilepsy, and cancer as will exploration of combinations of products known to A possible association between HIV and urogenital be eff ective. Specifi c research priorities are improved oral schistosomiasis has been recognised. Ndeff o Mbah and therapy for human African trypanosomiasis that is colleagues21 showed increased HIV positivity in females eff ective in both early and late stage disease; and infected with Schistosoma haematobium. The opportunity improved chemotherapy for leishmaniases, Chagas’ to reduce the risk of HIV in young females (5–15 years) disease, and buruli ulcer—current therapies are not ideal associated with S haematobium urogenital pathology by owing to the duration of required treatment, mode of annual praziquantel has yet to be recognised by the HIV administration, and toxicity. A short-duration macro- community, despite the need to achieve high coverage of fi laricidal treatment to kill or permanently sterilise adult this at-risk group irrespective of a direct link to HIV. The fi larial worms is still needed, because despite the effi cacy safety of praziquantel has been reconfi rmed during of the anti-Wolbachia antibiotic, doxycycline, the duration pregnancy and lactation.22 The longstanding policy to of treatment and eligibility criteria currently restrict its assure coverage of young females with praziquantel widespread use. Praziquantel has been donated for mass treatment should be implemented by both the NTD and drug administration in school-aged children for HIV constituencies. Neurocysticercosis infection caused schistosomiasis; however, it needs to be reformulated for by Taenia solium cysts has been associated with epilepsy paediatric use given that pre-school children are and estimates suggest some 30% of global epilepsy is frequently infected. The combination of praziquantel associated with neurocysticercosis.23 Bladder cancer with artesunate for treatment of both adults and juvenile associated with S haematobium and food-borne trematode forms of schistosomes might be considered.28 infections that cause cholioangiocarcinoma are estimated Research linked to implementation of programmes and to cause 60 000 deaths annually.24 The successful challenges that programmes face as they mature require schistosomiasis control programme in Egypt has seen a social science involvement to improve coverage and rapid decline in bladder cancer during the past adherence, and improved methodologies to evaluate 2 decades.25 Comorbidities associated with hookworm impact and address problems identifi ed in acceptability and schistosomiasis also exacerbate malaria pathology, adherence and coverage.29 Research to understand particularly in pregnancy, which reduces birthweight and interactions between social networks within communities increases risk of neonatal and infant mortality. Further, could help ensure optimum understanding and uptake of the mental health comorbidity of many NTDs and the drugs.30 Increasingly complex and diverse research impact these conditions have on the psycho-social status questions have emerged as programmes dependent on of individuals and families, particularly depressive illness mass drug administration have progressed. Such questions www.thelancet.com Published online September 14, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30171-4 7 Review

relate to the duration and frequency of mass drug in Africa; albendazole twice a year for lymphatic administration for diff erent diseases, the broad spectrum fi lariasis in L loa co-endemic areas; bednet coverage to eff ectiveness of the anthelminthics used and the impact of eliminate lymphatic fi lariasis; and the use of doxycycline vector control on transmission of fi lariasis.31 as a macrofi laricide or ivermectin four times per year in some areas of onchocerciasis endemicity, such as in Mapping disease distribution Brazil and Venezuela.31,38 Thomsen and colleagues39 Accurate mapping of disease distribution is a prerequisite examined a triple combination of diethylcarbamazine, for eff ective implementation. Onchocerciasis pro- albendazole, and ivermectin for fi lariasis and showed grammes have shown the importance of defi ning that microfi laria levels remain suppressed for a endemicity; in these programmes, levels of endemicity 24 month period thus providing an opportunity to were defi ned by rapid epidemiological assessment and reduce the frequency of mass drug administration in mapping.32 The serious adverse events associated with areas where onchocerciasis is not co-endemic. Loa loa co-endemicity with onchocerciasis meant a rapid Additionally, to reduce the problem of the limited eff ect mapping methodology was required to defi ne areas of of albendazole on trichuris infections, ivermectin highest risk.33 Similar rapid mapping using antigen should be considered; however, ivermectin is not detection methods are used to identify where lymphatic donated for trichuris infections or for scabies. Because fi lariasis mass drug administration should be instituted.34 extensive insecticide resistance exists in Africa, the The need to know the distribution of NTDs that can be value of bednets to eliminate Wuchereria bancrofti controlled or eliminated by preventive chemotherapy led transmission needs to be reassessed.40 to the development of online resources to ensure all requisite data are available and updated. The Global Cochrane systematic reviews: the deworming debate Trachoma Mapping Project is an example of how mobile In 2015, the Cochrane Collaboration challenged the phone and geographic information system technologies benefi ts of deworming for the control of soil-transmitted can be used: popu lation-based prevalence surveys are helminthiases after their analysis41 of randomised done in all districts where trachoma is suspected to controlled trials (RCTs). This fi nding provoked robust acquire data on burden and risk, thus enabling debate42 about whether RCTs are an appropriate way to prioritisation of interventions and policy determination measure the nutritional and educational benefi ts of for implementation of the surgery, antibiotics, facial preventive anthelminthic chemotherapy. Most RCTs do cleanliness, and environ mental improvement (SAFE) not take into account that recovery from nutritional strategy.35 Detailed mapping of foci of human African defi cits is a process that takes much longer than 1 year, trypanosomiasis due to Trypanasoma brucei gambiense especially if the quality and quantity of the nutrients infection has defi ned areas of highest risk for active assumed in the diet are limited. surveillance.36 Furthermore, a signifi cant proportion of individuals Use of remote sensing technologies to produce datasets treated with preventive chemotherapy are uninfected but that precisely defi ne zones of climate (rainfall indices, cloud are nevertheless treated for logistical reasons and thus no cover), physical parameters (altitude, soil type), and nutritional benefi ts are expected to accrue in this group. ecological parameters (forest cover, vegetation type) is RCTs normally calculate the mean benefi t of preventive increasingly important, as predictors of disease ecology chemotherapy on the entire treated group but the true refl ecting drivers of transmission of vector borne infections. benefi ts are obtained only by those infected and are Defi nable physical characteristics such as soil type are therefore greatly diluted. For the NTD global mapping tool associated with podoconiosis distribution.37 The NTD global Additionally, diff erent worm species have diff erent see http://www.NTDMap.org) mapping tool provides an interactive means to assist the patho logical eff ects—hookworm causes anaemia, planning and implementation of preventive chemotherapy ascariasis retards growth43—hence when the results of for NTDs, enabling visualisation of geographical preventive chemotherapy are evaluated it is important distribution of diseases and the priority areas requiring to recognise which species of soil-transmitted mass drug administration where co-implementation should helminthiases are removed. For example, an be initiated. The global mapping tool also complements the improvement in haemoglobin levels should not be For the Global Atlas of Global Atlas of Helminth Infections, provides information expected if hookworms are not the prevalent species in Helminth Infections see http:// on water and sanitation, and allows progress of interventions the population treated. On the basis of the evidence www.thiswormyworld.org to be tracked. from all studies including RCTs, WHO issued a consensus statement reiterating the justifi cation of the The need for alternative strategies— the operational present policy of preventive chemo therapy.42 Provision research agenda of deworming to infected populations refl ects equity Some preventive chemotherapy programmes require and ethical aspects and the intervention is recognised to alternative strategies to reach elimination targets, which reinforce the trust in the health and education need to be piloted and implemented. These alternative service, aspects that the Cochrane systematic review of strategies include: ivermectin twice a year for fi lariasis RCTs is unable to evaluate.

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Progress towards Roadmap goals 4 million since 2000. The prevalence of leprosy has Progress on specifi c diseases dropped by 90%: from 21·1 per 10 000 people in 1983 to Substantial progress towards WHO Roadmap goals and less than 0·24 per 10 000 people in 2014. A substantial regional targets has been achieved since 2010 (table). The decrease in the global disease burden has been achieved; Uniting to Combat NTDs initiative tracks progress on the number of leprosy cases has reduced from For Uniting to Combat NTDs ten NTDs towards the agreed targets against a scorecard 5·2 million in 1985, to 180 618 cases at the end of 2013, see http://unitingtocombat that is published annually. which has led to the suggestion that the public health ntds.org problem has been eliminated—defi ned by WHO as a Dracunculiasis (Guinea worm disease) prevalence of less than 1 case per 10 000. However, Since the introduction of the Guinea Worm Eradication although the problem of leprosy has been reduced by Programme in 1986, 16 countries have been certifi ed free multidrug therapy, pockets of high endemicity remain of Guinea Worm transmission, including 6 countries in several countries, including India, Brazil, and since 2010 (Burkina Faso, Côte d’Ivoire, Ghana, Niger, Indonesia, therefore this ancient and stigmatising Nigeria, and Togo). However, four countries remain disease should remain a priority.49 endemic—Chad, Ethiopia, Mali, and South Sudan—who reported only 22 cases in 2015 compared with 126 cases in Lymphatic fi lariasis 2014.44 Each of these endemic countries pose diff erent In 2014, 73 countries remained endemic for lymphatic challenges if transmission cessation is to be confi rmed. A fi lariasis; 18 countries are now entering the surveillance possible cycle of transmission that involves dogs, fi sh, and phase but 11 countries have not yet commenced mass amphibians as paratenic hosts was discovered in Chad, drug administration programmes. Some 23 countries meaning a change in approach could be required because have only implemented limited mass drug administration 503 dog infections were recorded in Chad in 2015; from and have not reached 100% geographical coverage. January, to June, 2016, 498 dogs have been reported Countries that have not achieved complete coverage will infected and four human cases have been identifi ed in not be able to reach the 2020 target of elimination. Chad. Human cases were also reported in South Sudan However, 18 countries have moved into a surveillance and Ethiopia in June, 2016.44,45 In Mali, access to endemic phase following transmission assessment surveys, an areas is curtailed due to insecurity. In South Sudan, strong evaluation which suggests transmission has been progress has been made to reduce the numbers of infected arrested.50 However, The Gambia appears to have villages but problems of access, population movement, eliminated transmission, without the introduction of cattle camps, and insecurity pose end-game challenges. mass drug administration, with long-term use of impregnated bednets for malaria control.51 A 2014 Human trypanosomiases estimate of the impact of mass drug administration Achievement of the target to reduce the number of during the past 13 years suggests more than 96·71 million chronic human African trypansomiasis cases to cases of lymphatic fi lariasis were prevented or cured; yet between 2000–3000 cases per year by 2015 is close: 36 million cases of hydrocoele and lymphoedema WHO reported 3796 cases in 2014 and less than 3000 in remain.52 The economic benefi ts estimated to have 2015. This fi gure was the lowest reported incidence for accrued during the fi rst 8 years of the programme exceed 75 years and was achieved by active surveillance of $24 billion. In 2014, 559 million people were treated for defi ned high-risk foci and donation of products for lymphatic fi lariasis and the cumulative number of chronic human African trypansomiasis therapy treatments reported was 5·62 billion to more than (pentamidine and nifurtimox–efl ornithine).46 The 1 billion individuals.53 availability of tiny insecticide impregnated targets for The fi lariasis test strip, which is based on the immune- glossina control,47 new diagnostic tests, and the prospect chromatographic test, has been introduced as an of an oral therapy to treat both phases of the disease— improved method for use in mapping and evaluation.53 fexnidazole, which is now in phase 2 and 3 trials calls This test will be used for transmission assessment for optimism. surveys to determine the impact of mass drug Chemotherapy for Chagas’ disease remains administration and allow for decision making with problematic; less than 1% of patients have access to regard to cessation or to evaluate any recrudescence. benznidazole. Despite an impact on parasite serological Lymphatic fi lariasis accounts for at least 2·8 million parameters, a randomised trial of benznidazole did not disability-adjusted life-years;17 this fi gure does not include signifi cantly reduce levels of cardiac clinical deterioration the substantial comorbidity of mental illness commonly 48 20 through 5 years of follow-up. experienced by patients and their caregiv ers. For WHO’s Global Programme to Eliminate Lymphatic Filariasis to Leprosy succeed, 100% geographical coverage of both mass drug 215 656 new cases of leprosy were reported in 2013 in administration and patient care is necessary and could be 103 countries. During the past 20 years, more than achieved through the implementation of morbidity 14 million patients have been cured of the disease, management and surgery.50 www.thelancet.com Published online September 14, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30171-4 9 Review

Onchocerciasis helminthiasis as stated in a previous resolution Three countries have been verifi ed as free of transmission (WHA 54.19).58 Schistosomiasis programmes will now of Onchocerca volvulus: Colombia, Ecuador, and Mexico. benefi t from the increased donation of praziquantel, Guatemala has submitted a dossier that indicates that because from 2016, 250 million tablets equivalent to transmission has stopped in all the previous endemic foci, 100 million treatments will be available. The number of while the northern focus in Venezuela is under post- school-age children treated in 2014 was 49·2 million, control surveillance. However, the cross-border focus equivalent to 34.6% of global coverage for this age group. For more on scale-up of straddling Brazil and Venezuela exemplifi es challenges of In spite of this signifi cant progress, scale-up remains treatment see http://www. remote areas; migratory Yanomami groups who require slow in the highest burden countries where 70% of the unitingtocombatntds.org treatment characterise the diffi culties of sustaining burden occurs. If the elimination goals for ivermectin distribution four times per year. Some infected schistosomiasis are to be met, endemic countries should individuals who remain positive have been hospitalised defi ne high priority intervention areas, access the for treatment with the macrofi laricide doxycycline.54 available donated drug, implement health education Closure of the African Programme for Onchocerciasis messages to emphasise the importance of safe water and Control at the end of 2015 and the creation of the sanitation provision in reduction of transmission, and Expanded Special Project for the Elimination of NTDs in recognise the importance of pre-school age children and Africa for the control of other preventive chemotherapy- their need for treatment if possible with a paediatric targeted NTDs will transfer the responsibility to provide formulation of praziquantel.59 The association between technical support to country programmes to the WHO HIV and urogenital schistosomiasis requires resolution Regional Offi ce for Africa. The African Programme for with strong policy enforcement through the regular Onchocerciasis Control delivered more than 1 billion treatment of school girls, women of childbearing age, treatments between 1997 and 2014 in 19 countries, built and throughout pregnancy and lactation as capacity through training or retraining of more than recommended by WHO and the original manufacturers 148 000 health workers and 1·46 million community of praziquantel.22 directed distributors, facilitated use of community structures for other health programmes, and empowered Soil-transmitted helminthiases more than 190 000 communities to direct their own Between 2008 and 2013, the number of children treated ivermectin treatment schedules.55 for soil-transmitted helminthiases doubled. WHO The African Programme for Onchocerciasis Control reported that 440 million pre-school and school-age made epidemiological progress towards nationwide children were treated in 2014 with anthelminthics elimination in Burundi, Chad, Guinea Bissau, Kenya, (albendazole and mebendazole)—rates of coverage have Malawi, Mali, Niger, and Senegal. Focal elimination in increased since 2008 and a global coverage of 44–51% has six countries (Cameroon, Ethiopia, Nigeria, Sudan, been achieved.6,60 The fi gures for treatment of soil- Tanzania, and Uganda) was achieved, but in Cameroon transmitted helminthiases do not include individuals there are diffi culties in high transmission zones that are receiving anthelminthics via fi lariasis and onchocerciasis co-endemic with L loa. In such zones, coverage and programmes that treat adults as well as younger age adherence are inadequate to satisfy the expectation that groups.31 The need to treat adults is recognised, if a transmission can be arrested without implementation of permanent reduction in transmission is to be achieved,61 additional strategies.55 as well as the importance of the role of the water, sanitation, and hygiene sector to sustain the gains regular Scabies deworming can provide.62 Scabies is caused by the ecto-parasitic mite Sarcoptes scabiei and is highly susceptible to ivermectin, which is Trachoma used in onchocerciasis and lymphatic fi lariasis The SAFE strategy for the elimination of trachoma with programmes. The results of a study56 in Fiji showed its four components—surgery, antibiotics, face washing, effi cacy of ivermectin for scabies compared with standard and environment—shows the multiple approaches treatments of topical permethrin cream. The lack of data required if public health goals are to be achieved.46 The on the impact of ivermectin on scabies after nearly Global Trachoma Mapping Project provided detailed 3 decades of use in mass drug administration programmes information for implementation of mass drug is a major defi cit, representing a missed opportunity. administration using azithromycin, identifi ed where the burden of trichiasis is highest for prioritisation of Schistosomiasis surgery, and identifi ed where implementation of the face The World Health Assembly resolution of 2012 washing and environment components of the SAFE (WHA 65.21)57 called for the elimination of schisto- strategy will pose the greatest challenge.36 The somiasis and reinforced the importance of regular implementation of mass drug administration in all treatment of at least 75% of school age children in areas endemic districts at 80% coverage for 3–5 years, at risk of both schistosomiasis and soil-transmitted depending on prevalence of active trachoma, will pose a

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signifi cant challenge notwithstanding the estimated generalisations about approaches to their control is backlog of 5 million cases of trichiasis surgery; Solomon63 diffi cult. However, progress has been made to defi ne has emphasised the benefi t of improved trichiasis strategies for control of specifi c diseases, which require an surgery technique in reducing recurrence of trachoma. approach that goes beyond the health sector.71 The vision for One Health is a culture change that recognises the Yaws importance of the link between humans, animals, and Yaws (Treponema pallidum pertenue) is a disabling skin ecosystems, providing added value by translation of the condition that has been identifi ed as a potential eradication One Health approach into zoonotic disease control. target on the basis of oral azithromycin effi cacy. WHO Successful application of One Health strategies are the use developed the Morges Strategy for Yaws Eradication by of dog vaccination in the control of human rabies in Latin 2020;64 the strategy will involve mass drug administration America, KwaZulu-Natal, the Philippines, and Bali,72 and of single dose azithromycin to entire endemic the control of the acute form of human sleeping sickness, communities, supported by surveillance until clinical Trypansoma brucei rhodesiense, in south east Uganda. In cases are no longer detected, and by treatment of all active Uganda,67 chemotherapy of the cattle reservoir, together cases and their contacts. Pilot interventions have been with vector control by spraying of cattle to selectively kill initiated in several countries: in Nsukka, Nigeria, mass the tsetse fl y Glossina fuscipes, has been shown to eff ectively drug administration with oral azithromycin interrupted reduce the incidence of sleeping sickness cases.67 The One transmission within 6–12 months. In India, after a 20 year Health approach can also be applied to the control of campaign using penicillin injection followed by sero- cysticercosis and echinococcosis, globally distributed surveillance of children for treponemal antibodies, WHO cestode infections, in which interventions focused on reported65 that yaws was no longer present in India and animal reservoirs (pigs and dogs) are essential components declared its eradication (technically elimination). of interventions to reduce human prevalence allied to behaviour change and curative therapy.73,74 Implementation strategies requiring collaboration with other sectors Water, sanitation, and hygiene Vector control Sustained control and elimination of soil-transmitted Vector control has been a major component of NTD helminthiases and schistosomiasis, require not only programmes over many decades. Many NTDs such as chemotherapy, but also access to clean and safe water lymphatic fi lariasis, visceral leishmaniasis, oncho- together with appropriate waste disposal and behaviour cerciasis, and Chagas’ disease have benefi ted from vector changes to reduce transmission. However, provision of control.66 Additionally, new approaches to the control of clean and safe water in the more remote areas where human African sleeping sickness using tiny target NTDs and other waterborne infections are most prevalent technology47 or selective spraying of cattle to control the poses a substantial challenge and the involvement of acute zoonotic form of disease have been shown to be other sectors is required. Engagement of the water, eff ective interventions but require implementation at sanitation, and hygiene sector and the inclusion of NTDs scale.67 Development of novel tools and methods to curb within this framework, refl ects a holistic policy approach the spread of (day-biting and outdoor-biting) Aedes aegypti within the SDG goals.62 mosquitoes that transmit dengue68 and Chikungunya69 is a high priority, reinforced by the emergence of Zika virus. Place of NTDs in the global health context Development of novel vector control methods will require towards 2030 substantially increased investment if they are to be During the past decade, NTDs have attracted increased implemented.6 Increasing levels of resistance to present attention and investment. Availability of drugs is no pyrethoid-based insecticides threaten the progress of the longer a barrier to achievement of universal health lymphatic fi lariasis elimination programme in Africa.40 coverage for most NTDs yet they remain a chronic Global warming, climate change, unplanned urbanisation, pandemic in the poorest sectors of society in endemic and global travel of people and goods, will have an impact countries who now have access to donated drugs. Further beyond the traditional populations associated with NTDs. progress will be driven by commitment of countries to The establishment of schistosomiasis in Corsica contribute to the relatively small costs of delivery— exemplifi es these threats; snail populations have been estimated at 1–3% of national health budgets—to ensure found in Corsica that are susceptible to infection with a access to donated products with a calculated annual value parasite strain from Africa, a hybrid of S haematobium and of $2–3 billion. In 2015, 1·1 billion people received Schistosoma bovis, therefore these strains could become preventive chemotherapy, representing a public health established in southern Europe.70 success, and 140 million children were dewormed in a single day in February, 2016, in India.75 However, progress Neglected zoonotic diseases: the One Health concept towards achievement of the 2020 WHO Roadmap targets Neglected zoonotic diseases occur in many settings, has been patchy. The resources allocated to NTDs are not caused by diverse groups of organisms, hence yet adequate to address the totality of the problem. The www.thelancet.com Published online September 14, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30171-4 11 Review

estimated requirements to achieve Roadmap goals are Contributors double the current $300 million annual funding DHM wrote the fi rst draft and took the lead role in development of the paper; LS and DE contributed to further development of the content and provided. However if vector control is included the structure of the paper, in particular the policy elements and editing, and estimated amount required would be ten times that agreed to the fi nal version. 6 amount. The challenge is to persuade endemic countries Declaration of interests to invest national resources to develop robust and DHM receives support from the UK Department for International dependable health delivery systems to ensure the gains Development as part of the COUNTDOWN NTD Implementation from NTD control or elimination are translated into Research award to the Liverpool School of Tropical Medicine and GlaxoSmithKline. LS is the Chair of the Executive Group of the Global long-term human development gains. Schistosomiasis Alliance. DE declares no competing interests. NTDs are tracers of equity in progress toward other 15 Acknowledgments SDGs and targets, including universal health coverage We thank Mark Bradley (GlaxoSmithKline), Antonio Montresor (WHO), (target 3.8), access to safe water (target 6.1), and sanitation and Adrian Hopkins (Mectizan Donation Program) for constructive and (target 6.2). NTD endemic populations are the least likely helpful comments and Joan Fahy (Liverpool School of Tropical Medicine) to have access to such services, hence use of NTDs as an for her assistance in organisation of the manuscript. indicator of progress is a logical step to justify these References 1 Liese B, Rosenberg M, Schratz A. Programmes, partnerships, and diseases in the SDG targets. Other SDG goals upon governance for elimination and control of neglected tropical which NTD interventions and partnerships are relevant diseases. 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