Neglected tropical diseases

1. NEGLECTED TROPICAL DISEASES (NTD) Dr Abhijit Chaudhury

2. Outline Origin of the “Brand Name”. Features and significance of NTDs. Spectrum of NTD and Evolving Scope Global Burden Indian Scenario Diagnostic Aspects Approaches to Control and Elimination: a. Mass Drug Administration b. Vaccination c. Public Health Measures 8. Conclusions.

3. 1. Origin of the “Brand Name”. The Millennium Development Goals ( MDGs ) : E ight international development goals that were established following the Millennium Summit of the United Nations in 2000. All 189 United Nations member states and at least 23 international organizations committed to help achieve the Millennium Development Goals by 2015. T he goals were: To eradicate extreme poverty and hunger To achieve universal primary education To promote gender equality and empowering women To reduce child mortality rates To improve maternal health To combat HIV/AIDS, malaria, and other diseases To ensure environmental sustainability To develop a global partnership for development

4. 1. Origin of the “Brand Name”. The outcome: New awareness and action plans for HIV/AIDS, Malaria, and TB. Establishment of Global Fund to fight the above three diseases (GFATM), US President’s Emergency Plans for AIDS Relief(PEPFAR), Funding by Gates Foundation, among others.

5. 1. Origin of the “Brand Name”. To combat HIV/AIDS, malaria, and other diseases---- The Forgotten Entity. In response, a group of concerned scientists and public health experts committed to the study of parasitic helminth and protozoan infections began meeting under the auspices of the World Health Organization (WHO) to discuss how global efforts to control these conditions could be scaled and expanded along the lines of PEPFAR and GFATM ------- THE ORIGIN

6. 1. Origin of the “Brand Name”. From these discussions an informal consensus was created that there are 13 major conditions, which could be targeted for mass drug administration or other large-scale interventions. The first published paper with the full term “neglected tropical diseases” in the title was a piece put forward by Molyneux , Hotez & Fenwick, in November 2005 in PLoS Medicine.

7. 1. Origin of the “Brand Name”. An interesting case study from India in 2001 discussed the need for establishing local research and development capacity for neglected infectious and tropical diseases, emphasising medicines [ Kettler HE, Modi R. Building local research and development capacity for the prevention and cure of neglected diseases : the case of India. Bull World Health Organ. 2001;79:742–7]. From 2005 and 2006, peer-reviewed papers using the term “neglected tropical diseases” as a medical subject heading started appearing in PubMed and other scientific literature databases.

8. 1. Origin of the “Brand Name”. In October 2007, the Public Library of Sciences published the inaugural issue of a new open-access journal, PLoS Neglected Tropical Diseases. In 2003, the creation of the Geneva-based Drugs for Neglected Diseases initiative ( DND i ; http://www.dndi.org) . Establishment of a new Department of Neglected Tropical Diseases at WHO (http://www.who.int/neglected_diseases/en/)

9. 2. Features and significance of NTDs. Neglected tropical diseases refer to a group of mainly chronic, debilitating and often stigmatising diseases that primarily affect the poorest of the poor living in remote rural and deprived urban settings of tropical and subtropical countries [ Utzinger J et al; Swiss Med Wkly. 2012:142:w13727]

10. A proxy for poverty and disadvantage Affect populations with low visibility and little political voice Do not travel widely Cause stigma and discrimination, especially of girls and women Have an important impact on morbidity and mortality Are relatively neglected by research Can be controlled, prevented and possibly eliminated using effective and feasible solutions Neglected Tropical Diseases common features

11. Distinguishing Features 1. The 13 NTDs represent the most common infections of people living in extreme poverty in sub-Saharan Africa, Asia, and Latin America and the Caribbean. 2. They disproportionately affect the “bottom billion,” which refers to the approximately 1.4 billion people who live below the World Bank poverty figure of US$1.25 per day. 3. Among the bottom billion, the NTDs result in chronic infections lasting years or even decades.

12. Distinguishing Features 4. The NTDs produce chronic disability that results in impaired child growth and intellectual and cognitive development, impaired pregnancy outcomes, and decreased worker productivity. 5. Through these mechanisms, the NTDs adversely affect not only health but also childhood education and ultimately economic productivity; the NTDs represent an underlying reason why the bottom billion cannot escape poverty. 6. Many of the NTDs also cause blindness and disfigurement that are psychologically devastating and result in social stigma.

13. Distinguishing Features 7. This high level of morbidity, economic impairment, and stigma does not necessarily translate into large numbers of deaths; overall, the NTDs cause high-morbidity but low-mortality conditions. 8. In contrast to emerging infections such as HIV/AIDS, SARS, and avian influenza, there is a “non-emerging” character about the NTDs. Instead, the NTDs have afflicted humankind for centuries and there are accurate descriptions of some of the NTDs in ancient texts.

14. Significance DALY = Disability Adjusted Life Years – Years of healthy life lost as a result of disability or premature life. As most of the NTDs are chronic condition, so instead of mortality, DALY parameter is used since it has a direct co-relation with the morbidity.

15. 3. Spectrum of NTD and Evolving Scope. The Original 13 ( Hotez et al, 2006,2007): A. HELMINTH INFECTIONS Ascariasis Trichuriasis Hookworm Schistosomiasis Lymphatic Filariasis Onchocerciasis Dracunculosis

16. 3. Spectrum of NTD and Evolving Scope. B. PROTOZOAN INFECTIONS 8. Leishmaniasis 9. Chagas Disease 10. African Trypanosomiasis C. BACTERIAL INFECTIONS 11. Trachoma 12.Leprosy 13. Buruli Ulcer

17. 3. Spectrum of NTD and Evolving Scope. WHO Additions (2010): Total 17 Foodborne Trematode Infections Cystic Echinococcosis Cysticercosis Endemic Syphilis Dengue and other Arboviral Infections. ( Ascariasis , Trichuriasis , Hookworm: Grouped under one heading of Soil Transmitted Helminths ).

18. 3. Spectrum of NTD and Evolving Scope. Meanwhile, the list of neglected tropical diseases has been further expanded and currently comprises over 40 diseases, which is reflected in the escalating scope of PLoS Neglected Tropical Diseases .

19. 4. Global Burden > I billion people suffer from one or more NTD. > 500,000 deaths, and > 25 million DALY/year Endemic in 149 countries - 2-5 NTD in >100 countries. - 6 or more NTD in about 30 countries. ( Source: WHO 2011)

20. DISEASE Approximate Global Prevalence (Millions) DALY (in Millions) Hookworm 576 1.0 Ascariasis 807 1.8 Trichuriasis 604 1.0 Lymphatic Filariasis 120 5.8 Scistosomiasis 207 1.7 Onchocerciasis 37 0.5 Drucunculiasis 0.001 <0.1

21. DISEASE Approximate Global Prevalence (Millions) DALY (in Millions) Leishmaniasis 12 2.0 African Trypanosomiasis >0.03 ND Chagas Disease 8 0.7 Trachoma 84 2.3 Leprosy 0.4 0.2 Buruli Ulcer <0.01 ND Dengue 50 0.6

22. 5.INDIAN AND SOUTH ASIAN SCENARIO

23. Disease Number of Cases in India (Percentage of Global Disease Burden) Number of Cases in India and South Asia(Percentage of Global Disease Burden) Estimated Number of DALYs in South Asia (Millions) ASCARIASIS 140M (17%) 287M (29%) 0.4-3.0 TRICHURIASIS 73M (12%) 147M (24%) 0.5-1.5 HOOKWORM 71M (12%) 130M (23%) 0.6-5.6 FILARIASIS <6M (5%) <60M (50%) 2.9

24. Disease Number of Cases in India (Percentage of Global Disease Burden) Number of Cases in India and South Asia(Percentage of Global Disease Burden) Estimated Number of DALYs in South Asia (Millions) Trachoma 1M (1-2%) 2M (2-4%) <0.1 Visceral Leishmaniasis ND 200,000-300,000 (40-60%) 0.4-1.0 Leprosy 87,190 Registered Cases (41%) 120,456 Registered (57%) 0.1 Dengue ND ND 0.4 Source: Lobo et al. 2011. PLOS Negl Trop Dis 5(10):e1222.doi10.1371 .

25. 6. DIAGNOSTIC ASPECTS The lack of rapid, accurate, simple-to-use, point-of-care tests for many of the neglected tropical diseases is an important feature for their general neglect and the under-appreciation of their disease burden. Microscopy remains the mainstay of diagnosis for majority of the NTDs. While microscopy of parasites is considered as highly specific , its sensitivity depends on the intensity of infection, which is a function of the number of parasitic elements in a sample

26. 6. DIAGNOSTIC ASPECTS Immunodiagnosis is applicable for most of the neglected tropical diseases, but may lack sensitivity and/or specificity. Antibodies produced against one helminth species are known to cross-react with antigens from other helminths . Moreover, antibodies produced against infectious agents do not give any indication of the severity of infection , and are often detectable for several months or years after an infection has cleared, and hence do not allow to distinguish between current and past infections The commercial availability of standardised test kits is still the exception rather than the norm

27. 6. DIAGNOSTIC ASPECTS The development and use of molecular tools such as polymerase chain reaction (PCR) tests for the diagnosis of neglected tropical diseases is the focus of multiple research groups, but the commercial availability of DNA amplification kits is rare. Moreover, the isolation of parasite DNA from stool or tissue is challenging, cumbersome and quite often not fruitful at all. According to some authors, multi-parasitic screenings based on molecular assays might one day replace microscopy and immunodiagnosis .

28. 7. Approaches to Control and Elimination Renewed momentum generated by unprecedented progress resulted in the World Health Assembly to adopt resolution WHA 66.12, in May 2013. Of the 17 neglected tropical diseases, two are targeted for eradication – dracunculiasis (guinea-worm disease) by 2015 and yaws by 2020 and four for elimination (blinding trachoma, human African trypanosomiasis , leprosy and lymphatic filariasis ) by 2020.

29. 7a. Mass Drug Administration Of the 850 new therapeutic products registered in 2000—11, 37 (4%) were indicated for neglected diseases, comprising 25 products with a new indication or formulation and eight vaccines or biological products . ( Pedrique et al. The Lancet Global Health,2013) A persistent insufficiency in drug and vaccine development for neglected diseases

30. 7a. Mass Drug Administration Mass interventions comprise of population-based drug administration (often together with other allied measures) Extremely successful in terms of reaching large numbers of affected populations, even in the most remote areas of Africa, Asia, and the Americas, and in achieving control and elimination targets. The medicines used in mass drug administration have an excellent safety profile and can be administered to large populations based on community-wide prevalence assessments.

31. 7a. Mass Drug Administration Once a threshold prevalence of a particular NTDhas been ascertained, WHO has established algorithms for treating large populations regardless of whether it has been determined if any given individual is currently infected. The drugs used in mass administration are either being donated by some of the major multinational pharmaceutical companies or they can be purchased as extremely low-cost generics.

32. 7a. Mass Drug Administration Pharmaceutical Donation Programmes Sanofi Aventis Eflornithine and melarsoprol support for sleeping sickness treatment Merck & Co Inc Mectizan for as long as needed for onchocerciasis and filariasis in Africa GlaxoSmithKline Albendazole for lymphatic filariasis atleast to 2020 Pfizer Azithromycin for trachoma 120 million doses Novartis MDT and clofazimine for leprosy; triclabendazole for fascioliasis Johnson & Johnson Mebendazole for intestinal worms Bayer Nifurtimox for Chagas and HAT to 2012 Merck KgaA Praziquantel for schistosomiasis to 2017.

33. 7a. Mass Drug Administration In order to increase coverage for the seven most common NTDs, it was proposed in 2005 to bundle the drugs in mass drug administration for these conditions in a “rapid impact package,” costing as little as US$0.50 per individual.

34. Seven Major NTDs Targeted by Rapid Impact Major Drugs Used Additional NTDs Targeted by Rapid Impact 1. Soil-transmitted helminth infections: ascariasis , trichuriasis , hookworm Albendazole or mebendazole Strongyloidiasis 2. Schistosomiasis Praziquantel Taeniasis Food-borne trematodiases 3. Lymphatic filariasis Ivermectin or diethylcarbamazine citrate + albendazole Strongyloidiasis , Scabies 4. Onchocerciasis Ivermectin Strongyloidiasis , Scabies 5. Trachoma Azithromycin Other bacterial infections Hotez PJ.2011.

35. 7a. Mass Drug Administration There are additional NTDs of great public health importance for which mass drug administration approaches are not immediately relevant but which in some cases could still be controlled or eliminated. Drucunculosis , African Trypanosomiasis , Chagas Disease, Visceral Leishmaniasis . Program of early case finding, delivering oral treatment, and vector control are more relevant for these diseases.

36. 7b. Vaccination: Hookworm Human Hookworm Vaccine Initiative (HHVI) is the group currently working on vaccines targeting this parasite. Sabin Vaccine Institute announced the start of Part II of its Phase I clinical trial of the Na -GST-1 (Glutathione S Transferase ) vaccine candidate in November, 2012.  Part II of the trial commenced in Americaninhas , Brazil, following successful vaccinations in Part I of the study, which began in Belo Horizonte, Brazil in late 2011. Ultimately, Na -GST-1 and Na -APR-1 would be used together a bivalent vaccine. Aim of the vaccine will be to reduce moderate to heavy infections in the host.

37. 7b. Vaccination: Schistosomes Only one schistosome antigen has entered into clinical trials. The Institut Pasteur has taken a recombinant 28 kDa GST cloned from S. haematobium through both phase 1 and 2 clinical testing in Europe and West Africa (Senegal and Niger). Sh28-GST ( Bilhvax ) is a recombinant protein formulated with an aluminum hydroxide adjuvant . Bilhvax appears to be immunogenic and well-tolerated in healthy adults from non-endemic (France) and S. haematobium endemic areas in Africa.

38. 7b. Vaccination: Schistosomes The most important vaccine target of the schistosome is the tegument. The tegument is thought to be involved in several key physiologic processes: parasite nutrition, osmoregulation , and the evasion of host immunity. Tetraspanins found in outer tegument play important role in maintaining the integrity of the tegument. Sm-TSP-2 has been selected by the HHVI for development as a human vaccine antigen.

39. 7b. Vaccination: Schistosomes The Sm -TSP-2 recombinant schistosomiasis vaccine would be intended primarily for school-aged children living in the S. mansoni endemic regions of sub-Saharan Africa and Brazil. The vaccine ideally would prevent the reacquisition of schistosomes in the blood stream following initial treatment with Praziquantel (vaccine-linked chemotherapy).

40. 7b. Vaccination: Leishmania Second Generation Vaccines: Recombinant protein vaccines . A variety of Leishmania vaccines consist of recombinant proteins; poly-proteins produced by DNA cloning. More recent efforts aim at increasing the immunogenicity of DNA cloned vaccines, including the use of genetic adjuvants and plasmid-based expression of viral replicons . Some of the important recombinant protein candidate vaccines include: surface expressed glycoprotein leishmaniolysin (gp63) , Leishmania activated C kinase (LACK ), parasite surface antigen (PSA ), Leishmania derived recombinant polyprotein (Leish-111f ) and serine proteases .

41. 7b. Vaccination: Leishmania Leish-111f is a single polyprotein composed of three molecules fused in tandem : the L. major homologue of eukaryotic thiol -specific antioxidant , TSA ; the L. major stress-inducible protein-1, LmSTI1 ; and the L. braziliensis elongation and initiation factor, LeIF . The Leish-111f product is the first defined vaccine for leishmaniasis in human clinical trials and has completed phase 1 and 2 safety and immunogenicity testing in normal, healthy human subjects. Efficacious against cutaneous or mucosal leishmaniasis .

42. 7c. Public Health Measures WHO recommends five public-health strategies for the prevention and control of neglected tropical diseases: expansion of preventive chemotherapy; intensified case-detection and case management; improved vector control; appropriate veterinary public health measures; provision of safe water, sanitation and hygiene . Universal health coverage is the single most powerful concept that public health has to offer.

43. Conclusion For almost all of the NTDs, there is a desperate need for research and development leading new innovations for control, including improved diagnostics, medicines, or vaccines. Several potential backup anthelminthic drugs previously developed for veterinary purposes could potentially be transitioned into human medicines, and there is a need to establish a product development public–private partnership (PD-PPP) for this purpose.

44. Conclusion Vaccines , developed for NTDs, have potential economic impact as well as their effects on health; hence termed Antipoverty Vaccines. For all seven NTDs targeted for rapid impact packages, there is a pervasive need for new diagnostics.

45. Conclusion There is an urgent need for better surveillance and disease burden assessments for most of the NTDs. L inking of mass drug administration, vaccinations , integrated vector management, and improved surveillance together as part of overall efforts to strengthen health systems in the region.