Eliminating Lymphatic Filariasis. Success in science, intervention and beyond..

Eliminating Lymphatic Filariasis Success in science, intervention and beyond.. Eric A. Ottesen, M.D. 30 January 2007

LF Disease

Adult parasites (W. bancrofti) in scrotal lymphatic Dreyer & Noroes

LF Disease Other clinical manifestations Filarial fevers Tropical Pulmonary Eosinophilia Chyluria Hematuria/Proteinuria others less well defined

LF Infection Asymptomatic microfilaremia Adult Worms L4 Human Mf L3 Mosquito L2

Why do we focus on LF now? Partly, it s because of LF s importance LF imposes a health burden affecting 120 million people 40 million with overt disease 80 million with hidden infection and disease 1.1 billion people at risk of infection 83 endemic countries throughout the tropics/sub-tropics leading cause of disability, stigma, economic loss

LF Endemic Countries & Territories 2006 8 Fourth GAELF, Fiji-29-31 Mar 2006

Why do we focus on LF now? It a really good science story? Research Understanding Tools Strategy Public Health Implementation bench bedside community

Towards Public Health Implementation? Research Understanding Tools Strategy Public Health Implementation 1 st step: to define a clear goal

Global Program to Eliminate LF (GPELF) Operational Goals 1) To interrupt LF transmission 2) To alleviate and prevent the suffering of those already affected

New understandings: pathogenesis of lymphedema/elephantiasis 1) Recognition that LF is an infection acquired in childhood % 40 30 20 26% Diagnosis by Antigen 10 6% 0 2 years 4 years age of children in cohort Haiti; Antigen Lammie et al

New understandings: pathogenesis of lymphedema/elephantiasis 2) Recognition of sub-clinical lymphatic damage Lymphoscintigraphy (legs) Ultrasound (scrotal lymphatic) normal LF (aysmptomatic mf+)

New understandings: pathogenesis of lymphedema/elephantiasis 3) Identifying the etiology and importance of filarial fevers (acute inflammatory episodes) ADL DLA

New understandings: pathogenesis of lymphedema/elephantiasis 4) Recognizing that bacterial superinfection was the principal determinant of disease progression Entry Lesions

Hygiene New understandings: management of lymphedema/elephantiasis Preventing bacterial infections is the primary goal of managing patients with lymphedema Treatment and prevention of skin lesions Exercise Elevation Shoes Bandages

LF genital disease: pathogenesis & management Pathogenesis: lymphatic distortion +/- bacterial infection Management: for hydrocele, surgery is cure for genital lymphedema/elephantiasis, hygiene

Global Program to Eliminate LF (GPELF) Operational Goals 1) To interrupt LF transmission 2) To alleviate and prevent the suffering of those already affected

For the LF program, the goal is elimination What does elimination mean? The incidence of infection must become zero Transmission must be interrupted What does it take to achieve elimination? Effective interventions Effective diagnostics

LF Infection Asymptomatic microfilaremia Adult Worms L4 Human Mf L3 Mosquito L2

Effective tools: for intervention The anti-filarial drugs DEC ALB Diethylcarbamazine (DEC) Ivermectin (IVR) L4 Adult Worms Human Mf DEC IVR Albendazole (ALB) L3 Mosquito L2

Effectiveness of Single Doses of Antifilarial Drugs 100 % Pre-treatment (mf/ml) 80 60 40 20 0 DEC Ivermectin Albendazole 0 1 3 6 12 Months Post Treatment (Meta-analysis 8-20 studies each)

ALBENDAZOLE, IVERMECTIN & DEC 2-Drug Regimens Microfilaraemia (% Pre-Rx) 100 90 80 70 60 50 40 30 20 10 0 Blood Microfilaria Levels (W. bancrofti) ALB+IVER ALB+DEC Months Post Treatment 0 1 2 3 6 9 11 15 30 Single-Dose Treatment Ismail et al. 96

What makes a disease eliminatable? Effective intervention tools Effective diagnostic tools

New diagnostic: antigen-detection test (W.bancrofti) High sensitivity (>95%) High specificity (99%) Uses finger-prick blood Rapid (1-10 minutes) Positive night and day Field-useable Commercially available (cost: $2.50/test for public health programs)

LF does have effective tools For intervention For diagnosis For managing LF disease

The challenge for all our programs? Research Understanding Tools Strategy Public Health Implementation

Creating a strategy for LF elimination: Previously Diagnose Treat Individual Individual

Creating a strategy for LF elimination: major paradigm shift Previously Now Diagnose Individual Population Treat Individual Population

Creating a strategy to eliminate LF: Interrupt transmission: 1 st major paradigm shift Identify all LF-endemic areas Treat entire at risk populations 2-drug, single-dose regimens once-yearly x 4-6 years by mass drug administration (MDA) Alleviate suffering / Prevent disease Introduce new principles of hygiene and patient care to prevent and manage LF disease

The challenge for all our programs Phase-1-------------------------------------------------------l? Research Understanding Tools Strategy Phase-2 Phase-3------------------l Public Health Implementation

Public Health Implementation Must speak a new language? Research Understanding Tools Strategy antigens primers receptors transduction pharmacokinetics IL-1, IL-4, IL-13 genomics proteomics Public Health Implementation partnerships collaborations alliances business plans cost-effectiveness health systems equity MDGs

Public Health Implementation Absolute requirements: Political commitment Resources Determination to work together (as partners)

LF Elimination: - scientific political commitment- 1993: International Task Force on Disease Eradication The 2 essential criteria for eradicability were met Other attributes (biological) favored eradicability LF elimination has been successful before! LF: one of 6 diseases eradicable or potentially eradicable

LF Elimination: - governmental political commitment- Ministries of Health individual commitment by MOH to establish national LF elimination programmes collective commitment : WHA Resolution 97 Urges Member States...to strengthen activities toward eliminating lymphatic filariasis as a public health problem... Requests the Director-General...to mobilize support for global and national elimination activities.

Public Health Implementation Absolute requirements: Political commitment Resources Determination to work together (as partners)

LF Elimination: -early donations of resources- To donate all albendazole required for LF elimination; to support selected research and program activities Merck and Co. Inc Whitehouse Station, NJ, USA, UK Arab Fund Japan To expand Mectizan Donation Program to provide ivermectin for LF treatment where onchocerciasis co-exists Long-term support of programme development and intervention in the countries and globally, through WHO and the LF support centres To support activities toward elimination of LF from all Arab Fund member countries To support programme training activities and efforts to eliminate LF from the Pacific island nations (PacELF)

What s the most important thing in real estate? Location Location Location

What s the most important thing in global health? Partnership Partnership Partnership

Public Health Implementation Absolute requirements: Political commitment Resources Determination to work together (as partners)

Global Alliance Partnership Strategic Plan for the Partners Targets Milestones Roles of partners

Global Alliance To Eliminate Lymphatic Filariasis WHO Arab Fund for Economic and Social Development Japan Liverpool School of Tropical Medicine Bill and Melinda Gates Foundation Unicef Health & Development International World Bank CDC US Centers for Disease Control and Prevention

Success requires partnership Public-sector partners Ministries of Health Overseas Development Agencies Private-sector partners Pharmaceutical companies Foundations NGOs, technical agencies, academia, others People partners people-power in the programmes in the communities

Success requires partnership Phase-1-------------------------------------------------------l? Research Understanding Tools Strategy Phase-2 Phase-3------------------l Public Health Implementation

LF Elimination The Global Program(me) (2000-2020)

Global Program to Eliminate LF (GPELF) Operational Goals 1) To interrupt LF transmission through MDAs 2) To alleviate and prevent the suffering of those already affected

Mass Drug Administration (MDA)

Countries with LF Elimination Programs (2006) 15 Pacific Island Countries Countries with active LF elimination programs Countries endemic for LF which have only incipient or not yet active elimination i programs Countries with active LF elimination programs and specific demonstration projects funded by the Gates Foundation

Global Programme Progress Number of treatments (millions) 450 400 350 300 250 200 150 100 50 45 40 35 30 25 20 15 10 5 Number of country programmes 0 2000 2001 2002 2003 2004 2005 0 Treatments administered (both single and dual drug) Country programmes

MDA Reduces Microfilaria Prevalence Egypt Vanuatu K. Bahary K. Qebly K. Tahoria Tahoria Sola Mos ina Port R. S. River Prevalence (%) 14 12 10 8 6 4 2 Prevalence (%) 35 30 25 20 15 10 5 Sakau Wanur Orap Unmet 0 Pre-Rx Year 1 Year 2 Year 3 0 Pre-RX Year 1 Year 2 Year 3 Haiti Papua New Guinea Leogane Mapou Masson Barrier Jeudi Site 1 Site 2 Site 3 Site 4 Prevalence (%) 18 16 14 12 10 8 6 4 2 0 Pre-Rx Year 1 Year 2 Year 3 Prevalence (%) 90 80 70 60 50 40 30 20 10 0 Pre-RX Year 1 Year 2 Year 3 Year 4

Impact of MDA on Microfilaria Clearance at Sentinel Sites After 2 or 3 MDAs 13% 43% Total clearance 50%-99% clearance <50% clearance 44%

The Global Programme to Eliminate Lymphatic Filariasis on track and doing well... but are there still problems/challenges?

Are there still problems/challenges for LF? Very definitely!? Research Understanding Tools Strategy Public Health Implementation

Are there still problems/challenges for LF? Very definitely! Understanding? Research Public Health Tools Implementation Strategy WHO/TDR Scientific Working Group May 2005 Gates Foundation Grant to GAELF 2006-2010

Facing the facts.. Our programmes in many places, are now starving for funds are extremely well organized and well run are highly popular with communities are successful in achieving their targets are ridiculously inexpensive for the benefit attained could be successfully and fully implemented if funds were available LF has proven to be a major challenge to market

So what should be done? It s time for a 2 nd major paradigm shift

What s the most important thing in global health? Partnership Partnership Partnership

Programme success 2 nd major paradigm shift Strategy to ensure LF elimination: Previously Now Implementation LF alone with NTDs Advocacy/fundraising LF alone with NTDs

Package of Neglected Tropical Diseases ( Targets of Opportunity / Rapid impact Diseases ) Lymphatic filariasis (LF) Onchocerciasis Schistosomiasis Soil-transmitted helminthiasis (STH) Trachoma

The devil is in the detail.. What could/should be integrated? MDA Medications and their delivery IEC/Social mobilization Logistics Monitoring & Evaluation Morbidity management Fundraising & Advocacy

Promise of the Future for NTDs Success in implementation: from exploiting the synergies among public health initiatives sharing similar strategies Lymphatic Filariasis GPELF Onchocerciasis APOC Schistosomiasis - SCI Soil Transmitted Helminths PPC Trachoma ITI Micronutrient Initiative Success in resource mobilization: from attractiveness of integrated management of packages of programmes targeting important but otherwise-neglected diseases Arguably the best buy in global health today!

Comparative Treatment Costs (Range) HIV/AIDS Ref: Clinton Foundation, Bertozzi, etal 2004, Bautista 2003 TB Ref: Global TB Control 2005 Malaria Ref: Chmia, 2003; Molyneux et al 2005 NTD Package Ref: Brady et al 2006 0 100 200 300 400 500 600 700 800 900 1000 Cost per patient treatment per year (US dollars)

Global Disease Burden (DALYs) DALYs (in millions) Ischemic heart disease 58.6 Diarrheal diseases 62.0 Unipolar depression 67.3 HIV / AIDS 84.5 Neglected tropical diseases 56.6 Lower Respiratory Infections 91.4 Cerebrovascular diseases 49.2 Malaria 46.5 Road traffic accidents 38.7 Tuberculosis 34.7

Integrating Neglected Tropical Disease Control

Global Network for Neglected Tropical Diseases http://www.gnntdc.org Schistosomiasis Control Initiative International Trachoma Initiative Helen Keller International Liverpool School - GAELF Human Hookworm Vaccine Initiative Earth Institute at Columbia Univ. Task Force for Child Survival Lymphatic Filariasis Support Center Mebendazole Donation Intiative Mectizan Donation Program

New NTD Control Projects The Global Network for Neglected Tropical Disease Control 8 / 56 Countries Geneva Global Burundi Rwanda Exxon Mobil Equatorial Guinea USAID Burkina Faso Ghana Mali Niger Uganda

The Buzz on NTDs The world is now paying attention to these [neglected] It Comprehensive, quickly We learned diseases became that and Africa-wide making clear this that integration progress this control story is in of unprecedented is a malaria not long just process, and about NTDs ways, the but it is staggering together worth with ambitious would doing, numbers probably and goals, of we the are cost excellent world s learning no more citizens interventions, by than doing overwhelmed $3 that billion and process. a growing year, by HIV, or just evidence AIDS, Dominique TB, two days of and multiple of Kyelem, malaria. Pentagon benefits Burkina And it s spending. for Faso not health. just If each Ministry The the story of attention the of about billion Health, to one people Lymphatic billion long-neglected people in the rich Filariasis who world diseases are devoted Control afflicted is a the positive Program with disabling, equivalent sign that oftentimes of one health $3 is a stigmatizing, responsibility neglected shared tropical by the diseases, international such community. as human hookworm coffee a year infection to the and cause, elephantiasis several million it s children all about every the faces -Dr. Margaret Chan, Director-General of the World year Health would of dying be children Organization spared of and death sick and mothers debility, who and haunt world those who have seen them...what struck me, and what I think struck would us be all that spared the these grave challenges risks when are disease all interconnected. and despair - run Clinton unchecked. Global A Initiative, new Global Closing Network Remarks for Neglected Tropical Disease Control is helping make this opportunity a reality. - Jeffrey Sachs, Director of the Earth Institute, Scientific American January 2007

World s first peer-reviewed, open-access journal devoted to the NTDs Launch supported by Bill and Melinda Gates Foundation Papers on pathology, epidemiology, treatment, control, prevention Magazine section devoted to policy and advocacy International editorial board half of the Associate Editors are from endemic countries Accepting submissions in early 2007 It is expected that the journal will be both catalytic and transformative in promoting science, policy, and advocacy for these diseases of the poor. Peter Hotez, Editor-in-Chief

Successes, Challenges, Way Forward Must recognize that we have extraordinary opportunities to make enormous impact on the health and economies of the developing world, at very low cost. we simply cannot do it. alone Success will come from exerting flexibility, changing old habits, creating new partnerships new coalitions of coalitions No longer speak solely of LF and the Global Programme to eliminate it -- now it s LF and Beyond the NTDs & other Global Health challenges

maybe this will be the new NTD face of LFelimination, schisto control,.

Costs for Treating 5 Neglected Diseases at 2006 Target Levels in Sub Saharan Africa Cost per person - treat each disease separately $1.07 Total cost - treat each disease separately $109 million Cost per person - treat packaged NTDs $0.57 Total cost - treat packaged NTDs $58 million

Outcomes Projected from Integrated Treatment of 5 NTDs in SSA (at 2006 Levels) 10.5 million children protected from STH 14.7 million adults protected from STH 5 million cases of skin disease and itching prevented 570,000 pregnant women protected from anemia 100,000 people protected from severe kidney or bladder disease 65,000 cases of hydrocele prevented 28,000 cases of lymphedema prevented 25,000 cases of blindness prevented 5,000 people protected from life-threatening liver disease