Combating Infectious Diseases and the Disease Control Priorities Project: A Convergence of Epidemiology, Economics and Research World Bank Washington, D.C. November 8, 2006 Joel G. Breman, MD, DTPH Fogarty International Center National Institutes of Health

Outline DCPP Objectives Burdens - Global - Infectious Diseases Malaria Case Study Intervention Cost-Effectiveness - Best Buys - One Million Dollars Main Messages

Objectives of DCPP (1) To decrease illness, disability, death, and economic burden by:  Developing an evidence base to inform decision-making by: Providing estimates of the cost-effectiveness and impact of single interventions and packages Collaborating in defining disease burdens globally and regionally Summarizing implementation experience in different regions and globally

Objectives of DCPP (2)  Communicating major findings “Best buys” and the “worst buys” Disseminating the results Stimulating national priority setting and program implementation

Disease Burdens Deaths Disability-Adjusted Life Years Global Infectious Diseases

Leading Causes of Death in High and Low-/Middle-Income Countries (LMICs), 2001 (Total = million) High Income (% total deaths) (n =7.89 million (14%) 1. Ischemic heart disease (17.3) 2. Cerebrovascular disease (9.9) 3. Trachea, bronchus, lung cancer (5.8) 4. Lower respiratory infections (4.4) 5. Chronic obstructive pulmonary disease (3.8) LMICs (% total deaths) (n = million (86%) 1. Ischemic heart disease (11.8) 2. Cerebrovascular disease (9.5) 3. Lower respiratory infections (7.0) 4. HIV/AIDS (5.3) 5. Perinatal conditions (5.1) Mathers et al., 2006, in Lopez et al, Global Burden of Disease and Risk Factors

High Income (% total deaths) (n = 7.89 million (14%) 6. Colon and rectum cancers (3.3) 7. Alzheimer’s and other dementias (2.6) 8. Diabetes mellitus (2.6) 9. Breast cancer (2.0) 10. Stomach cancer (1.9) Total: 53.6% (ID = 4.4%) LMICs (% total deaths) (n = million (86%) 6. Chronic obstructive pulmonary disease (4.9) 7. Diarrheal diseases (3.7) 8. Tuberculosis (3.3) 9. Malaria (2.5) 10. Road traffic accidents (2.2) Total: 55.3% (ID = 21.8%) Mathers et al., 2006, in Lopez et al, Global Burden of Disease and Risk Factors Leading Causes of Death in High and Low-/Middle-Income Countries (LMICs), 2001

Disability-Adjusted Life Years (DALYS) Burden of Disease on a Defined Population Aggregate of premature mortality, morbidity, and disability Adjustments made for life expectancy long-term disability (weighted) Valid indicator of population health Tied to effectiveness of interventions

Disease Burden by Income, 2001 Mathers et al, 2006, in Lopez et al, Global Burden of Disease and Risk Factors Countries Population in millions (%) For all diseases, no. in millions (%) For infectious and parasitic diseases, no. in millions (%) Infectious diseases burden (%)* Low- and Middle-Income 5,219 (85) 1,387 (90) 321 (99) 29 High Income 929 (15) 149 (10) 3 (1) 4 Total 6,148 (100) 1,536 (100) 324 (100) 27 Disability-Adjusted Life Years (DALYs) *includes respiratory infections

Leading Causes of Disability-Adjusted Life Years (DALYs), Globally, 2001 (n = 1.54 billion) Cause% total 1. Perinatal conditions Lower respiratory infection Ischemic heart disease Cerebrovascular disease HIV/AIDS Diarrheal diseases Unipolar depressive disorders Malaria Chronic obstructive pulmonary disease Tuberculosis 2.3 Total (ID= 19.1%) 41.1 Mathers et al, 2006 in Lopez et al, Global Burden of Disease and Risk Factors

Disease Burden, Low and Middle Income Countries, by World Bank Region, 2001 Disability-Adjusted Life Years (DALYs) Region Population in millions (%) For all diseases, no. in millions (%) For infectious and parasitic diseases, no. in millions (%) Infectious diseases burden in region,%* Sub-Saharan Africa 668 (13) 345 (25) 173 (54) 59 South Asia 1,388 (27) 409 (29) 88 (27) 31 Middle East/North Africa 310 (6) 66 (5) 7 (2) 16 East Asia/Pacific 1,850 (35) 346 (25) 37 (12) 14 Latin America/Caribbean 526 (10) 104 (8) 10 (3) 13 Europe/Central Asia 477 (9) 117 (8) 5 (2) 6 Total 5,219 (100) 1,387 (100) 320 (100) 29 Mathers et al, 2006, in Lopez et al, Global Burden of Disease and Risk Factors *includes respiratory infections

SSA = Sub Saharan Africa; SA = South Asia; ME/NA = Middle East/North Africa; EA/P = East Asia/Pacific; LA/C = Latin America/Caribbean; E/CA = Europe/Central Asia Mathers et al, 2006, in Lopez et al, Global Burden of Disease and Risk Factors Disease burden by region, % Disease Disease Burden In LMICs DALYs, % SSA SA ME/NA EA/P LA/C E/CA Respiratory inf Malaria TB Measles STD Diarrheal disease Infectious Burden, Low- and Middle-Income Countries, by World Bank Region, 2001 HIV/AIDS

Leading Causes of Disability-Adjusted Life Years (DALYs) in Sub-Saharan African Region, 2001 Total DALYs % 1. HIV/AIDS Malaria Lower respiratory infections Perinatal conditions Diarrheal diseases Measles Tuberculosis Whooping cough Road traffic accidents Protein-energy malnutrition 1.6 Total 61.2 (ID=56.5%) Mathers et al. in Global Burden of Disease and Risk Factors, 2006

Malaria Manifestations Burden Interventions

Manifestations of the Malaria Burden Infected Mosquito Infected Human Chronic effects Anemia Neurologic Cognitive Developmental Impaired growth and development Malnutrition Acute febrile illness Severe illness Anemia Hypoglycemia Cerebral malaria Death Respiratory distress Pregnancy Fetus Maternal Acute illness Anemia Low birth weight Abortion, stillbirth Infant and fetal mortality Long-term sequelae Long-term sequelae Hypovolemia

Number of malaria deaths Cause of malaria-related death Cerebral malaria 110,000 Severe anemia190, ,000 Respiratory distress110,000 Hypoglycemia153, ,000 Low birth weight62, ,000 Total deaths from malaria625,000-1,824,000 Deaths from Malaria: Children Under Five and Total, Africa ,000-2,806,000 ● Under fives ● Total, all ages * Sources Breman, Alilio and Mills, 2004; Murphy and Breman, 2001 *Children under 5 represent 65 percent of all deaths in Africa as per Snow and others (2003).

Source: Lopez, Begg, and Bos Under-Five Deaths from AIDS, Malaria, and Other Causes, per Thousand Births, 1990 and 2001, Sub-Saharan Africa

Source: World Bank 2004 (CD-ROM version). Rate of Progress in Reducing Under-Five Mortality, : China, India, Latin America, and Sub-Saharan Africa

Plasmodium falciparum in 2002 Clinical Cases Region Population at risk (million) Cases (M) (%) (million) Africa ( ) (57%) Americas 554 (2 - 8) (1%) South East Asia1, ( ) (34%) Western Pacific (9 - 26) (4%) Eastern Med (5 - 25) (4%) Europe 41 (0 - 1) (<1%) Total2, (298 – 659) (100%) Snow et al, Nature 2005

Acute Febrile Episodes and Malaria-Associated Febrile Episodes in African Children 0-4 years Living in Endemic Areas, Millions 1995 population: total 585 million, 521 million (89%) in malarious areas; children <5 years 104 million, 94 million in malarious areas; assume <5 year population grows ~ 3.2% per year and will double by Febrile Illness Malaria J. Breman, AJTMH,

Environmental and Behavioral Modification Genetic modification of vectors Future Interventions Vaccines (preerythrocytic, blood stage, transmission- blocking) Protection (insecticide- impregnated materials) Control of the Malaria Burden Current Interventions Drugs (treatment, prevention) Insecticides (house spraying, larvicides)

Intermittent preventive treatment in pregnancy with drug switch Insecticide-treated bed nets Insecticide residual spraying Intermittent preventive treatment/ pregnancy (SP) Cost-effectiveness ratio ($ per DALY averted) Cost-Effectiveness of Interventions Against Malaria in Sub-Saharan Africa R. Laxminarayan et al (DCPP authors), 2006 in Disease Control Priorities in Developing Countries

Table CERs for ITNs, IRS, and IPT Intervention Mean cost per DALY averted90 percent range ITNs (net + insecticide treatment) Deltamethrin Permethrin (1 treatment) Permethrin (2 treatments) ITNS (without provision of nets) Deltamethrin52-7 Permethrin (1 treatment)63-9 Permethrin (2 treatments) IRS (1 round) DDT95-13 Deltamethrin Lambda-cyhalothrin Malathion128-18

Table CERs for ITNs, IRS, and IPT (2) Intervention Mean cost per DALY averted90 percent range IRS (2 rounds) DDT Deltamethrin Lambda-cyhalothrin Malathion IPT Incremental costs Average costs

Incremental Cost-Effectiveness Ratio of an Intervention Costs B – Costs A Effectiveness B – Effectiveness A Interventions studied: personal = 204 population = 115

,0001,2001,4001,600 HIV/AIDS - peer programs Voluntary counseling/testing STI diagnosis/treatment Condom promotion/distribution Blood/needle safety Tuberculosis coinfection prevention/treatment Mother/child prevention Home care Antiretroviral treatment Cost-effectiveness ratio ($ per DALY averted) Cost-Effectiveness of Interventions Against HIV/AIDS in Sub-Saharan Africa Laxminarayan et al (DCPP authors), 2006, in Jamison et al, Disease Control Priorities in Developing Countries

Tuberculosis

The Neglected Tropical Diseases: Humanity’s Ancient Diseases of Stigma and Poverty 13 Parasitic and Bacterial Infections Rural Areas of Low-Income Countries Poverty-Promoting Conditions Child Development & Education Pregnancy Worker Productivity Burdened humanity for centuries “The Biblical Diseases” Disabling and deforming Associated with intense stigma River Blindness Guinea Worm Lymphatic Filariasis Leprosy

Ranking of Communicable Diseases By DALYs Disease ConditionDisease Burden HIV-AIDS84.5 million Neglected Tropical Diseases 56.6 million Malaria46.5 million Tuberculosis34.7 million Hotez PJ, Molyneux DH, Fenwick A, Ottesen E, Ehrlich Sachs S, Sachs JD PLoS Medicine 2006; 3: e102

,00010,000 Soil-transmitted helminths: Albendazole Leishmaniasis: case finding and treatment Onchocerciasis: Ivermectin Trachoma: trichiasis surgery Trachoma: drug treatments Cost-effectiveness ratio ($ per DALY averted ) Source: DCPP Authors Cost-Effectiveness of Interventions Related to Low-Burden Diseases in LMICs; Helminths, Leishmaniasis, Onchocerciasis, Trachoma

“Best Buys” Neglected Opportunities

“Best Buys” Neglected Opportunities in Sub-Saharan Africa (SSA) and South Asia (SA) (1) Low Cost Opportunity Cost per DALY averted ($) Burden of disease DALYs (10 6 ) ● Childhood Immunization - Second measles vaccination - Increase coverage - DTP, polio, measles, BCG SSA SA 1 – – ● Traffic Injuries - Increase speeding penalties - Speed bumps SSA SA 2 – 12 not evaluated 6.4 not evaluated Laxminarayan et al (DCPP authors), 2006, in Jamison et al, Disease Control Priorities in Developing Countries

Higher Cost Buys

Perspective: Cost-Effectiveness and Coverage Interventions to scale back Interventions for which scaling up is inefficient Cost-effective interventions used widely Neglected opportunities Current Coverage Cost Effectiveness LowHigh Low High Laxminarayan et al, 2006, in Jamison et al, Disease Control Priorities in Developing Countries, 2 nd ed.

Perspective: Cost-Effectiveness and Coverage HIV/AIDS poor treatment adherence (programs) deep brain stimulation Malaria drugs, insecticide treated nets Leishmaniasis treatment Avertable Burden of Disease Cost Effectiveness Low High Low High Laxminarayan et al, 2006, in Jamison et al, Disease Control Priorities in Developing Countries, 2 nd ed. Parkinson’s disease

A Million Dollars Invested

How Much Health Will a Million Dollars Buy? Service or Intervention  Reducing under-5 mortality Expanding immunization coverage (EPI diseases) Switch to artemisinin- combination therapy (ACT) where malaria is drug-resistant Improved neonatal care (newborn resuscitation) Adding vaccines to EPI (Hib and hepatitis B) DALYs Averted ($ per DALY) 50, ,000 ($2-20) 50, ,000 ($8-20) 2, ,000 ($10-400) 4,000-24,000 ($40-250)

Research and Product Development

Share of Disease Burden Averted with Existing, Improved or New Interventions Not avertable, research needed Avertable with current interventions and coverage 0 a b c Effective coverage Source: WHO, Investing in Health Research and Development Avertable if cost- effective interventions applied more widely Avertable only with interventions that are less cost- effective

Research Needs Efficacy of Control Methods High Training SomeHighModerate Research Support Needs Low Research, Training, and Support Needs According to Understanding of Diseases and Efficacy of Control Methods

Research Needs Efficacy of Control Methods High Training SomeHighModerate Research Support Needs Low Smallpox Guinea worm Poliomyelitis H. influenzae type B Measles Tetanus Malaria Dengue HIV/AIDS Influenza Tuberculosis Cancers Alzheimers Research, Training, and Support Needs According to Understanding of Diseases and Efficacy of Control Methods Onchocerciasis Diarrheal diseases

Expected Results of R&D New basic knowledge Mechanisms of disease Epidemiology and risk factors Disease modeling and surveillance New and improved tools Drugs Vaccines Diagnostics Devices Prostheses and equipment Vector control Environmental modification Behavioral, social, and economic change

Expected Results of R&D (2) New and improved intervention methods Treatment algorithms and guidelines Intervention packaging Costing and cost-effectiveness Delivery: health systems and health services

Condition Global Disease Burden (million) DALYs* R&D Funding ($Millions) R&D Funding per DALY* Cardiovascular $63.45 HIV/AIDS $24.26 Malaria $6.20 Tuberculosis $10.88 Diabetes $ Dengue $94.16 Disease Burden and Research and Development Funding Malaria and R&D Alliance: Science, 13 January 2006: *Disability-Adjusted Life Year. DCPP estimates in millions are: cardiovascular = 208.8; HIV = 71.5; malaria = 40.0; tuberculosis = 36.1; Diabetes = 20.0; dengue = 0.5

Main Messages [Better data are needed]

Main Messages 1. Unfinished infectious diseases agenda. IDs predominate in Sub-Saharan Africa and South Asia Children under five years suffer preventable IDs in all regions All countries have vulnerable groups (immunodepressed, metabolic disorders, aged)

The Age Distribution of Deaths Under Age-5, Low- and Middle-Income Countries, 2001 Total deaths, including stillbirths = million 23% 28% 25% 24% 0% 5% 10% 15% 20% 25% 30% StillbirthsNeonatal deathsPost-neonatal infant deaths (aged 28 days to 1 year) Child deaths (aged 1 to less than 5 years) Age category Percent distribution of deaths under Age-5 D. T. Jamison, et al, 2006 in Global Burden of Disease and Risk Factors

Main Messages 2.Three critical ID challenges are facing developing countries and the world: ●Preventable levels of mortality and disability from malaria, TB, diarrhea, and pneumonia. ●Unchecked HIV/AIDS pandemic. ●Emerging Infections – Infectious causes of “non-communicable diseases”. – Be prepared for an influenza pandemic due to a novel virus, and other perils.

Source: Dr. Anthony Fauci, 2005

Main Messages 3. “Very good buys”, infectious disease control/prevention Vaccination Malaria control HIV prevention 4. “Not so good buys” Treatment of latent TB, no HIV Treatment of HIV/AIDS if poor adherence

Main Messages 5. Continued generation and diffusion of new knowledge and products are key to improvements in health in the 21st century. Future investment is needed: Research and development Training leaders in research and operations; strengthening institutions Focus on low- and middle-income countries Collaboration and shared goals

Vertical Disease Control

Horizontal Disease Control

Integrated Disease Control

Books Published by Oxford University Press for DCPP in 2006  Disease Control Priorities in Developing Countries, second edition  Priorities In Health  Global Burden of Disease and Risk Factors

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RankSouth Asia (GNI: $450) Sub Sahara Africa (GNI: $460) East Asia and the Pacific (GNI: $900) Europe and Central Asia (GNI: $1,970) Middle East and North Africa (GNI: $2,200) Latin America and the Caribbean (GNI: $3,580) High–income countries (GNI: $26,500) 1Perinatal conditions a HIV/AIDSCerebrovascular diseases Ischemic heart disease Ischemic heart disease Perinatal conditions a Ischemic heart disease 2Lower Respiratory infections MalariaPerinatal onditions a Cerebrovascular diseases Perinatal conditions a Unipolar depressive disorders Cerebrovascular diseases 3Ischemic heart disease Lower Respiratory infections Chronic obstructive pulmonary disease Unipolar depressive disorders Traffic accidentsHomicide and violence Unipolar depressive disorders 4Diarrheal diseases Diarrheal diseases Ischemic heart disease Self-inflicted injuries Lower respiratory infections Ischemic heart disease Alzheimer and other dementias 5Unipolar depressive disorders Perinatal conditions a Unipolar depressive disorders Chronic obstructive pulmonary disease Diarrheal diseasesCerebrovascular diseases Tracheal and lung cancer Note - GNI: GNI per Capita (US$); a) This cause category includes ‘conditions arising in the perinatal period’(less or equal to 28 days) as defined in the International Classification of Diseases, principally low birthweight, prematurity, birth asphyxia, and birth trauma, and does not include all causes of deaths occurring in the perinatal period. Source: Mathers, CD., Lopez A.D., and Murray CJL, 2006; World Development Indicators, 2003 Table 2.