Combating Infectious Diseases and the Disease Control Priorities

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

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

Objectives of DCPP (1) To decrease illness, disability, death, and economic burden by: Developing an evidence base to inform decision-making by: n Providing estimates of the cost-effectiveness and impact of single interventions and packages n Collaborating in defining disease burdens globally and regionally n Summarizing implementation experience in different regions and globally www. dcp 2. org

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

Disease Burdens l Deaths l Disability-Adjusted Life Years l Global l Infectious Diseases

Leading Causes of Death in High and Low-/Middle-Income Countries (LMICs), 2001 (Total = 56. 24 million) High Income (% total deaths) LMICs (% total deaths) (n =7. 89 million (14%) (n = 48. 35 million (86%) 1. Ischemic heart disease (11. 8) (17. 3) 2. Cerebrovascular disease (9. 5) (9. 9) 3. Lower respiratory 3. Trachea, bronchus, lung infections (7. 0) cancer (5. 8) 4. HIV/AIDS (5. 3) 4. Lower respiratory infections (4. 4) 5. Perinatal conditions (5. 1) 5. Chronic obstructive Mathers et al. , 2006, in Lopez et al, Global Burden of Disease and Risk Factors pulmonary disease (3. 8) 1.

Leading Causes of Death in High and Low-/Middle-Income Countries (LMICs), 2001 High Income (% total deaths) LMICs (% total deaths) (n = 7. 89 million (14%) (n = 48. 35 million (86%) 6. 7. 8. 9. 10. Colon and rectum cancers (3. 3) Alzheimer’s and other dementias (2. 6) Diabetes mellitus (2. 6) Breast cancer (2. 0) Stomach cancer (1. 9) 6. 7. 8. 9. 10. Chronic obstructive pulmonary disease (4. 9) Diarrheal diseases (3. 7) Tuberculosis (3. 3) Malaria (2. 5) Road traffic accidents (2. 2) Total: 53. 6% (ID = 4. 4%) Total: 55. 3% (ID = 21. 8%) Mathers et al. , 2006, in Lopez et al, Global Burden of Disease and Risk Factors

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

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

Leading Causes of Disability-Adjusted Life Years (DALYs), Globally, 2001 Cause (n = 1. 54 billion) % total Perinatal conditions 5. 9 2. Lower respiratory infection 5. 6 3. Ischemic heart disease 5. 5 4. Cerebrovascular disease 4. 7 5. HIV/AIDS 4. 7 6. Diarrheal diseases 3. 9 7. Unipolar depressive disorders 3. 4 8. Malaria 2. 6 9. Chronic obstructive pulmonary disease 10. Tuberculosis 2. 3 Total (ID= 19. 1%) 41. 1 1. Mathers et al, 2006 in Lopez et al, Global Burden of Disease and Risk Factors 2. 5

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

Infectious Burden, Low- and Middle-Income Countries, by World Bank Region, 2001 Disease Burden In LMICs DALYs, % SSA Disease burden by region, % SA ME/NA EA/P LA/C E/CA Respiratory inf. 6. 3 36 40 4 14 4 3 HIV/AIDS 5. 1 79 10 1 4 3 1 Diarrheal disease 4. 2 37 38 4 15 4 1 Malaria 2. 9 89 6 2 3 1 . 1 TB 2. 6 22 38 2 30 3 4 Measles 1. 7 59 28 2 10 0 1 0. 7 23. 5 40 39 4 9 5 2 STD 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

Leading Causes of Disability-Adjusted Life Years (DALYs) in Sub-Saharan African Region, 2001 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Total DALYs HIV/AIDS Malaria Lower respiratory infections Perinatal conditions Diarrheal diseases Measles Tuberculosis Whooping cough Road traffic accidents Protein-energy malnutrition Total % 17. 8 10. 3 8. 4 6. 3 6. 1 4. 6 2. 4 1. 9 1. 8 1. 6 61. 2 (ID=56. 5%) Mathers et al. in Global Burden of Disease and Risk Factors, 2006

Malaria l Manifestations l Burden l Interventions

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

Deaths from Malaria: Children Under Five and Total, Africa 2001 Cause of malaria-related death ● Number of malaria deaths Under fives Cerebral malaria 110, 000 Severe anemia 190, 000 -974, 000 Respiratory distress 110, 000 Hypoglycemia 153, 000 -267, 000 Low birth weight 62, 000 -363, 000 Total deaths from malaria ● 625, 000 -1, 824, 000 Total, all ages* 962, 000 -2, 806, 000 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).

Under-Five Deaths from AIDS, Malaria, and Other Causes, per Thousand Births, 1990 and 2001, Sub-Saharan Africa Source: Lopez, Begg, and Bos 2006.

Rate of Progress in Reducing Under-Five Mortality, 1960 -2000: China, India, Latin America, and Sub-Saharan Africa Source: World Bank 2004 (CD-ROM version).

Plasmodium falciparum in 2002 Clinical Cases Region Africa Americas South East Asia Population at risk (million) Cases (M) (%) (million) 521 365 (215 - 374) (57%) 55 4 (2 - 8) (1%) 1, 314 119 (66 - 224) (34%) Western Pacific 142 15 (9 - 26) (4%) Eastern Med. 176 12 (5 - 25) (4%) 4 1 (0 - 1) (<1%) Europe Total Snow et al, Nature 2005 2, 211 515 (298 – 659) (100%)

Acute Febrile Episodes and Malaria-Associated Febrile Episodes in African Children 0 -4 years Living in Endemic Areas, 1995 -2020 2000 1919 1800 1600 960 1000 846 Malaria Millions 1200 800 600 423 400 188 200 0 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 2018 1995 J. Breman, AJTMH, 2001 2020 Febrile Illness 1400

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

Cost-Effectiveness of Interventions Against Malaria in Sub-Saharan Africa Intermittent preventive treatment/ pregnancy (SP) Insecticide residual spraying Insecticide-treated bed nets Intermittent preventive treatment in pregnancy with drug switch 0 5 10 15 20 25 Cost-effectiveness ratio ($ per DALY averted) R. Laxminarayan et al (DCPP authors), 2006 in Disease Control Priorities in Developing Countries 30

Table 21. 6. CERs for ITNs, IRS, and IPT Mean cost per DALY averted 90 percent range Deltamethrin 11 5 -21 Permethrin (1 treatment) 12 6 -20 Permethrin (2 treatments) 17 9 -31 Deltamethrin 5 2 -7 Permethrin (1 treatment) 6 3 -9 Permethrin (2 treatments) 11 6 -17 9 5 -13 Deltamethrin 10 6 -14 Lambda-cyhalothrin 10 6 -14 Malathion 12 8 -18 Intervention ITNs (net + insecticide treatment) ITNS (without provision of nets) IRS (1 round) DDT

Table 21. 6. CERs for ITNs, IRS, and IPT (2) Intervention Mean cost per DALY averted 90 percent range IRS (2 rounds) DDT 17 11 -24 Deltamethrin 18 12 -27 Lambda-cyhalothrin 19 12 -28 Malathion 24 15 -34 IPT Incremental costs 13 9 -21 Average costs 24 16 -35

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

Cost-Effectiveness of Interventions Against HIV/AIDS in Sub-Saharan Africa Antiretroviral treatment Home care Mother/child prevention Tuberculosis coinfection prevention/treatment Blood/needle safety Condom promotion/distribution STI diagnosis/treatment Voluntary counseling/testing HIV/AIDS - peer programs 0 200 400 600 800 1, 000 1, 200 1, 400 1, 600 Cost-effectiveness ratio ($ per DALY averted) 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 n n n 13 Parasitic and Bacterial Infections Rural Areas of Low-Income Countries Poverty-Promoting Conditions n n Burdened humanity for centuries n n Child Development & Education Pregnancy Worker Productivity “The Biblical Diseases” Disabling and deforming n Associated with intense stigma River Blindness Guinea Worm Leprosy Lymphatic Filariasis

Ranking of Communicable Diseases By DALYs Disease Condition Disease Burden HIV-AIDS 84. 5 million Neglected Tropical Diseases 56. 6 million Malaria 46. 5 million Tuberculosis 34. 7 million Hotez PJ, Molyneux DH, Fenwick A, Ottesen E, Ehrlich Sachs S, Sachs JD PLo. S Medicine 2006; 3: e 102

Cost-Effectiveness of Interventions Related to Low-Burden Diseases in LMICs; Helminths, Leishmaniasis, Onchocerciasis, Trachoma: drug treatments Trachoma: trichiasis surgery Onchocerciasis: Ivermectin Leishmaniasis: case finding and treatment Soil-transmitted helminths: Albendazole 1 10 100 Cost-effectiveness ratio ($ per DALY averted) Source: DCPP Authors 1, 000 10, 000

“Best Buys” Neglected Opportunities

“Best Buys” Neglected Opportunities in Sub-Saharan Africa (SSA) and South Asia (SA) (1) Cost per DALY averted ($) Low Cost Opportunity Burden of disease DALYs (106) ● Childhood Immunization - Second measles vaccination - Increase coverage - DTP, polio, measles, BCG SSA SA 1– 5 8 13. 5 – 31. 3 28. 4 ● 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

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

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

A Million Dollars Invested

How Much Health Will a Million Dollars Buy? Service or Intervention Reducing under-5 mortality n Expanding immunization coverage (EPI diseases) n Switch to artemisinincombination therapy (ACT) where malaria is drug-resistant n Improved neonatal care (newborn resuscitation) n Adding vaccines to EPI (Hib and hepatitis B) DALYs Averted ($ per DALY) 50, 000 -500, 000 ($2 -20) 50, 000 -125, 000 ($8 -20) 2, 500 -100, 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 Effective coverage Avertable if costeffective interventions applied more widely a Avertable only with interventions that are less costeffective b Source: WHO, 1996. Investing in Health Research and Development c

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

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

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

Disease Burden and Research and Development Funding Global Disease Burden (million) DALYs* R&D Funding ($Millions) R&D Funding per DALY* Cardiovascular 148. 190 9402 $63. 45 HIV/AIDS 84. 458 2049 $24. 26 Malaria 46. 486 288 $6. 20 Tuberculosis 34. 736 378 $10. 88 Diabetes 16. 194 1653 Condition Dengue 0. 616 58 $102. 07 $94. 16 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. l IDs predominate in Sub-Saharan Africa and South Asia l Children under five years suffer preventable IDs in all regions l 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 = 13. 758 million Percent distribution of deaths under Age-5 30% 25% 28% 25% 23% 24% 20% 15% 10% 5% 0% Stillbirths Neonatal deaths Post-neonatal infant deaths Child deaths (aged 1 to (aged 28 days to 1 year) less than 5 years) Age category 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 l Vaccination l Malaria control l HIV prevention 4. “Not so good buys” l Treatment of latent TB, no HIV l 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 21 st 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 v Disease Control Priorities in Developing Countries, second edition v Priorities In Health v Global Burden of Disease and Risk Factors

Please Visit Our Web Site at: www. dcp 2. org

Table 2. Rank South 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: $26, 500) 1 Perinatal conditionsa HIV/AIDS Cerebrovascular diseases Ischemic heart disease Perinatal conditionsa Ischemic heart disease 2 Lower Respiratory infections Malaria Perinatal onditionsa Cerebrovascular diseases Perinatal conditionsa Unipolar depressive disorders Cerebrovascular diseases 3 Ischemic heart disease Lower Respiratory infections Chronic obstructive pulmonary disease Unipolar depressive disorders Traffic accidents Homicide and violence Unipolar depressive disorders 4 Diarrheal diseases Ischemic heart disease Self-inflicted injuries Lower respiratory infections Ischemic heart disease Alzheimer and other dementias 5 Unipolar depressive disorders Perinatal conditionsa Unipolar depressive disorders Chronic obstructive pulmonary disease Diarrheal diseases Cerebrovascular diseases Tracheal and lung cancer Note - GNI: GNI per Capita (US$); 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