Conquering Malaria Through Actions Linking Control to Research Joel G. Breman, MD, DTPH Martin Alilio, Ph.D. Fogarty International Center National Institutes of Health Global Disease Programs and Policy Course School of Public Health Johns Hopkins University 12 May 2003

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

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 Tuberculosis Ebola/Marburg Influenza Cancers Alzheimer’s

Conquering Malaria: Through Actions Linking Control to Research Background: ecology and natural history Burden: manifestations and toll Interventions: strategies and effectiveness Successes and challenges: historical and current Multilateral initiatives: –Roll Back Malaria –Multilateral Initiative on Malaria The way forward

Conquering Malaria: Through Actions Linking Control to Research Background: ecology and natural history Burden: manifestations and toll Interventions: strategies and effectiveness Successes and challenges: historical and current Multilateral initiatives: –Roll Back Malaria –Multilateral Initiative on Malaria The way forward

Intrinsic and Extrinsic Factors Linked to the Malaria Burden Human MosquitoParasite Social, behavioral, economic and political factors Environmental conditions Control and prevention measures

Malaria Transmission Cycle

Plasmodia Causing Human Malarias Plasmodium falciparum P. Vivax (relapsing) P.malariae P.ovale (relapsing)

Conquering Malaria: Through Actions Linking Control to Research Background: ecology and natural history Burden: manifestations and toll Interventions: strategies and effectiveness Successes and challenges: historical and current Multilateral initiatives: –Roll Back Malaria –Multilateral Initiative on Malaria The way forward

Mendis K, Sina B J, Marchesini P, Carter R (2001) The neglected burden of P.vivax malaria. American Journal of Tropical Medicine and Hygiene 64; Supplement titled "The Intolerable Burden of Malaria: A New Look at the Numbers" Global distribution of Plasmodium vivax maximum distribution 19 th century (pink) late 20 th century (purple)

Infected Mosquito Infected Human Chronic effects Anemia Neurologic/ cognitive Developmental Impaired growth and development Malnutrition Manifestations of the Malaria Burden Acute febrile illness Severe illness Hypoglycemia Anemia Cerebral malaria Death Respiratory distress Pregnancy Fetus Maternal Acute illness Anemia Impaired productivity Low birth weight Infant mortality

% of all deaths Rank Malaria Respiratory inf Diarrhoea HIV/AIDS4 9.0 Measles5 8.4 Low birth weight6 5.8 Leading causes of death for children under 5, in the WHO African Region, 2000

Number of estimated cases/year 1,000,000, ,000,000 10,000,000 1,000, ,000 10,000 1,000 Worldwide Africa Asia Americas East Med USA 2000 cases WHO 1997 Sturchler 1989 Baudon 1987 WHO 1997 Brinkman 1991 Sturchler 1989 Snow 1999 Sturchler 1989 WHO 1997 PAHO 1991 E Med WHO 1997 Sturchler 1989 CDC 1994 Estimated World and Regional Malaria Cases

Estimated World and Regional Malaria Deaths Number of estimated cases/year 3,000,000 2,500,000 2,000,000 1,500,000 1,000, ,000 0 Worldwide Africa Americas USA Murray (dev) 1996 Najera 1996 Sturchler 1989 WHO 1997 Breman/Campbell (,5 yrs) 1988 Najera 1996 Bruce-Chwatt (<10 yrs) 1952 WHO 1997 Sturchler 1989 Snow 1999 Sturchler 1989

MARA/ARMA Model of Malaria Transmission, 2003

Acute Febrile Episodes and Malaria-Associated Febrile Episodes in African Children 0-4 years Living in Endemic Areas, Millions Febrile Illness Malaria

“The Ears of the Hippopotamus” Where Malaria Patients are Managed... and Die Dispensary 15% Home >80% Hospital 5%

Contribution (%) of Specific Gaps to African Childhood Malaria Morbidity (up to 8.76 million children affected) * Cerebral malaria 7% Hypoglycemia 9% Respiratory disease 9% Low birth weight 11% Severe anemia 64% *maximum estimate; all children <5 years of age except cerebral malaria (<10 years)

Contribution (%) of Specific Gaps to African Childhood Malaria (up to 1.82 million children die) Severe Anemia 53% Low birth weight 20% Hypoglycemia 15% Respiratory disease 6% Cerebral malaria 6%

Disability–adjusted Life Years (DALYs, 1000s), All Cause and Malaria-related, 2002 Population DALYs from all deaths (%) DALYs from malaria deaths (%) DALYs from malaria /total (%) World6,122,2101,467,25742, Africa 655, ,884 (24.4)36,012 (85.2) 10.1 Americas 837, ,217 (9.9) 108 (0.2) 0.07 East Med. 493, ,221 (9.3) 2,050 (4.8) 1.5 Europe 874, ,223 (10.3) 20 (0.04) 0.01 SE Asia1,559, ,844 (28.5) 3,680 (8.7) 0.9 West Pacific1,701, ,868 (17.6) 409 (1.0) 0.2

Conquering Malaria: Through Actions Linking Control to Research Background: ecology and natural history Burden: manifestations and toll Interventions: strategies and effectiveness Successes and challenges: historical and current Multilateral initiatives: –Roll Back Malaria –Multilateral Initiative on Malaria The way forward

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)

Estimated Cost of Malaria Control in an Endemic Area: One Million People, One Round of Residual House Spraying Insecticide One application (tons) Price/tonTotal cost Cost per capita DDT147 $3,950 $580,650$0.58 Malathion220 $4,300 $946,000$0.95 Deltamethrin110$20,000$2,200,000$2.20 Pyrimiphos- methyl 220$16,000$3,520,000$3.52

Estimated Cost of Malaria Control: One Million People, One Full-dose Treatment, 1999 Drug Tablets in millions (dose) Price/ 1000 tabs Total cost Cost per capita Chloroquine (3 days) (100 mg) $6.05 $68,063$0.08 Sulfadoxine- pyrimethamine (one dose) 2.5 (500 mgS/ 25 mgP) $47.00 $117,500$0.12 Quinine (7 d)31.5 (300 mg) $41.25$1,299,375$1.30 Artesunate (5 d)13.5 (50 mg)$365.00$4,927,500$4.93

Type of Control Vector Control Environmental modification (urban)* Chemical and biological larvicides* Indoor residual insecticide spraying* Outdoor residual insecticide spraying *costly and effective

Type of Control Personal protection (2) Insecticide–impregnated materials: nets, curtains, clothing* House screening House location Repellents Fumigants * Shown cost effective for low-income countries

Type of Control Antiplasmodial (3) Patient management: early diagnosis, treatment, referral, education Chemoprophylaxis Intermittent treatment (pregnancy)* Radical therapy for relapses (P.vivax, P.ovale) * cost effective

Antenatal care in Africa Proportion of Pregnant Women Seeking Antenatal Clinic Care Countries Zambia Rwanda Zimbabwe Botswana Kenya Uganda Malawi Tanzania Ghana Namibia Comoros Cote d'Ivoire Senegal Liberia Togo Benin Cameroon Madagascar Guinea Sudan Mozambique CAR Burkina Faso Nigeria Eritrea Mali-96 Niger Chad

Type of Control Social Action Mobilization of individual, family, community Health education Management Effectiveness Health systems effectiveness (quality), efficiency Leadership, planning, policies, strategies, tactics Surveillance Monitoring and evaluation

Conquering Malaria: Through Actions Linking Control to Research Background: ecology and natural history Burden: manifestations and toll Interventions: strategies and effectiveness Successes and challenges: historical and current Multilateral initiatives: –Roll Back Malaria –Multilateral Initiative on Malaria The way forward

1899, (large scale) demonstration of successful Anopheline control in Cuba: antilarval and adult measures (large-scale) 1899–1914, multiple demonstrations of control by reduction of Anopheline larvae and adults –1899, Sierra Leone (antilarval); Cuba (large-scale); Malaysia (antilarval) –1904–1914, Panama Canal Zone; control by larviciding, large-scale environmental modification 1927, elimination of A. albimanus in Barbados (first area-wide success with invading species) Successes

Successes (2) , large-scale control by pyrethrum spraying in South Africa, Netherlands and India – , Elimination of invading A.gambiae from Brazil – , A.gambiae eliminated from northern Egypt – , Interruption of transmission by anti-mosquito measures in Cyprus, Sandinia, Guyana, Venezuela and Greece; indoor residual spraying with DDT, a major strategy

Successes (3) –Multiple projects and programs using insecticide-impregnated bed nets demonstrate overall mortality reduction and decrease in several malaria indices See the Western Kenya insecticide-treated bed net trial, AJTMH, 2003; 68:1-173, 23 papers.

Insecticide-treated bednets in pregnancy, western Kenya, Among Gravidae 1-4, ITNs were associated with öDuring pregnancy  38% reduction in peripheral parasitemia  21% reduction in all cause anemia (Hb < 11 g/dl)  47% reduction in severe malarial anemia At delivery  23% reduction in placental malaria  28% reduction in LBW  25% reduction in any adverse birth outcome

Eradication Programs Human Hookworm, 1909 Yellow fever, 1915 Aedes aegypti, Anopheles gambiae, Malaria, Yaws, 1950 Smallpox, 1958, Poliomyelitis, 1985 Dracunculiasis, 1987 Animal Bovine contagious pleuropneumonia (cows), 1884 Glanders (horses, mules) Piroplasmosis (cattle, “Texas fever” Dourine (STD of horses) Rinderpest Sheep pox

Malaria in Sri Lanka Plasmodium falciparum Plasmodium vivax

Conquering Malaria: Through Actions Linking Control to Research Background: ecology and natural history Burden: manifestations and toll Interventions: strategies and effectiveness Successes and challenges: historical and current Multilateral initiatives: –Roll Back Malaria –Multilateral Initiative on Malaria The way forward

Conquering Malaria: Through Actions Linking Control to Research Background: ecology and natural history Burden: manifestations and toll Interventions: strategies and effectiveness Successes and challenges: historical and current Multilateral initiatives: –Roll Back Malaria –Multilateral Initiative on Malaria The way forward

Essential Strategies for Dealing with Malaria Use simple, cost-effective tools. Abolish “malaria taxes” and distribute insecticide-treated bednets. Promote and fund research in all its dimensions. Fund demonstration projects on and use of integrated vector management strategies. Scale-up operations.

Essential Strategies for Dealing with Malaria (2) Provide financial assistance to poorer countries. Engage public-private partnerships. Insure targeted diagnosis and treatment. Slow drug resistance. Integrate malaria treatment into existing programs. Invest in malaria drug and combination therapy development and distribution.

Prompt and effective treatment reduces mortality by at least 50% Mortality further reduced if treatment is available in home Drug resistance can be delayed through combination therapy including artesunates Insecticide-treated nets can reduce all cause mortality by 20% New rapid diagnostic techniques becoming available at lower cost Application of epidemiological and geographical information can help predict epidemics Promising developments

Research Agenda Pathogenesis Drug development Vaccine development Diagnostics Clinical and community-based trials Entomology

Research Agenda (2) Clinical issues –anemia –neurologic and cognition –pregnancy-related Health services delivery Social, legal, ethical

Controversies Drugs –Combination artemisinin-based compounds for treatment –Chemoprophylaxis for high risk persons Burden –Malaria as a cause or risk-factor (co- morbidity) –Cognition and developmental issues

For More Information Joel Breman Martin Alilio