Defining and Defeating the Intolerable Burden of Malaria

1. Defining and Defeating the Intolerable Burden of Malaria Joel G. Breman, MD, DTPH Fogarty International Center U.S. National Institutes of Health BioVisionAlexandria 2008 New Life Sciences: From Promises to Practice Alexandria, Egypt April 14, 2008

2. Our GoalMalaria Free Mothers and Children and all others

3. Defining Malaria and its Conquest • Manifestations • Burden • Goals • Interventions • Progress • Research

4. Transmission of Plasmodium from Mosquito to Human…to Mosquito P. falciparum P. vivax P. ovale P. malariae P. knowlsei White and Breman, 2008 (after Hoffman), Harrison’s Principles of Internal Medicine

5. Defining Malaria and its Conquest • Manifestations • Burden • Goals • Interventions • Progress • Research

6. Manifestations of the Malaria Burden Anemia Long-term sequelae Hypoglycemia Acute febrile illness Severe illness Respiratory distress Death Hypovolemia Infected Mosquito Cerebral malaria Anemia Chronic effects Impaired growth and development Neurologic Cognitive Infected Human Malnutrition Developmental Low birth weight Abortion, stillbirth Infant and fetal mortality Fetus Pregnancy Acute illness Long-term sequelae Maternal Anemia Breman, Alilio, Mills, 2004, Am J Trop Med Hyg

7. Overlap of Cerebral Malaria, Anemia, Respiratory Distress in Children Mali Kenya 31/58 (53%) Marsh et al, 1995, NEJM Ranque et al 2008, Ped Inf Dis J ( ) = number of patients % = CFR

8. Defining Malaria and its Conquest • Manifestations • Burden • Goals • Interventions • Progress • Research

9. Global Malaria and Endemicity, 2003

10. Global Distribution of Malaria Anopheline Vectors Kizewski et al., 2004, Am J Trop Med Hyg

11. Plasmodium falciparum in 2005Clinical Cases Snow et al, 2005, Nature

12. Burden of Malaria on Health Systems in Sub-Saharan Africa, 1999-2004 Total DALYs% HIV/AIDS 17.8 Malaria10.3 Lower respiratory infections 8.4 Perinatal conditions 6.3 Diarrheal diseases 6.1 Measles 4.6 Tuberculosis 2.4 Whooping cough 1.9 Road traffic accidents 1.8 Protein-energy malnutrition 1.6 Total61.2 Leading Causes of Disability-Adjusted Life Years (DALYs) in Sub-Saharan African Region, 2001 FEVER HISTORY OUTPATIENTS DEATHS ADMISSIONS HOSPITAL Source: Mathers, et al., 2006, Global Burden of Disease and Risk Factors Source: WHO 2005

13. Deaths from Malaria: Children Under Fiveand Total, Africa 2001 Number of malaria deaths Cause of malaria-related death • Under fives Severe anemia 190,000-974,000 Hypoglycemia 153,000-267,000 Low birth weight 62,000-363,000 Cerebral malaria 110,000 Respiratory distress 110,000 Total deaths from malaria 625,000-1,824,000 962,000-2,806,000 • Total, all ages Sources Breman, Alilio and Mills, 2004, Am J Trop Med Hyg; Murphy and Breman, 2001, Am J Trop Med Hyg

14. Population at Risk of P. vivax and Clinical Cases Per Year (in millions) Price et al, 2007, Am J Trop Med Hyg

15. Surveys of P. falciparum, Eastern Mediterranean Regional Office (EMRO), 1985-2007 Countries With Widespread Transmission, 2006 Breman and Holloway, 2007, Am J Trop Med Hyg

16. Malaria in Eastern Mediterranean Region, WHO: Countries Having Interrupted or Limited Transmission ( ) local transmission Breman and Holloway, 2007, Am J Trop Med Hyg

17. Community Surveys of P. falciparum Prevalence Conducted between 1985 and 2007 in AFRO Guerra et al, 2008, PLoS Med MARA/ARMA (http://www.mara.org.za)

18. Community Surveys of P. falciparum Prevalence Conducted between 1985 and 2007 in AMRO and SEARO-WPRO Guerra et al, 2008, PLoS Med

19. Malaria Cases and Death in South East Asia Region of WHO, 2004 DEMOCRATIC PEOPLE’S REPUBLIC OF KOREA 0.5% Malaria Cases = 2,525,715 Malaria Deaths = 3,768 Malaria Danger in Central Asia and Kazakhstan Cases of Malaria in the European Region , 2005 Breman and Holloway, 2007 Am J Trop Med Hyg

20. Defining Malaria and its Conquest • Manifestations • Burden • Goals • Interventions • Progress • Research

21. RBM strategy Prompt access to effective treatment Insecticide-treated nets (ITNs) Prevention and control in pregnant women Epidemics Abuja target (by 2005), RBM (2007) 80% patients using correct/affordable treatment w/in 24 hrs 80% of children <5 years and pregnant women having ITNs 80% of pregnant women using intermittent preventive treatment 60% detected w/in 2 weeks of onset 60% responded to w/in 2 weeks Roll Back Malaria’s Goals, Strategies, and Targets To Halve the Burden of Malaria by 2010Abuja Malaria Summit, April 2000, revised 2007 RBM, WHO, 2008

22. Major Manifestations of Malaria Anemia Lennart Nielson (Karolinska Instituteg), Hedvig Perlmann (Stockholm University) Martin Weber Cerebral malaria Roll Back Malaria Info Sheet George Grau Low birthweight Rick Steketee National Human Genome Research Institute

23. Selected Severe Patient Management Clinical Malaria Conditions Requiring Diagnosis and Reporting * * * Breman and Holloway, 2007, Am J Trop Med Hyg

24. Selected Severe Clinical Malaria Conditions Requiring Diagnosis, Assessment and Reporting (2) * * * a in addition to antimalarial drugs; referral to a secondary or temporary care facility for patients requiring parenteral therapy and intensive supportive care. b consider exchange transfusion for parasitemia >10% * essential measurement Breman and Holloway, 2007, Am J Trop Med Hyg

25. Defining Malaria and its Conquest • Manifestations • Burden • Goals • Interventions • Progress • Research

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

27. Cost-Effectiveness of Interventions Against Malaria in Sub-Saharan Africa Intermittent preventive treatment/ pregnancy (SP) Insecticide residual spraying Artemisinin comb. therapy (resistance) Insecticide-treated bed nets Intermittent preventive treatment 0 5 10 15 20 25 30 Cost-effectiveness ratio ($ per DALY averted) Laxminarayan et al (DCPP authors), 2006, in Jamison et al, Disease Control Priorities in Developing Countries, 2nd ed.

28. Malaria: Prevention and Treatment • Treatment with a new group of antimalarials – the artemisinin compounds, in combination with lumefantrine, amodiaquine, sulfadoxine–pyrimethamine, or others Artemesia annua Spread of chloroquine resistance

29. The Process for the Microbial Production of Artemisinin WHO/Tropical Diseases Research/Crump Verband Forschender Arzneimittelhersteller e.V. Hale et al, 2007, Am J Trop Med Hyg

30. Insecticide Treated Materials Work Sleep Inside the Net

31. Anopheles Mosquito, Larva Breeding Sites

32. Insecticides recommended by the World Health Organization for Indoor Residual Spraying *DDT, dichlorodiphenyltrichloroethane Photo: World Health Organization Sadasivaiah et al, 2007, Am J Trop Med Hyg

33. 9000 8000 7000 DDT 6000 OP 5000 4000 C thousands of kg 3000 PY 2000 1000 0 1995 1997 1998 2001 2004 1996 1999 2000 2002 2003 2005 thousands of kg Insecticides Used for Malaria Vector Control, 1995-2006 Vector Surveillance Capacity in Sub-Saharan Africa, 2006 Entomological Capacity, 2006 no capacity basic for control or research basic/advanced for control, advanced in research WHO, 2004, Sadasavaiah, Tozan, Breman, 2007

34. Flamboyant Trees on the Grounds of the Lamumba Health Clinic in Kisumu, Kenya Omlin et al, 2007, Am J Trop Med

35. Malaria Diagnostics: Microscopy and Rapid Diagnostic Testing Blood Smears RDT

36. Global Fund: HIV/AIDS, Tuberculosis, and Malaria per-capita funding levels Countries with President’s Malaria Initiative and World Bank Booster Funding Source: UNICEF, 2007

37. Defining Malaria and its Conquest • Manifestations • Burden • Goals • Interventions • Progress • Research

38. Rwanda: Malaria Progress Vital Statistics Population: 9.3 million Women 15-45 yrs: 2.7 million Children <5 yrs: 4.0 million Infant mortality: 152 (2005) Malaria Risk: 4.8 million Cases: 1.4 million (2005) Deaths <5yrs: 510 (2006) Roll Back Malaria

39. Ethiopia: Malaria Progress Vital Statistics Population: 77.3 million < 5 mortality: 123 Malaria Risk: 52.5 million Cases (est): 12 million (2006) (reported): 3.7 million Child Deaths : 94,400 Roll Back Malaria

40. Zambia: Malaria Progress Malaria Cases: 2.1 million (2005) Vital Statistics Population: 11.7 million Roll Back Malaria

41. Results from Zanzibar Island, Tanzania Population: 1,116,001 (2006)

42. Results from Zanzibar Outpatient Malaria Cases (Confirmed and non-confirmed) per 1000 of the population Proportion of malaria confirmed cases Ali, et al 2007, EARN Meeting

43. Defining Malaria and its Conquest • Manifestations • Burden • Goals • Interventions • Progress • Research

44. Research Needs: Disease Burden that Can or Cannot be Averted with Existing Interventions Disease Burden: Biomedical research to identify new and improved interventions Not Avertable Increase effectiveness or reduce costs of existing interventions Already averted Avertable coverage Broader implementation of cost-effective interventions; identify obstacles to expansion of coverage

45. Research and Development Categories and Results for Implementation New basic understanding • Fundamental research • Basic epidemiology, risk factors, modeling New and improved tools • Drugs • Vaccines • Diagnostics • Devices • Vector control • Environmental modification • Behavioral, social, and economic change

46. Research and Development Categories and Results for Implementation New and improved intervention methods • Treatment algorithms and guidelines • Intervention packaging • Priority setting via costing and cost-effectiveness studies • Delivery: health systems and health services • New and improved policy instruments

47. Multiple pathologies Anemia Low birthweight Malnutrition HIV Enteritis Sepsis Neurocognitive Neglected diseases Host factors Immunity and vaccines Genetic susceptibility Plasmodium falciparum vivax Antigenic diversity Drug resistance Anopheles Transmission dynamics Human Correlation of Entomologic Inoculation Rate with clinical manifestations Special conditions Epidemics Urbanization Migration Malaria Research Needs: Major Gaps and Controversies Requiring Attention

48. Fetal Growth Velocity and Impact of Intermittent Preventive Treatment for Malaria of Mothers Rogerson et al, 2007

49. Overlapping Burden of Neglected Diseases and Malaria(leprosy, lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminths and trachoma) Neglected Tropical Diseases, 2007

50. Malaria Transmission to Human and MosquitoVaccine Targets White and Breman, 2007 (adapted from Hoffman), Harrison’s Principles of Internal Medicine