Conquering Malaria Through Actions Linking Control to Research

Joel G. Breman, MD, DTPHMartin Alilio, Ph.D.

Fogarty International CenterNational Institutes of Health

Global Disease Programs and Policy CourseSchool of Public Health

Johns Hopkins University12 May 2003

Research, Training, and Support Needs Research, Training, and Support Needs According to Understanding of Diseases According to Understanding of Diseases andand

Efficacy of Control MethodsEfficacy of Control Methods

Research Needs

Efficacy of

Control Methods

High HighTraining

Some HighModerateResearch Support Needs

Low Low

Research, Training, and Support Needs Research, Training, and Support Needs According to Understanding of Diseases According to Understanding of Diseases andand

Efficacy of Control MethodsEfficacy of Control Methods

Research Needs

Efficacy of

Control Methods

High HighTraining

Some HighModerateResearch Support Needs

Low Low

SmallpoxGuinea wormPoliomyelitisH. influenzae type BMeaslesTetanus

Malaria Dengue

HIV/AIDSTuberculosis

Ebola/Marburg InfluenzaCancers

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

Controland

prevention measures

Malaria Transmission Cycle

Plasmodia Causing Human Malarias

Plasmodium falciparumP. Vivax (relapsing)P.malariaeP.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" 1-106.

Global distribution of Plasmodium vivax

maximum distribution 19th century (pink) late 20th century (purple)

Infected Mosquito

Infected Human

Chronic effects

AnemiaNeurologic/ cognitiveDevelopmental

Impaired growth and development

Malnutrition

Manifestations of the Malaria Burden

Acute febrile illness

Severe illness

Hypoglycemia

Anemia

Cerebral malaria

DeathRespiratory distress

Pregnancy

Fetus

MaternalAcute illness

AnemiaImpaired productivity

Low birth weight Infantmortality

% of all deathsRankMalaria 1 20.3

Respiratory inf. 2 17.2Diarrhoea 3 12.3HIV/AIDS 4 9.0Measles 5 8.4

Low birth weight 6 5.8

Leading causes of death for children under 5,

in the WHO African Region, 2000

Num

ber o

f est

imat

ed c

ases

/yea

r

1,000,000,000

100,000,000

10,000,000

1,000,000

100,000

10,000

1,000

Worldwide AfricaAsia

AmericasEast Med

USA2000

cases

WH

O 1

997

Stur

chle

r 198

9

Bau

don

1987

WH

O 1

997

Brin

kman

199

1

Stur

chle

r 198

9

Snow

199

9

Stur

chle

r 198

9

WH

O 1

997

PAH

O 1

991

E M

ed W

HO

199

7

Stur

chle

r 198

9

CD

C 1

994

Estimated World and Regional Malaria Cases1987-1999

Estimated World and Regional Malaria Deaths1952-1999

Num

ber o

f est

imat

ed c

ases

/yea

r 3,000,000

2,500,000

2,000,000

1,500,000

1,000,000

500,000

0

Worldwide

Africa

Americas

USA

Mur

ray

(dev

)19

96

Naj

era

1996

Stur

chle

r 198

9

WH

O 1

997

Bre

man

/Cam

pbel

l(,5

yrs

) 198

8

Naj

era

1996

Bru

ce-C

hwat

t (<

10 y

rs) 1

952

WH

O 1

997

Stur

chle

r 198

9

Snow

199

9

Stur

chle

r 198

9

Stur

chle

r 198

9

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, 1995-20202000

1800

1600

1400

1200

1000

800

600

400

200

0

Mill

ions

846

423

188

1919

960

400

Febrile Illness

Malaria

1995 2020

“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 malaria7%

Hypoglycemia9%

Respiratory disease

9%

Low birth weight11%

Severe anemia64%

*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 Anemia53%

Low birth weight20%

Hypoglycemia15%

Respiratory disease

6%

Cerebral malaria6%

Disability–adjusted Life Years (DALYs, 1000s),All Cause and Malaria-related, 2002

PopulationDALYs fromall deaths (%)

DALYs from malaria deaths (%)

DALYs from malaria/total (%)

World 6,122,210 1,467,257 42,280 2.9

Africa 655,476 357,884 (24.4) 36,012 (85.2) 10.1

Americas 837,967 145,217 (9.9) 108 (0.2) 0.07

East Med. 493,091 136,221 (9.3) 2,050 (4.8) 1.5

Europe 874,178 151,223 (10.3) 20 (0.04) 0.01

SE Asia 1,559,810 418,844 (28.5) 3,680 (8.7) 0.9

West Pacific 1,701,689 257,868 (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

ModificationGenetic

modification of vectorsFuture Interventions

Vaccines (preerythrocytic,

blood stage, transmission-

blocking)

Protection (insecticide-impregnated

materials)

Control of the Malaria BurdenCurrent 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

InsecticideOne application

(tons) Price/ton Total costCost per

capita

DDT 147 $3,950 $580,650 $0.58

Malathion 220 $4,300 $946,000 $0.95Deltamethrin 110 $20,000 $2,200,000 $2.20Pyrimiphos-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)

11.25 (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 $1.30Artesunate (5 d) 13.5 (50 mg) $365.00 $4,927,500 $4.93

Type of ControlVector Control

• Environmental modification (urban)*• Chemical and biological larvicides*• Indoor residual insecticide spraying*• Outdoor residual insecticide spraying

*costly and effective

Type of ControlPersonal protection (2)

• Insecticide–impregnated materials:nets, curtains, clothing*

• House screening• House location• Repellents• Fumigants

* Shown cost effective for low-income countries

Type of ControlAntiplasmodial (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 AfricaAntenatal care in AfricaProportion of Pregnant Women Seeking Antenatal Clinic CareProportion of Pregnant Women Seeking Antenatal Clinic Care

0

10

20

30

40

50

60

70

80

90

100

Countries

ZambiaRwanda

ZimbabweBotswanaKenyaUgandaMalawiTanzaniaGhanaNamibiaComoros

Cote d'IvoireSenegalLiberiaTogoBeninCameroonMadagascarGuineaSudanMozambiqueCAR

Burkina FasoNigeriaEritreaMali-96NigerChad

Type of ControlSocial 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)• 1935-1939, large-scale control by

pyrethrum spraying in South Africa, Netherlands and India

• 1939-1957– 1939-1940, Elimination of invading A.gambiae

from Brazil– 1942-1945, A.gambiae eliminated from

northern Egypt– 1946-1957, Interruption of transmission by

anti-mosquito measures in Cyprus, Sandinia, Guyana, Venezuela and Greece; indoor residual spraying with DDT, a major strategy

Successes (3)

• 1987-2003– 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, 1997-1999

Among Gravidae 1-4, ITNs were associated with During 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 ProgramsHuman

Hookworm, 1909

Yellow fever, 1915

Aedes aegypti, 1934-42

Anopheles gambiae, 1939-68

Malaria, 1955-1973Yaws, 1950

Smallpox, 1958, 1966-80

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

0

100000

200000

300000

400000

500000

600000

1963 1968 1973 1978 1983 1988 1993

Year

Num

ber o

f cas

es

0

10

20

30

40

50

60

P.falciparum

as % of total m

alaria

DDT spraying

endsFirst report of chloroquine

resistant P.falciparum

Plasmodium falciparumPlasmodium 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 InformationFor More InformationJoel Breman jbreman@nih.govMartin Alilio aliliom@mail.nih.gov