Epidemiology and control of malaria Epidemiology and control of malaria (with a focus on sub-Saharan Africa)(with a focus on sub-Saharan Africa)

Grant Dorsey, MD, PhDGrant Dorsey, MD, PhDDivision of Infectious DiseasesDivision of Infectious Diseases

University of California, San FranciscoUniversity of California, San Francisco

Burden of DiseaseBurden of Disease

Over 40% of the world’s population live in endemic areasOver 40% of the world’s population live in endemic areasEstimated 500 million clinical cases and 1-2 million deaths/yearEstimated 500 million clinical cases and 1-2 million deaths/year3rd most common cause of death due to a communicable agent3rd most common cause of death due to a communicable agent

Annual malaria mortality rates per 100,000 Annual malaria mortality rates per 100,000 population since 1900population since 1900

0

50

100

150

200

250

1900 1930 1950 1970 1990 1997

World excluding sub-Saharan Africa

sub-Saharan Africa

Burden of Malaria in AfricaBurden of Malaria in Africa

One African child dies of One African child dies of malaria every 30 secondsmalaria every 30 secondsHigher in poor and rural Higher in poor and rural areasareasIn all malaria-endemic In all malaria-endemic countries in Africa, malaria countries in Africa, malaria accounts for 25-40% of accounts for 25-40% of outpatient visits and 20-outpatient visits and 20-50% of hospital 50% of hospital admissionsadmissions

Malaria mortality in African childrenMalaria mortality in African children

Unique Epidemiological Aspects Unique Epidemiological Aspects of Malaria in Africaof Malaria in Africa

Infection is incredibly common and heterogeneous Infection is incredibly common and heterogeneous – High density of mosquitoesHigh density of mosquitoes– Mosquitoes like to bite humans and live indoorsMosquitoes like to bite humans and live indoors– Very little vector control in Africa Very little vector control in Africa

Gold standard for measuring the frequency of Gold standard for measuring the frequency of infection is termed the entomological inoculation infection is termed the entomological inoculation rate (EIR) rate (EIR)

EIR = number of bites by anopheles mosquito per night x EIR = number of bites by anopheles mosquito per night x proportion of mosquitoes carrying malaria parasites in proportion of mosquitoes carrying malaria parasites in their salivary glands x 365 days per yeartheir salivary glands x 365 days per year

Unique Epidemiological Aspects of Unique Epidemiological Aspects of Malaria in Africa cont.Malaria in Africa cont.

Clinical consequences of infection vary greatlyClinical consequences of infection vary greatly– Disease manifestations range from asymptomatic Disease manifestations range from asymptomatic

parasitemia to life-threatening illnessparasitemia to life-threatening illness– Risk of illness and death strongly influenced by Risk of illness and death strongly influenced by

development of “semi-immunity” over one’s lifetimedevelopment of “semi-immunity” over one’s lifetime– High risk groups include young children, pregnant High risk groups include young children, pregnant

women, HIV-infected patients, and non-immune women, HIV-infected patients, and non-immune adults (i.e. travelers)adults (i.e. travelers)

Estimating risk of infection, disease, and deathEstimating risk of infection, disease, and death

~ 50 billion infections with malaria parasites each ~ 50 billion infections with malaria parasites each year in Africayear in Africa

~ 1:100 infections leads to clinical illness = 500 ~ 1:100 infections leads to clinical illness = 500 million cases of malaria each yearmillion cases of malaria each year

~ 1:50 cases of malaria results in the severe form of ~ 1:50 cases of malaria results in the severe form of disease = 10 million cases of severe malaria each disease = 10 million cases of severe malaria each yearyear

~ 1:5 cases of severe malaria leads to death = 1-2 ~ 1:5 cases of severe malaria leads to death = 1-2 million deaths due to malaria each yearmillion deaths due to malaria each year

Transmission intensity, incidence, and ageTransmission intensity, incidence, and age

0

1

2

3

4

5

6

<1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 -20 -25 -30 -40 -50>=60

Age (years)

Dielmo, Senegal – 200 infections/year

0

1

2

3

4

5

6

<1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 -20 -25 -30 -40 -50>=60

Age (years)

Ndiop, Senegal – 20 infections/year

In the 20th century, the boundary of malaria transmission was In the 20th century, the boundary of malaria transmission was progressively rolled back from the northprogressively rolled back from the north

Elimination < 1960

Elimination 1960 - 1975

Elimination 1975 - 2007

Elimination program ongoing

Elimination newly targeted

Funding Source

$0.19

International2

Domestic

1 Estimated based on Mapping Malaria Risk in Africa project updated for 2007 population levels2 Includes funding allocations by the Global Fund, World Bank, and US President’s Malaria Initiative

DR CongoDR Congo South AfricaSouth Africa SwazilandSwaziland TanzaniaTanzania

(mainland)(mainland)

BotswanaBotswana ZambiaZambia

$0.91

$2.41 $2.53

$3.17

$4.43

UAEUAE

~$22Estimated annual malaria financing per population at risk1

Countries targeting elimination do not currently spend more per Countries targeting elimination do not currently spend more per population at risk than some control programs…population at risk than some control programs…

$0.36

1 Includes both reported and unconfirmed cases as estimated by the national program and/or partners2 Based on 2003 estimates

DR CongoDR Congo South AfricaSouth Africa UAEUAE22TanzaniaTanzania

(mainland)(mainland)

BotswanaBotswanaZambiaZambia

$5.76

$10.74

$40

$800

$200,000

OmanOman22

>$10m

Estimated annual malaria financing per case1

……but do spend significantly more per case, which will continue to but do spend significantly more per case, which will continue to increase as incidence declines furtherincrease as incidence declines further

Available tools for the control and Available tools for the control and elimination of malariaelimination of malaria

1. Effective case management1. Effective case management

2. Insecticide treated bednets (ITNs) 2. Insecticide treated bednets (ITNs)

3. Vector control3. Vector control

4. Chemoprevention4. Chemoprevention

5. Vaccine5. Vaccine

Effective case management in the Effective case management in the era of ACTsera of ACTs

ACT’s have now become the standard of care ACT’s have now become the standard of care throughout the worldthroughout the world– Artesunate+mefloquineArtesunate+mefloquine– Artemether-lumefantrineArtemether-lumefantrine– Artesunate+amodiaquineArtesunate+amodiaquine– Dihydroartemisinin-piperaquineDihydroartemisinin-piperaquine

Excellent efficacy unless resistance to partner drugExcellent efficacy unless resistance to partner drug– Early reports of artemisinin resistance in Thai-Cambodia Early reports of artemisinin resistance in Thai-Cambodia

borderborder

May decrease transmission through anti-May decrease transmission through anti-gametocyte effectsgametocyte effectsConcern about drug availability and costConcern about drug availability and cost

Effective case managementEffective case managementIssues in resource poor settingsIssues in resource poor settings

Government recommends one first-line Government recommends one first-line therapy for the whole countrytherapy for the whole country– Policy based on clinical surveillance studiesPolicy based on clinical surveillance studies– Drug subsidized for the public sector Drug subsidized for the public sector – ACTs currently too expensive in the private ACTs currently too expensive in the private

sectorsector

Most fevers are treated empirically as Most fevers are treated empirically as malaria at homemalaria at home– Urgent need to promote rationale use of ACTsUrgent need to promote rationale use of ACTs

Joint malaria training programJoint malaria training program

Objective: Objective: To evaluate the impact of integrated team-To evaluate the impact of integrated team-based training of health care workers on malaria case based training of health care workers on malaria case management.management.Design and Participants: Design and Participants: Malaria surveillance data 120 Malaria surveillance data 120 days before and after training were compared for all days before and after training were compared for all patients presenting to eight government-run health patients presenting to eight government-run health centers. centers. Setting: Setting: The eight sites represent the diversity of The eight sites represent the diversity of malaria transmission in Uganda. Data were collected one malaria transmission in Uganda. Data were collected one year after artemether-lumefantrine was introduced as the year after artemether-lumefantrine was introduced as the recommended first-line treatment for uncomplicated recommended first-line treatment for uncomplicated malaria. malaria. Intervention: Intervention: Six day integrated team-based training Six day integrated team-based training course targeting clinical, laboratory and records staff with course targeting clinical, laboratory and records staff with site visits approximately 6 and 12 weeks post training. site visits approximately 6 and 12 weeks post training.

Proportion of patients suspected of having Proportion of patients suspected of having malaria referred for a blood smearmalaria referred for a blood smear

Age less than 5 years

0%

20%

40%

60%

80%

100%

Kabalep=0.06

Kamwezi p=0.29

Kihihi p=0.11

Walukubap<0.0001

Kyenjojo p<0.0001

Omugu p=0.46

Nagongerap=0.26

Aduku p=0.0008

Pre-training Post-training

Proportion of patients with a positive blood Proportion of patients with a positive blood smear treated for malariasmear treated for malaria

Age less than 5 years

0%

20%

40%

60%

80%

100%

Kabalep=0.85

Kamwezi p=0.68

Kihihi p=0.64

Walukubap=0.21

Kyenjojo p=0.33

Omugu p=0.12

Nagongerap=0.64

Aduku p=0.41

Pre-training Post-training

Proportion of patients with a negative blood Proportion of patients with a negative blood smear treated for malariasmear treated for malaria

Age less than 5 years

0%

20%

40%

60%

80%

100%

Kabalep=0.006

Kamwezi p=0.11

Kihihi p=0.0002

Walukubap<0.0001

Kyenjojo p=0.0001

Omugu p=0.07

Nagongerap=0.0005

Aduku p=0.02

Pre-training Post-training

Proportion of patient prescribed antimalarial Proportion of patient prescribed antimalarial therapy who were given a correct regimentherapy who were given a correct regimen

Age less than 5 years

0%

20%

40%

60%

80%

100%

Kabalep=0.41

Kamwezi p=0.002

Kihihi p=0.13

Walukubap=0.97

Kyenjojo p=0.09

Omugu p=0.20

Nagongerap=0.0003

Aduku p=0.05

Pre-training Post-training

Insecticide treated bednets (ITNs)Insecticide treated bednets (ITNs)

Several randomized trials in a range of endemic settings Several randomized trials in a range of endemic settings have documented the efficacy of ITNshave documented the efficacy of ITNs– Interventions done at the population levelInterventions done at the population level– ~ 10 fold reduction in transmission~ 10 fold reduction in transmission– ~ 2 fold decrease in incidence of clinical malaria~ 2 fold decrease in incidence of clinical malaria– ~ 20% reduction in all cause childhood mortality~ 20% reduction in all cause childhood mortality

One of the most cost effective interventions availableOne of the most cost effective interventions available– Bednets cost only a few dollarsBednets cost only a few dollars

Long lasting ITNsLong lasting ITNs– Insecticide impregnated into netsInsecticide impregnated into nets– Last 5 yearsLast 5 years

Remaining issues are coverage and distributionRemaining issues are coverage and distribution

Vector controlVector control

Primary tool indoor residual spraying (IRS)Primary tool indoor residual spraying (IRS)– Very effective in low transmission areasVery effective in low transmission areas– Starting to be used in higher transmission settings in Starting to be used in higher transmission settings in

AfricaAfrica– Limited data on what is the best insecticide and how Limited data on what is the best insecticide and how

often to sprayoften to spray– Very expensiveVery expensive

Other vector control measuresOther vector control measures– LarvicideLarvicide– Genetically modified mosquitoesGenetically modified mosquitoes

0%

10%

20%

30%

40%

50%

60%

Aug-06

Sep-06

Oct-06

Nov-06

Dec-06

Jan-07

Feb-07

Mar-07

Apr-07

May-07

Jun-07

Jul-07

Aug-07

Sep-07

Oct-07

Nov-07

Dec-07

Sm

ear p

ositi

vity

Age less than 5 years Age 5 years or older

IRS in moderate endemic setting in UgandaIRS in moderate endemic setting in Uganda

IRS

ChemopreventionChemoprevention

Two main strategiesTwo main strategies– ChemoprophylaxisChemoprophylaxis– Intermittent preventative therapyIntermittent preventative therapy

Target groupsTarget groups– Pregnant womenPregnant women– HIV infected patientsHIV infected patients

Daily trimethoprim-sulfamethoxazoleDaily trimethoprim-sulfamethoxazole

– Infants and young childrenInfants and young childrenActive area of researchActive area of research

Summary of studies evaluating IPTi with SP given at the time of routine immunizations

Study parameterCountry and year(s) of recruitment

Tanzania 1999-00

Ghana2000-02

Mozambique2002-04

Ghana2003

Ghana2004

Gabon2002-05

EIR*/year

Transmission

Age at dosing, months

Incidence in placebo group†

# enrolled, placebo/intervention

Preventive efficacy, % (95% CI) Clinical malaria Hospital admission Anemia

29

Perennial

2, 3, 9

0.36

351/350

at 12 mo.62 (44-75)30 (8-47)50 (8-73)

418

Seasonal

3, 4, 9, 12

1.02

1242/1243

at 15 mo.25 (14-34)13 (-5-27)36 (11-53)

38

Perennial

3, 4, 9

0.43

755/748

at 12 mo.23 (2-39)19 (4-31)

13 (-17-35)

not reported

Perennial

3, 9, 15

1.16

600/600

at 18 mo.23 (12-32)31 (3-51)24 (4-39)

400

Perennial

3, 9, 15

1.20

535/535

at 18 mo.20 (11-29)9 (-23-34)7 (-8-20)

50

Perennial

3, 9, 15

0.16

595/594

At 18 mo.17 (-24-44)not reported22 (-1-40)

Control of Malaria in Africa cont.Control of Malaria in Africa cont.VaccinesVaccines

1973 vaccine made from whole malaria parasites killed 1973 vaccine made from whole malaria parasites killed by irradiation could protect healthy persons from infectionby irradiation could protect healthy persons from infection– Not a viable option for large scale productionNot a viable option for large scale production

Decades of research failed to develop an effective Decades of research failed to develop an effective vaccinevaccine– Limited understanding of immune correlates of protectionLimited understanding of immune correlates of protection– Organism extremely diverse and complicatedOrganism extremely diverse and complicated

Recent vaccine trialsRecent vaccine trials– RTS,S vaccineRTS,S vaccine

Surface protein found in form of parasite injected by mosquitoes Surface protein found in form of parasite injected by mosquitoes conjugated to Hep B surface Agconjugated to Hep B surface AgPilot study in 360 Gambian men: 34% efficacy in protecting against Pilot study in 360 Gambian men: 34% efficacy in protecting against malaria infection but waned to 0% by 15 weeksmalaria infection but waned to 0% by 15 weeks1500 children in Mozambique: 30% reduction in clinical malaria and 1500 children in Mozambique: 30% reduction in clinical malaria and 58% reduction in severe malaria after 6 months58% reduction in severe malaria after 6 monthsPlans for large phase III trial underwayPlans for large phase III trial underway

Success Story in South AfricaSuccess Story in South AfricaArea of low seasonal transmission in setting of Area of low seasonal transmission in setting of highly competent national malaria control programhighly competent national malaria control programWide scale implementation of IRS (A+B) and AL (C) Wide scale implementation of IRS (A+B) and AL (C)