Sw

SSMBSMMa

b

c

d

e

f

g

h

i

j

a

ARRAA

KALEImTM

0d

Acta Tropica 121 (2012) 166– 174

Contents lists available at SciVerse ScienceDirect

Acta Tropica

jo ur nal homep age : www.elsev ier .com/ locate /ac ta t ropica

ahel, savana, riverine and urban malaria in West Africa: Similar control policiesith different outcomes

erign J. Ceesaya, Kalifa A. Bojanga, Davis Nwakanmaa, David J. Conwaya,b, Ousmane A. Koitac,eydou O. Doumbiac, Daouda Ndiayed, Tinzana F. Coulibalyc, Mahamadou Diakitéc, Sekou F. Traoréc,amadou Coulibalyc, Jean-Louis Ndiayed, Ousmane Sarrd, Oumar Gayed, Lassana Konatéd, Ngayo Syd,

abacar Fayed, Ousmane Fayed, Nafomon Sogobac, Musa Jawaraa, Adama Daoc, Belco Poudiougouc,ory Diawarac , Joseph Okebea , Lansana Sangaréc , Ismaela Abubakara , Aliou Sissakoc , Ayouba Diarrac ,oussa Kéitac , Balla Kandehe , Carole A. Longf , Rick M. Fairhurst f , Manoj Duraisinghg , Robert Perryh ,arc A.T. Muskavitch i, Clarissa Valimg, Sarah K. Volkmang, Dyann F. Wirthg, Donald J. Krogstadj,∗

International Center for Excellence in Malaria Research (ICEMR) in West Africa at the Medical Research Council Laboratories, Fajara, GambiaLondon School of Hygiene and Tropical Medicine, London, UKUniiversity of Bamako, MaliUniiversity Cheikh Anta Diop, Dakar, SenegalNational Malaria Control Programmes and Ministries of Health of The Gambia, Senegal and MaliLaboratory of Malaria and Vector Research, NIAID, NIH, Bethesda, MD, United StatesHarvard School of Public Health, Boston, MA, United StatesPresident’s Malaria Initiative in Mali and SenegalBoston College, Chestnut Hill, MA, United StatesTulane School of Public Health and Tropical Medicine, New Orleans, LA, United States

r t i c l e i n f o

rticle history:eceived 31 July 2011eceived in revised form 9 November 2011ccepted 9 November 2011vailable online 19 November 2011

eywords:rtemisinin Combination Therapies

a b s t r a c t

The study sites for the West African ICEMR are in three countries (The Gambia, Senegal, Mali) and arelocated within 750 km of each other. In addition, the National Malaria Control Programmes of these coun-tries have virtually identical policies: (1) Artemisinin Combination Therapies (ACTs) for the treatmentof symptomatic Plasmodium falciparum infection, (2) Long-Lasting Insecticide-treated bed Nets (LLINs)to reduce the Entomololgic Inoculation Rate (EIR), and (3) sulfadoxine–pyrimethamine for the Intermit-tent Preventive Treatment of malaria during pregnancy (IPTp). However, the prevalence of P. falciparummalaria and the status of malaria control vary markedly across the four sites with differences in the dura-

ong-Lasting Insecticide Treated bed nets tion of the transmission season (from 4–5 to 10–11 months), the intensity of transmission (with EIRsfrom unmeasurably low to 4–5 per person per month), multiplicity of infection (from a mean of 1.0 to

ntomologic inoculation rate

ntermittent preventive treatment ofalaria during pregnancy

ransmission intensityultiplicity of infection

means of 2–5) and the status oare at the threshold of malaria

data on the population-based

interventions or combinations

Abbreviations: ACT, Artemisinin-Combination Treatment; CDC, Centers for Disease CInoculation Rate; EMEA, European Medicines Agency; FDA, Food and Drug AdministrationPreventive Treatment of malaria during Pregnancy; IRS, Indoor Residual Spraying; ITN, IMultiplicity Of Infection; MRC, Medical Research Council; NGO, Non-Governmental OrganInstitutes of Health; PMI, President’s Malaria Initiative; PSC, Pyrethrum Spray Catch; TDR, WDiseases; USAID, United States Agency for International Development; WHO, World Hea

∗ Corresponding author. Tel.: +1 504 988 6618.E-mail addresses: krogstad@tulane.edu, donkrogstad@gmail.com (D.J. Krogstad).

001-706X/$ – see front matter © 2011 Elsevier B.V. All rights reserved.oi:10.1016/j.actatropica.2011.11.005

f malaria control (from areas which have virtually no control to areas thatelimination). The most important priority is the need to obtain comparableprevalence, incidence and transmission of malaria before new candidate

of interventions are introduced for malaria control.© 2011 Elsevier B.V. All rights reserved.

ontrol (and Prevention); DDT, DichloroDiphenylTrichloroethane; EIR, Entomologic; ICEMR, International Center of Excellence for Malaria Research; IPTp, Intermittentnsecticide Treated bed Net; LLIN, Long-Lasting Insecticide-Treated bed Nets; MOI,ization; NIAID, National Institutes of Allergy and Infectious Diseases; NIH, National

orld Health Organization Special Programme for Research and Training in Tropicallth Organization.

Tropic

1

1s

f(fBii“HmAtsmcitt2topea

1e

c2tTtFS[IDIi

FA

R

S.J. Ceesay et al. / Acta

. Introduction

.1. Overview of the history of malaria and malaria control inub-Saharan Africa

As evidenced by the overlapping distributions of Plasmodiumalciparum malaria and the sickle cell gene in sub-Saharan AfricaFig. 1; Wellems and Fairhurst, 2005), P. falciparum has had a pro-ound effect on the survival of Africans for millennia (Allison, 1954;eet, 1946). In addition, beginning in the 19th century, malaria

n Africa has exerted similar effects on Europeans and other vis-tors (Shah, 2010). More recently (in the 1950s and 1960s), aglobal” malaria eradication campaign supported by the Worldealth Organization, the World Bank and others actually ignoredalaria in sub-Saharan Africa (Cohen et al., 2010; Pampana, 1969).s a result, the focus of malaria control in sub-Saharan Africa since

hat time has been to minimize morbidity (e.g., cerebral malaria,evere malarial anemia) and mortality, but not to interrupt trans-ission (WHO, 2000). However, current thinking about malaria

ontrol has recently been transformed by a substantial increasen support and by data suggesting that it may possible to con-rol malaria (i.e., to reduce its prevalence by ≥50% and interruptransmission) using interventions available today (Ceesay et al.,008). Thus, if effective malaria control can be achieved usingechnology that is available now, the benefits of control and thepportunity for malaria elimination may not need to be post-oned 10–15 years or more for the development of a safe andffective vaccine (Jongwutiwes et al., 2010) or post-artemisininntimalarials.

.2. The recent global commitment to malaria control andlimination

Today, more resources than ever before are available for theontrol and potential elimination of malaria (Roberts and Enserink,007) based on support from private foundations (Gates Founda-ion, Malaria Foundation, Medicines for Malaria Venture, Wellcomerust, Burroughs-Wellcome Fund) (McCoy et al., 2009), interna-ional programmes and agencies (Roll-Back Malaria, The Globalund, President’s Malaria Initiative, World Health Organizationpecial Programme for Research and Training in Tropical DiseasesTDR] and the World Bank) and national programmes: Nationalnstitutes of Health (including the ICEMR Program), the Centers for

isease Control and Prevention (CDC) and the President’s Malaria

nitiative (PMI) in the U.S. and the Medical Research Council (MRC)n the U.K.

ig. 1. Distributions of Plasmodium falciparum and the HbS Allele in sub-Saharanfrica.

eproduced with permission (TE Wellems & RM Fairhurst, 2005; Nat Genet).

a 121 (2012) 166– 174 167

1.3. The conceptual transition: moving from the reduction ofmorbidity and mortality to the interruption of transmission andpotential elimination

Previous thinking about malaria control in Africa has focusedon the prevention of life-threatening illness and death – on reduc-ing morbidity and mortality (Chuma et al., 2009; WHO, 2000).This is because reductions in morbidity and mortality can beachieved using health center-based strategies to identify personswith symptomatic infections (who are at the greatest risk of morbid-ity and mortality; especially children ≤5 years of age and pregnantwomen). In contrast, in order to interrupt transmission, the individ-uals of greatest interest may be those with asymptomatic infectionswho are living in the community and infecting the anophelinemosquito pool while they remain parasitemic and asymptomatic(which may be 6–8 months or longer; especially for children ≥10years of age and adults). Although it will always be important toprevent morbidity and mortality by treating individuals with symp-tomatic infections, when the programmatic objective changes fromreducing morbidity and mortality to the interruption of transmis-sion and the potential elimination of malaria (Feachem et al., 2010;Feachem and Sabot, 2008; Moonen et al., 2010; Sabot et al., 2010;Tatem et al., 2010; Tatem and Smith, 2010; Greenwood, 2009; Hayet al., 2008; Mendis et al., 2009; Águas et al., 2008; Mills et al.,2008), the strategic priorities inevitably shift from symptomatic toasymptomatic infection and from the clinic to the community.

1.4. The potential for malaria control and elimination

The previous malaria eradication campaign failed because resis-tance developed to the strategies on which it was based: (1)treatment of bloodstream infection with chloroquine to reducethe reservoir of human infection and (2) spraying residual insec-ticides such as DDT under the eaves of houses to interruptiontransmission by killing the anopheline vector as it rested after tak-ing a blood meal (Cohen et al., 2010; Pampana, 1969). Becauseresistance to antimalarial drugs and insecticides remains a seri-ous problem (Wongsrichanali et al., 2002; Cortes et al., 2003;Brown, 1958), there has been concern about whether it is feasibleor wise to propose a second campaign for global malaria controland elimination (Roberts and Enserink, 2007). Although justifiableskepticism remains, the most important new information in thepast 5–10 years is a series of reports describing improvements inmalaria control using interventions that are available today suchas insecticide (permethrin)-impregnated bed nets and Artemisinin-Combination Therapies (ACTs) (Feachem et al., 2010; O’Meara et al.,2010; Greenwood, 2009; Mendis et al., 2009; Águas et al., 2008;Ceesay et al., 2008; Nahlen and Low-Beer, 2007).

1.5. Policy consensus on the approach to malaria control

Based on these reports (Feachem et al., 2010; Feachem andSabot, 2008; Moonen et al., 2010; Sabot et al., 2010; Tatem et al.,2010; Tatem and Smith, 2010; Greenwood, 2009; Hay et al., 2008;Mendis et al., 2009; Águas et al., 2008; Ceesay et al., 2008; Millset al., 2008), which often describe ≥50% decreases in morbidityand mortality, most international and national malaria controlprogrammes now endorse the same three malaria control strate-gies (Table 1): (1) treatment of symptomatic infection with ACTs,(2) use of long-lasting insecticide (permethrin)-treated bed nets(LLINs), and (3) intermittent preventive treatment during preg-

nancy (IPTp) with sulfadoxine + pyrimethamine. However, becausemalaria control policies are virtually identical across the countriesof West Africa, an obvious question is why the results (the levels ofmalaria control) are so different in countries that appear similar,

168 S.J. Ceesay et al. / Acta Tropica 121 (2012) 166– 174

Table 1Current consensus malaria control policies in West Africa.

(1) Artemsinin-combination treatments (ACTs) for the treatment ofpersons with symptomatic uncomplicated Plasmodium falciparuminfection using either Coartem (artemether + lumefantrine; TheGambia, Senegal, Mali), Falcimon or Arsucam(artesunate + amodiaquine; The Gambia, Senegal, Mali), orDuocotexin (dihydroartemisinin + piperaquine; Senegal).

(2) Long-Lasting Insecticide-treated bed Nets (LLINs) to reduce thefrequency of malaria transmission from the anopheline vector tohumans for pregnant women and their infants (Mali, Senegal) orthe entire population (The Gambia).

(3) Intermittent Preventive Treatment withpyrimethamine + sulfadoxine (Fansidar) during Pregnancy (IPTp)to reduce the frequency of placental malaria and its consequencesfor the newborn by using therapeutic doses (75 mg

ac

1

heURNomowt

ipowbeiei

taaop

2m

2

gIsrs(Ma

occurring. In addition, these complexities are exacerbated by urbanreferral patterns, which may inadvertently lead to higher frequen-cies of drug-resistant parasites at urban referral centers than ruralfield sites.

Monthly Rainfall in Millimeters

0

50

100

150

200

250

300

pyrimethamine, 1500 mg sulfadoxine) of Fansidar during both thesecond and third trimesters.

re geographically close and have essentially identical malariaontrol policies?

.6. Rationale for creation of the ICEMR network

The National Institute of Allergy and Infectious Diseases (NIH)as supported basic research on malaria for decades with lessmphasis on field studies which have typically involved CDC,SAID, NGOs and other international agencies (NIAID Malariaesearch Program, 2011). In contrast, the rationale for the ICEMRetwork was to link basic and applied studies of malaria bybtaining data on the epidemiology and transmission of malaria atultiple field sites and using those data to identify: (1) the current

bstacles to malaria control and (2) the basic science questions thatill need to be resolved in order to eliminate the current obstacles

o malaria control and its potential elimination.As described in the original RFA (RFA-09-017), the roles of the

ndividual ICEMRs are to obtain and analyze those data, but not toerform prospective, controlled studies of individual interventionsr combinations of interventions. For that reason, these studiesill require baseline data from each of the participating field sites

efore new interventions are implemented in order to assess theffects of those interventions in subsequent years. Likewise, thenclusion of sites with different intensities of transmission withinach ICEMR (as required by the RFA) will also pose major challengesn terms of interpreting the results obtained.

In addition, in this case (the West African ICEMR), the essen-ially identical malaria control policies in The Gambia, Senegalnd Mali (Table 1) potentially provide an opportunity to evalu-te the impacts of differences in malaria endemicity (intensityf transmission) and implementation on the outcomes of thoseolicies.

. Baseline data on the epidemiology and transmission ofalaria in West Africa (The Gambia, Senegal and Mali)

.1. Geographic and climatic similarities and differences

From the perspectives of geography and climate, the countries ofreatest interest because of their involvement in the West AfricanCEMR (The Gambia, Senegal, Mali) are contiguous (Fig. 2), haveimilar geography (lush regions in areas with high rainfall, savanaegions and arid sahelian regions with little or no rainfall), similareasons (rainy season from July or August to October or November)

Fig. 3) and similar African populations (Bambara, Fulani, Jola,

andinka, Songhai, Wolof). As a result, the transmission, incidencend prevalence of P. falciparum malaria vary seasonally in parallel

Fig. 2. Map of West Africa with ICEMR-Participating Countries.Reproduced with permission (Amy K. Bei).

across the four study sites (October–November peaks in the rainyseason; May–June low points at the end of the dry season).

2.2. Epidemiologic and transmission-based differences amongstudy sites

The prevalence of malaria and the intensity of transmission varystrikingly across these sites despite similar seasonality (Table 2)and relatively short distances between them (≤750 km). Two ofthe three rural sites have a low prevalence of infection associatedwith the microhabitat-based transmission observed commonlywith Anopheles gambiae (Sogoba et al., 2007; Okech et al., 2004).In contrast, the third rural site (Dioro in Mali, Fig. 4) has virtuallyyear-round transmission (June–July to May) from a combination ofseasonal rainfall (June–July to October–November) and irrigationfrom the Niger River to grow rice (flooding of an initial 8000 ha fromAugust to December and a second 8000 ha from January to May).Because these large expanses of stagnant water provide abundantbreeding sites, the human biting rates in such irrigated regions arehigh (Sogoba et al., 2007). As a result, the intensity of transmis-sion (as estimated from the Entomologic Inoculation Rate = EIR andthe multiplicity of infection = MOI) in areas such as Dioro are higherthan in areas with microhabitat-based transmission. The fourth site(an urban site at a clinic in the city of Thies in Senegal) illustratesthree of the unresolved issues related to urban malaria at the begin-ning of a decade when urbanization is increasing, and at the endof which ≥50% of the African population is expected to be urbanrather than rural: (1) large numbers of persons seeking care forsymptomatic P. falciparum infection, (2) limited data on the preva-lence of asymptomatic infection in the community, and (3) limitedinformation on breeding sites and the areas where transmission is

DecNovOctSepAugJulJunMayAprMarFebJan

Thies Gambissa ra Kenieroba Dioro

Fig. 3. Monthly rainfall in mm for the 4 study sites.

S.J. Ceesay et al. / Acta Tropica 121 (2012) 166– 174 169

Table 2Prevalence of malaria and the intensity of transmission across the four field sites.

Individual study sites Dioro Kenieroba Thies GambissaraCountry Mali Mali Senegal GambiaLocation (GIS coordinates and

description)13.45 N, −6.27 W385 km from Bamako

12.11 N, −8.33 W73 km from Bamako

14.81 N, −16.92 W72 km from Dakar

13.32 N, − 14.22 W500 km from Banjul

Population (size of the relevantcommunity)

13,605 in 8 study villages 6000 total 400,000 catchmentpopulation

182,586 catchment population

Ecological environment Sahel (rural)Niger River flood plain,inland delta

South-Savanna (rural)Niger River, microhabitats,scattered breeding sites

UrbanCoastal rainfall scatteredbreeding sites

Savanna (rural)Gambia River many breedingsites

Transmission (endemicity, seasonal vs.year-round)

Virtually year-roundHyperendemicJune–July to May

SeasonalHyperendemicJuly–November

SeasonalHypoendemicSeptember–December

SeasonalHypoendemicAugust–November

Peak Rainy season EIR (/person/mo) 4.8 per month 1.74 [0.93–2.79] 1.0 per month 0.93 per monthDry season EIRs (/person/mo) Not available 0.01 [0.00–0.08] Not available Not availablePeak Biting rates (mean/person/night) 200–300 per night 58.7 [54.5–63.2] <3.0 per night 0.5 per nightRelevant anopheline vector(s),

non-gambiae vectors, . . .A. gambiaemin An. funestus

A. gambiaemin An. funestus

A. gambiaeEIR < 5 per year

A. gambiaeAn. arabiensis

Rainy season prevalence 84% for 2–9 year olds 41–62% all ages 10.6% all ages 2.7% all agesDry season prevalence (ethnicity of the

population)Not availableBambara

17–22% all agesMalinke

Not availableWoloff, Sereres mostly,also Toucouleur

Not availableSaharahule, Fula, Mandinka

Current intervention strategies: (bednet usage)

ACTs for treatment, SP IPTin pregnancy, Bed nets(ITNs, high)

ACTs for treatment, SP IPTin pregnancy, Bed nets(ITNs, moderate)

ACTs for treatment, SP IPTin pregnancy, Bed nets(ITNs)

ACTs for treatment, SP IPT inpregnancy, Bed nets (ITN, high)

Economic activity and occupationalstatus

Irrigation for growing rice Subsistence agriculture:non-irrigated land,farming, fishing

Urban occupations Subsistence farming: rice,other crops

Ages most affected by malaria Children ≤ 5 yearsMorbidity 74% in ≤5 years

Children ≤ 5 years Ages 4–20 years Historically ≤ 5 years, now11–15 years

2

bFtaaamIiac

2

cmquaotcoa

tciibcI

54% in general population

.3. Policies for malaria control and their implementation

The increased support for malaria control now being providedy PMI, the U.S. Agency for International Development, the Globalund, the World Bank, Roll Back Malaria, World Health Organiza-ion, Gates Foundation, Wellcome Trust and other agencies offersn unprecedented opportunity to develop and implement rationalpproaches to malaria control. As a result, malaria control policiesre now remarkably uniform across West Africa. However, thereay be less uniformity in the implementation of those policies.

n addition, with the resources now available, there is increasingnterest in strategies with the potential to improve malaria controlnd simultaneously address unresolved scientific questions (espe-ially questions related to the elimination of malaria).

.4. Study design and data analysis challenges

Based on the need for effective antimalarial drugs the greatestoncerns in West Africa today are about the effectiveness of anti-alarial treatment (ACTs) and bed nets (LLINs). To address those

uestions, it will be necessary to perform comparative studiessing one or more malaria control regimens known to be effectivend one or more alternative regimens. In contrast to studiesf investigational drugs, studies of public health interventionsypically involve regimens that have been FDA-, EMEA- or hostountry-approved and are therefore not investigational. In termsf study design, non-inferiority study designs are often the mostppropriate.

In terms of study design, there is also a need for randomizationo control for as yet unknown variables with the potential to causeonfounding. Although the randomization of symptomatic subjectss relatively straightforward when they present individually (e.g.,

n comparative studies of antimalarial treatment regimens), it maye considerably more difficult (and can be close to impossible) inommunity-based studies of strategies such as ITNs, LLINs or IRS.n those situations, it may be realistic (even necessary) to allocate

subjects within the same households or communities to the samepreventive strategies.

3. Sahel: effects of combinations of malaria controlinterventions

3.1. Community-based study with pre- and post-interventionevaluations

Because large areas of land (8000 ha at a time) are floodedeach year to grow rice in the commune of Dioro near Segou inMali (Fig. 4), malaria transmission begins with the annual rainsin mid-June or early July (Fig. 3) and continues for 10–11 monthsthrough May of the following year. In order to examine the effects ofthree interventions on malaria, a census was obtained and baselinemalaria studies were performed in October 2006 in collaborationwith the Millennium Village Project. These studies were followedone month later by the introduction of three interventions: (1)ACTs (artemether + lumefantrine = Coartem) for the treatment ofsymptomatic P. falciparum infection, (2) universal coverage withLLINs based on one net for every 1.8 individuals, and (3) IPTpwith sulfadoxine + pyrimethamine (Fansidar) during the secondand third trimesters of pregnancy. One year later (December 2007),the baseline studies of malaria infection, disease and transmissionperformed in October 2006 were repeated to test for changes frombaseline which had persisted for ≥12 months.

The results of this study demonstrated that interventionsnow available can reduce the frequency of infection and diseasein humans, and can simultaneously reduce transmission frommosquitoes to humans (reduce the EIR). In comparison to otherreports, the strength of this study is that the same evaluationswere performed one month before and one year after the intro-

duction of the control interventions – thus permitting one to infera cause-and-effect relationship between the introduction of thesethree interventions and subsequent reductions in the prevalence,incidence and transmission of malaria.

170 S.J. Ceesay et al. / Acta Tropica 121 (2012) 166– 174

(SegouR

3ii

fltweti

4

4K

RrFr

Fig. 4. Location of the Dioro

eproduced with permission (Google.com).

.2. Intensity of human exposure to mosquitoes with year-roundrrigation and the effects of intervention on the entomologicnoculation rate

One of the inadvertent results of irrigation to grow rice onooded land is the creation of breeding sites for the mosquito vec-or, A. gambiae (Fig. 5). As a result, human biting rates in regionsith irrigation may reach 200–300 per person per night (Sogoba

t al., 2007). In light of these biting rates, the results of the three con-rol interventions in 2006–2007 (virtual elimination of mosquitoesnside houses, >40% reduction in the EIR) are highly encouraging.

. Savana: microhabitat-based rainy season transmission

.1. Overview of transmission and morbidity of malaria inenieroba, Mali

Kenieroba (70 km south of Bamako and 4–5 km from the Niger

iver in Mali) (Fig. 6) provides an example of microhabitat-basedainy season transmission by A. gambiae. Recent data from Diakité,airhurst and their colleagues in 2008 suggest that annual attackates for uncomplicated P. falciparum malaria are ∼60% among

Fig. 5. Creation of breeding sites with irrigation to grow rice.

) Irrigation Scheme in Mali.

children less than 18 years of age in this community (773 slide-confirmed cases of uncomplicated P. falciparum malaria among1300 children within the 5 month transmission season from Julyto November).

4.2. Natural selection for red blood cell polymorphisms

Data obtained from Kenieroba during the past several yearsillustrate the continuing selective pressure(s) exerted by P. falci-parum malaria in West Africa. For example, 60% of children ≤10years of age in the village of Kenieroba have one or more redblood cell (RBC) polymorphisms that may protect against malariaby impairing the cytoadherence of P. falciparum-infected RBCs andthus ameliorating the microvascular inflammation that causes thesymptoms of uncomplicated P. falciparum malaria in the population(Personal communication: RM Fairhurst, CA Long).

4.3. Persistent dry season transmission

In addition, recent studies by Sogoba, Doumbia and theircolleagues have examined the issue of persistent dry season trans-mission. At times when pyrethrum spray catches (PSCs) and humanlanding rates have found no evidence of adult mosquitoes inKenieroba, their studies suggest there are previously undetectedbreeding sites along the banks of the Niger River. If those breedingsites persist during the dry season, they may account for previ-ously unexplained dry season transmission (new human infections)in villages such as Kenieroba at times when adult anophelinemosquitoes are rare or undetectable.

5. Riverine: decreasing P. falciparum infection in TheGambia

5.1. Decreases in malaria admissions, deaths and positive thicksmears

From 1999 to 2007, there were significant decreases in the num-bers of in-patient admissions, deaths and positive thick smearsreported from health centers and hospitals in The Gambia (Ceesayet al., 2008; Fig. 7). These data are striking; they suggest that malaria

S.J. Ceesay et al. / Acta Tropica 121 (2012) 166– 174 171

Fig. 6. Village of Kenieroba on the Niger River 60 km south of Bamako in Mali.Reproduced with permission (Google.com).

Fig. 7. Decreased malaria in The Gambia, from 1999 to 2007.Reproduced with permission (Ceesay et al., 2008; The Lancet).

172 S.J. Ceesay et al. / Acta Tropica 121 (2012) 166– 174

R

cmetdht

5t

siwt

5

d1ttmcsaas

6

6A

i

Fig. 8. Location of the city of Thies in Senegal.eproduced with permission (GraphicMaps.com).

ontrol is feasible today in The Gambia and raise the possibility thatalaria elimination may be feasible in sub-Saharan Africa. How-

ver, multiple interventions and changes have been introduced byhe Gambian National Malaria Control Programme during the pastecade. As a result, it is difficult to attribute these decreases inuman infection and disease to any one intervention or combina-ion of interventions.

.2. Recent changes in malaria endemicity during the 2010ransmission season

With increased rains and flooding during the 2010 transmissioneason, there has been a resurgence of malaria in The Gambia dur-ng the past year (Gambian National Malaria Control Programme),

hich has likewise been observed – although not yet reported – inhe neighboring countries of Senegal and Mali.

.3. The need for population-based data

The decreases in malaria cases, deaths and positive smears inata from health centers and hospitals in The Gambia (Fig. 8) from999 to 2007 (Ceesay et al., 2008) and recent evidence for year-o-year variability highlight the need for population-based data onhe prevalence, incidence and transmission of malaria in order to

onitor and evaluate the effects of individual interventions andombinations of interventions over time. For this reason, baselinetudies of the prevalence, incidence and transmission of malaria are

priority in order to obtain population-based data that can serves a comparator for the evaluation of candidate interventions inubsequent years.

. Urban malaria: the cty of Thies in Senegal

.1. The Increasing importance of urban malaria in sub-Saharan

frica

The consensus of demographers is that the urbanization alreadyn progress across sub-Saharan Africa will continue during the

Fig. 9. Plots of IC50 values for chloroquine and artemisinin.Reproduced with permission (Ndiaye et al., 2010; Am J Trop Med Hyg).

coming decade, such that ≥50% of the population will be urbanby the end of 2020 (Keiser et al., 2005). For this reason, we haveincluded an urban site in the city of Thies (which has ∼400,000inhabitants and is 70 km east of Dakar, Fig. 8) as a comparator forthe rural site at Gambissara in The Gambia and the two rural sitesat Dioro and Kenieroba in Mali.

In contrast, the advantages of urban sites are that they provideaccess to larger populations than can be followed prospectively inrural areas, and permit one to sample segments of the populationwith greater access to proprietary antimalarial drugs and privatemedical care. Conversely, the major disadvantage of urban sites isthat they rely almost exclusively on passive case detection (personsseeking help because they believe they may have malaria) becauseof the larger populations, which make community-wide surveysfor population-based data more expensive.

6.2. Results of preliminary studies performed at the Thies urbansite

During each of the past four years, an average of 2000–3000 per-sons have been tested for P. falciparum infection at the Thies urbansite under the auspices of the University Cheikh Anta Diop andthe Ministry of Health. On average, 10–25% of the persons testedhave been positive by thick smear and have therefore been treatedfree of charge with an ACT (Coartem [artemether + lumefantrine],Falcimon or Arsucam [artesunate + amodiaquine] or Duocotexin[dihydroartemisinin + piperaquine]) based on the policies of theMOH, PMI and the National Malaria Control Programme of Senegal.

6.3. Ex Vivo testing of P. falciparum isolates from infected subjects

In addition, during the past several years, Ndiaye and hiscolleagues have examined parasite isolates from infected symp-tomatic subjects in Thies for their ability to replicate in vitrousing an assay based on a fluorescent dye [4-6-diamidino-2-phenylindole = DAPI] rather than radioisotopes to measure nucleicacid synthesis (Ndiaye et al., 2010). Those studies (Fig. 9) indicatethat isolates with high IC50s for chloroquine and artemisinin arepresent among infected subjects in this region of Senegal.

7. Discussion and conclusions

7.1. Ranges of study sites and intervention strategies

The three rural sites and one urban site we have identifiedrepresent a broad range of environments (sahel, savanna, river-

ine and urban), human impact (from infection in a majority of thepopulation in Dioro to infection as an uncommon event in TheGambia), transmission seasons (microhabitat-based transmissionfor 4–5 months per year to 10–11 months of transmission per

Tropic

ytcgC(

7o

maepp

7c

ucwssiS

obiga1

A

eIcsCLBaWsAnABSW(MclAaEPZ

S.J. Ceesay et al. / Acta

ear with irrigation) and malaria control (from limited control tohe threshold of elimination) (Table 2). In contrast, the malariaontrol policies that have been established in The Gambia, Sene-al and Mali by PMI and the three respective National Malariaontrol Programmes are virtually identical (ACTs, LLINs, IPTp)Table 1).

.2. The relationship between malaria control interventions andutcomes

As noted above, the relationship between combinations ofalaria control interventions and outcomes in The Gambia, Senegal

nd Mali is unclear because of potentially confounding differ-nces across the four study sites and the region, and becauseolicies that are identical on paper may be substantially different inractice.

.3. Potential monitoring and evaluation strategies andhallenges

The strategies available for monitoring and evaluation arenlikely to include the randomization of communities to differentombinations of control interventions, and each of the study sitesill also change over time. In fact, even the timing of the malaria

eason varies across the study sites because June and July are thetart of the transmission season in Dioro and Kenieroba, but notn Gambissara or Thies where transmission begins in August andeptember.

Therefore, the only way to evaluate and interpret the effectsf control interventions at the different study sites is to obtainaseline data for use as comparators after the introduction of new

nterventions in subsequent years. For this reason, the major initialoal is to obtain baseline data on the epidemiology, human impactnd transmission of malaria at the four study sites during the first–2 years of support.

cknowledgments

The studies described here have been supported by a coop-rative agreement from the National Institutes of Allergy andnfectious Diseases (NIAID U19 AI 089696) for an internationalenter of excellence in malaria research (ICEMR) award to a con-ortium involving the University of Bamako in Mali, the Universityheikh Anta Diop in Senegal, the Medical Research Council (MRC)aboratories in The Gambia, Harvard School of Public Health,oston College, London School of Hygiene and Tropical Medicinend the Tulane School of Public Health and Tropical Medicine.e thank our many colleagues for administrative and financial

upport (Abdoulie Barry, Ron Cail, Salif Camara, Rosie Chavez,bou Alassane Diallo, Khady Touré Diop, Ramona Gonski, Shan-on Joyce, Dembo Kanteh, Glen McGugan, Carmen Mejia, Papalioune Ndao, Seybatou Magatte Ndaw, Peter Noble, Malla Rao,renda Rodriguez, Mamkumbah Sanneh, Moussa Dien Sarr, IPingh, Paula Strickland, Don Van Noy, Joan Vivestomas, Tonuali, James Clint Welty, Kijuana Yarls), advice and mentoring

Tumani Corrah, Abarahmane Dia, Amadou Diallo, Souleymanneboup, Saliou Ndiaye, Omar Ndir), information technology and

omputing support (Christopher Whalen, Brian Moyer), pub-

ic health and malaria control partnerships (Moussa Thior, Mrs.dam Jagne Sonko, Claude-Emile Rwagacondo), and for generousccess to their personal expertise (Jennifer Anderson, Thomas P.isele, Ivo Foppa, Nicholas Manoukis, Meredith McMorrow, Davidarker, Robert Perry, Margaret Pinder, Jon Eric Tongren, Sixteigirumugabe).

a 121 (2012) 166– 174 173

References

Águas, R., White, L.J., Snow, R.W., Gomes, M.G.M., 2008. Prospects for malaria erad-ication in sub-Saharan Africa. PLoS One 3 (3), e1767.

Allison, A.C., 1954. The distribution of the sickle-cell trait in East Africa and else-where, and its apparent relationship to the incidence of subtertian malaria.Trans. R. Soc. Trop. Med. Hyg. 48, 312–318.

Beet, E.A., 1946. Sickle cell disease in the Balovale District of Northern Rhodesia. EastAfr. Med. J. 23, 75–86.

Brown, A.W.A., 1958. The insecticide-resistance problem: a review of developmentsin 1956 and 1958. Bull. WHO 18 (3), 309–321.

Ceesay, S.J., Casals-Pascual, C., Erskine, J., Anya, S.E., Duah, N.O., Fulford, A.J.C., Sesay,S.S.S., Abubakar, I., Dunyo, S., Sey, O., Palmer, A., Fofana, M., Corrah, T., Bojang,K.A., Whittle, H.C., Greenwood, B.M., Conway, D.J., 2008. Changes in malariaindices between 1999 and 2007 in The Gambia: a retrospective analysis. Lancet372 (9649), 1545–1554.

Chuma, J., Abuya, T., Memusi, D., Juma, E., Abhwale, W., Ntwiga, J., Nyandigisi, A., Tet-teh, G., Shretta, R., Amin, A., 2009. Reviewing the literature on access to promptand effective malaria treatment in Kenya: implications for meeting the Abujatargets. Malar. J. 8 (10), 243.

Cohen, J.M., Moonen, B., Snow, R.W., Smith, D.L., 2010. How absolute is zero: anevaluation of historical and current definitions of malaria elimination. Malar. J.9, 213.

Cortes, A., Felger, I., Beck, H.P., 2003. Molecular parasitology of malaria in Papua NewGuinea. Trends Parasitol. 19 (6), 246–249.

Feachem, R.G.A., Phillips, A.A., Hwang, J., Cotter, C., Wielgosz, B., Greenwood, B.M.,Sabot, O., Rodriguez, M.H., Abeyasinghe, R.R., Ghebreyesus, T.A., Snow, R.W.,2010. Malaria elimination 1: shrinking the malaria map: progress and prospects.Lancet 376 (9752), 1566–1578.

Feachem, R.G.A., Sabot, O., 2008. A new global malaria eradication strategy. Lancet371 (9624), 1633–1635.

Greenwood, B.M., 2009. Can malaria be eliminated? Trans. R. Soc. Trop. Med. Hyg.103 (Suppl. 1), S2–S5.

Hay, S.I., Smith, D.L., Snow, R.W., 2008. Measuring malaria endemicity from intenseto interrupted transmission. Lancet Infect. Dis. 8 (6), 369–378.

Jongwutiwes, S., Putaporntip, C., Hughes, A.L., 2010. Bottleneck effects on vaccine-candidate antigen diversity of malaria parasites in Thailand. Vaccine 28 (18),3112–3117.

Keiser, J., Utzinger, J., Caldas de Castro, M., Smith, T.A., Tanner, M., Singer, B.H., 2005.Urbanization in sub-Saharan Africa and implications for malaria control. Am. J.Trop. Med. Hyg. 71 (2 Suppl), 118–127.

McCoy, D., Kembhavi, G., Patel, J., Luintel, A., 2009. The Bill & Melinda GatesFoundation’s grant-making programme for global health. Lancet 373 (9675),1645–1653.

Mendis, K., Rietveld, A., Warsame, M., Bosman, A., Greenwood, B.M., Wernsdorfer,W.H., 2009. From malaria control to eradication: the WHO perspective. Trop.Med. Int. Health 14 (7), 802–809.

Mills, A., Lubell, Y., Hanson, K., 2008. Malaria eradication: the economic, financialand institutional challenge. Malar. J. 7 (Suppl. 1), S11.

Moonen, B., Cohen, J.M., Snow, R.W., Slutsker, L., Drakeley, C., Smith, D.L., Abeyas-inghe, R.R., Rodriguez, M.H., Maharaj, R., Tanner, M., Targett, G., 2010. Malariaelimination 3: operational strategies to achieve and maintain malaria elimina-tion. Lancet 376 (9752), 1592–1603.

Nahlen, B.L., Low-Beer, D., 2007. Building to collective impact: the Global Fund sup-port for measuring reduction in the burden of malaria. Am. J. Trop. Med. Hyg. 77(Suppl. 6), 321–327.

Ndiaye, D., Patel, V., Demas, A., LeRoux, M., Ndir, O., Mboup, S., Lakshmanan, V.,Daily, J.P., Wirth, D.F., 2010. A non-radioactive DAPI-based high-throughput invitro assay to assess Plasmodium falciparum responsiveness to antimalarials –increased sensitivity of P. falciparum to chloroquine in Senegal. Am. J. Trop. Med.Hyg. 82 (2), 228–230.

NIAID Malaria Research Program, 2011. www.niaid.nih.gov/topics/malaria/Pages/default.aspx, October 14th, 2011.

Okech, B.A., Gouagna, L.C., Walczak, E., Kabiru, E.W., Beier, J.C., Yan, G., Githure, J.I.,2004. The development of Plasmodium falciparum in experimentally infectedAnopheles gambiae (Diptera: Culicidae) under ambient microhabitat tempera-ture in western Kenya. Acta Trop. 92 (2), 99–108.

O’Meara, W.P., Mangeni, J.N., Steketee, R.W., Greenwood, B.M., 2010. Changes inthe burden of malaria in sub-Saharan Africa. Lancet Infect. Dis. 10 (8), 545–555.

Pampana, E.J., 1969. A Textbook of Malaria Eradication, second ed. Oxford, London,pp. 1–510.

Roberts, L., Enserink, M., 2007. Did they really say . . . eradication? Science 318(5856), 1544–1545.

Sabot, O., Cohen, J.M., Hsiang, M.S., Kahn, J.G., Basu, S., Tang, L., Zheng, B., Gao, Q.,Zou, L., Tatarsky, A., Aboobakar, S., Usas, J., Barrett, S., Cohen, J.L., Jamison, D.T.,Feacham, R.G.A., 2010. Malaria elimination 4: costs and financial feasibility ofmalaria elimination. Lancet 376 (9752), 1604–1615.

Shah, S., 2010. The Fever: How Malaria has Ruled Humankind for 500,000 Years.Sarah Crichton, New York, pp. 1–241.

Sogoba, N., Doumbia, S.O., Vounatsou, P., Bagayoko, M.M., Dolo, G., Traoré, S.F., Maïga,

H.M., Touré, Y.T., Smith, T., 2007. Malaria transmission dynamics in Niono, Mali:the effect of the irrigation systems. Acta Trop. 101 (3), 232–240.

Tatem, A.J., Smith, D.L., 2010. International population movements and regional Plas-modium falciparum malaria elimination strategies. Proc. Natl. Acad. Sci. U.S.A.107 (27), 1222–12227.

1 Tropic

T

W

74 S.J. Ceesay et al. / Acta

atem, A.J., Smith, D.L., Gething, P.W., Kabaria, C.W., Snow, R.W., Hay, S.I., 2010.Malaria elimination 2: ranking of elimination feasibility between malaria-endemic countries. Lancet 376 (9752), 1579–1591.

ellems, T.E., Fairhurst, R.M., 2005. Malaria-protective traits at odds in Africa? Nat.Genet. 37 (11), 1160–1162.

a 121 (2012) 166– 174

World Health Organization (WHO), 2000. The Abuja declaration on Roll Back Malariain Africa by the African Heads of States and Governments, 25th April, Abuja,Nigeria. WHO, Geneva.

Wongsrichanali, C., Pickard, A.L., Wernsdorfer, W.H., Meshnick, S.R., 2002. Epidemi-ology of drug-resistant malaria. Lancet Infect. Dis. 2 (4), 209–218.