TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE (2003) 97,1 -9

The effect of mass administration of sulfadoxine-pyrimethamine combined with artesunate on malaria incidence: a double-blind, community-randomized,

placebo-controlled trial in The Gambia

Lorenz von Seidlein1-23, Gijs Walraven12, Paul J. M. Milligan1, Neal Alexander2, Fandingding Manneh4,

Jacqueline L. Deen1, Roz Coleman1, Musa Jawara1, Steve W. Lindsay5, Chris Drakeley2, Sarah De Martin2, Piero OUiaro6, Steve Bennett2, Maarten Schim van der Loeff1'2, Kunle Okunoye1, GeofT A. T. Targett2, Keith P. W. J. Me Adam1, Justin F. Doherty1'2, Brian M. Greenwood2 and Margaret Pinder1 'Medical Research Council Laboratories, Pajara, The Gambia; 2London School of Hygiene and Tropical Medicine, London, UK; 3International Vaccine Institute, Seoul, Korea; "Department of State for Health, The

Gambia; s University of Durham, Durham, UK;6 World Health Organization, Geneva, Switzerland

Abstract

A double-blind, community-randomized, placebo-controlled trial was conducted in a rural area of The

Gambia between June and December 1999 to test whether a reduction in the infectious reservoir can

reduce malaria transmission. Overall 14 017 (85%) individuals living in the study area were treated with

either placebo or sulfadoxine-pyrimethamine (SP) combined with a single dose of artesunate (AS).

Following the mass drug administration (MDA) 1375 children aged 6 months to 10 years were kept

under surveillance for clinical malaria in 18 villages throughout the 1999 malaria transmission season.

During a 20-week surveillance period 637 episodes of malaria were detected. The mean incidence rate

was 2.5/100 child-weeks in the placebo villages, and 2.3/100 child-weeks in villages that received the SP +AS. The mean rate ratio, adjusted for individual and village-level covariates, was 0.91 (95% CI

0.68-1.22, P= 0.49). During the first 2 months of surveillance, the malaria incidence was lower in

treated villages. After 2 months the incidence was slightly higher in the MDA group but this was not

statistically significant. Overall, no benefit of the MDA could be detected. The reason for die absence of

an impact on malaria transmission is probably the very high basic reproductive number of malaria, and

the persistence of mature gametocytes, which are not affected by AS treatment.

Keywords: malaria, Plasmodiumfakiparum, chemotherapy, sulfadoxine-pyrimethamine, artesunate, Africa

Introduction

In sub-Saharan Africa it has been estimated that

more than 200 million individuals suffer from malaria

attacks annually, of whom one million die (Snow et al.,

1999). In addition to causing human suffering, malaria

takes its toll through the costs of treatment and lost

labour. The damage to the economies of 31 African

countries caused by malaria has been estimated at

US874 billion between 1980 and 1995 (Gallup & Sachs, 2001). By discouraging foreign investment and

tourism, interrupting education and impairing child

development, malaria jeopardizes future economic

growth. Alternative malaria control strategies are ur

gently needed.

Following the introduction of artemisinin derivatives

for case management in Thailand, it was observed that

malaria transmission dropped by over 40% in some

areas (Price et al., 1996). A reduction in gametocyte

prevalence following the institution of first-line treat

ment with artemisinin derivatives has been suggested as

one possible explanation for this success. This well-

documented reduction in gametocyte prevalence and

the gametocyte reservoir (Meshnick et al., 1996) could

be used as a malaria control strategy in sub-Saharan

Africa. However, in contrast to Thailand, in the malar

ia-endemic countries of sub-Saharan Africa many

malaria infections are asymptomatic and the majority

of Plasmodium falciparum infections remain untreated

(von Seidlein et al.3 2002). In addition, none of the

countries in sub-Saharan Africa have the infrastructure

of Thailand's malaria control programme or are able

to assure prompt diagnosis and same day treatment

(Wongsrichanalai et al., 2000). In The Gambia, case

management alone will treat only a fraction of the

gametocyte carriers. In contrast, mass administration of an artemisinin derivative irrespective of disease status

might reduce the incidence of P. falciparum infections.

Indirect mass administration of antimalarials such as

Address for correspondence: Lorenz von Seidlein, Inter

national Vaccine Institute, Kwanak, P.O. Box 14, Seoul

151-600, Korea; phone +82 2 872 2801, fax +82 2 872 2803,

e-mail lseidlein@ivi.int

the addition of chloroquine to salt (Pinotti's method)

has been associated with the emergence of antimalarial

resistance (Payne, 1988). In contrast, direct mass ad

ministration has not been linked to die emergence of

antimalarial resistance. In sub-Saharan Africa, direct

mass administration of antimalarials was used as early

as 1931 (Barber et aL, 1932). Programmes using direct

mass administration of antimalarials in Zanzibar and

Tanzania did not have any impact on malaria, but in

Uganda, Nigeria, India, Malaysia and Indonesia direct

mass administration of antimalarial drugs had a trans ient impact on malaria transmission (De Zulueta et al,,

1964; Singh et al., 1968; Dola, 1974; Molineaux &

Gramiccia, 1980; McCormack & Lwihula, 1983; Hii

et al., 1987; Doi et al., 1989). The administration of

chloroquine and primaquine without other control

measures to more than one million Nicaraguans in

November 1981 probably prevented thousands of cases

of malaria but ultimately had no impact on the trans

mission of P. falciparum (Garfield & Vermund, 1983;

Garfield, 1999). One malaria control programme using

insecticide-impregnated bednets, larvivorous fish and

multiple rounds of mass drug administration (MDA)

succeeded in eliminating malaria from Aneityum,

Vanuatu (Kaneko et al., 2000).

During a randomized, double-blind, controlled trial

conducted in Gambian children in 1998, it was found

that the combination of sulfadoxine-pyrimethamine

(SP, Fansidar®) with either three doses or one dose of artesunate (AS), a water-soluble artemisinin derivative,

not only rapidly cleared asexual P. falciparum, but also

reduced the incidence and density of gametocytaemia

compared to treatment with SP alone (von Seidlein

et al., 2000). It was hypothesized that mass administra

tion of an artemisinin derivative at the nadir of malaria transmission might reduce, at least transiently, the

gametocyte reservoir in The Gambia, where malaria is

highly seasonal. The malaria incidence is highest be

tween September and November following the rainy

season and reaches its low point in June, at the end of

dry season (Greenwood & Pickering, 1993). Following

die onset of the rainy season and the rapid proliferation

of the vector population, the remaining gametocyte

Article number = 020212

L. VON SEIDLEIX ETAL.

carriers are thought to be responsible for igniting the

next malaria season. The potential benefit of a reduc

tion in malaria transmission is not limited to the indivi

dual who takes part in intervention but all individuals living in the treated community. To evaluate in a

statistically meaningful fashion the effect of an inter

vention aimed at reducing malaria transmission, such

as MDA or the evaluation of a transmission-blocking

vaccine requires, therefore, a cluster-randomized study

design. To test the hypothesis that MDA can reduce or

at least delay transmission in The Gambia we rando

mized 18 villages in The Gambia to receive either

placebo or SP and single-dose AS, which was given just

prior to the malaria transmission season.

Methods

A double-blind, placebo-controlled, cluster-

randomized trial was conducted in a 275 km2 rural area of The Gambia to the east of Farafenni (13°28'N,

16°34'W) between June and December 1999. The rural population lives in discrete villages, and no human

habitation was found outside the villages, thus the

village was used as a unit of randomization. Villages

can be as close as 2 km to each other. Travel of infected

humans or infective mosquitoes between untreated and

treated villages could introduce infections into treated villages and compromise a trial in which villages were

randomized to control or treatment groups. Thus, in

addition to randomized villages where the effect of the

intervention was measured, all inhabitants of the 24

non-randomized villages in the study area were treated

with SP and AS so as to minimize possible dilution of

the effect of the intervention (Fig. 1).

Intervention

Following discussions at the national and district

level, members of the government district health team,

accompanied by members of the study team, explained

the purpose and methods of the study and answered

questions during meetings open to all villagers. The

village elders deliberated in the presence of the village

chief (alkafo) whether to participate in the proposed

study. The consent of the village to participate in the

study was given by the alkalo. At the time of drug

administration, each participant gave verbal consent

which was recorded by a translator and a fieldworker who signed a consent form.

Each individual received (i) SP + AS or (ii) a placebo

identical to SP plus pyridoxine as an AS placebo.

Adults received three tablets of SP (500 mg sulfadoxine

and 25 mg pyrimethamine; Cosmos, Nairobi); children

received half a tablet of SP if their bodyweight was

< 10 kg and an additional quarter tablet for every 5 kg

increment in weight. A placebo (Cosmos) which had

an identical physical appearance to SP was used as a

comparator for this antimalarial. In addition to SP,

adults received four tablets of AS (50 mg; Sanofi,

Gentilly) and children received 4 mg AS per kg body-weight. Pyridoxine tablets (25 mg; Chanelle, Lough-

rea) which had a similar but not identical appearance to

AS were used as the comparator for AS. Women who

thought they were pregnant and children aged

< 6 months were excluded from the trial.

Villagers were asked to come on a specified day to a

central location in the village. All study drugs were

administered under direct supervision. Participation

was recorded in a census list. Individuals on the census

list who had not participated were visited 2 weeks later

and offered the study drugs. Drug administration

started on 1 June 1999 and was completed by 28 June

1999.

The drugs allocated to each of the 18 surveillance

villages were delivered to die study site in identical

containers. One nurse administered the drugs in the

surveillance villages and was aware of the identity of the

drugs. Following the completion of drug administra

tion, the nurse left the study area. Neither study per

sonnel nor the study population were aware which of

the 18 villages under surveillance had received placebo.

In the surrounding 24 villages, SP combined with AS

was distributed in an open fashion.

Impact evaluation Study villages were surveyed weekly during 20 weeks

^KGEYENSANJAL

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TAIBOTtJ O if KATABA MBAP 9NYANGKUNDA

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THE GAMBIA

DISTRICT CAPITAL

• SURVEILLANCE VILLAGE: TREATED

O SURVEILLANCE VILLAGE: PLACEBO

if TREATED VILLAGE: NOT INCLUDED IN SURVEILLAN

MAIN ROAD

Fig. 1. Map of the study area. The study was conducted in an 275 km2 area 10-30 km east of Farafenni, The Gambia (13°28'N; 16°34'W). Villages were randomized to receive sulfadoxine-pyrimethamine (SP) combined with artesunate (AS) (filled circle) or

placebo (empty circle). To minimize dilution of the intervention, villages which were not randomized received SP + AS (stars).

MASS DRUG ADMINISTRATION AND MALARIA INCIDENCE

of the malaria season to assess the effect of the interven

tion. The incidence rate of clinical malaria in children

aged < 11 years was chosen as the primary endpoint.

A malaria episode was defined as a temperature of

37.5 °C or higher in the presence of P. fakiparum parasitaemia > 5000/(oL (Molineaux & Gramiccia,

1980; Alonso et al.> 1993). Secondary endpoints were

(i) the prevalence of P. fakiparum infections in adults

measured during weekly surveillance; (ii) the preva

lence of malaria anaemia, defined here as haematocrit

< 33% (Behrman et als 1996) and parasitaemia in children at the end of the malaria transmission season

(November); and (iii) malaria-related mortality in chil

dren.

We assumed that the mean incidence of malaria

among children aged < 11 years would be about one

attack per child during a transmission season of about

20 weeks (August to December), with a coefficient of

variation between pair-matched villages of 0.25 (Hayes

& Bennett, 1999). We assumed that 20% of children

would be lost to follow-up by the end of the study,

losses occurring at a constant weekly rate. Recruiting a

mean of 70 children per village, a trial with 18 villages

randomized in matched pairs would have 90% power

(using a significance level of 0.05) to detect a 40%

reduction in incidence of malaria (Smith & Morrow,

1996).

A dejure census was taken or updated in the 42 study

villages in the study area. In the 18 surveillance villages,

spleen rate, haematocrit and parasite prevalence were

obtained for all children aged < 11 years prior to the

MDA to allow matching of villages. The census and the

baseline studies were completed in May 1999. To

reduce the variability in malaria incidence, villages were

matched into nine pairs based on population size,

spleen rate in children aged < 5 years, and distance

from the river (Table 1). Distance from a vector reser

voir such as a river can be used as a proxy measure of

exposure to the vector (Lindsay et a/., 1993a). Which

village in each pair was to receive the intervention and

which the placebo was randomly determined.

Surveillance started on 20 July 1999 and ended on 2

December 1999. All children in the 18 surveillance

villages were visited weekly to detect malaria attacks.

Their axillary temperature was recorded with a digital

thermometer. A blood film was taken if the tempera

ture was *s 37.5 CC. In addition to the active surveil

lance, staff at the health care centres (HCCs) in

Ngeyen Sanjal and Farafenni recorded visits from in

dividuals residing in the study villages. At the HCC,

the name and the village of the patient were recorded as

well as their temperature, results of a rapid malaria test (ICT), and the treatment administered to the patient.

During a single large cross-sectional survey undertaken

during the 18th week of surveillance, all children in the

18 villages were asked to provide a finger-prick blood sample for a blood film and haematocrit. When a child

in a study village died, a verbal autopsy was conducted

(Smith & Morrow, 1996). The questionnaire was re

viewed by three experienced physicians and a consen

sus was obtained on the likely causes of death. To

measure P. fakiparum prevalence, a blood film was

obtained from 10 individuals aged > 14 years in each village every week. Eligible individuals were visited

following a computer-generated random order. Once

all individuals in a village were visited a new list was

provided. Thus, the number of finger-prick samples per

individual was kept to a minimum. Blood films were collected daily from the field and results were returned

the following evening. Malaria cases were treated with

chloroquine in the field according to government

guidelines or were referred to the nearest health centre.

The surveillance for adverse events following the drug

administration had an active and a passive component.

Study participants were encouraged by study staff at

the time of drug distribution to inform a member of the

study team about adverse events following drug admin

istration. One month after drug administration, 90 randomly selected villagers from the 42 study villages

were asked whether they had experienced any symp toms following the MDA and, if" so, how long these symptoms had lasted.

Laboratory methods

Thick blood films were left to dry for 12-24 h,

Giemsa-stained and examined under 1000-fold magni fication. Parasite counts were noted per high power

field and 50 fields were counted before a slide was declared negative. Parasite density was estimated as

suming that one parasite per high power field equals 500 parasites/uL (Greenwood & Armstrong, 1991). Each slide was read by the same two experienced

microscopists; discrepancies were reviewed by a third senior microscopist whose reading was considered final

and entered in the database. Parasites other than P. falciparum were not detected. Haematocrit was meas

ured by microhaematocrit centrifugation.

Entomology and meteorology

Mosquitoes were caught in four huts in four study

villages (Yallal, Kumbija, Kani Kunda and Bambali).

Only huts in which one individual slept and no insecti cide-treated bednet was used were included. In each village four huts were randomly selected. Light-trap catches were conducted once a week from 19:00 in the

evening to dawn of the following morning. CDC minia ture light-traps were hung 1.5 m above the ground near

the head end of the bed. The individual sleeping in the

room closed the trap at dawn and switched off the electricity. The traps were collected and returned to

the field station on the same morning. The contents of

the traps were transferred into a labelled container which was stored at -20 °C in a freezer. Female anophelines were identified based on morphological characteristics (Gillies & DeMeillon, 1968). Precipi

tation was measured at Yallal meteorological station using a standard pluviograph.

Data analysis

The incidence rates (number of attacks divided by

the total time at risk) for MDA and placebo villages

were compared using the paired t test, after transform

ing rates to logarithms. A 95% CI was calculated for

the geometric mean of the pair-wise rate ratios. The

analysis was first done unadjusted and secondly after

adjusting for the effects of covariates. Incidence of malaria increased with increasing age up to 3-4 years

and then decreased in older age groups, and was also

associated with the baseline spleen rate in the village

and village size, both matching variables but included

as covariates, as some villages were imperfectly

matched. To examine the effects of these variables on

the rate ratio estimate, we calculated an aggregated

residual for each village, defined as the ratio of the

observed number of malaria cases to the predicted

number of cases from a Poisson regression model that

included the covariates, but excluded the intervention

effect (Bennett et al.} 2002). The effect of age was

modelled as a quadratic term. The ratio of the aggre gated residuals for the villages in each pair provided

covariate-adjusted estimates of the rate ratios, from which a geometric mean and 95% CI was calculated. In a secondary analysis, protective effects of malaria

treatment were allowed for by deducting 2 weeks from

the time at risk following treatment with chloroquine, SP or antibiotics with antimalarial action. In a third

analysis, additional cases diagnosed at the health centre were included.

Coverage was estimated from the census data. The de jure population excluding individuals who had

moved away permanently and infants aged < 6 months

made up the denominator. All individuals who were

Table 1. Malaria-related baseline characteristics and summary of follow-up in nine matched village pairs in The Gambia, 1999

MASS DRUG ADMINISTRATION AND MALARIA INCIDENCE

observed taking the study drugs were included in the

numerator. Infants aged < 6 months were not included

since they were protected by maternally-acquired immunity, had not yet been exposed to a malaria

transmission season and were less likely to carry game-

tocytes. Pregnant women are at risk of being gameto-cyte carriers and were included in the denominator, but

were not eligible to receive medication due to safety

concerns.

Analyses were performed using Stata 7 (Stata Corp.,

College Station, TX, USA). The study was approved by the ethics committees of the Gambia Government/ Medical Research Council and the London School of Hygiene and Tropical Medicine, UK.

Results

Coverage achieved with mass drug administration

Overall, 14017 of 16442 (85%) individuals living in

the study area were treated with either SP + AS or

placebo. In the 18 surveillance villages 3404 of 3829 (89%) individuals were treated (range 82-98%). In the

surrounding villages the mean coverage was 84%

(range 60-100%). The most frequent explanations why 2425 individuals did not take the medication were

travel at the time of distribution (1190; 49%), refusal

(825; 34%) and pregnancy (89; 4%). No explanation

was available for 321 (13%) individuals who did not take the medication. The reasons for not taking part in

the MDA were similar in surveillance and surrounding villages. Coverage was inversely related to the size of the village (Spearman's r2 = 0.42; P= 0.006).

Baseline comparability

Villages which received SP + AS did not differ appre

ciably from control villages in demographic character istics or in characteristics associated with malaria transmission (Table 2).

Meteorological and entomological observations The rains started in the week that MDA began. By

the time MDA was completed, 117 mm of rainfall had been measured (Fig. 2). The anopheline population

had increased to a mean catch of 55 anophelines/night during the last week of MDA. In the following 2 weeks the anopheline population increased eight-fold to 435 mosquitoes/night.

Compliance with surveillance

The parents of 1388/1482 (94%) children gave con sent for their children to participate in the 20-week

surveillance programme. Between 1071/1388 (77%)

and 1260/1364 (91%) resident children were examined

Table 2. Baseline characteristics in 18 study villages in The Gambia, 1999

Drug

Characteristic8 Placebo

n = 9

MDA

Population/village

Population aged < 6 years (%)

Distance to the river (km)

Mean spleen rateb (%) Coverage of study drugs (%)

P. faldparum prevalence in May0 (%)

Gametocyte prevalence in May0 (%)

Haematocrit in May' (%)

Percentage anaemic in Mayc>d (%)

187.3 (74-340)

35.9 (15-67)

4.9 (3.0-9.0)

13.7 (0.0-27.6)

89.6 (81.8-92.9)

42.9 (12.9-60.9)

3.6(0.0-17.6)

33.1 (30.5-34.8)

61.2(43.5-80.8)

218.8 (59-460) 50.0 (14-92)

5.2 (3.0-8.5)

18.0 (2.6-58.0)

90.8(81.3-98.3)

41.6 (15.5-72.2)

1.9 (0.0-7.8)

33.7 (31.3-35.1)

65.4 (46.9-82.6)

'Mean of the village means (range).

bSpleen rate = number of children with palpable spleen/number of children examined. cIn children aged < 5 years.

dAnaemia was defined as haematocrit < 33%.

5 6

Weeks

10

80-0

70-0

60-0

50-0

40-0 I

30-0 f§

20-0

100

00

Fig. 2. The rainfall and the prevalence of anophelines in relation to mass drug administration in The Gambia, 1999. The mean number of catches in four villages (Bambali, Kumbija, Kanikunda, and Yallal) is shown.

L. VON SEIDLEIN ETAL.

weekly by fieldworkers and 24019 of 27 760 (87%)

planned visits took place. The 203/1388 (15%) chil

dren who missed two or more consecutive visits did not differ significantly in age, gender or their home village

from children who had missed one or no consecutive visits during the 20 weeks of follow-up. Of the 3600 slides that should have been obtained from adults,

3138 (87%) were collected. Compliance with surveil lance is summarized in Table 1. Compliance was lowest

in village pair 9, Daro Rahman and Misira, due to

political as well as logistical problems. Analyses which

omitted these two villages yielded similar results as the analyses including the two villages.

Impact on malaria incidence in children

During 20 weeks of surveillance, 637 episodes of

malaria were detected; the mean incidence rate was 2.5/100 child-weeks in the placebo villages, and 2.3/

100 child-weeks in villages that received SP + AS. The

mean rate ratio, adjusted for individual and village-level

covariates, was 0.91 (95% CI 0.68-1.22, P=0.49),

(Table 3). Similar results were obtained when 2 weeks

were deducted from the time at risk after each antima-

larial treatment (adjusted mean rate ratio = 0.88, 95%

CI 0.69-1.11). An additional 77 cases were diagnosed

at the health centre, mainly from villages close to the

clinic. When these cases were included, similar results

were again obtained (mean rate ratio = 1.0, 95% CI

0.79-1.28).

During the first 6 weeks of surveillance (20 July to 31

August 1999) the mean malaria incidence rate in trea

ted villages was 0.54 attacks/100 child-weeks compared

to 1.35 attacks/100 child-weeks in villages which had

not received treatment (P= 0.009, Table 4). The dif

ference in incidence rates decreased during the second month and during September the incidence rate was higher in villages which had been treated with SP + AS than in control villages (P= 0.17). Incidence rates were similar during the remainder of the surveillance period. The overall incidence rate of malaria was 2.4/100

person-weeks at risk, with a coefficient of variation of

the true incidence rates within village pairs of 0.19

(Hayes & Bennett, 1999). Since the intervention effect was negligible, this approximates to the natural varia tion in village incidence rates. Using these estimates to calculate the trial's power, the pair-matched trial had

over 90% power to detect a 30% reduction in malaria incidence, using a significance level of 0.05. The esti

mate of the coefficient of variation among all the villages (ignoring pair-matching) was 0.39. In the ab

sence of pair-matching the trial would have had 43%

power to detect a 30% reduction in malaria incidence.

Impact on the prevalence o/P. falciparum infections in adults

Overall the prevalence of P. falciparum infections was 17% (95% CI 13-22%) in the treated villages and 19%

(95% CI 15-23%) in control villages (P= 0.63). Dur ing the first month of surveillance, the mean prevalence

of P. falciparum infections in adults was significantly

lower in the intervention villages 3% (95% CI 1-6%)

than in the control villages 13% (95% CI 9-17%; P= 0.003). By the third month of surveillance, the

prevalence of P. falciparum infections was the same in

Table 3. Incidence rates of malaria in children and incidence rate ratios in 18 study villages in The Gambia, 1999

AID A, mass drug administration.

'Adjustment for the covariates of age, village baseline spleen rate, and village population size.

Table 4. Malaria incidence rates in each month of surveillance, The Gambia, 1999

MDA, mass drug administration.

'Geometric mean rate ratio, adjusted for age, spleen rate and village size. In some months, incidence was zero in some smaller

villages; the village pair was excluded when the rate ratio for that month was calculated (one village pair in Jul/Aug, Sep and Oct; two village pairs in Nov).

bWilcoxon matched pairs signed-rank test was used to compare adjusted incidence rates between MDA and placebo within village pairs, rather than the r-test on log-transformed values, because of zero incidence in some small villages.

MASS DRUG ADMINISTRATION AND MALARIA INCIDENCE

treated and untreated villages. During the fourth

month of surveillance more P. fcdciparum infections were observed in the treated villages compared to con trols (P= 0.10).

Impact on parasitaemia and anaemia in children at the end of the malaria season

In a cross-sectional survey 5 months after MDA 1036/1364 (76%) of children aged < 11 years gave a

finger-prick blood sample. There was no significant

difference in haematological or parasitological para meters between the children resident in the interven

tion or control villages (Table 5). There was, however, a trend for more frequent P. falciparum infections in villages which had received treatment (66%) than in

placebo-treated villages (55%; P= 0.11).

Impact on malaria related childhood mortality

In the nine villages treated with SP + AS, six children aged < 11 years died during the 5 months of surveil

lance. Verbal autopsies suggested that five had died of

malaria. In the placebo-treated villages, six children

died during the surveillance period; three of these

deaths were likely to have been due to malaria (P=0.64).

Surveillance for adverse effects

Passive surveillance for adverse events found one

individual who complained of pruritus after taking

SP + AS. The symptoms resolved spontaneously within 48 h. Active surveillance found that 25 of 75 indivi duals (33%) who took SP + AS remembered one or

more complaints within 2 d of taking the drug, includ

ing dizziness (13/75; 17%), fever (6/75; 8%), diarrhoea

(5/75; 7%), vomiting (5/75; 7%) and itching (4/75;

5%). In contrast two of 15 individuals (13%) who had received placebo remembered complaints (P= 0.12).

Discussion

We conducted the first double-blind, placebo-

controlled, community-randomized trial to evaluate the

effect of an antimalarial mass administration. We failed

to detect any overall benefit of mass administration of a

single dose of SP combined with AS. We measured as the primary endpoint of the trial the impact of the

intervention on die incidence of malaria attacks in

children. As the majority of malaria episodes in adults are asymptomatic we measured the prevalence of para

sitaemia in adults. Neither was reduced over the whole

malaria season. An initial reduction in malaria inci

dence and prevalence of P. falciparum infections dis

appeared after die second month of surveillance and

a rebound in the incidence and the prevalence of

P. falciparum infections was observed.

The time required, following a reduction in gameto-

cyte prevalence, until rates of infection in treated and

untreated villages become equal depends on the basic reproductive number (Ro) (Anderson & May, 1991) of

the infection. At the end of the dry season a small

proportion of the population (10-20%) remain asymp

tomatic carriers of parasites and approximately 1 -2%

of the population harbour gametocytes (Molineaux & Gramiccia, 1980). Following the mass administration of SP and AS few gametocyte carriers could have remained in the treated villages as the effect of artemisi-nins on gametocyte numbers is substantial. However, potential exposure to infective mosquitoes in the study villages is high, varying between villages from 0 to 165 infective bites per person per season (Bogh, 1999). In the presence of abundant, highly susceptible and mo

bile vectors a small number of gametocyte carriers seem to suffice to start the next malaria season.

Mosquitoes can travel several kilometres from the major breeding sites on the landward edge of die seasonally flooded river plain (Thomas & Lindsay,

2000). Thus, dispersion of" mosquitoes throughout the study area could not be avoided. The lack of commun ity protection has been observed in large-scale bednet trials in The Gambia where diere was no overall reduc tion in the number of infective mosquitoes in inter vention villages compared to control villages (Lindsay etal.t 1993b).

The MDA covered 89% of the study population. It is doubtful if higher coverage could be achieved during

routine public health campaigns outside a research setting. Even a complete coverage of all villagers can

not prevent the importation of infection by travellers.

We attempted to minimize die importation of gameto cytes into the study villages, and thus a dilution of die

effect of the intervention, by extending the drug admin

istration to the surrounding villages. However, we had no control over individuals travelling into the study area from further away.

The antimalarial drugs were administered at the very

end of the dry season and MDA was completed by the time of the rapid expansion of the vector population.

An earlier administration of the drugs could have

resulted in a further reduction of the gametocyte reser voir but at the price of a lower coverage as many

villagers return to their farms only at the very end of the dry season for a period of intense agricultural activity.

A combination of a single dose of SP with a single dose of AS was chosen for the MDA as it has been

shown that this combination significantly reduces die gametocyte incidence and density compared to SP

alone (von Seidlein et a/., 2000). It is also highly effec

tive against asexual parasitaemias. No significant differ ence in die effect on gametocytes was detected between

three doses and a single dose of AS in a study con

ducted in Gambian children in 1998. However mem

brane feeding studies conducted in 1999, have shown that a small proportion of surviving gametocytes can

infect mosquitoes and treatment with three doses of AS

results in significantly lower infection rates in mosqui

toes than single dose AS (Targett et al., 2001). The 8-aminoquinolines including primaquine and tafenaquine

have a gametocytocidal effect, however their potential for haemolysis in glucose-6-phosphate dehydrogenase-deficient individuals raises the issue of whether or not it would be appropriate to use them for MDA.

The study design, extending drug administration to surrounding villages, could have resulted in an overall

Table 5. Haematological and parasitological parameters in children aged < 11 years in November 1999 in study villages in The Gambia

Parameter* Placebo MDA

Asexual parasitaemia

Gametocytaemia

Packed cell volume

Percentage anaemic in November0

Difference in PCV between May and November

55.0% (40.2-69.9%) 3.4% (1.1-5.7%)

31.4% (30.1-32.7%)

53.3% (40.8-65.9%)

2.0% (0.5-3.5%)

65.6% (53.7-77.4%) 0.11 3.7% (0.7-7.2%) 0.86

32.2% (31.5-33.0%) 0.28

44.5% (37.2-51.8%) 0.22 1.7% (0.3-3.1%) 0.68

'Mean of percentages for each village (range).

br test (paired). 'Anaemia was defined as haematocrit < 33%.

L. VON SEIDLEIN ETAL.

reduction of malaria attacks and P. falciparum infec

tions throughout the study area. At very low rates of

attack and infection it might have been impossible to

recognize an effect. However the malaria season of 1999 was unusually intense and long, resulting in a

higher prevalence of P. falciparum infections in the

study area than in the preceding year.

While the intervention failed to reduce malaria trans

mission it appears that the intervention did not cause

any severe adverse events which could be recalled 1

month later. One-third of the individuals who had

received SP + AS remembered transient complaints,

including dizziness, fever, diarrhoea, vomiting and itch

ing; none of them severe. Nevertheless, these events are likely to influence compliance if multiple drug doses were to be used. Active and passive surveillance de

tected 287 inadvertent fetal exposures to AS and SP

(Deen et aL, 2001). No teratogenic effect was found in

any of the exposed infants.

Attack rates and parasite prevalence were initially

lower in treated villages. A similar temporary benefit

likely to be due to the prophylactic effect of SP has been observed following the intermittent presumptive

treatment of Tanzanian infants with SP (Schellenberg et al.y 2001). During the third month of surveillance,

the attack rates and during the fourth month of surveil

lance the parasite prevalence were higher in the treated

villages. Such rebound has been observed following the use of chemoprophylaxis in malaria-endemic regions

(Fryauff«a/., 1997; Menendez era/., 1997). Concomi

tant immunity, depending on the presence of subclini-

cal P. falciparum infections, could have been ablated by

the combination therapy and exposed treated indivi

duals to a higher risk of detectable parasitaemia. But as

neither the rebound in incidence nor in prevalence of

P. falciparum infections reached statistical significance, an apparent rebound could have been due to chance.

We have shown in a double-blind, randomized trial that the inclusion of an artemisinin derivative in a single

MDA had no impact on malaria transmission in a rural

area of The Gambia. The lack of success of our inter vention is most likely to be due to the very high basic

reproductive number of malaria in the study area.

Importation of gametocytes, migration of infective

mosquitoes, and non-compliance are formidable bar

riers to the success of MDA in highly endemic regions,

such as rural Gambia. The combination of MDA with

large-scale vector control measures may be more pro

mising. However the Garki project should serve as a

warning (Molineaux & Gramiccia, 1980). Under

favourable circumstances, including well-qualified staff

and good supervision the combination of mass admin

istration of sulfalene-pyrimethamine with residual

spraying of propoxur failed to interrupt malaria trans

mission for any length of time. MDA may be more

successful in highland areas in Africa where exposure to

malaria vectors is low and the dispersal of vectors is

more limited.

Acknowledgements

Foremost we would like to thank the residents in the study

area for taking the time to participate in this trial. We are grateful to the microscopists, fteldworkers and data entry staff

who dedicated extended periods of time to this project. We

thank Ric Price and Nick White for providing suggestions,

Hilton Whittle for generous advice and safety monitoring, Bob

Snow for his advice, Pam Njie for pharmaceutical advice and

support, Tumani Corrah for clinical advice, Claus Begh, Sian

Clark, Paul Emerson, Robin Bailey, Umberto D'Alessandro,

Ismaela Abubakar and Shabbar Jaffar. We thank Elf Sanofi,

France for the generous donation of AS tablets.

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Received 19 June 2002; revised 17 September 2002;

accepted for publication 25 September 2002