Clin Infect Dis. 2007 Zongo 1453 61

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CSE THEME ARTICLE CID 2007:45 (1 December) 1453

C S E T H E M E A R T I C L EM A J O R A R T I C L E

CSE Global Theme Issue on Poverty and Human Development

Randomized Comparison of Amodiaquine plus

Sulfadoxine-Pyrimethamine, Artemether-Lumefantrine,and Dihydroartemisinin-Piperaquine for the Treatmentof Uncomplicated Plasmodium falciparum Malariain Burkina Faso

Issaka Zongo,1 Grant Dorsey,2 Noel Rouamba,1 Christian Dokomajilar,2 Yves Sere,1 Philip J. Rosenthal,2 and Jean Bosco Ouedraogo1

1Institut de Recherche en Sciences de la Sante, Bobo-Dioulasso, Burkina Faso; and 2Department of Medicine, University of California, San Francisco

Background. Combination antimalarial therapy is advocated to improve treatment efficacy and limit selection of drug-resistantparasites. We compared the efficacies of 3 combination regimens in Bobo-Dioulasso, Burkina Faso: amodiaquine plus sulfadoxine-pyrimethamine, which was recently shown to be highly efficacious at this site; artemether-lumefantrine, the new national first-line antimalarial regimen; and dihydroartemisinin-piperaquine (DP), a newer regimen.

Methods. We enrolled 559 patients 6 months of age with uncomplicated Plasmodium falciparum malaria and randomizedthem to the 3 regimens. We analyzed the risk of recurrent parasitemia by day 28 and day 42, both unadjusted and adjusted byPCR methods to distinguish recrudescence and new infection.

Results. Complete data were available for 517 (92.5%) of the enrolled subjects. Early treatment failures occurred in 5 patientstreated with amodiaquine plus sulfadoxine-pyrimethamine and in 2 patients each treated with the other regimens. The day 28risk of recurrent parasitemia, unadjusted by genotyping, was significantly higher for patients receiving artemether-lumefantrinethan for patients receiving amodiaquine plus sulfadoxine-pyrimethamine (20.1% vs. 6.2%; risk difference, 13.8%; 95% confidenceinterval, 7.0%20.7%) or dihydroartemisinin-piperaquine (20.1% vs. 2.2%; risk difference, 17.9%; 95% confidence interval, 11.6%24.1%). Similar differences were seen for children !5 years of age (54% of the study population) and when outcomes wereextended to 42 days. Significant differences were not seen between outcomes for patients receiving amodiaquine plus sulfadoxine-

pyrimethamine and outcomes for those receiving dihydroartemisinin-piperaquine. Recrudescences were uncommon (occurringin !5% of patients) in all treatment groups. No serious adverse events were noted.

Conclusions. All regimens were highly efficacious in clearing infection, but considering the risks of recurrent malaria aftertherapy, the amodiaquine plus sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine regimens were more efficaciousthan the artemether-lumefantrine regimen (the new national regimen in Burkina Faso) for the treatment of uncomplicated P.falciparum malaria.Trial registration. ISRCTN.org identifier: ISRCTN94367569.

The control of malaria is jeopardized by the increasing prev-

alence of drug-resistant disease [1]. A consensus has emerged

that uncomplicated Plasmodium falciparum malaria should be

treated with artemisinin-based combination therapies (ACTs)

to improve efficacy and limit the selection of drug-resistant

parasites [2, 3]. All ACTs include a potent artemisinin analogue

and a longer-acting partner drug. The most widely adopted

Received 1 May 2007; accepted 11 June 2007; electronically published 22 October 2007.

Reprints or correspondence: Dr. Philip J. Rosenthal, Box 0811, San Francisco General

Hospital, University of California, San Francisco, CA 94143 ([email protected]).

Clinical Infectious Diseases 2007;45:145361

2007 by the Infectious Diseases Society of America. All rights reserved.

1058-4838/2007/4511-0009$15.00

DOI: 10.1086/522985

ACT in Africa is artemether-lumefantrine, which has recently

been selected as first-line therapy by 20 countries [47] and

was chosen for this purpose by Burkina Faso in 2005 [8]. How-

ever, as is the case in many countries, routine provision of

artemether-lumefantrine for uncomplicated malaria has not

been widely implemented in Burkina Faso because of limita-tions on resources and drug availability.

In West Africa, where resistance to older regimens is less

common than it is in other areas, the combination of amo-

diaquine plus sulfadoxine-pyrimethamine (AQSP) has shown

excellent antimalarial efficacy [911]. AQSP is inexpensive and

provides extended drug levels after treatment, offering a po-

tential advantage over some ACT regimens. Indeed, when com-

pared with artemether-lumefantrine therapy in Burkina Faso,


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1454 CID 2007:45 (1 December) CSE THEME ARTICLE

treatment with AQSP provided similarly strong activity against

infecting parasites but better protection against new infections,

such that the rate of recurrent malaria within 28 days after

therapy was significantly lower with the AQSP regimen [7].

Treatment with dihydroartemisinin-piperaquine, a newer

ACT, has shown excellent antimalarial efficacy in available trials

[1218] and appears to offer advantages over artemether-lu-

mefantrine, including simpler dosing and the longer half-lifeof piperaquine, compared with that of lumefantrine. We com-

pared the antimalarial efficacy and safety of AQSP, artemether-

lumefantrine, and dihydroartemisinin-piperaquine for the

treatment of uncomplicated malaria in Bobo-Dioulasso, Bur-

kina Faso.

PATIENTS AND METHODS

Study site. Subjects were recruited from 3 government health

dispensaries in Bobo-Dioulasso, in western Burkina Faso. In

this region, malaria is holoendemic, with transmission prin-

cipally occurring during the rainy season (MayOctober). Thestudy was approved by the institutional review boards of the

Institut de Recherche en Sciences de la Sante/Centre Muraz

(Bobo-Dioulasso, Burkina Faso) and the University of Cali-

fornia, San Francisco.

Patients. Consecutive patients with fever or a history of

recent fever were referred for a Giemsa-stained thick blood

smear, and those with a positive smear result were assessed by

study clinicians for the following inclusion criteria: age 6

months; weight 5 kg; fever (axillary temperature 37.5C)

or fever symptoms within the previous 24 h; absence of history

of serious adverse effects related to studymedications, including

sulfa allergy; no evidence of a concomitant febrile illness; pro-vision of informed consent by the patient or parents or guard-

ians, as well as the ability to participate in a 42-day follow-up;

no history of treatment with any antimalarial drug other than

chloroquine in the previous 2 weeks; no danger signs or evi-

dence of severe malaria [19]; P. falciparum monoinfection, with

a parasite density of 2000200,000 parasites per mL of blood;

and hemoglobin level 5.0 g/dL. Patients who satisfied the

inclusion criteria were randomized; those who were excluded

were referred to the dispensary staff for care. Patients were

excluded after randomization if slide reevaluation demon-

strated a parasite density or species outside of the inclusion

criteria or if the subject experienced repeated vomiting of studymedication on day 0.

Baseline evaluation, randomization, and treatment alloca-

tion. Randomized patients were assigned a study number,

interviewed and examined, and referred for treatment alloca-

tion by a study nurse not involved in enrollment or assessment

of treatment outcomes. Patients were randomly assigned on

the basis of a computer-generated code provided by an off-site

investigator to oral treatment with the 3 study regimens: (1)

artemether-lumefantrine (Coartem; Novartis) administered in

tablets containing 20 mg of artemether plus 120 mg of lu-

mefantrine at a dosage of 1 tablet (for patients weighing 514

kg), 2 tablets (for patients weighing 1524 kg), 3 tablets (for

patients weighing 2534 kg), or 4 tablets (for patients weighing

35 kg) twice daily for 3 days; (2) dihydroartemisinin-pipe-

raquine (Duocotexcin; Holleypharm) administered in tablets

containing 40 mg of dihydroartemisinin and 320 mg of pi-peraquine at a dosage of 6.4 mg of dihydroartemisinin and 51.2

mg of piperaquine per kg of body weight once daily for 3 days;

or (3) AQSP, consisting of amodiaquine (Flavoquine; Aventis)

administered at a dosage of 10 mg per kg of body weight on

days 0 and 1 and 5 mg per kg of body weight on day 2 plus

sulfadoxine-pyrimethamine (Fansidar; Roche) administered at

a dosage of 25 mg of sulfadoxine and 1.25 mg of pyrimethamine

per kg of body weight on day 0. Scored tablets were split and

crushed with water for young children. All treatments were

directly observed at the clinic or at home for evening doses.

The study was not blinded. Patients were observed for 30 min,

and doses were readministered if vomiting occurred; those with

repeated vomiting on day 0 were excluded from the study prior

to enrollment and were referred for treatment with quinine.

Paracetamol (10 mg per kg of body weight every 8 h) was

provided for treatment of febrile symptoms. Children with he-

moglobin levels !10 g/dL were treated according to Integrated

Management of Childhood Illness guidelines with ferrous sul-

fate for 14 days and antihelminthic treatment, if appropriate.

Follow-up procedures and classification of treatment out-

comes. Patients were asked to return to the clinic for follow-

up on days 1, 2, 3, 7, 14, 21, 28, 35, and 42 and at any time

that they were ill. Subjects who did not return for a scheduledappointment were visited at home. Each visit included com-

pletion of a standardized history form, a physical examination,

and, except on day 1, a fingerprick for thin and thick blood

smear and filter paper storage. Hemoglobin levels were assessed

on day 0 and either day 42 or the day of clinical failure. Thick

smears were assessed for parasite density and gametocytes. Thin

smears to determine speciation were performed for patients

who experienced clinical treatment failure after day 3. Patients

were followed up for 42 days, and their outcomes were assessed

according to World Health Organization (WHO) guidelines as

early treatment failure (defined as the presence of danger signs,

complicated malaria, or failure to adequately respond to ther-apy during days 03), late clinical failure (defined as the pres-

ence of danger signs, complicated malaria, or fever and para-

sitemia during days 442), late parasitological failure (defined

as asymptomatic parasitemia without clinical findings during

days 742), or adequate clinical and parasitological response

(defined as the absence of parasitemia throughout follow-up)

[20]. Secondary outcomes included the resolution of fever, par-

asite clearance, change in hemoglobin level, presence of ga-


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metocytes during follow-up, and the occurrence of adverse

events. Patients who experienced treatment failure receivedqui-

nine (10 mg per kg of body weight orally 3 times per day for

7 days). Patients with evidence of severe malaria or danger

signs (i.e., convulsions, lethargy, inability to drink or breast-

feed, repeated vomiting, or the inability to stand or sit because

of weakness) were referred for treatment with parenteral qui-

nine. Patients were excluded from the study during follow-upfor the use of antimalarial drugs outside of the study, serious

adverse events requiring a change in treatment, withdrawal of

informed consent, or loss to follow-up (defined as not being

located within 24 h during days 13 or within 48 h during days

442).

At each follow-up visit, study clinicians assessed patients for

adverse events and graded them according to scales from the

WHO and the National Institutes of Health. Adverse events

were defined as untoward medical occurrences, following In-

ternational Conference on Harmonization guidelines, and se-

rious adverse events were defined as experiences resulting in

death, life-threatening experiences, inpatient hospitalization,

persistent or significant incapacity, or medical or surgical in-

tervention to prevent a serious outcome.

Laboratory procedures. Blood smears were stained with a

2% Giemsa solution for 30 min. Positive screening smear find-

ings were reassessed at a central laboratory. Parasite densities

were calculated from thick smears as the number of asexual

parasites per 200 leukocytes (or per 500 leukocytes if the par-

asite density was !10 parasites per 200 leukocytes), assuming

a leukocyte count of 8000 leukocytes/mL. Smear findings were

considered to be negative when microscopic examination of

100 high-power fields did not reveal parasites. Counts wereperformed by 2 microscopists; discrepant readings were re-

solved by a third reader. Gametocytes were recorded as present

or absent. Thin blood smears performed on day 0 and on the

day of clinical failure were evaluated for parasite species. He-

moglobin levels were measured from finger-prick blood sam-

ples using a portable spectrophotometer (HemoCue).

Whenever blood specimens were collected, 4 drops were

placed onto filter paper, labeled, air-dried, and stored in sealed

plastic bags at ambient temperature. Parasite DNA was sub-

sequently extracted using Chelex (BioRad Laboratories) [21].

For patients experiencing treatment failure after day 6, parasites

collected at baseline and at the time of treatment failure weregenotyped in a stepwise fashion using msp-2, msp-1, and 4

microsatellites [22]. If, for any of the 6 loci, an allele was not

shared between day 0 and the day of recurrence, the infection

was classified as a new infection. If at least 1 allele was shared

between day 0 and the day of recurrence at all 6 loci, the

infection was classified as a recrudescence.

Statistical analysis. We hypothesized that the risk of re-

current parasitemia after 42 days would differ between the

group receiving the artemether-lumefantrine regimen and ei-

ther the group receiving AQSP or the group receiving dihy-

droartemisinin-piperaquine. On the basis of a prior study [7]

that had determined the risk of recurrent parasitemia to be

15% with artemether-lumefantrine therapy and 5% with AQSP

therapy, we calculated that 176 patients would be needed in

each treatment arm (allowing for a 10% loss to follow-up) to

detect a 10% difference in the rate of recurrent parasitemiawith a 2-sided type I error of 0.05 and 80% power.

Data were entered using Epi Info software, version 6.04 (Cen-

ters for Disease Control and Prevention), and were analyzed

using Stata software, version 8.0 (StataCorp). Efficacy and safety

data were evaluated using a modified intention-to-treatanalysis

that included all enrolled patients. Risks of recurrent parasi-

temia after 28 and 42 days (adjusted and unadjusted by ge-

notyping) were estimated using the Kaplan-Meierproduct-limit

formula. Data were censored for patients who did not complete

follow-up and, for adjusted outcomes, for new infections or

infections due to agents other than P. falciparum. Comparisons

of treatment efficacy were made using risk differences withexact95% CIs. Categorical variables were compared using x2 or

Fishers exact test, and continuous variables were compared

using the independent samples t test. P values were 2-sided

without adjustment for multiple comparisons and were con-

sidered to be statistically significant if .P .05

RESULTS

Enrollment and follow-up. Of 843 screened patients, 580 ful-

filled initial inclusion criteria and were randomized; of these

patients, 21 were excluded before enrollment, and 559 were

enrolled and treated with study drugs (figure 1). At enrollmentthere was no significant difference between treatment groups

with respect to sex, age, temperature, parasite density, previous

use of antimalarial drugs, or mean hemoglobin level (table 1).

Gametocyte carriage was rare. The proportion of patients who

did not complete therapy because of repeated vomiting on day

0 (none were excluded for vomiting after day 0), protocol vi-

olation, or withdrawal of consent did not differ between the 3

treatment groups (4 of 186 patients for the AQSP group, 3 of

191 patients for the artemether-lumefantrine group, and 8 of

194 patients for the dihydroartemisinin-piperaquine group;

, for all pairwise comparisons). During 42 days of fol-P .22

low-up, 517 (92.5%) of 559 subjects completed the study. Therewas no difference in the risk of withdrawal between the treat-

ment arms ( for all comparisons). The most commonP1 .05

reason for study discontinuation was withdrawal of informed

consent.

Treatment efficacy. Nine patients experienced early treat-

ment failure, including 5 patients in the AQSP group (2 with

danger signs [1 with convulsions and 1 with vomiting] and 3

with severe malaria [1 with altered consciousness and 2 with


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Figure 1. Trial profile comparing antimalarial treatment regimens. AL, artemether-lumefantrine; AQSP, amodiaquine plus sulfadoxine-pyrimethamine;DP, dihydroartemisinin-piperaquine.

jaundice]) and 2 each in the artemether-lumefantrine and dih-

ydroartemisinin-piperaquine groups (all with convulsions). Ef-

ficacy outcomes were assigned on the basis of time to early

treatment failure or recurrent parasitemia, according to WHO

recommendations [20]. Outcomes were assessed after 28 and 42

days and considered with and without genotyping to distinguish

recrudescence from new infection. Considering outcomes un-

adjusted by genotyping, AQSP and dihydroartemisinin-pipera-

quine regimens were superior to the artemether-lumefantrine

regimen at both day 28 and day 42 after the initiation of therapy

(table 2). Similar differences were seen with evaluation of out-

comes in only those patients !5 years of age. In this group, the

28-day risk of treatment failure was 18.8% for the artemether-

lumefantrine regimen, compared with 8.5% for the AQSP reg-

imen and 4.2% for the dihydroartemisinin-piperaquine regimen.

Risk difference 95% CIs were 0.7%20% for the artemether-

lumefantrine regimen versus the AQSP regimen and5.8%23.4%

for the artemether-lumefantrine regimen versus the dihydroar-

temisinin-piperaquine regimen. The 42-day risk of treatmentfail-

ure was 30.9% for the artemether-lumefantrine regimen, com-

pared with 17.8% for the AQSP regimen and 12.2% for the

dihydroartemisinin-piperaquine regimen. Risk difference 95%

CIs were 0.9%25.4% for the artemether-lumefantrine regimen

versus the AQSP regimen and 7.1%30.2% for the artemether-

lumefantrine regimen versus the dihydroartemisinin-piperaquine

regimen. Most treatment failures were seen on or after day 21

in the artemether-lumefantrine group, day28 in the AQSPgroup,

and day 35 in the dihydroartemisinin-piperaquine group

(figure 2).

Our genotyping methodology included a step-wise algorithm

incorporating 6 markers that was recently validated for the

discrimination of outcomes in Bobo-Dioulasso [23]. Genotyp-

ing was successful for all of the samples that were tested. Con-

sidering only early treatment failures and recrudescences, all

tested regimens demonstrated excellent efficacy, with a risk of

treatment failure of!5% at day 28 and day 42 for all subjects


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Table 1. Baseline characteristics of patients receiving either amodiaquine plus sulfadoxine-pyri-

methamine, artemether-lumefantrine, or dihydroartemisinin-piperaquine for the treatment of malaria.

Characteristic

Treatment group

Amodiaquine plus

sulfadoxine-

pyrimethamine

(n p 184)

Artemether-

lumefantrine

(n p 188)

Dihydroartemisinin-

piperaquine

(n p 187)

Male sex 87 (47) 93 (49) 95 (51)

Age, median years (interquartile range) 4.1 (2.59) 4.0 (37) 4.0 (2.58)

Age !5 years 100 (54) 103 (55) 100 (53)

Temperature, mean C SD 38.5 1.3 38.5 0.9 38.6 0.9

Chloroquine use within the prior 2 weeks 22 (12) 20 (11) 22 (12)

Parasite density, geometric mean parasites/mL 22,884 27,110 25,260

Gametocytes present 1 (0.5) 0 3 (1.6)

Hemoglobin level, mean g/dL SD 10.3 2.3 10.2 2.0 10.1 2.4

NOTE. Data are no. (%) of patients, unless otherwise indicated.

(table 2) and for those subjects !5 years of age (data not

shown). There were no statistically significant differences be-

tween groups with respect to the risk of genotype-adjusted

treatment failure. Only 1 recrudescence occurred after day 28

(this recrudescence occurred at day 42 in a patient treated with

artemether-lumefantrine).

Secondary outcomes. Fever clearance was slower among

patients who received the artemether-lumefantrine regimen

than among patients who received the other 2 regimens; per-

sistence of fever on day 1 was significantly more common in

the artemether-lumefantrine group (table 3). More than 80%

of patients in all groups cleared fever by day 2. Parasiteclearance

was slower in the AQSP group than in the other 2 groups.

Persistent parasitemia on day 2 was significantly more commonin the AQSP group, but by day 3, parasites had cleared in at

least 99% of subjects in each treatment group. Gametocytes

appeared infrequently (in 5% of subjects) after treatment in

all 3 groups. Hemoglobin levels increased after therapy in all

groups, but on the last day of follow-up, the mean hemoglobin

level was significantly lower in the artemether-lumefantrine

group, compared with the other 2 groups.

Adverse events. All tested regimens appeared to be well

tolerated. No serious adverse events were observed. Abdominal

pain was reported more often in the AQSP and artemether-

lumefantrine groups, headache was reported more often in the

artemether-lumefantrine group, and pruritis was reported moreoften in the AQSP group (table 3).

DISCUSSION

We compared the efficacy against uncomplicated malaria of 3

drug regimens of particular interest in Burkina Faso. AQSP is

a combination of 2 older drugs that has shown surprisingly

good efficacy in different parts of Africa [911, 24, 25] and is

advocated under current WHO guidelines for the treatment of

malaria where its efficacy has been established and newer ACTs

are unavailable [26]. Artemether-lumefantrine is a leading ACT

that has shown excellent antimalarial efficacy in Asia [2729]

and Africa [46]. Dihydroartemisinin-piperaquine is a newer

ACT that has not yet been widely studied but which, in available

trials, has shown excellent efficacy in Asia [1618] and Africa

[15]. In Bobo-Dioulasso, all 3 regimens were highly efficacious.

For each therapy, early treatment failures or recrudescences

after treatment were seen in !5% of patients. However, in Af-

rica, recurrent malaria after therapy is commonly attributable

to either recrudescence or new infection, and the most practical

means of comparing regimens may be to compare their impacts

on recurrent malaria. By this measure, both AQSP and dihy-

droartemisinin-piperaquine were superior to artemether-lu-mefantrine, with marked decreases in the risk of recurrent ma-

laria during 6 weeks of follow-up.

The use of ACTs to treat uncomplicated malaria is now

strongly advocated [3]. The ACT selected as first-line therapy

by the largest number of African countries, artemether-lume-

fantrine, benefits from coformulation, approval in multiple

countries in the developing world and Europe, and demon-

strated excellent efficacy and safety [30, 31]. However, disad-

vantages of artemether-lumefantrine therapy include the need

for twice-per-day dosing, irregular bioavailability, and recom-

mendation for ingestion with a fatty meal to improve drug

levels. Dihydroartemisinin-piperaquine is a newer coformu-lated ACT that requires only single daily dosing and lacks di-

etary concerns. In limited studies, dihydroartemisinin-pipera-

quine showed outstanding antimalarial efficacy in Asia [1618]

and Africa [15]. Two recent studies directly compared the an-

timalarial efficacies of artemether-lumefantrine and dihydroar-

temisinin-piperaquine. In Papua, Indonesia [16], and in central

Uganda [32], both regimens showed excellent efficacy based on

genotype-corrected recrudescence after therapy. However, in


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Table 2. Treatment efficacy outcomes.

Risk category

Risk of treatment failure, % (95% CI) Risk difference, % (95% CI)

AQSP group AL group DP group

AL group

vs. AQSP group P

AL group

vs. DP group P

AQSP group

vs. DP group P

28-Day risk

Unadjusted by genotyping 6.2 (3.511.0) 20.1 (14.926.7) 2.2 (0.85.8) 13.8 (7.020.7) !.001 17.9 (11.624.1) !.001 4.0 (08.2) .06

Adjusted by genotyping 3.9 (1.98.0) 3.4 (1.57.3) 2.2 (0.85.8) 0.1 (4.4 to 3.3) .79 1.1 (2.3 t o 4.6) .51 1 .7 (1 .9 t o 5.2 .36

42-Day risk

Unadjusted by genotyping 11.6 (7.617.4) 30.9 (24.738.3) 7.5 (4.412.5) 19.4 (11.027.7) !.001 23.5 (15.631.3) !.001 4.1 (2.1 to 10.3) .19

Adjusted by genotyping 3.9 (1.98.0) 4.1 (2.08.5) 2.2 (0.85.8) 0.2 (3.9 t o 4.3) .91 1.9 (1.8 t o 5.6) .32 1 .7 (1.9 to 5.2) .36

NOTE. AL, artemether-lumefantrine; AQSP, amodiaquine plus sulfadoxine-pyrimethamine; DP, dihydroartemisinin-piperaquine.

Figure 2. Cumulative risk of treatment failure, unadjusted by genotyping. AL, artemether-lumefantrine group; AQSP, amodiaquine plus sulfadoxine-

pyrimethamine group; DP, dihydroartemisinin-piperaquine group.

both studies, treatment with dihydroartemisinin-piperaquine

was followed by significantly fewer new infections during 42

days of follow-up. Thus, as confirmed in our study, dihydroar-

temisinin-piperaquine appears to offer benefits over arte-

mether-lumefantrine, including simplified dosing and greater

posttreatment prophylactic efficacy.

Despite the selection of ACTs as first-line antimalarial ther-

apy by most African countries, including Burkina Faso, im-

plementation of changes in malaria therapy have been slow, in

part because of the considerable expense and limited availability

of new ACTs. The WHO recommends 1 non-ACT regimen,

treatment with AQSP, under limited circumstances [26]. AQSP

showed surprisingly good antimalarial efficacy in older studies

in East Africa [33, 34], but its efficacy was poor in Tanzania

[35] and appears to be decreasing in Uganda [36], likely as a

result of high levels of resistance to both amodiaquine and

sulfadoxine-pyrimethamine in East Africa. In contrast, AQSP

remains an excellent antimalarial regimen in parts of West Af-

rica, where resistance to both component drugs is uncommon

[10, 11]. In a recent comparison in Burkina Faso, AQSP and

artemether-lumefantrine both showed outstanding efficacy

based on measures of recrudescence, but AQSP demonstrated

superior posttreatment prophylaxis against new infections over

a month of follow-up [7]. In this study, the superior efficacy

of AQSP over artemether-lumefantrine in Bobo-Dioulasso was

confirmed. Further, the efficacy of AQSP was not significantly

different from that of dihydroartemisinin-piperaquine, al-

though trends favored dihydroartemisinin-piperaquine in all

comparisons.

Debate persists regarding the importance of a posttreatment

prophylactic effect of an antimalarial drug. Some have argued

that recrudescences entail greater clinical risk than new infec-

tions after therapy and, thus, that prevention of new infections

is relatively unimportant [37], but clinical data do not support

this assertion. In trials in Uganda, clinical presentations and

the likelihood of progression to complicated malaria were the


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Table 3. Secondary outcomes.

Outcome

Treatment group

Amodiaquine plus

sulfadoxine-

pyrimethamine

Artemether-

lumefantrine

Dihydroartemisinin-

piperaquine

Fever clearancea

Fever on day 1b,c

60/184 (33) 91/188 (48) 70/187 (37)

Fever on day 2 35/182 (19) 26/188 (14) 23/186 (12)

Fever on day 3 18/180 (10) 15/187 (8) 17/184 (9)

Parasite clearance

Parasitemia on day 2b,d

49/179 (27) 5/186 (3) 6/184 (3)

Parasitemia on day 3 2/175 (1) 0/185 (0) 0/182 (0)

Appearance of gametocytese

10/183 (5) 3/188 (2) 7/184 (4)

Hemoglobin level on last day of follow-up,

mean g/dL SDb,c,f

11.8 1.4 11.3 1.6 11.6 1.6

Adverse event

Cough 50/184 (27) 52/188 (28) 49/187 (26)

Abdominal painc,d

24/102 (24) 21/104 (20) 10/112 (9)

Headachec

14/101 (14) 22/104 (21) 11/111 (10)

Pruritisb,d

34/184 (18) 11/188 (6) 5/187 (3)

Vomiting 26/184 (14) 27/188 (14) 20/187 (11)

Anorexia 10/184 (5) 6/188 (3) 8/187 (4)

Diarrhea 9/184 (5) 13/188 (7) 14/187 (7)

Weakness 6/184 (3) 3/188 (2) 5/187 (3)

NOTE. Data are proportion (%) of patients, unless otherwise indicated.a

Subjective fever within the previous 24 h or temperature 37.5 C or prior early treatment failure.b

Amodiaquine plus sulfadoxine-pyrimethamine group vs. artemether-lumefantrine group ( ).P! .05c

Artemether-lumefantrine group vs. dihydroartemisinin-piperaquine group ( ).P! .05d

Amodiaquine plus sulfadoxine-pyrimethamine group vs. dihydroartemisinin-piperaquine group ( ).P! .05e

Only includes patients without gametocytes on day 0.f

Day 42 or day of recurrent symptomatic malaria on which rescue therapy was administerd (patients with early

treatment failure excluded).

same with recrudescent or new malaria episodes [38]. It hasalso been suggested that, in areas where reinfection is common,

posttreatment prophylaxis would have only a minor impact on

malarial incidence [39], but, in fact, with high transmission

intensity, the impact of a protective intervention should be

large. Indeed, this benefit may be greatest in regions with sea-

sonal transmission, such as Bobo-Dioulasso, where the post-

treatment prophylactic effect of a therapy may cover a good

portion of the transmission season.

Both amodiaquine and sulfadoxine-pyrimethamine have

caused rare but severe toxicities when used for long-term che-

moprophylaxis, and artemisinins are embryotoxic and have

caused irreversible neurological changes when administered in

high doses to laboratory animals. However, a good deal of

experience argues against major concerns regarding toxicities

of our study regimens when used for short-term antimalarial

therapy, although the tolerability of the AQSP regimen has been

lower than that of other regimens in some studies [40]. In our

study, reports of some adverse events differed between regi-

mens, but all regimens appeared to be well tolerated.

Our results suggest that choices for optimal antimalarial ther-

apy in Africa should be reevaluated. First, in regions where theefficacies of amodiaquine and sulfadoxine-pyrimethamine re-

main good, as in Burkina Faso, consideration should be given

for the use of AQSP for the treatment of uncomplicated ma-

laria, especially when, as a result of the unavailability of ACTs,

the alternative is an unacceptable monotherapy. Second, among

ACTs, dihydroartemisinin-piperaquine appears to offer partic-

ularly promising features, including easy dosing and outstand-

ing antimalarial efficacy, suggesting that this new regimen

should be strongly considered for first-line therapy for malaria

in Africa.

Acknowledgments

We thank the clinical study teams at the Colsama, Sarfalao, and Ouezzin-

ville dispensaries in Bobo-Dioulasso; the clinical officers; the patients and

their parents or guardians; and Christian Dokomajilar and Bryan Green-

house, for their assistance with genotyping samples.

Financial support. Doris Duke Charitable Foundation (2004047 to

P.J.R.), Holley Cotec Pharmaceuticals, International Atomic EnergyAgency

(RAF/6025), and National Budget of the Institut de Recherche en Sciences

de la Sante, Burkina Faso. P.J.R. is a Doris Duke Charitable Foundation

Distinguished Clinical Scientist.

Potential conflicts of interest. All authors: no conflicts.


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