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EFFICACY OF AMODIAQUINE ALONE AND COMBINED WITH SULFADOXINE-PYRIMETHAMINE AND OF SULFADOXINE PYRIMETHAMINE COMBINED WITH ARTESUNATE

CLAUDE E. RWAGACONDONational Malaria Control Program, Kigali, Rwanda; Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium

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FRANCOIS NIYITEGEKANational Malaria Control Program, Kigali, Rwanda; Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium

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JOSEPH SARUSHINational Malaria Control Program, Kigali, Rwanda; Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium

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CORINE KAREMANational Malaria Control Program, Kigali, Rwanda; Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium

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VERONIQUE MUGISHANational Malaria Control Program, Kigali, Rwanda; Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium

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JEAN-CLAUDE DUJARDINNational Malaria Control Program, Kigali, Rwanda; Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium

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CHANTAL VAN OVERMEIRNational Malaria Control Program, Kigali, Rwanda; Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium

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JEF VAN DEN ENDENational Malaria Control Program, Kigali, Rwanda; Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium

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UMBERTO D’ALESSANDRONational Malaria Control Program, Kigali, Rwanda; Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium

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The safety and the efficacy of amodiaquine (AQ) alone, AQ plus sulfadoxine-pyrimethamine (SP) (AQ plus SP), and artesunate (ART) plus SP (ART plus SP), three possible alternatives to chloroquine (CQ), were investigated in 379 Rwandan children 6–59 months old with uncomplicated Plasmodium falciparum malaria who visited one urban/peri-urban health center and two rural health centers. The three treatment regimens were well tolerated and no serious adverse effects were observed. Children treated with AQ plus SP had less clinical failures than those treated with ART plus SP (odds ratio [OR] = 0.25, 95% confidence interval [CI] = 0.06–0.81, P = 0.01) or AQ alone (OR = 0.33, 95% CI = 0.07–1.10, P = 0.08). Even after new infections were excluded, AQ plus SP was still significantly more efficacious than ART plus SP (P = 0.05). At day 14, the mean packed cell volume was significantly higher in the AQ plus SP group compared with the ART plus SP group (P = 0.02) and with the AQ alone group (P = 0.01). In Rwanda, AQ plus SP has been chosen to replace CQ as a first-line treatment. However, this is considered an interim measure and new combinations, possibly co-formulated, should be identified and tested.

INTRODUCTION

Over the past 20 years, malaria treatment and control have been undermined by the emergence of resistance to widely used antimalarial drugs.1 Chloroquine (CQ) resistance in Plasmodium falciparum, which was first documented in east Africa in 1978, is now widespread in sub-Saharan Africa, resulting in the use of sulfadoxine-pyrimethamine (SP) in several countries.2 In Africa, CQ resistance has resulted in increased malaria mortality3 and morbidity, e.g., transient clinical improvement and poor hematologic recovery.4 Furthermore, poor efficacy results in increased drug costs for patients and the health system.4

Drug combinations for the treatment of P. falciparum malaria might delay the emergence and spread of resistance.5–7 This is an approach that has already been used for highly drug-resistant infectious diseases such as tuberculosis, infection with human immunodeficiency virus, or acquired immunodeficiency syndrome, and the combination of mefloquine (MQ) and artesunate (ART) has already been successfully used in the treatment of P. falciparum malaria in Thailand.8

The artemisinin derivatives cause a rapid and substantial decrease in the parasite load when used for treating patients with malaria. However, their short half-lives result in frequent recrudescent infections when used alone and for less than seven days.9 Combination with a longer-acting drug (e.g., CQ, MQ, or SP) solves the problem of recrudescence, allows a short course of artesunate (ART) to be given, and protects against the emergence of resistant strains because parasites are much less likely to be resistant to both drugs.10

Until recently, CQ and SP have been used in Rwanda as first- and second-line drugs for the treatment of uncomplicated malaria. However, in vivo tests carried out in 1999–2000 in four sentinel sites showed clinical failure (early and late) with CQ ranging from 16.7% to 56.1%, with three of them more than 50% (http://www.eanmat.org). Similarly, SP clinical failure estimated in 2000 in three sites ranged from 11.6% to 44.7%. At a consensus meeting on the antimalarial drug policy held in Kigali, Rwanda in February 2001, the assembly, after having examined such data, decided that a change was needed in the first-line drug used, and that data on the efficacy of other possible drug combinations should be collected. We therefore investigated the safety and the efficacy of amodiaquine (AQ) alone, AQ and SP, and ART and SP.

MATERIALS AND METHODS

Study site.

The study was conducted in one urban/peri-urban health center, Kicukiro, near the capital of Kigali, and in two rural health centers: Rukara, near the eastern border of Uganda near the Kagera National Park and Mashesha, which is surrounded by rice fields and is located at an altitude of 900 meters above sea level. Malaria is one of the major health problems in Rwanda and represents the first reason of visiting health facilities.11 Malaria transmission is not uniform, it is stable with seasonal peaks in the valleys and unstable in the hills, with some districts at high risk of epidemics. The major vectors are Anopheles gambiae and An. funestus. Malaria incidence seems to have increased in recent years. Possible explanations for this increase are environmental changes, demographic pressure, population movements due to war, increasing mean temperatures, and loss of efficacy of commonly used antimalarial drugs.

Patients.

Children between 6 and 59 months of age with fever (body temperature ≥37.5°C) and a presumptive diagnosis of clinical malaria were screened for malaria infection. Children weighing five or more kilograms with a monoinfection with P. falciparum and a parasite density between 1,000 and 100,000 parasites/μL were recruited in the study if a parent or guardian gave informed consent. Children were excluded if they had 1) danger signs (unable to drink or breast-feed, vomiting more than twice in the past 24 hours, recent history of convulsions, an unconscious state or unable to sit or stand), 2) signs of severe malaria,12 3) a packed cell volume (PCV) less than 15%, 4) a clear history of adequate malaria treatment in the preceding 72 hours, or 5) any evidence of chronic disease.

Study design.

All enrolled children were randomly assigned to receive either a standard dose of AQ alone (10 mg/kg/day for three days), AQ and SP (25 mg/kg of sulfadoxine and 1.25 mg/kg of pyrimethamine), or ART (Dafra Pharma, Beerse, Belgium) (4 mg/kg/day for three days) and SP. All doses were given under direct supervision. Each child received paracetamol (10 mg/kg/dose) when needed, and the parents were instructed to administer it when the child had a fever. Children were observed for one hour for vomiting and a replacement dose was given if necessary. Patients (parent/guardian) were asked to return to the clinic 24 and 48 hours later for drug administration and for scheduled tests at 72 hours and at days 7, 14, 21, and 28. If the patient did not report for scheduled visits, every effort was taken by the nurses to locate him or her at his or her home address. Parents were encouraged to return to the health center any time the child was not feeling well. A blood slide for parasitemia was prepared at days 0, 3, 7, 14, 21, and 28. The PCV was measured at days 0 and 14. In one of the sites (Rukara), the PCV was measured at day 14 only in children who had a PCV ≤ 25% at day 0. Blood blots on filter paper were prepared for molecular biology studies on days 0, 14, 21, and 28 or on any day of recurrent parasitemia after day 14. Children who experienced treatment failure were treated with a full course of quinine. The study was reviewed and approved by the Ministry of Health of Rwanda.

Laboratory methods.

Thick blood films were stained with Giemsa. Parasite density was determined on the basis of the number of parasites per 200 leukocytes on a thick film assuming a total leukocyte count of 8,000/μL. If gametocytes were seen, the gametocyte count was extended to 1,000 leukocytes. The PCV was measured by microhematocrit centrifugation. If the child had a second episode of parasitemia, blood samples on filter paper from the first and second episodes were used to type parasite strains. DNA was purified as described previously,13 and a nested polymerase chain reaction was adopted for the analysis of two polymorphic genetic markers from P. falciparum: the three sequence families of the merozoite surface protein-1 (MSP-1) block 2 repeat region and the two sequence families of the MSP-2 repeat region. A recrudescent infection was defined as one that showed at least one match in the size of one allele for both the MSP-1 and MSP-2 genes between the first and second samples. If any clone of a polyclonal primary infection was detected during a second episode it was considered a recrudescence.

Statistical methods.

Data were double entered and validated using Epi-Info version 6.4b software (Centers for Disease Control and Prevention, Atlanta, GA). Analyses were done with SPSS release 10.0.05 for Windows (SPSS, Inc., Chicago, IL). Outcomes were defined according to the clinical or parasitologic response. Clinical responses were classified into three groups: early treatment failure (ETF), late treatment failure (LTF), and adequate clinical response (ACR), as previously defined.14 In addition, children with fever and parasitemia between days 14 and 28 were also classified as LTF. Children were considered parasitologic failures if they received rescue treatment on or before day 28 or if they were parasitemic between days 14 and 28.

In a secondary analysis, children were considered not to be parasitologic or clinical failures if their parasitemia between days 14 and 28 was classified as a new infection, rather than a recrudescent infection. Chi-square analysis was used to compare the failure rates between groups and 95% confidence intervals (CIs) were computed for the corresponding odds ratio (OR).

RESULTS

Three-hundred seventy-nine children satisfying the entry criteria were recruited between May and August 2001: 124 (32.7%) from Kicukiro, 155 (40.9%) from Mashesha, and 100 (26.4%) from Rukara. The groups had similar demographic and clinical characteristics at enrollment (Table 1). One child in the AQ plus SP group was lost to follow-up between days 15 and 28. The three treatment regimens were well tolerated and no serious adverse events were observed.

No ETFs or LTFs were observed during the first 14 days after treatment. However, after day 14, there were 29 LTFs: 9 in the AQ (8.7%) group, 4 (3.1%) in the AQ plus SP group, and 16 (11.1%) in the ART plus SP group (Table 2). The AQ plus SP regimen was more efficacious than ART plus SP (OR = 0.25, 95% CI = 0.06–0.81, P = 0.01) and AQ alone (OR = 0.33, 95% CI = 0.07–1.10, P = 0.08). No significant difference between AQ alone and ART plus SP was found. Differences between groups decreased slightly when new infections were excluded (Table 2). However, AQ plus SP was still significantly more efficacious than ART plus SP (P = 0.05).

Only four children were parasitemic without fever at day 14: two in the AQ group, one in the AQ plus SP group, and one in the ART plus SP group. However, by day 21, 43 children were parasitemic: 13 (12.7%) in the AQ group, 11 (8.3%) in the AQ plus SP group, and 19 (13.8%) in the ART plus SP group (P = 0.34). At the end of follow-up at day 28, 24 (23.3%) children in the AQ group, 22 (16.8%) in the AQ plus SP group, and 42 (29.1%) in the ART plus SP group had been or were parasitemic after initial clearance of the infection (Table 2). At day 28, parasitologic failure for the three treatments varied between sites (Table 2). Overall, AQ plus SP was significantly more effective than ART plus SP (OR = 0.49, 95% CI = 0.27–0.87, P = 0.02). The AQ plus SP regimen was particularly efficacious in the urban/peri-urban site of Kicukiro (P = 0.004). However, the difference was not statistically significant (P = 0.11) in Mashesha, and the percentage of parasitologic failures was higher in the AQ plus SP group (P = 0.38) in Rukara. Even when new infections were excluded, AQ plus SP was still more efficacious than ART plus SP, although the difference was not statistically significant (OR = 0.59, 95% CI = 0.29–1.18, P = 0.14). No significant differences were found when AQ alone was compared with AQ plus SP or with ART plus SP. Gametocyte rates were low (the highest value was 6% at day 3 for the AQ plus SP group) and not significantly different between the three treatment groups.

The PCV was measured in all children at day 0. It was also measured in all children in Kicukiro and Mashesha and in only 11 in Rukara (only those who had a PCV ≤ 25% at day 0) at day 14. The mean PCV at day 0 was similar in the three treatment groups. At day 14, the mean PCV was not different between the AQ alone group and the ART plus SP group. However, at day 14 the mean PCV was significantly higher in the AQ plus SP group compared with the ART plus SP group (P = 0.02) and the AQ alone group (P = 0.01) (Table 3). A similar result was obtained when the analysis was restricted to children with PCVs ≤ 25% at day 0. The mean ± SD PCV was significantly higher in the AQ plus SP group (31.9 ± 2.73) compared with the AQ alone group (29.8 ± 4.25) and the ART plus SP group (28.2 ± 3.95) (P = 0.02).

DISCUSSION

In this study, AQ alone, AQ plus SP, and ART plus SP were equally effective in the treatment of uncomplicated malaria, at least until day 14, when all patients were classified as ACR according to the standard definition of the World Health Organization,14 with only four of them parasitemic. Differences between treatments and sites became evident between days 15 and 28 of follow-up. The LTFs were significantly less frequent in children treated with AQ plus SP than in those treated with ART plus SP, and they remained significantly lower even after excluding new infections. The AQ plus SP regimen was particularly efficacious in Kicukiro, where unfortunately no background data on CQ and SP resistance are available, and in Mashesha, while in Rukara no difference between the three treatments was found. In vivo tests (14-day follow-up) carried out in 2000 reported 11.5% SP treatment failures in Mashesha (ETF = 4.6%, LTF = 6.9%) and 44.6% in Rukara (ETF = 21.2%, LTF = 23.4%) (http://www.eanmat.org). At the same time, parasitologic resistance to SP was estimated to be 20.9% (RI = 4.7%, RII = 14.0%, RIII 2.3%) in Mashesha and 71.4% (RI = 20.4%, RII = 31.5%, RIII = 11.1%) in Rukara (National Malaria Control Program, Kigali, Uganda, unpublished data). Artemisinin derivatives cause a rapid and substantial decrease in the parasite load. However, they have a short half-life and recrudescent infections are frequent when these drugs are used alone and for less than seven days. Combination with a longer-acting drug solves the problem of recrudescence and allows a shorter course of ART.6 In The Gambia, where resistance to SP was low, ART plus SP was safe, well tolerated, and effective.15,16 Where SP resistance is high, such as in Rukara, it could be expected that after initial clearing of parasitemia, there would be a large number of patients with a recrudescence and consequently a high parasitologic and treatment failure. We did not observe such a phenomenon, but a dramatic improvement of treatment efficacy after combining SP with AQ or ART was observed. However, in Rukara the treatment and parasitologic failures were not significantly different between the three treatment regimens, suggesting that efficacy was mainly due to the activity of AQ and ART.

In previous studies, patients receiving AQ plus SP showed more effective control of clinical symptoms and a higher cure rate without evidence of serious side effects.17 This was confirmed by a recent study in Uganda, in which AQ plus SP was more efficacious than its single components, although the difference was significant only for SP alone.18 In our study, patients treated with AQ plus SP had a significantly lower risk of parasitologic or clinical failure than those treated with ART plus SP. Moreover, the mean PCV at day 14, an indirect index of drug efficacy, was significantly higher in children treated with AQ plus SP compared with the other two groups.

The first consequence of using drugs in combination is that the initial frequencies of malaria parasites resistant to all the drugs used is greatly reduced, such that the evolution of resistance is delayed compared with when its single components are used alone. The second consequence is that the higher the number of genes involved in determining resistance (and these are likely to be higher for drug combinations), the more frequently they will be broken down during recombination in meiosis. The emergence and spread of a resistant strain should be delayed, and the useful therapeutic life of the combination should be much longer than its single components.10 Amodiaquine, its metabolites, and SP have similar terminal half-lives, whereas ART has a shorter half-life. The use of two drugs with extremely different half-lives might not be an important factor in areas of low malaria transmission. The combination of ART plus MQ was adopted by some Asian countries, such as Thailand, as a near-desperate therapeutic choice in the face of multidrug resistance when the efficacy of MQ decreased sharply.19 The use of ART plus MQ has halted the progression of MQ resistance.8 If one considers the high infection rate that occurs in areas of high transmission, the impact of a combination such as ART plus MQ might be minimal because the probability of MQ alone contacting parasites and possibly selecting resistant ones would be higher. In such a situation, the use of drugs with similar terminal half-lives such as AQ plus SP could have an additional advantage because the two drugs would “protect” each other for a similar period of time.18

The standard 14-day follow-up recommended by the World Health Organization for areas of intense transmission of malaria was extended until 28 days after treatment. This was considered necessary because it was the first time that the two combinations were tested in Rwanda and a high cure rate for the three regimens was expected. Had the follow-up period been restricted to 14 days, it would have been impossible to find any difference between the three study groups. It is often stated that a 14-day follow-up would limit misclassification18 because it is assumed that most of the infections occurring between days 15 and 28 are new ones and not recrudescences. However, it is interesting to notice that in our study the great majority of the infections detected after day 14 were classified as recrudescences, although the technique used has its own limitations. For example, some genotypes detected during the follow-up may not be detected at day 0 because they represent a minority of the parasite population and the infection would be wrongly classified as a new infection. Daily differences in the diversity of an infection have also been observed,20 and in places where there are few circulating parasite genotypes, new infections might have a similar genotype to the one eliminated by the drug.21

Extending the follow-up period to 28 days needs more resources and commitment from the staff involved in the study. It will be difficult to propose a 28-day follow-up for the long-term monitoring of commonly used drugs. However, when comparing new drugs or new combinations that are likely to be almost 100% efficacious at day 14, an extended follow-up, at least until day 28, might be the best option.

We recorded no major drug-related adverse effects. So far, serious and life-threatening adverse effects linked to the use of AQ have been reported only during prophylaxis. The estimated risk for adverse effects associated with the prophylactic use of AQ is approximately 1:2,100 treatments for agranulocytosis, 1:15,500 for hepatotoxicity, and 1:30,000 for aplastic anemia, with a total case fatality rate of 1:15,650.22 Therefore, the risk of fatal adverse effects due to AQ is of the same order of magnitude as that for SP.22 Three recent trials on ART plus AQ versus AQ reported a decrease in serial neutrophil counts in 60% of children, with a small number of them developing neutropenia without an apparent clinically ill effect.23 Since in areas of high transmission, repeated dosing can increase the risk of serious toxic effects and these are likely to be observed only after treating a large number of patients, there is a need for setting up a good surveillance system for the detection of rare adverse effects in countries that have chosen AQ or combinations containing AQ as the first-line drug for the treatment of uncomplicated malaria.

At the national consensus meeting on the national antimalarial treatment policy in Rwanda held in Kigali in February 2001, it was decided to abandon CQ, and after a long discussion, three possible alternatives were identified, namely AQ plus SP, ART plus SP, and AQ plus ART. The first two options being recommended as interim measures because of the high prevalence of SP resistance reported from some sentinel sites. At that time, no information on the efficacy of the drug combinations was available. Our study fills this gap and indicates that when one compares AQ plus SP with ART plus SP, the former regimen is the best option. The Rwandan Ministry of Health has already implemented this change in policy. Several questions remain unanswered. First, it is unclear whether AQ plus SP will maintain its efficacy because high levels of resistance to SP have already been observed in some parts of Rwanda and because of possible increases in resistance to AQ. Second, the two drugs are not co-formulated and compliance to the new treatment might be extremely difficult. The implementation of AQ plus SP is considered an interim measure. However, it will require time and resources to be fully operational and available at all health facilities. It will be important to start identifying new drug combinations, possibly co-formulated, and test their efficacies. Co-formulation is likely to increase patient compliance because it will decrease the “risk” of monotherapy with only one of the two drugs. The possibility of having a co-formulated ART plus AQ regimen in the near future might be an important step forward.

Table 1

Baseline characteristics in the three groups of patients*

AQ alone (n = 103) AQ + SP (n = 132) ART + SP (n = 144)
* AQ = amodiaquine; SP = sulfadoxine-pyrimethamine; ART = artesunate; PCV = packed cell volume.
Mean age, months (SD) 28.2 (15.7) 29.5 (16.7) 25.6 (14.9)
Mean (range) weight, kg 10.9 (5.4–19.0) 11.2 (6.0–25.0) 10.4 (6.0–20.0)
Mean temperature (°C) (SD) 38.2 (0.76) 38.3 (0.72) 38.5 (0.70)
Geometric mean (range) asexual Plasmodium falciparum/μL 11,970 (1,100–98,960) 12,114 (1,000–98,960) 12,667 (1,160–96,000)
Patients with gametocytes, no. (%) 0 (0.0) 2 (1.5) 4 (2.8)
Mean (SD) PCV 30.1 (4.2) 30.7 (5.1) 30.5 (4.8)
Table 2

Parasitologic failure at days 14 and 28 and clinical failure between days 14 and 28, by group and by sentinel site*

AQ alone n = 103 (%) AQ + SP n = 132 (%) ART + SP n = 144 (%)
* AQ = amodiaquine; SP = sulfadoxine-pyrimethamine; ART = artesunate; LTF = late treatment failure.
Parasitologic failure at day 14 2 (1.9) 1 (0.8) 1 (0.7)
Parasitologic failure at day 28 n = 103 n = 131 n = 144
    Kicukiro 3/21 (14.3) 8/47 (17.0) 24/56 (42.9)
    Mashesha 13/51 (25.5) 4/52 (7.7) 9/52 (17.3)
    Rukara 8/31 (25.8) 10/32 (31.3) 9/36 (25.0)
    Total 24 (23.3) 22 (16.8) 42 (29.1)
Parasitologic failure at day 28 adjusted by molecular results
    Only new infections excluded 18 (17.5) 17 (12.9) 29 (20.1)
    New and untyped infections excluded 15 (14.6) 14 (10.6) 25 (17.4)
LTF at day 28 n = 103 n =131 n = 144
    Kicukiro 0/21 (0.0) 2/47 (4.2) 10/56 (17.9)
    Mashesha 7/51 (13.7) 0/52 (0.0) 4/52 (7.7)
    Rukara 2/31 (6.5) 2/32 (6.3) 2/36 (5.6)
    Total 9 (8.7) 4 (3.1) 16 (11.1)
LTF at day 28 adjusted by molecular results
    Only new infections excluded 7 (6.8) 3 (2.3) 12 (8.3)
Table 3

Mean PCV (SD) at day 14 by treatment and site*

AQ alone (n = 76) AQ + SP (n = 102) ART + SP (n = 112)
* PCV = packed cell volume; AQ = amodiaquine; SP = sulfadoxine-pyrimethamine; ART = artesunate.
Kicukiro (n = 124) 31.5 (7.1) 34.1 (4.2) 32.4 (4.7)
Mashesha (n = 155) 32.4 (3.6) 33.9 (3.1) 33.0 (3.0)
Rukara (n = 11) 32.9 (4.6) 30.9 (2.1) 31.8 (5.7)
Total 32.2 (4.8) 33.8 (3.6) 32.7 (4.0)

Authors’ addresses: Claude E. Rwagacondo, Francois Niyitegeka, Joseph Sarushi, Corine Karema, and Veronique Mugisha, National Malaria Control Program, Kigali, Rwanda, Telephone: 250-570-205, Fax: 250-576-784, E-mail: crwagacondo@hotmail.com. Jean-Claude Dujardin, Chantal van Overmeir, Jef van den Ende, and Umberto D’Alessandro, Prince Leopold Institute of Tropical Medicine, Nationalestraat 155, B-2000 Antwerp, Belgium, Telephone: 32-3-247-6354, Fax: 32-3-247-6362; E-mail: udalessandro@itg.be

Acknowledgments: We thank the patients and their parents, as well as the staff at the health centers, for their contributions to this study. We also thank Dr Ambrose Talisuna for his comments on the manuscript. This study was conducted under the Umbrella of the East Africa Network for Monitoring Antimalarial Treatment (EANMAT).

Financial support: The study was supported by the Belgian Development Co-operation (DGIS) in collaboration with the Prince Leopold Institute of Tropical Medicine (Antwerp, Belgium).

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