EFFICACY OF AMODIAQUINE ALONE AND COMBINED WITH SULFADOXINE-PYRIMETHAMINE AND OF SULFADOXINE PYRIMETHAMINE COMBINED WITH ARTESUNATE CLAUDE E. RWAGACONDO, FRANCOIS NIYITEGEKA, JOSEPH SARUSHI, CORINE KAREMA, VERONIQUE MUGISHA, JEAN-CLAUDE DUJARDIN, CHANTAL VAN OVERMEIR, JEF VAN DEN ENDE, AND UMBERTO D’ALESSANDRO National Malaria Control Program, Kigali, Rwanda; Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium Abstract. 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 inves- tigated 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, re- sulting in the use of sulfadoxine-pyrimethamine (SP) in sev- eral countries. 2 In Africa, CQ resistance has resulted in in- creased malaria mortality 3 and morbidity, e.g., transient clini- cal 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 ma- laria 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, infec- tion with human immunodeficiency virus, or acquired immu- nodeficiency 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 uncompli- cated 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 clini- cal 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 effi- cacy of other possible drug combinations should be collected. We therefore investigated the safety and the efficacy of amo- diaquine (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 uni- form, it is stable with seasonal peaks in the valleys and un- stable 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 diag- nosis of clinical malaria were screened for malaria infection. Children weighing five or more kilograms with a monoinfec- tion with P. falciparum and a parasite density between 1,000 and 100,000 parasites/L were recruited in the study if a par- ent or guardian gave informed consent. Children were ex- cluded 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 Am. J. Trop. Med. Hyg., 68(6), 2003, pp. 743–747 Copyright © 2003 by The American Society of Tropical Medicine and Hygiene 743