Low Efficacy of Amodiaquine or Chloroquine Plus Sulfadoxine-Pyrimethamine against Plasmodium falciparum and P. vivax Malaria in Papua New Guinea Jutta Marfurt, Ivo Müeller, Albert Sie, Peter Maku, Mary Goroti, John C. Reeder, Hans-Peter Beck, and Blaise Genton* Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, Basel, Switzerland; Papua New Guinea Institute of Medical Research, Goroka, Maprik, and Madang, Papua New Guinea Abstract. Because of increasing resistance to 4-aminoquinolines in Papua New Guinea, combination therapy of amodiaquine (AQ) or chloroquine (CQ) plus sulfadoxine-pyrimethamine (SP) was introduced as first-line treatment against uncomplicated malaria in 2000. The purpose of this study was to monitor in vivo efficacy of the current standard combination therapy against Plasmodium falciparum and P. vivax malaria. Studies were conducted between 2003 and 2005 in the Simbu, East Sepik, and Madang Provinces in Papaua New Guinea according to the revised protocol of the World Health Organization (WHO) for assessment of antimalarial drug efficacy. Children between six months and seven years of age with clinically overt and parasitologically confirmed P. falciparum or P. vivax malaria were treated according to the new policy guidelines (i.e., AQ plus SP given to patients weighing < 14 kg and CQ plus SP given to patients weighing  14 kg). Children were monitored up to day 28 and classified according to clinical and parasitological outcome as adequate clinical and parasitological response (ACPR), early treatment failure (ETF), late clinical failure (LCF), or late parasitological failure (LPF). For P. falciparum malaria, polymerase chain reaction (PCR)–corrected treatment failure rates up to day 28 ranged between 10.3% and 28.8% for AQ plus SP and between 5.6% and 28.6% for CQ plus SP, depending on the region and the year of assessment. Overall treatment failure rate with AQ or CQ plus SP for P. vivax malaria was 12%. Our results suggest that the current first-line treatment in Papua New Guinea is not sufficiently effective. According to the new WHO guidelines for the treatment of malaria, a rate of parasitological resistance greater than 10% in the two dominant malaria species in the country justifies a change in treatment policy. INTRODUCTION Malaria is a serious health problem in Papua New Guinea and access to safe and effective treatment still remains the mainstay in the control of the disease. The 4-aminoquinoline drugs amodiaquine (AQ) and chloroquine (CQ) have been first-line treatment against uncomplicated malaria until the late 1990s. However, resistance of Plasmodium falciparum to CQ was first documented in 1976 1,2 and numerous studies in different provinces at different times showed the problem to be widespread. Within two decades, resistance to the 4-ami- noquinolines AQ and CQ increased gradually with a slow shift from RI to RII and RIII types. 3–9 The first documented evidence for P. vivax resistance in Papua New Guinea was reported in 1989 10,11 and showed a similar increasing trend as for P. falciparum. 12 Although pyrimethamine in combination with CQ has been used in mass drug administration campaigns in the 1960s, 13 the combination of sulfadoxine-pyrimethamine (SP) was not previously part of the standard treatment against uncompli- cated malaria and was used only in combination with quinine to treat severe or treatment failure malaria in Papua New Guinea. Despite the low use of SP, resistance of P. falciparum to this drug combination was first described in Papua New Guinea in 1980. 14 Thereafter, P. falciparum resistance to SP as well as reduced efficacy of SP against P. vivax have been reported in Madang Province. 15–18 In view of the low efficacy of the 4-aminoquinolines used as first-line regimen against malaria, health authorities in Papua New Guinea were prompted to revise the antimalarial treat- ment policy in 1997. Combination therapy for uncomplicated malaria has been advocated for some years to improve clinical effectiveness and to delay the development and spread of resistance to individual drugs. 19,20 Although evidence for suc- cess of the combination regimen of AQ or CQ plus SP was scarce at that time 21 and there was evidence for in vivo as well in vitro resistance against either of the drugs in Papua New Guinea, the decision to investigate the possible change to this combination regimen was made. Based on efficacy studies conducted between 1998 and 1999 that showed that the com- binations were efficacious with treatment failure rates below 5%, 22 the Papua New Guinean Department of Health chose the combination of AQ plus SP for young children and CQ plus SP for others to replace monotherapy with AQ or CQ as the standard first-line treatment against uncomplicated ma- laria in 2000. Since the introduction of the new drug policy, little data has been collected to monitor the efficacy of the new standard treatment. Two studies conducted at health facilities in Maprik and Madang in 2001 recorded treatment failure rates up to day 14 of 3% and 8%, respectively (Reeder JC, unpub- lished data). These data showed some clinical resistance to the combination regimen one year after its introduction. Fur- ther molecular studies substantiated these finding by showing a high prevalence of mutations in CQ resistance–associated marker genes (P. falciparum chloroquine resistance trans- porter gene and P. falciparum multidrug-resistance gene 1) and appearance of mutations in the gene encoding P. falci- parum dihydrofolate reductase, which is known to confer re- sistance to SP. 23,24 The purpose of our study was to monitor the clinical effi- cacy of the current first-line regimen of AQ or CQ plus SP against P. falciparum and P. vivax malaria in Papua New Guinea after its official implementation in 2000. Within the framework of a project for the clinical and molecular moni- toring of drug resistant malaria in Papua New Guinea, we conducted in vivo studies according to the revised protocol of the World Health Organization (WHO) for assessment of * Address correspondence to Blaise Genton, Ifakara Health Re- search & Development Centre, P.O. Box 78373, Dar es Salaam, Tan- zania. E-mail: Blaise.Genton@unibas.ch Am. J. Trop. Med. Hyg., 77(5), 2007, pp. 947–954 Copyright © 2007 by The American Society of Tropical Medicine and Hygiene 947