Therapeutic Efficacies of Artesunate-Sulfadoxine-Pyrimethamine and Chloroquine-Sulfadoxine-Pyrimethamine in Vivax Malaria Pilot Studies: Relationship to Plasmodium vivax dhfr Mutations

Abstract

Artemisinin-derivative combination therapies (ACT) are highly efficacious against multidrug-resistant Plasmodium falciparum malaria. Few efficacy data, however, are available for vivax malaria. With high rates of chloroquine (CQ) resistance in both vivax and falciparum malaria in Papua Province, Indonesia, new combination therapies are required for both species. We recently found artesunate plus sulfadoxine-pyrimethamine (ART-SP) to be highly effective (96%) in the treatment of falciparum malaria in Papua Province. Following a preliminary study of CQ plus sulfadoxine-pyrimethamine (CQ-SP) for the treatment of Plasmodium vivax infection, we used modified World Health Organization criteria to evaluate the efficacy of ART-SP for the treatment of vivax malaria in Papua. Nineteen of 22 patients treated with ART-SP could be evaluated on day 28, with no early treatment failures. Adequate clinical and parasitological responses were found by day 14 in all 20 (100%) of the patients able to be evaluated and by day 28 in 17 patients (89.5%). Fever and parasite clearance times were short, with hematological improvement observed in 70.6% of the patients. Double (at positions 58 and 117) and quadruple (at positions 57, 58, 61, and 117) mutations in the P. vivax dihydrofolate reductase (PvDHFR) were common in Papuan P. vivax isolates (46 and 18%, respectively). Treatment failure with SP-containing regimens was significantly higher with isolates with this PvDHFR quadruple mutation, which included a novel T3M mutation at residue 61 linked to an S3T (but not an S3N) mutation at residue 117. ART-SP ACT resulted in a high cure rate for both major Plasmodium species in Papua, though progression of DHFR mutations in both species due to the continued use of SP monotherapy for clinically diagnosed malaria threatens the future utility of this combination.High rates of chloroquine (CQ) resistance and CQ treatment failure have been found in both vivax and falciparum malaria in Papua Province (formerly Irian Jaya), Indonesia (2,3,5,21,28,38), and new combination therapies are required for each species. Artemisinin-derivative combination therapies (ACT) are being used increasingly for the treatment of multidrug-resistant Plasmodium falciparum malaria (29) because of their excellent efficacy (23,31,39,41), their ability to slow or reverse the emergence of resistance (24, 30), and their ability to reduce malaria transmission (24, 30). Despite the coexistence of falciparum and vivax malaria in many parts of the world where malaria treatment is usually based on clinical diagnosis, there have been few studies assessing the efficacy of artemisinin derivatives in treating vivax malaria and none in the area of CQ-resistant P. vivax. Studies of artesunate (ART) monotherapy for P. vivax infection have demonstrated rapid clearance of fever and parasites (1,6,33,43). However, with its very short half-life, no ART remains by the time of the first relapse of P. vivax infection, approximately 3 weeks after treatment begins, resulting in a high frequency of...

Different Allele Prevalence in the Dihydrofolate Reductase and Dihydropteroate Synthase Genes in Plasmodium vivax Populations from China

“…Results from in vitro drug assays with limited numbers of field samples and tests using a yeast expression system are generally agreeable with this assumption. 18,20,38 Furthermore, limited clinical assessments of the efficacy of SP have associated pvdhfr quadruple mutations and increased risks of clinical resistance to SP, 19,22,23,25 suggesting that molecular genotyping data for pvdhfr and pvdhps should provide useful information about SP resistance in P. vivax .…”

“…In regions of extensive SP use, two mutant genotypes at residue 117 (S117T and S117N) have been observed; the former has been associated with highly mutated pvdhfr and may be a key mutation for subsequent acquisition of additional mutations and development of high resistance to SP. 19,22 In Thailand, for example, the pvdhfr T61M mutation, which has reached a high level of prevalence (> 60%), is mostly linked with the S117T mutation. 17,27 Consistent with the scarcity of the S117T mutation in China, highly mutated pvdhfr (triple or quadruple mutations) was also rare.…”

“…16 To date, some 20 mutations have been detected in pvdhfr ; among them mutations at codons 57, 58, 61, 117, and 173, corresponding to positions 50, 51, 59, 108 and 164 in pfdhfr , respectively, are associated with pyrimethamine resistance. [17][18][19][20] A structural study has confirmed that the most common mutations (S58R and S117N) cause structural changes in P . vivax DHFR and lead to decreased binding to pyrimethamine.…”

“…21 A limited number of clinical studies have associated pvdhfr quadruple mutations with increased risks of SP treatment failure. 19,22,23 For pvdhps , mutations at codons 382, 383, 512, 553, and 585, corresponding to codons 436, 437, 540, 581, and 613 in pfdhps , respectively, are predicted to confer increased resistance to sulfadoxine. 24 The ubiquitous mutation V585 in global parasite isolates was proposed to be the key amino acid affecting the conformation of the drug binding domain, 24 and other mutations may further reduce the sensitivity to sulfadoxine.…”

Diagnosis and Treatment of Plasmodium vivax Malaria

“…41,42 Mefloquine, 43 atovaquone + proguanil, 44 halofantrine, 45 piperaquine, 46 artesunate, 47,48 and pyronaridine, 49 all show good efficacy against chloroquine-resistant (CQR) P. vivax in clinical trials.…”