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

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 T→M mutation at residue 61 linked to an S→T (but not an S→N) 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.

青蒿素类联合疗法（Artemisinin-derivative combination therapies, ACT）对多重耐药恶性疟原虫疟疾疗效极佳。然而，目前针对间日疟的疗效数据却较为匮乏。印度尼西亚巴布亚省的间日疟与恶性疟均存在高比例氯喹（chloroquine, CQ）耐药株，因此针对这两种疟原虫均需开发新型联合疗法。本团队前期研究发现，青蒿琥酯联合磺胺多辛-乙胺嘧啶（artesunate plus sulfadoxine-pyrimethamine, ART-SP）在巴布亚省的恶性疟治疗中有效率达96%。在完成氯喹联合磺胺多辛-乙胺嘧啶（CQ-SP）治疗间日疟原虫感染的预实验后，本研究采用改良世界卫生组织（World Health Organization, WHO）标准，评估了ART-SP方案在巴布亚省治疗间日疟的疗效。接受ART-SP治疗的22名患者中，共有19名可在第28天完成疗效评估，且未出现早期治疗失败病例。所有可评估患者中，20名（100%）在第14天达到充分的临床与寄生虫学应答，17名（89.5%）在第28天达成该应答标准。患者发热与寄生虫清除时长较短，70.6%的患者出现血液学指标改善。巴布亚省分离的间日疟原虫样本中，间日疟原虫二氢叶酸还原酶（PvDHFR）的双突变（位于58、117位）与四重突变（位于57、58、61、117位）较为常见，检出率分别为46%与18%。携带该PvDHFR四重突变的分离株，其含磺胺多辛-乙胺嘧啶方案的治疗失败率显著更高；该四重突变包含一处新型的61位残基T→M突变，且与117位残基S→T（而非S→N）突变相关联。尽管临床确诊疟疾时持续单用磺胺多辛-乙胺嘧啶可能导致两种疟原虫的DHFR突变不断演化，进而威胁该联合疗法的未来应用前景，但ART-SP方案在巴布亚省针对两种主要疟原虫均展现出了极高的治愈率。