Medicines for Malaria Venture, Geneva, Switzerland.
Infectious Diseases Research Collaboration, Tororo Hospital, Tororo, Uganda.
Malar J. 2019 Apr 10;18(1):126. doi: 10.1186/s12936-019-2756-4.
Today, the development of new and well-tolerated anti-malarial drugs is strongly justified by the emergence of Plasmodium falciparum resistance. In 2014-2015, a phase 2b clinical study was conducted to evaluate the efficacy of a single oral dose of Artefenomel (OZ439)-piperaquine (PPQ) in Asian and African patients presenting with uncomplicated falciparum malaria.
Blood samples collected before treatment offered the opportunity to investigate the proportion of multidrug resistant parasite genotypes, including P. falciparum kelch13 mutations and copy number variation of both P. falciparum plasmepsin 2 (Pfpm2) and P. falciparum multidrug resistance 1 (Pfmdr1) genes.
Validated kelch13 resistance mutations including C580Y, I543T, P553L and V568G were only detected in parasites from Vietnamese patients. In Africa, isolates with multiple copies of the Pfmdr1 gene were shown to be more frequent than previously reported (21.1%, range from 12.4% in Burkina Faso to 27.4% in Uganda). More strikingly, high proportions of isolates with multiple copies of the Pfpm2 gene, associated with piperaquine (PPQ) resistance, were frequently observed in the African sites, especially in Burkina Faso and Uganda (> 30%).
These findings were considered to sharply contrast with the recent description of increased sensitivity to PPQ of Ugandan parasite isolates. This emphasizes the necessity to investigate in vitro susceptibility profiles to PPQ of African isolates with multiple copies of the Pfpm2 gene and estimate the risk of development of PPQ resistance in Africa. Trial registration Clinicaltrials.gov reference: NCT02083380. Study title: Phase II efficacy study of artefenomel and piperaquine in adults and children with P. falciparum malaria. https://clinicaltrials.gov/ct2/results?cond=&term=NCT02083380&cntry=&state=&city=&dist= . FSFV: 23-Jul-2014; LSLV: 09-Oct-2015.
如今，疟原虫耐药性的出现强烈证明了新的、耐受性良好的抗疟药物的开发是合理的。在 2014-2015 年，进行了一项 2b 期临床研究，以评估单剂口服 Artefenomel（OZ439）-哌喹（PPQ）在亚洲和非洲患有无并发症恶性疟的患者中的疗效。
在治疗前采集的血样提供了机会，以调查包括疟原虫 Kelch13 突变在内的多种耐药寄生虫基因型的比例，以及疟原虫原虫质蛋白酶 2（Pfpm2）和疟原虫多药耐药 1（Pfmdr1）基因的拷贝数变异。
仅在越南患者的寄生虫中检测到经过验证的 Kelch13 耐药突变，包括 C580Y、I543T、P553L 和 V568G。在非洲，Pfmdr1 基因的多个拷贝的分离株比以前报道的更为常见（21.1%，范围从布基纳法索的 12.4%到乌干达的 27.4%）。更引人注目的是，与哌喹（PPQ）耐药相关的 Pfpm2 基因多个拷贝的分离株在非洲地区频繁出现，尤其是在布基纳法索和乌干达（>30%）。
这些发现被认为与最近对乌干达寄生虫分离株对 PPQ 敏感性增加的描述形成鲜明对比。这强调了有必要研究非洲分离株中 Pfpm2 基因多个拷贝对 PPQ 的体外敏感性谱，并估计非洲开发 PPQ 耐药的风险。试验注册临床Trials.gov 参考：NCT02083380。研究标题： Artefenomel 和哌喹在恶性疟患者中的成人和儿童中的 II 期疗效研究。https://clinicaltrials.gov/ct2/results?cond=&term=NCT02083380&cntry=&state=&city=&dist=. FSFV：23-Jul-2014；LSLV：09-Oct-2015。
