Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated malaria and prevalence of Pfk13 and Pfmdr1 polymorphisms after a decade of using artemisinin-based combination therapy in mainland Tanzania
Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated malaria and prevalence of Pfk13 and Pfmdr1 polymorphisms after a decade of using artemisinin-based combination therapy in mainland Tanzania
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DOI：
10.1186/s12936-019-2730-1
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发表时间：
2019-03-21
期刊：
影响因子：
3
通讯作者：
Udhayakumar, Venkatachalam
中科院分区：
文献类型：
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作者：
Ishengoma, Deus S.;Mandara, Celine I.;Udhayakumar, Venkatachalam
背景：世界卫生组织建议定期进行治疗效果研究（TES），以监测一线和二线抗疟疾药物的效果。2016年，通过2016年4月至10月在坦桑尼亚Kibaha、Mkuzi、Mlimba和Ujiji四个哨点进行的TES试验，评估了蒿甲醚-甲苯胺（AL）治疗无并发症恶性疟疾的有效性和安全性。该研究还评估了青蒿素和甲苯胺（伴侣药）耐药性的分子标记。方法：在四个地点招募符合条件的患者，使用标准剂量的AL治疗，并通过临床和实验室评估监测28天。主要结果为PCR校正治愈率、第3天阳性率、AL安全性、恶性疟原虫kelch 13（密码子位置440 ~ 600）和恶性疟原虫耐多药1 （Pfmdr1）基因（密码子N86Y、Y184F和D1246Y）单核苷酸多态性的流行情况，这些基因分别是青蒿素和氨苯曲明耐药标志物。结果：入组的344例患者中，3例退出，6例失访；对335例（97.4%）患者进行结果分析。经PCR校正后，2例患者治疗失败（1例早期治疗失败，1例复发感染），临床和寄生虫学应答率为98%。第3天阳性率为0 ~ 5.7%。常见的不良反应包括咳嗽、腹痛、呕吐和腹泻。2例患者发生严重不良事件；1例在第一次给药后死亡，另1例在第二次给药后（第0天）需要住院治疗，但完全康复。在入组（第0天）收集的344份样本中，Pfk13和Pfmdr1基因的测序成功率分别为92.7%和100%。6例（1.9%）患者在Pfk13中存在非同义突变，这些突变先前均未与青蒿素耐药性相关。Pfmdr1在134份（39.0%）样本中检测到NFD单倍型（密码子N86、184F和D1246）；从Mlimba的33.0%到Mkuzi的45.5%不等。4个位点间差异无统计学意义（p = 0.578）。所有样本都有一个Pfmdr1基因拷贝。结论：本研究显示AL疗效高，安全性与文献报道一致。没有已知的对青蒿素耐药的Pfk13突变，但Pfmdr1单倍型的高患病率与对氟苯曲明的敏感性降低有关（但在受试者中未观察到疗效降低）。继续进行TES检测和监测对青蒿素及其伙伴药物的耐药性标志对于早期发现耐药寄生虫和为循证疟疾治疗政策提供信息至关重要。
Background: The World Health Organization recommends regular therapeutic efficacy studies (TES) to monitor the performance of first and second-line anti-malarials. In 2016, efficacy and safety of artemether-lumefantrine (AL) for the treatment of uncomplicated falciparum malaria were assessed through a TES conducted between April and October 2016 at four sentinel sites of Kibaha, Mkuzi, Mlimba, and Ujiji in Tanzania. The study also assessed molecular markers of artemisinin and lumefantrine (partner drug) resistance.Methods: Eligible patients were enrolled at the four sites, treated with standard doses of AL, and monitored for 28 days with clinical and laboratory assessments. The main outcomes were PCR corrected cure rates, day 3 positivity rates, safety of AL, and prevalence of single nucleotide polymorphisms in Plasmodium falciparum kelch 13 (Pfk13) (codon positions: 440-600) and P. falciparum multi-drug resistance 1 (Pfmdr1) genes (codons: N86Y, Y184F and D1246Y), markers of artemisinin and lumefantrine resistance, respectively.Results: Of 344 patients enrolled, three withdrew, six were lost to follow-up; and results were analysed for 335 (97.4%) patients. Two patients had treatment failure (one early treatment failure and one recrudescent infection) after PCR correction, yielding an adequate clinical and parasitological response of > 98%. Day 3 positivity rates ranged from 0 to 5.7%. Common adverse events included cough, abdominal pain, vomiting, and diarrhoea. Two patients had serious adverse events; one died after the first dose of AL and another required hospitalization after the second dose of AL (on day 0) but recovered completely. Of 344 samples collected at enrolment (day 0), 92.7% and 100% were successfully sequenced for Pfk13 and Pfmdr1 genes, respectively. Six (1.9%) had non-synonymous mutations in Pfk13, none of which had been previously associated with artemisinin resistance. For Pfmdr1, the NFD haplotype (codons N86, 184F and D1246) was detected in 134 (39.0%) samples; ranging from 33.0% in Mlimba to 45.5% at Mkuzi. The difference among the four sites was not significant (p = 0.578). All samples had a single copy of the Pfmdr1 gene.Conclusion: The study indicated high efficacy of AL and the safety profile was consistent with previous reports. There were no known artemisinin-resistance Pfk13 mutations, but there was a high prevalence of a Pfmdr1 haplotype associated with reduced sensitivity to lumefantrine (but no reduced efficacy was observed in the subjects). Continued TES and monitoring of markers of resistance to artemisinin and partner drugs is critical for early detection of resistant parasites and to inform evidence-based malaria treatment policies.