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Emergence of Indigenous Artemisinin-Resistant Plasmodium falciparum in Africa

To the Editor: Plasmodium falciparum has developed resistance to artemisinin in many countries in Southeast Asia. Artemisinin combination therapy is the first-line treatment for malaria in the majority of countries in which the disease is endemic, and its efficacy is particularly important in…
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Correspondence

February 22, 2017DOI: 10.1056/NEJMc1612765

Article

To the Editor:

Plasmodium falciparum has developed resistance to artemisinin in many countries in Southeast Asia.1,2 Artemisinin combination therapy is the first-line treatment for malaria in the majority of countries in which the disease is endemic, and its efficacy is particularly important in Africa, where malaria is the most widespread.3 We report here an artemisinin-resistant strain of P. falciparum that was contracted in Africa.

On January 28, 2013, falciparum malaria was diagnosed in a 43-year-old man (identified here as CWX) at a hospital in Jiangsu Province, China. The patient had returned to China on December 3, 2012, after working for 20 months in Equatorial Guinea, where he had been treated for malaria six times. The date and therapeutic regimen associated with each episode are unknown, with the exception of the last episode, when the patient received parenteral artesunate monotherapy starting on November 20, 2012. Before his arrival in Equatorial Guinea, the patient had no history of malaria.

On the patient’s presentation in Jiangsu Province, microscopy revealed P. falciparum parasites in peripheral blood, with an initial parasite density of 4221 per microliter. A monospecies infection was identified on polymerase-chain-reaction assay. The patient received a course of eight tablets of a combination of dihydroartemisinin (40 mg) and piperaquine (320 mg) under direct observation. The parasitemia declined over the next 3 days, but parasites were still detected on day 3 after treatment (Figure 1A). By day 7, no parasites were detected. In contrast, three other isolates that originated from the same country were negative for asexual parasites as of day 3.

In vitro ring-stage survival assay3 revealed a 2.29% survival rate for the CWX isolate, which was substantially higher than the rate in control P. falciparum strains (including wild-type strain 3D7) and in another isolate from a Chinese worker (SBC) who had returned to China from Equatorial Guinea in 2013 but lower than the rate in an artemisinin-resistant parasite line with a C580Y kelch13 mutation (Figure 1B, and the Methods section in the Supplementary Appendix, available with the full text of this letter at NEJM.org). Polymorphisms in the P. falciparum gene encoding kelch13 (K13) have been linked to artemisinin resistance in Southeast Asia. Sequencing of K13 in the CWX isolate revealed a previously unreported nonsynonymous single-nucleotide polymorphism (SNP) that resulted in a switch from a methionine to an isoleucine at amino acid position 579 (M579I).

In order to determine whether the CWX strain was indigenous to Equatorial Guinea, we performed whole-genome sequencing (European Nucleotide Archive accession number, PRJEB18721), and compared the SNPs with those of 245 P. falciparum isolates collected worldwide.4 Principal component analysis showed that the CWX strain was of African origin and had not been recently imported from elsewhere in the world (Figure 1C, and Fig. S2 in the Supplementary Appendix).

There is a perennially high rate of malaria transmission throughout Equatorial Guinea, and artemisinin combination therapies are commonly used for treatment.5 Awareness of artemisinin resistance is prudent in Equatorial Guinea and countries with similar malaria transmission dynamics in order to monitor for the potential emergence of artemisinin resistance in Africa.

Feng Lu, Ph.D.
Jiangsu Institute of Parasitic Diseases, Wuxi, China

Richard Culleton, Ph.D.
Nagasaki University, Nagasaki, Japan

Meihua Zhang, M.Sc.
Shanghai East Hospital, Shanghai, China

Abhinay Ramaprasad, M.Sc.
King Abdullah University of Science and Technology, Thuwal, Saudi Arabia

Lorenz von Seidlein, Ph.D.
Mahidol University, Bangkok, Thailand

Huayun Zhou, M.D.
Guoding Zhu, M.D.
Jianxia Tang, Ph.D.
Yaobao Liu, M.Sc.
Weiming Wang, M.D.
Yuanyuan Cao, M.Sc.
Sui Xu, M.Sc.
Yaping Gu, M.D.
Julin Li, M.D.
Chao Zhang, Ph.D.
Qi Gao, Ph.D.
Jiangsu Institute of Parasitic Diseases, Wuxi, China

Didier Menard, Ph.D.
Institut Pasteur du Cambodge, Phnom Penh, Cambodia

Arnab Pain, Ph.D.
King Abdullah University of Science and Technology, Thuwal, Saudi Arabia

Haitao Yang, M.D.
Jiangsu Institute of Parasitic Diseases, Wuxi, China

Qingfeng Zhang, Ph.D.
Shanghai East Hospital, Shanghai, China

Jun Cao, Ph.D.
Jiangsu Institute of Parasitic Diseases, Wuxi, China

Supported by a grant (2016YFC1200500) from the National Key Research and Development Program of China, grants (81271870, 81630063, and 81601790) from the National Natural Science Foundation of China, grants (BK20150001 and BK20130114) from the Natural Science Foundation of Jiangsu Province, a grant (1500219094) from the Fundamental Research Funds for the Central Universities of China, grants (BE2016631 and BM2015024) from the Jiangsu Provincial Department of Science and Technology, a grant (16K21233, to Dr. Culleton) from the Japan Society for the Promotion of Science, and a grant (BAS/1/1020-01-01, to Dr. Pain) from King Abdullah University of Science and Technology.

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

This letter was published on February 22, 2017, at NEJM.org.

5 References
  1. 1

    Dondorp AM, Nosten F, Yi P, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2009;361:455-467
    Free Full Text | Web of Science | Medline

  2. 2

    Ashley EA, Dhorda M, Fairhurst RM, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2014;371:411-423
    Free Full Text | Web of Science | Medline

  3. 3

    Witkowski B, Amaratunga C, Khim N, et al. Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies. Lancet Infect Dis 2013;13:1043-1049
    CrossRef | Web of Science | Medline

  4. 4

    Manske M, Miotto O, Campino S, et al. Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing. Nature 2012;487:375-379
    CrossRef | Web of Science | Medline

  5. 5

    World malaria report 2014. Geneva: World Health Organization, 2014 (http:/www.who.int/malaria/publications/world_malaria_report_2014/en/).

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