In the JournalsPerspective

Drug-resistant malaria spreads in Asia, prompting calls for new treatments

More than 80% of malaria parasites circulating in northeast Thailand and Vietnam between 2016 and 2018 were resistant to a widely used frontline malaria drug combination, according to findings from two studies published in The Lancet Infectious Diseases.

The frontline treatment, dihydroartemisinin-piperaquine, failed in approximately half of malaria cases in western and northeastern Cambodia, northeastern Thailand and southwestern Vietnam between 2015 and 2018, researchers found.

“These worrying findings indicate that the problem of multidrug resistance in [Plasmodium] falciparum has substantially worsened in southeast Asia since 2015,” Olivo Miotto, PhD, from the Wellcome Sanger Institute and University of Oxford, said in a news release. “This highly successful resistant parasite strain is capable of invading new territories and acquiring new genetic properties, raising the terrifying prospect that it could spread to Africa where most malaria cases occur, as resistance to chloroquine did in the 1980s, contributing to millions of deaths.”

Resistance proliferates

Building on a 2018 study that showed resistance to dihydroartemisinin-piperaquine spread undetected for 5 years in Cambodia, Miotto and colleagues conducted a genomic epidemiology study tracking the emergence and spread of a multidrug-resistant malaria strain with a KEL1/PLA1 colineage between 2007 and 2018. Parasites of this colineage carry gene variants that make them resistant to both components of dihydroartemisinin-piperaquine.

Miotto and colleagues analyzed 1,673 P. falciparum samples from 19 provinces across Cambodia, Laos, northeast Thailand and Vietnam, including 1,615 in which KEL1/PLA1 status could be identified. They found that KEL1/PLA1 parasites had spread rapidly from Cambodia — the only country where they were found before 2009 — to all the surveyed countries, with the prevalence being higher than 50% in all regions except Laos.

Several emergent genetic subgroups of KEL1/PLA1 carried novel mutations in the chloroquine resistance transporter (crt) gene, which enables parasites to better resist piperaquine, “suggesting a proliferation of biologically fit, multidrug-resistant parasites,” the researchers explained.

Findings from the multicountry randomized trial Tracking Resistance to Artemisinin Collaboration also concluded that dihydroartemisinin-piperaquine is not efficacious in Asia, with failure rates reaching 27% in northeastern Cambodia, 62% in western Cambodia, 53% in southwestern Vietnam and 87% in northeastern Thailand. Further, 74% of resistant parasite samples from Cambodia, Thailand and Vietnam between 2015 and 2018 carried crt mutations associated with piperaquine resistance, compared with 5% between 2011 and 2013, when these mutations were reported only in western Cambodia.

“With the spread and intensification of resistance, our findings highlight the urgent need to adopt alternative first-line treatments,” study author Tran Tinh Hien, MD, PhD, FRCP, director of clinical research for the Oxford University Clinical Research Unit, said in a the release. “One option is to switch the partner drug piperaquine to a drug that is currently effective such as mefloquine or pyronaridine — as Cambodia and Thailand have already done.”

However, Hien noted that resistance to these partner drugs also may develop in the presence of artemisinin resistance, and triple artemisinin-based combination therapies may serve as another option.

In a related editorial, Didier Ménard, PhD, from the Pasteur Institute in France, and David A. Fidock, PhD, professor of microbiology and immunology and medical sciences at Columbia University in New York, noted that the two studies highlight the rapid pace at which P. falciparum’s resistance to malaria combination drug therapy has spread throughout Asia.

“These two studies highlight the urgent need to adopt new and effective treatments (such as the triple artemisinin-based combined therapies or the artemisinin-based combined therapy artesunate plus pyronaridine),” they wrote. “These findings also demonstrate the advantages of implementing a regional strategy rather than country-specific programs to address population movements and to integrate regional clinical and genetic surveillance systems into a coordinated campaign, with the goal of achieving malaria elimination in southeast Asia.” by Joe Gramigna

References:

Amato R, et al. Lancet Infect Dis. 2018;doi:10.1016/S1473-3099(18)30068-9.

Hamilton WL, et al. Lancet Infect Dis. 2019;10.1016/S1473-3099(19)30392-5.

Ménard D, Fidock DA. Lancet Infect Dis. 2019;10.1016/S1473-3099(19)30394-9.

van der Pluijm RW, et al. Lancet Infect Dis. 2019;10.1016/S1473-3099(19)30391-3.

Disclosures: The authors report no relevant financial disclosures.

More than 80% of malaria parasites circulating in northeast Thailand and Vietnam between 2016 and 2018 were resistant to a widely used frontline malaria drug combination, according to findings from two studies published in The Lancet Infectious Diseases.

The frontline treatment, dihydroartemisinin-piperaquine, failed in approximately half of malaria cases in western and northeastern Cambodia, northeastern Thailand and southwestern Vietnam between 2015 and 2018, researchers found.

“These worrying findings indicate that the problem of multidrug resistance in [Plasmodium] falciparum has substantially worsened in southeast Asia since 2015,” Olivo Miotto, PhD, from the Wellcome Sanger Institute and University of Oxford, said in a news release. “This highly successful resistant parasite strain is capable of invading new territories and acquiring new genetic properties, raising the terrifying prospect that it could spread to Africa where most malaria cases occur, as resistance to chloroquine did in the 1980s, contributing to millions of deaths.”

Resistance proliferates

Building on a 2018 study that showed resistance to dihydroartemisinin-piperaquine spread undetected for 5 years in Cambodia, Miotto and colleagues conducted a genomic epidemiology study tracking the emergence and spread of a multidrug-resistant malaria strain with a KEL1/PLA1 colineage between 2007 and 2018. Parasites of this colineage carry gene variants that make them resistant to both components of dihydroartemisinin-piperaquine.

Miotto and colleagues analyzed 1,673 P. falciparum samples from 19 provinces across Cambodia, Laos, northeast Thailand and Vietnam, including 1,615 in which KEL1/PLA1 status could be identified. They found that KEL1/PLA1 parasites had spread rapidly from Cambodia — the only country where they were found before 2009 — to all the surveyed countries, with the prevalence being higher than 50% in all regions except Laos.

Several emergent genetic subgroups of KEL1/PLA1 carried novel mutations in the chloroquine resistance transporter (crt) gene, which enables parasites to better resist piperaquine, “suggesting a proliferation of biologically fit, multidrug-resistant parasites,” the researchers explained.

Findings from the multicountry randomized trial Tracking Resistance to Artemisinin Collaboration also concluded that dihydroartemisinin-piperaquine is not efficacious in Asia, with failure rates reaching 27% in northeastern Cambodia, 62% in western Cambodia, 53% in southwestern Vietnam and 87% in northeastern Thailand. Further, 74% of resistant parasite samples from Cambodia, Thailand and Vietnam between 2015 and 2018 carried crt mutations associated with piperaquine resistance, compared with 5% between 2011 and 2013, when these mutations were reported only in western Cambodia.

“With the spread and intensification of resistance, our findings highlight the urgent need to adopt alternative first-line treatments,” study author Tran Tinh Hien, MD, PhD, FRCP, director of clinical research for the Oxford University Clinical Research Unit, said in a the release. “One option is to switch the partner drug piperaquine to a drug that is currently effective such as mefloquine or pyronaridine — as Cambodia and Thailand have already done.”

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However, Hien noted that resistance to these partner drugs also may develop in the presence of artemisinin resistance, and triple artemisinin-based combination therapies may serve as another option.

In a related editorial, Didier Ménard, PhD, from the Pasteur Institute in France, and David A. Fidock, PhD, professor of microbiology and immunology and medical sciences at Columbia University in New York, noted that the two studies highlight the rapid pace at which P. falciparum’s resistance to malaria combination drug therapy has spread throughout Asia.

“These two studies highlight the urgent need to adopt new and effective treatments (such as the triple artemisinin-based combined therapies or the artemisinin-based combined therapy artesunate plus pyronaridine),” they wrote. “These findings also demonstrate the advantages of implementing a regional strategy rather than country-specific programs to address population movements and to integrate regional clinical and genetic surveillance systems into a coordinated campaign, with the goal of achieving malaria elimination in southeast Asia.” by Joe Gramigna

References:

Amato R, et al. Lancet Infect Dis. 2018;doi:10.1016/S1473-3099(18)30068-9.

Hamilton WL, et al. Lancet Infect Dis. 2019;10.1016/S1473-3099(19)30392-5.

Ménard D, Fidock DA. Lancet Infect Dis. 2019;10.1016/S1473-3099(19)30394-9.

van der Pluijm RW, et al. Lancet Infect Dis. 2019;10.1016/S1473-3099(19)30391-3.

Disclosures: The authors report no relevant financial disclosures.

    Perspective
    Philip J. Rosenthal

    Philip J. Rosenthal

    As has been characterized over the last decade, P. falciparum, the most virulent human malaria parasite, has developed tolerance (delayed clearance after therapy) to artemisinins, our most important antimalarials, in the Greater Mekong Subregion of Southeast Asia. Artemisinins plus other agents — artemisinin-based combination therapy (ACT) — provide our first-line regimens to treat falciparum malaria. One ACT, dihydroartemisinin-piperaquine, is the standard treatment in parts of Asia. Recently, P. falciparum also developed resistance to piperaquine in this region, and failures of therapy with dihydroartemisinin-piperaquine have become alarmingly common. New reports offer updates. Van der Pluijm and colleagues describe results that are part of an ongoing multi-arm trial but were deemed important enough to publish before trial completion. Treatment efficacies for dihydroartemisinin-piperaquine were terrible as low as 13% at a site in Thailand, and well below desired levels (less than 90%) at sites in Cambodia and Vietnam. Hamilton and colleagues report that the resistant parasites represent a specific P. falciparum lineage that emerged in Cambodia and has spread to surrounding countries and diversified.

    What is the relevance of these new results? For Southeast Asia, dihydroartemisinin-piperaquine should be avoided, but other ACTs remain efficacious, and poor malaria outcomes are uncommon. For the long term, new treatment approaches are needed, including triple artemisinin combinations now under study and novel antimalarials under development. For the remainder of the malaria-infected world, close surveillance for the progression of drug resistance is needed because spread of ACT resistance from southeast Asia to other areas, in particular Africa, may have devastating consequences.

    • Philip J. Rosenthal, MD, FASTMH
    • Professor of medicine, University of California, San Francisco
      Editor-in-Chief, The American Journal of Tropical Medicine and Hygiene

    Disclosures: Rosenthal reports no relevant financial disclosures.