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Ahead of Print -Effects of Mefloquine Use on Plasmodium vivax Multidrug Resistance - Volume 20, Number 10—October 2014 - Emerging Infectious Disease journal - CDC

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Ahead of Print -Effects of Mefloquine Use on Plasmodium vivax Multidrug Resistance - Volume 20, Number 10—October 2014 - Emerging Infectious Disease journal - CDC


Volume 20, Number 10—October 2014


Effects of Mefloquine Use on Plasmodium vivax Multidrug Resistance

Nimol Khim, Voahangy Andrianaranjaka, Jean Popovici, Saorin Kim, Arsene Ratsimbasoa, Christophe Benedet, Celine Barnadas, Remy Durand, Marc Thellier, Eric Legrand, Lise Musset, Michela Menegon, Carlo Severini, Bakri Y.M. Nour, Magali Tichit, Christiane Bouchier, Odile Mercereau-Puijalon, and Didier Ménard
Author affiliations: Institut Pasteur, Phnom Penh, Cambodia (N. Khim, J. Popovici, S. Kim, C. Benedet, D. Ménard)Institut Pasteur, Antananarivo, Madagascar (V. Andrianaranjaka)Université d’Antananarivo, Antananarivo (A. Ratsimbasoa)Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia (C. Barnadas)University of Melbourne, Melbourne (C. Barnadas)Hôpital Avicenne, Bobigny, France (R. Durand)Centre Hospitalier Universitaire Pitié Salpetrière, Paris, France (M. Thellier)Institut Pasteur, Cayenne, French Guiana (E. Legrand, L. Musset)Istituto Superiore di Sanità (ISS), Rome, Italy (M. Menegon, C. Severini)University of Gezira, Wad Medani, Sudan (B.Y.M. Nour)Institut Pasteur, Paris (M. Tichit, C. Bouchier, O. Mercereau-Puijalon)


Numerous studies have indicated a strong association between amplification of the multidrug resistance-1gene and in vivo and in vitro mefloquine resistance of Plasmodium falciparum. Although falciparum infection usually is not treated with mefloquine, incorrect diagnosis, high frequency of undetected mixed infections, or relapses of P. vivax infection triggered by P. falciparum infections expose non–P. falciparumparasites to mefloquine. To assess the consequences of such unintentional treatments on P. vivax, we studied variations in number of Pvmdr-1 (PlasmoDB accession no. PVX_080100, NCBI reference sequence NC_009915.1) copies worldwide in 607 samples collected in areas with different histories of mefloquine use from residents and from travelers returning to France. Number of Pvmdr-1 copies correlated with drug use history. Treatment against P. falciparum exerts substantial collateral pressure against sympatric P. vivax, jeopardizing future use of mefloquine against P. vivax. A drug policy is needed that takes into consideration all co-endemic species of malaria parasites.
Since World War II, antimalarial drugs have been intensively used to prevent or treat malaria (1). As observed with other antimicrobial agents, their use (or frequent misuse, when malaria diagnosis was based only on clinical symptoms without parasitologic confirmation) led to the emergence, selection, and spread of resistant parasites (2). This resistance became a global problem during the 1960s, when Plasmodium falciparum parasites developed resistance to chloroquine, the most widely used antimalarial drug at that time (3). In particular, resistant parasites that emerged in the Greater Mekong subregion of Asia later spread to Africa, triggering a dramatic increase in malaria and malaria-related deaths, particularly among children (4). During the 1980s, a similar scenario was observed with sulfadoxine-pyrimethamine (SP) when this association was recommended to replace chloroquine as first-line treatment in uncomplicated falciparum malaria (5,6). Since then, biological and molecular investigations using laboratory and field isolates have demonstrated that resistance of P. falciparum to antimalarial drugs is mediated by 2 major mechanisms: 1) a modification of the parasite target (i.e., mutations in dihydrofolate reductase [dhfr] or in dihydropteroate synthetase [dhps] genes) or 2) an increase of the efflux of the drug away from its site of action (i.e., mutations in the chloroquine resistant transportergene or the multidrug resistance-1 [mdr-1] gene or in an increased number of copies of the mdr-1 gene). These molecular events have been intensively studied and are well known for P. falciparum but not for other Plasmodium species, mainly because of the ability to culture in vitro P. falciparumerythrocytic stages.
Our understanding of the molecular mechanisms of antimalarial drug resistance developed by P. vivax is less comprehensive. Although Aotus andSaimiri monkey models have provided useful information about P. vivax biology, most of the data have been gained through comparative studies investigating polymorphisms in orthologous genes encoding resistance to pyrimethamine (dhfr gene), sulfadoxine (dhps gene), or chloroquine (chloroquine resistant transporter or mdr-1 genes). For instance, mutations in codons 57, 58, 61, 117, and 173 of P. vivax DHFR (corresponding to codons 51, 59, 108, and 164 of P. falciparum DHFR) are involved in resistance to pyrimethamine, although P. vivax infections are not usually treated directly with SP (7). This resistance was confirmed by heterologous expression studies, invalidating the common idea that P. vivax was “intrinsically resistant” to pyrimethamine (8), which suggests that the high frequency of mixed P. falciparum/P. vivax infections that are not detected by microscopy (911) or relapses of P. vivax infection after P. falciparum infections probably exposes P. vivax parasites to antimalarial drugs used to treat falciparum malaria infections, especially those with a long half-life, and selects P. vivax genetic traits conferring antimalarial drug resistance.
The impact of antimalarial drugs, especially those with long half-lives (such as mefloquine), on the sympatric Plasmodium species is not clearly understood. In areas where P. falciparum and P. vivax are co-endemic, such as South America and Southeast Asia, mefloquine has been widely used (alone in monotherapy or in combination with artemisinin derivatives) to treat uncomplicated falciparum malaria (12). In both areas, emergence of P. falciparum parasites resistant to mefloquine has been demonstrated from therapeutic efficacy studies (treatment failure) or in vitro testing (increased IC50 [half maximal inhibitory concentration]) and has been associated with the amplification of P. falciparum mdr-1 (Pfmdr-1) gene (1316). Recently, several studies performed on P. vivax samples collected in Southeast Asia (Thailand, Laos, Cambodia, and Myanmar) (1719), South America (Brazil, Honduras) (20,21), and Africa (Mauritania) (22) have shown that mdr-1 amplification does occur in P. vivax.
In this context, and to confirm the impact of the mefloquine drug pressure on P. vivax parasite populations, we used a real-time PCR to assess the number of P. vivax mdr-1 (Pvmdr-1) gene copies to evaluate the worldwide distribution of Pvmdr-1 amplification in samples collected from travelers with vivax malaria returning to France and from residents in areas with different histories of mefloquine use (French Guiana, Cambodia, Madagascar, and Sudan).
Ms Khim is a PhD student at the Malaria Molecular Epidemiology Unit in Institut Pasteur in Cambodia. Her research interests include clinical epidemiology and antimalarial drug resistance in vivax malaria and more generally are focused on developing molecular tools for improving the surveillance of resistance to antimalarial drugs in Cambodia.


We thank all the patients and healthcare workers involved in this study and the staff of the Ministries of Health of Madagascar and Cambodia for their collaboration.
Sample collections and field laboratory work were supported in Madagascar by the Global Fund project for Madagascar round 3 (Community Action to Roll Back Malaria grant no. MDG-304-G05-M) and a Natixis Banques Grant; in Cambodia by the Global Fund Grant Malaria Programme Round 9 (CAM-S10-G14-M); in French Guiana and from French travelers by the French Ministry of Health (InVS agency, Paris); and in Sudan by a grant from the World Health Organization, Global Malaria Programme (HQ/07/100294). Additional funding was provided by the French Ministry of Foreign Affairs (D.M.), the Fondation Pierre Ledoux–Jeunesse Internationale (C.B.), and the Genomics Platform, Pasteur Génopôle, Pasteur Institute (France).


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Technical Appendix

Suggested citation for this article: Kim N, Andrianaranjaka V, Popovici J, Kim S, Ratsimbasoa A, Benedet C, et al. Effects of mefloquine use onPlasmodium vivax multidrug resistance. Emerg Infect Dis [Internet]. 2014 Oct [date cited]. http://dx.doi.org/10.3201/eid2010.140411
DOI: 10.3201/eid2010.140411

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