Institut Pasteur reports emergence of resistance in Madagascar

from Andriantsoanirina et al. Antimicrobial Agents & Chemotherapy

P. falciparum drug resistance in Madagascar: facing the spread of unusual pfdhfr and pfmdr-1 haplotypes and the decrease of dihydroartemisinin susceptibility.

Over the past decades, the emergence and subsequent spread of Plasmodium falciparum chloroquine (CQ)- and sulfadoxine/pyrimethamine (SP)-resistant parasites across malaria endemic areas have been a challenge to malaria control programs (41, 44). Substantial advances have been made towards understanding the genetic basis of antimalarial drug resistance (14). Molecular evolutionary studies have concluded that the CQ-resistant P. falciparum chloroquine resistance transporter (pfcrt) and high level pyrimethamine-resistant dihydrofolate (pfdhfr) alleles have emerged in a limited number of independent foci, from which they have rapidly spread in the vicinity, then invaded continent-wide areas and been transferred between continents (1, 36). These lessons of the past have stimulated firstly changes in antimalarial treatment policy by introducing combination of drugs that act on different targets and secondly implementation of effective monitoring systems to detect at the earliest possible time the emergence of resistant parasites based on the assessment of antimalarials therapeutic efficacy (25, 46), decreased parasite in vitro drug sensitivity (4) and increasing prevalence of molecular markers related to drug resistance (24).

In the South-Western Indian Ocean, according to data published from 2002 to 2006, the epidemiological features of the P. falciparum CQ- and SP-resistance differ considerably between Madagascar and the Comoros islands, two closely located countries (43). In vitro CQ-resistance was moderate in Madagascar (29, 33, 45) although therapeutic efficacy was declining. During that time period, CQ-resistance was high in the Comoros Islands (22, 23, 30). Likewise, pyrimethamine resistance was absent from Madagascar (28, 32), but present at high levels in the Comoros Islands (23). The most recent in vivo data based on WHO 28-day follow-up protocol, conducted in 2006-2007 in multi-sites, have confirmed that resistance in Madagascar remains rare, except for CQ. Indeed, the prevalence of clinical failures for amodiaquine, SP and the artesunate plus amodiaquine combination was < 5%, while failure rate for chloroquine was 44% (19). However, the recent demonstration of the introduction of P. falciparum multidrug resistant parasites into Madagascar from the Comoros Islands (18) or the emergence of the uncommon dihydrofolate reductase I164L genotype in P. falciparum parasite (17) suggest that the situation is currently changing in Madagascar.

In this context and in order to help the rationalization of the malaria elimination policy, recently launched by the Malagasy government (withdrawal of CQ in favour of artesunate plus amodiaquine combination -ASAQ- as first-line treatment and SP usage for intermittent preventive treatment for pregnant women), a large scale survey was designed and carried out between the years 2006-2008. The aim was to provide a comprehensive spatio-temporal picture of the P. falciparum resistance in several geographic areas of Madagascar. We report here the prevalence of P. falciparum parasites harboring mutations correlated with resistance to some quinolines namely pfcrt and P. falciparum multidrug resistance gene 1 (pfmdr-1) or SP-resistance (pfdhfr, pfdhps), or presenting an increased pfmdr-1 gene copy number along with the in vitro response of parasites for a panel of drugs including chloroquine, mefloquine, amodiaquine, quinine or artemisinin derivatives. In addition, information related to risk factors contributing to the spread of antimalarial drug resistance such as the antimalarials resistance in the neighboring islands of the Comoros Archipelago, drug pressure and population movement in Madagascar was collected (8, 42).

http://aac.asm.org/content/53/11/4588.abstract