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    • br Introduction Plasmodium falciparum malaria continues to b

    2019-10-16


    Introduction Plasmodium falciparum malaria continues to be a major global cause of mortality and morbidity. Malaria treatment and control has been complicated by the emergence of resistance to widespread antimalarial drug use. The most common method for measuring antimalarial resistance is estimating the in vivo efficacy of the antimalarial, such as sulfadoxine–pyrimethamine (SP). Since 2003, SP has been used in the intermittent preventive treatment for pregnant women (IPTp-SP) in many Sub-Saharan African countries, including in Senegal since 2003 (WHO, 2004). sulfadoxine–pyrimethamine in combination with amodiaquine was also recently recommended by the WHO for seasonal malaria chemoprevention (SMC) in some malaria-endemic countries (WHO Global Malaria Programme, 2012). Due to the recent recommendation to use artemisinin combination therapies (ACTs) for the treatment of uncomplicated malaria (WHO, 2010), it is no longer acceptable to carry out in vivo efficacy studies of SP used alone for the treatment of uncomplicated malaria. Nonetheless, it is critical to assess parasite SP resistance in order to monitor the efficacy of SP use in IPTp and SMC. Antimalarial drug sensitivity testing provides information on the frequency of resistant phenotypes among the populations of 7112 mass being transmitted, as well as the possible cross-resistance patterns of antimalarial drugs. Isolates are defined as resistant to pyrimethamine when the 50-percent inhibitory concentration (IC50) is greater than 2000nM (Aubouy et al., 2003). In vitro methods to measure parasite resistance to individual components is a useful adjunct to in vivo studies (Desjardins et al., 1979, Smilkstein et al., 2004, Baniecki et al., 2007, Laufer et al., 2007, Kurth et al., 2009, Ndiaye et al., 2010). In vivo and in vitro drug sensitivity tests present numerous technical and cost limitations, and these limitations have led to a search for genetic markers of resistance. As in vivo drug efficacy cannot be routinely monitored in IPTp-SP, an alternative method to track SP resistance is to study the frequency of molecular markers that are associated with SP resistance in the parasite population. The mechanism of action of SP is well documented: point mutations at codons 50, 51, 59, 108, and 164 in the dhfr gene (Bzik et al., 1987, Cowman et al., 1988, Peterson et al., 1988, Peterson et al., 1990, Foote et al., 1990, Basco et al., 1995, Reeder et al., 1996) are found to confer resistance to pyrimethamine, while mutations at codons 437, 540, 581, and 613 of the dhps gene confer resistance to sulfadoxine (Brooks et al., 1994, Triglia and Cowman, 1994, Bickii et al., 1998, Warhurst, 2001, Warsame et al., 2001). The single dhfr 108 mutation can increase in vitro resistance to pyrimethamine by 100-fold relative to wild-type (Reeder et al., 1996, Sirawaraporn et al., 1997), and the progressive addition of mutations altering Cys50 to Arg (C50R), Asn51 to Ile (N51I), Cys59 to Arg (C59R), and Ile164 to Leu (I164L) in the gene can yield higher levels of SP resistance both in vitro and in vivo (Reeder et al., 1996, Sirawaraporn et al., 1997). The triple dhfr mutant genotype consisting of N51I, C59R, and S108N shows in vitro resistance to pyrimethamine that is 225 times higher than a wild-type lab strain (Basco et al., 1995, Nzila-Mounda et al., 1998), and has a strong association with in vivo SP treatment failure (Basco et al., 1998, Kublin et al., 2002, Happi et al., 2005). Sulfadoxine is the most common of the sulfones and sulfonamide class of drugs used in prophylaxis and/or treatment for human malaria caused by P. falciparum. A change at codon A437G in dhps is the first step in resistance to sulfa drugs, followed by sequential mutations at K540E, A581G, and A613S/T, which cause a further increase in drug resistance (Triglia et al., 1997). The quintuple mutant genotype consisting of the double dhps mutant genotype (A437G, K540E) in combination with the dhfr triple mutant genotype (S108N, N51I, C59R) also predicts clinical failure (Omar et al., 2001, Kublin et al., 2002, Mugittu et al., 2004, Staedke et al., 2004, Alker et al., 2008).