The evolution of pyrimethamine resistant dhfr in Plasmodium falciparum of south-eastern Tanzania: comparing selection under SP alone vs SP+artesunate combination

Abstract

BackgroundSulphadoxine-pyrimethamine (SP) resistance is now widespread throughout east and southern Africa and artemisinin compounds in combination with synthetic drugs (ACT) are recommended as replacement treatments by the World Health Organization (WHO). As well as high cure rates, ACT has been shown to slow the development of resistance to the partner drug in areas of low to moderate transmission. This study looked for evidence of protection of the partner drug in a high transmission African context. The evaluation was part of large combination therapy pilot implementation programme in Tanzania, the Interdisciplinary Monitoring Programme for Antimalarial Combination Therapy (IMPACT-TZ)MethodsThe growth of resistant dhfr in a parasite population where SP Monotherapy was the first-line treatment was measured for four years (2002-2006), and compared with the development of resistant dhfr in a neighbouring population where SP + artesunate (SP+AS) was used as the first-line treatment during the same interval. The effect of the differing treatment regimes on the emergence of resistance was addressed in three ways. First, by looking at the rate of increase in frequency of pre-existing mutant dhfr alleles under monotherapy and combination therapy. Second, by examining whether de-novo mutant alleles emerged under either treatment. Finally, by measuring diversity at three dhfr flanking microsatellite loci upstream of the dhfr gene.ResultsThe reduction in SP selection pressure resulting from the adoption of ACT slowed the rate of increase in the frequency of the triple mutant resistant dhfr allele. Comparing between the two populations, the higher levels of genetic diversity in sequence flanking the dhfr triple mutant allele in the population where the ACT regimen had been used indicates the reduction in SP selection pressure arising from combination therapy.ConclusionThe study demonstrated that, alleles containing two mutations at the dhfr have arisen at least four times independently while those containing triple mutant dhfr arose only once, and were found carrying a single unique Asian-type flanking sequence, which apparently drives the spread of pyrimethamine resistance associated dhfr alleles in east Africa. SP+AS is not recommended for use in areas where SP cure rates are less than 80% but this study reports an observed principle of combination protection from an area where pyrimethamine resistance was already high.

Learning, Misallocation, and Technology Adoption: Evidence from New Malaria Therapy in Tanzania

“…When it was introduced throughout the African continent in 2000, SP was extremely effective, as demonstrated by randomized controlled trials in malaria-endemic settings, in the treatment of falciparum malaria, the most prevalent type of malaria parasite in Africa. By 2003, parasitic resistance had reduced the effectiveness of SP by half in most of the places it was once effective (Malisa et al, 2011). …”

“…The proportion of individuals receiving effective treatment is a function of the (local) resistance to antimalarial therapies other than ACT. For example, in many areas of Tanzania, more than half of P. falciparum samples had acquired resistance to sulphadoxine pyrimethamine (SP) by 2004 (Malisa et al, 2011). In the extreme case, one might argue that only ACT was maximally effective, meaning that only those individuals in the treatment district post-intervention would plausibly change from positive to negative malarial status in the above defined time span.…”

Quantification of markers of antimalarial drug resistance from an area of high malaria transmission: Comparing frequency with prevalence

“…This study has quantified the difference between prevalence and frequency when reporting field data on antimalarial drug resistance obtained by direct counting of SNPs or haplotypes. Until recently, frequency method is still a common reporting method 2009; Roper et al, 2003;Malisa et al, 2010Malisa et al, , 2011. We found greater frequencies than prevalences for the sensitive haplotypes and resistant haplotypes conferring high resistance to pyrimethamine (CIRN) and sulfadoxine (SGEAA), but greater prevalences than frequencies in haplotypes conferring mild resistance to pyrimethamine (CNCN, CNRN, and CICN) and to sulfadoxine (AAKAA) in 2000 and 2006 isolates from the two study sites.…”

“…At the time of sample collection in 2000, Sulfadoxine/pryrimethamine (SP) was still a second line treatment and it only replaced chloroquine (CQ) as the recommended first-line antimalarial treatment on the Tanzanian mainland in August 2001, after 18 years of its use as a second-line treatment since 1983. Clearly, the SP drug selection pressure was very low and a result of monitoring of resistant dhfr and dhps allelic haplotypes in the same area found that the frequency of the most resistant allele, the double dhps-triple dhfr (SGAA-CIRN) mutant genotype, increased by only 1% during 17 years of SP second line use, but there was a dramatic increase by a 45% during five (2001 to 2006) years of SP first line use (Malisa et al, 2011). Consequently, as a result of low selection the proportion of mildly resistant alleles also remained low leading to the observed higher prevalences than frequencies.…”

Novel 4-ferrocenyl-8-(phenylthio)-1,2,3,4-tetrahydroquinoline: Design, synthesis and spectral characterization

“…In the *Coresponding author: aleksandra.minic@pr.ac.rs context of antimalarial treatments, it is known that metalcontaining compounds may possess antiparasitic activity (Gambino & Otero, 2012;Salas et al, 2013;Biot et al, 2012). Ferroquine (FQ), an analogue of chloroquinoline (CQ), has been developed as an important antimalarial drug; it is currently in the Phase II Sanofi portfolio for uncomplicated P. falciparum malaria (Malisa et al, 2011;Supan et al, 2012). In terms of developing new drugs based on FQ, this led to the preparation of a numerous analogues (N'Da, & Smith, 2014).…”