Browsing by Author "Pearce, Richard J"
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Item The evolution of pyrimethamine resistant dhfr in Plasmodium falciparum of south-eastern Tanzania: comparing selection under SP alone vs SP +artesunate combination(Malaria Journal, 2011) Malisa, Allen L; Pearce, Richard J; Mutayoba, Ben M; Abdullah, Salim; Mshinda, Hassan; Kachur, Patrick S; Bloland, Peter; Roper, CallyBackground: Sulphadoxine-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) Methods: The 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 Results: The 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. Conclusion: The 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.Item The genetic change in P. falciparum populations of rural Tanzania resulting from national policy on firstline malaria treatment and pilot Sulfadoxine/pyrimethamine and Artesunate combination(Malaria Journal, 2010-10) Malisa, Allen L; Pearce, Richard J; Abdullah, Salim; Mshinda, Hassan; Kachur, Patrick; Bloland, Peter; Roper, CallyTheory predicts that we can protect the efficacy of future antimalarials by changing treatment practice or drug formulation, but the potential success of such interventions rests upon their impact on drug pressure in the field. So far, gathering field data on the relationship between policy, drug pressure, recombination and the evolution of resistance has been entirely challenging. To test these predictions, dhfr and dhps frequency changes were measured in two rural districts of Rufiji and Kilombero/Ulanga during 2000-2006, and the frequencies of the two genes compared prior, during and after antimalarial policy change from first line CQ to first line SP in 2001. Furthermore, while SP first line was maintained in Kilombero/Ulanga, pilot combination therapy of SP+Artesunate (ART) was introduced in Rufiji in 2002 to replace SP and dhfr and dhps frequency changes compared between the two districts. Size polymorphisms at three sets of microsatellite loci linked to dhfr and three other sets of unlinked microsatellite loci were analysed. Genetic analysis of SP resistance genes was carried out on 9,662 Plasmodium falciparum infections identified in a series of annual cross sectional surveys conducted in the two districts between 2000-2006. The frequency of dhfr and dhps resistance alleles did not change significantly while SP was the recommended second-line treatment, but highly significant changes occurred during the subsequent year after the switch to first line SP. The frequency of the triple mutant dhfr allele increased by 37% -63% and that of double mutant dhps allele increased 200%-300%. A strong association between these unlinked alleles also emerged; confirming that they are co-selected by SP. Distribution of major lineages indicates that there is extensive genetic exchange among the geographic regions. Combination therapy had visible effect on the frequencies of dhfr and dhps resistance alleles. The findings of this study provide insight on the interplay between policy, drug pressure, recombination and the evolution of resistance.Item Media, health workers, and policy makers’ relationship and their impact on antimalarial policy adoption: a population genetics perspective(Sokoine University of Agriculture, Tanzania., 2010-04) Malisa, Allen L; Pearce, Richard J; Mutayoba, Benezeth; Abdullah, Salim; Mshinda, Hassan; Kachur, Patrick; Bloland, Peter; Roper, CallyDrug resistance negatively impacts malaria treatments, making treatment policy revision unavoidable. So far, studies relating sociopolitical and technical issues on policy change with malaria parasite genetic change are lacking.We have quantified the effect of malaria treatment policy on drug pressure and the influence of the media, policy makers, and health worker relationship on parasite population genetic change in Kilombro/Ulanga district. Cross-sectional surveys of asymptomatic infections conducted before, during and after the switch from chloroquine to sulphadoxine/pyrimethamine were used for genetic analysis of SP resistance genes in 4,513 asymptomatic infections identified, and their frequency change was compared with retrospective study of the documented process of policy change. Highly significant changes of dhfr and dhps resistance alleles occurred within one year of switch to SP first line, followed by a decline of their rate of selection caused by reduction of SP usage, as a result of negative media reports on SP usage and lack of adequate preparations.Item Reduced variatio around drug-resistant dhfr alleles in African plasmodium falciparum(Oxford University Press, 2005-05-25) Pearce, Richard J; Malisa, Allen L; Kachur, Patrick; Barnes, Karen; Brian, Sharp; Roper, CallyWe have measured microsatellite diversity at 26 markers around the dhfr gene in pyrimethamine-sensitive and -resistant parasites collected in southeast Africa. Through direct comparison with diversity on sensitive chromosomes we have found significant loss of diversity across a region of 70 kb around the most highly resistant allele which is evidence of a selective sweep attributable to selection through widespread use of pyrimethamine (in combination with sulfadoxine) as treatment for malaria. Retrospective analysis through four years of direct and continuous selection from use of sulfadoxinepyrimethamine as first-line malaria treatment on a Plasmodium falciparum population in KwaZulu Natal, South Africa, has revealed how recombination significantly narrowed the margins of the selective sweep over time. A deterministic model incorporating selection coefficients measured during the same interval indicates that the transition was toward a state of recombination-selection equilibrium. We compared loss of diversity around the same resistance allele in two populations at either extreme of the range of entomological inoculation rates (EIRs), namely, under one infective bite per year in Mpumalanga, South Africa, and more than one per day in southern Tanzania. EIRs determine effective recombination rates and are expected to profoundly influence the dimensions of the selective sweep. Surprisingly, the dimensions were broadly consistent across both populations. We conclude that despite different recombination rates and contrasting drug selection histories in neighboring countries, the region-wide movement of resistant parasites has played a key role in the establishment of resistance in these populations and the dimensions of the selective sweep are dominated by the influence of high initial starting frequencies.