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Plasmodium falciparum resistance to anti-malarial drugs in Papua New Guinea: evaluation of a community-based approach for the molecular monitoring of resistance.

Marfurt J, Smith TA, Hastings IM, Müller I, Sie A, Oa O, Baisor M, Reeder JC, Beck HP, Genton B - Malar. J. (2010)

Bottom Line: In the community samples, the frequencies of mutations in pfcrt and pfmdr1 were high and did not show significant changes over time.This variation did not correlate well with treatment failure rates.Testing community samples for molecular drug resistance markers is a complementary tool that should help decision-making for the best treatment options and appropriate potential alternatives.

View Article: PubMed Central - HTML - PubMed

Affiliation: Swiss Tropical Institute, Department of Medical Parasitology and Infection Biology, and Department of Public Health and Epidemiology, Socinstrasse 57, PO Box, CH-4002 Basel, Switzerland.

ABSTRACT

Background: Molecular monitoring of parasite resistance has become an important complementary tool in establishing rational anti-malarial drug policies. Community surveys provide a representative sample of the parasite population and can be carried out more rapidly than accrual of samples from clinical cases, but it is not known whether the frequencies of genetic resistance markers in clinical cases differ from those in the overall population, or whether such community surveys can provide good predictions of treatment failure rates.

Methods: Between 2003 and 2005, in vivo drug efficacy of amodiaquine or chloroquine plus sulphadoxine-pyrimethamine was determined at three sites in Papua New Guinea. The genetic drug resistance profile (i.e., 33 single nucleotide polymorphisms in Plasmodium falciparum crt, mdr1, dhfr, dhps, and ATPase6) was concurrently assessed in 639 community samples collected in the catchment areas of the respective health facilities by using a DNA microarray-based method. Mutant allele and haplotype frequencies were determined and their relationship with treatment failure rates at each site in each year was investigated.

Results: PCR-corrected in vivo treatment failure rates were between 12% and 28% and varied by site and year with variable longitudinal trends. In the community samples, the frequencies of mutations in pfcrt and pfmdr1 were high and did not show significant changes over time. Mutant allele frequencies in pfdhfr were moderate and those in pfdhps were low. No mutations were detected in pfATPase6. There was much more variation between sites than temporal, within-site, variation in allele and haplotype frequencies. This variation did not correlate well with treatment failure rates. Allele and haplotype frequencies were very similar in clinical and community samples from the same site.

Conclusions: The relationship between parasite genetics and in vivo treatment failure rate is not straightforward. The frequencies of genetic anti-malarial resistance markers appear to be very similar in community and clinical samples, but cannot be used to make precise predictions of clinical outcome. Thus, indicators based on molecular data have to be considered with caution and interpreted in the local context, especially with regard to prior drug usage and level of pre-existing immunity. Testing community samples for molecular drug resistance markers is a complementary tool that should help decision-making for the best treatment options and appropriate potential alternatives.

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Comparison of mutant allele frequencies between clinical and community samples at two study sites in Papua New Guinea in the year 2003. Error bars denote 95% confidence intervals calculated from 10,000 bootstrap samples of the data.
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Figure 2: Comparison of mutant allele frequencies between clinical and community samples at two study sites in Papua New Guinea in the year 2003. Error bars denote 95% confidence intervals calculated from 10,000 bootstrap samples of the data.

Mentions: Comparison of the drug resistance profile in community and clinical samples was only possible in the Karimui and South Wosera areas in 2003. In Karimui, the allele frequencies in health centre samples were close to those from community samples for the same year (Table S4, Additional file 4 and Figure 2). In the Wosera, there were small effects of both, year and source of the samples on the allele and haplotype frequencies (both values 0.011). Despite the rather similar allele frequencies in community and health centre samples, the differences in haplotype frequencies between health centre and community samples were statistically significant for each locus except pfmdr1 (Table 2).


Plasmodium falciparum resistance to anti-malarial drugs in Papua New Guinea: evaluation of a community-based approach for the molecular monitoring of resistance.

Marfurt J, Smith TA, Hastings IM, Müller I, Sie A, Oa O, Baisor M, Reeder JC, Beck HP, Genton B - Malar. J. (2010)

Comparison of mutant allele frequencies between clinical and community samples at two study sites in Papua New Guinea in the year 2003. Error bars denote 95% confidence intervals calculated from 10,000 bootstrap samples of the data.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2820042&req=5

Figure 2: Comparison of mutant allele frequencies between clinical and community samples at two study sites in Papua New Guinea in the year 2003. Error bars denote 95% confidence intervals calculated from 10,000 bootstrap samples of the data.
Mentions: Comparison of the drug resistance profile in community and clinical samples was only possible in the Karimui and South Wosera areas in 2003. In Karimui, the allele frequencies in health centre samples were close to those from community samples for the same year (Table S4, Additional file 4 and Figure 2). In the Wosera, there were small effects of both, year and source of the samples on the allele and haplotype frequencies (both values 0.011). Despite the rather similar allele frequencies in community and health centre samples, the differences in haplotype frequencies between health centre and community samples were statistically significant for each locus except pfmdr1 (Table 2).

Bottom Line: In the community samples, the frequencies of mutations in pfcrt and pfmdr1 were high and did not show significant changes over time.This variation did not correlate well with treatment failure rates.Testing community samples for molecular drug resistance markers is a complementary tool that should help decision-making for the best treatment options and appropriate potential alternatives.

View Article: PubMed Central - HTML - PubMed

Affiliation: Swiss Tropical Institute, Department of Medical Parasitology and Infection Biology, and Department of Public Health and Epidemiology, Socinstrasse 57, PO Box, CH-4002 Basel, Switzerland.

ABSTRACT

Background: Molecular monitoring of parasite resistance has become an important complementary tool in establishing rational anti-malarial drug policies. Community surveys provide a representative sample of the parasite population and can be carried out more rapidly than accrual of samples from clinical cases, but it is not known whether the frequencies of genetic resistance markers in clinical cases differ from those in the overall population, or whether such community surveys can provide good predictions of treatment failure rates.

Methods: Between 2003 and 2005, in vivo drug efficacy of amodiaquine or chloroquine plus sulphadoxine-pyrimethamine was determined at three sites in Papua New Guinea. The genetic drug resistance profile (i.e., 33 single nucleotide polymorphisms in Plasmodium falciparum crt, mdr1, dhfr, dhps, and ATPase6) was concurrently assessed in 639 community samples collected in the catchment areas of the respective health facilities by using a DNA microarray-based method. Mutant allele and haplotype frequencies were determined and their relationship with treatment failure rates at each site in each year was investigated.

Results: PCR-corrected in vivo treatment failure rates were between 12% and 28% and varied by site and year with variable longitudinal trends. In the community samples, the frequencies of mutations in pfcrt and pfmdr1 were high and did not show significant changes over time. Mutant allele frequencies in pfdhfr were moderate and those in pfdhps were low. No mutations were detected in pfATPase6. There was much more variation between sites than temporal, within-site, variation in allele and haplotype frequencies. This variation did not correlate well with treatment failure rates. Allele and haplotype frequencies were very similar in clinical and community samples from the same site.

Conclusions: The relationship between parasite genetics and in vivo treatment failure rate is not straightforward. The frequencies of genetic anti-malarial resistance markers appear to be very similar in community and clinical samples, but cannot be used to make precise predictions of clinical outcome. Thus, indicators based on molecular data have to be considered with caution and interpreted in the local context, especially with regard to prior drug usage and level of pre-existing immunity. Testing community samples for molecular drug resistance markers is a complementary tool that should help decision-making for the best treatment options and appropriate potential alternatives.

Show MeSH
Related in: MedlinePlus