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Grandesso F, Ouedraogo P, Issakha Diar MS, Hilario JS, Kouassi F, et al.
Epicentre Scientific Day 2024. 23 May 2024
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Malar J. 21 February 2024; DOI:10.21203/rs.3.rs-3959166/v1
Fuente IMdl, Benito MJS, Gisbert FB, García L, González V, et al.
Malar J. 21 February 2024; DOI:10.21203/rs.3.rs-3959166/v1
BACKGROUND
Malaria genetic diversity is an important indicator of malaria transmission. Pfmsp1 and pfmsp2 are a frequent molecular epidemiology tool to assess the genetic diversity. This study aims to assess the genetic diversity and the description of multiplicity of infection (MOI) of P. falciparum in Yambio County, South Sudan. Additionally, it assesses the association of specific alleles or multiplicity of infection with antimalarial drugs resistance haplotypes and severity of infection, major challenges in malaria control strategies.
METHODS
There were collected 446 malaria samples from patients in Yambio county. After P. falciparum confirmation, pfmsp1 and pfmsp2 allelic families were genotyped. Frequencies of each alleles were described and multiplicity of infection was calculated. The association between MOI and complicated malaria was assessed using U-Mann Whitney test. The Kruskal-Wallis test was used to compare MOI between collection sites, age groups and antimalarial resistance haplotypes.
RESULTS
For pfmsp1, monomorphic K1 allele infection was predominant (37.0%) in every location and for pfmsp2 locus, monomorphic 3D7 was predominant (44.8%). 71.9% of samples were polyclonal infections (overall MOI = 1.96). The high diversity and polyclonal infections are associated with molecular markers of resistance, and high MOI has been related with a lower risk of severity of infections. There was not find evidence of association between a specific allele and an infection trait.
CONCLUSION
High genetic diversity and high level of polyclonal infections have been found in this study, confirming the general high transmission, and highlighting the need for control measures to be intensified in Yambio county, South Sudan.
Malaria genetic diversity is an important indicator of malaria transmission. Pfmsp1 and pfmsp2 are a frequent molecular epidemiology tool to assess the genetic diversity. This study aims to assess the genetic diversity and the description of multiplicity of infection (MOI) of P. falciparum in Yambio County, South Sudan. Additionally, it assesses the association of specific alleles or multiplicity of infection with antimalarial drugs resistance haplotypes and severity of infection, major challenges in malaria control strategies.
METHODS
There were collected 446 malaria samples from patients in Yambio county. After P. falciparum confirmation, pfmsp1 and pfmsp2 allelic families were genotyped. Frequencies of each alleles were described and multiplicity of infection was calculated. The association between MOI and complicated malaria was assessed using U-Mann Whitney test. The Kruskal-Wallis test was used to compare MOI between collection sites, age groups and antimalarial resistance haplotypes.
RESULTS
For pfmsp1, monomorphic K1 allele infection was predominant (37.0%) in every location and for pfmsp2 locus, monomorphic 3D7 was predominant (44.8%). 71.9% of samples were polyclonal infections (overall MOI = 1.96). The high diversity and polyclonal infections are associated with molecular markers of resistance, and high MOI has been related with a lower risk of severity of infections. There was not find evidence of association between a specific allele and an infection trait.
CONCLUSION
High genetic diversity and high level of polyclonal infections have been found in this study, confirming the general high transmission, and highlighting the need for control measures to be intensified in Yambio county, South Sudan.
Journal Article > ResearchFull Text
Malar J. 10 November 2023; Volume 22 (Issue 1); 345.; DOI:10.1186/s12936-023-04740-x
Molina-de la Fuente I, Sagrado Benito MJ, Lasry E, Ousley J, García L, et al.
Malar J. 10 November 2023; Volume 22 (Issue 1); 345.; DOI:10.1186/s12936-023-04740-x
BACKGROUND
Seasonal malaria chemoprevention (SMC) using sulfadoxine-pyrimethamine plus amodiaquine (SP-AQ), is a community-based malaria preventive strategy commonly used in the Sahel region of sub-Saharan Africa. However, to date it has not been implemented in East Africa due to high SP resistance levels. This paper is a report on the implementation of SMC outside of the Sahel in an environment with a high level of presumed SP-resistance: five cycles of SMC using SPAQ were administered to children 3–59 months during a period of high malaria transmission (July–December 2019) in 21 villages in South Sudan.
METHODS
A population-based SMC coverage survey was combined with a longitudinal time series analysis of health facility and community health data measured after each SMC cycle. SMC campaign effectiveness was assessed by Poisson model. SPAQ molecular resistance markers were additionally analysed from dried blood spots from malaria confirmed patients.
RESULTS
Incidence of uncomplicated malaria was reduced from 6.6 per 100 to an average of 3.2 per 100 after SMC administration (mean reduction: 53%) and incidence of severe malaria showed a reduction from 21 per 10,000 before SMC campaign to a mean of 3.3 per 10,000 after each cycle (mean reduction: 84%) in the target group when compared to before the SMC campaign. The most prevalent molecular haplotype associated with SP resistance was the IRNGE haplotype (quintuple mutant, with 51I/59R/108N mutation in pfdhfr + 437G/540E in pfdhps). In contrast, there was a low frequency of AQ resistance markers and haplotypes resistant to both drugs combined (< 2%).
CONCLUSIONS
The SMC campaign was effective and could be used as an additional preventive tool in seasonal malaria settings outside of the Sahel, especially in areas where access to health care is unstable. Malaria case load reduction was observed despite the high level of resistance to SP.
Seasonal malaria chemoprevention (SMC) using sulfadoxine-pyrimethamine plus amodiaquine (SP-AQ), is a community-based malaria preventive strategy commonly used in the Sahel region of sub-Saharan Africa. However, to date it has not been implemented in East Africa due to high SP resistance levels. This paper is a report on the implementation of SMC outside of the Sahel in an environment with a high level of presumed SP-resistance: five cycles of SMC using SPAQ were administered to children 3–59 months during a period of high malaria transmission (July–December 2019) in 21 villages in South Sudan.
METHODS
A population-based SMC coverage survey was combined with a longitudinal time series analysis of health facility and community health data measured after each SMC cycle. SMC campaign effectiveness was assessed by Poisson model. SPAQ molecular resistance markers were additionally analysed from dried blood spots from malaria confirmed patients.
RESULTS
Incidence of uncomplicated malaria was reduced from 6.6 per 100 to an average of 3.2 per 100 after SMC administration (mean reduction: 53%) and incidence of severe malaria showed a reduction from 21 per 10,000 before SMC campaign to a mean of 3.3 per 10,000 after each cycle (mean reduction: 84%) in the target group when compared to before the SMC campaign. The most prevalent molecular haplotype associated with SP resistance was the IRNGE haplotype (quintuple mutant, with 51I/59R/108N mutation in pfdhfr + 437G/540E in pfdhps). In contrast, there was a low frequency of AQ resistance markers and haplotypes resistant to both drugs combined (< 2%).
CONCLUSIONS
The SMC campaign was effective and could be used as an additional preventive tool in seasonal malaria settings outside of the Sahel, especially in areas where access to health care is unstable. Malaria case load reduction was observed despite the high level of resistance to SP.
Journal Article > ResearchFull Text
Am J Trop Med Hyg. 25 September 2023; Online ahead of print; tpmd230382.; DOI:10.4269/ajtmh.23-0382
Molina-de la Fuente I, Sagrado Benito MJ, Ousley J, Gisbert FdB, García L, et al.
Am J Trop Med Hyg. 25 September 2023; Online ahead of print; tpmd230382.; DOI:10.4269/ajtmh.23-0382
Artemisinin-combined treatments are the recommended first-line treatment of Plasmodium falciparum malaria, but they are being threatened by emerging artemisinin resistance. Mutations in pfk13 are the principal molecular marker for artemisinin resistance. This study characterizes the presence of mutations in pfk13 in P. falciparum in Western Equatoria State, South Sudan. We analyzed 468 samples from patients with symptomatic malaria and found 15 mutations (8 nonsynonymous and 7 synonymous). Each mutation appeared only once, and none were validated or candidate markers of artemisinin resistance. However, some mutations were in the same or following position of validated and candidate resistance markers, suggesting instability of the gene that could lead to resistance. The R561L nonsynonymous mutation was found in the same position as the R561H validated mutation. Moreover, the A578S mutation, which is widespread in Africa, was also reported in this study. We found a high diversity of other pfk13 mutations in low frequency. Therefore, routine molecular surveillance of resistance markers is highly recommended to promptly detect the emergence of resistance-related mutations and to limit their spread.
Journal Article > ResearchFull Text
Malar J. 27 February 2018; Volume 17 (Issue 1); 98.; DOI:10.1186/s12936-018-2242-4
Grais RF, Laminou IM, Woi-Messe LC, Makarimi R, Bouriema SH, et al.
Malar J. 27 February 2018; Volume 17 (Issue 1); 98.; DOI:10.1186/s12936-018-2242-4
BACKGROUND
In Niger, malaria transmission is markedly seasonal with most of the disease burden occurring in children during the rainy season. Seasonal malaria chemoprevention (SMC) with amodiaquine plus sulfadoxine-pyrimethamine (AQ + SP) is recommended in the country to be administered monthly just before and during the rainy season. Moreover, clinical decisions on use of SP for intermittent preventive treatment in pregnancy (IPTp) now depend upon the validated molecular markers for SP resistance in Plasmodium falciparum observed in the local parasite population. However, little is known about molecular markers of resistance for either SP or AQ in the south of Niger. To address this question, clinical samples which met clinical and biological criteria, were collected in Gabi, Madarounfa district, Maradi region, Niger in 2011-2012 (before SMC implementation). Molecular markers of resistance to pyrimethamine (pfdhfr), sulfadoxine (pfdhps) and amodiaquine (pfmdr1) were assessed by DNA sequencing.
RESULTS
Prior to SMC implementation, the samples showed a high proportion of clinical samples that carried the pfdhfr 51I/59R/108N haplotype associated with resistance to pyrimethamine and pfdhps 436A/F/H and 437G mutations associated with reduced susceptibility to sulfadoxine. In contrast mutations in codons 581G, and 613S in the pfdhps gene, and in pfmdr1, 86Y, 184Y, 1042D and 1246Y associated with resistance to amodiaquine, were less frequently observed. Importantly, pfdhfr I164L and pfdhps K540E mutations shown to be the most clinically relevant markers for high level clinical resistance to SP were not detected in Gabi.
CONCLUSIONS
Although parasites with genotypes associated with the highest levels of resistance to AQ + SP are not yet common in this setting, their importance for deployment of SMC and IPTp dictates that monitoring of these markers of resistance should accompany these interventions. This study also highlights the parasite heterogeneity within a small spatial area and the need to use caution when extrapolating results from surveys of molecular markers of resistance in a single site to inform regional policy decisions.
In Niger, malaria transmission is markedly seasonal with most of the disease burden occurring in children during the rainy season. Seasonal malaria chemoprevention (SMC) with amodiaquine plus sulfadoxine-pyrimethamine (AQ + SP) is recommended in the country to be administered monthly just before and during the rainy season. Moreover, clinical decisions on use of SP for intermittent preventive treatment in pregnancy (IPTp) now depend upon the validated molecular markers for SP resistance in Plasmodium falciparum observed in the local parasite population. However, little is known about molecular markers of resistance for either SP or AQ in the south of Niger. To address this question, clinical samples which met clinical and biological criteria, were collected in Gabi, Madarounfa district, Maradi region, Niger in 2011-2012 (before SMC implementation). Molecular markers of resistance to pyrimethamine (pfdhfr), sulfadoxine (pfdhps) and amodiaquine (pfmdr1) were assessed by DNA sequencing.
RESULTS
Prior to SMC implementation, the samples showed a high proportion of clinical samples that carried the pfdhfr 51I/59R/108N haplotype associated with resistance to pyrimethamine and pfdhps 436A/F/H and 437G mutations associated with reduced susceptibility to sulfadoxine. In contrast mutations in codons 581G, and 613S in the pfdhps gene, and in pfmdr1, 86Y, 184Y, 1042D and 1246Y associated with resistance to amodiaquine, were less frequently observed. Importantly, pfdhfr I164L and pfdhps K540E mutations shown to be the most clinically relevant markers for high level clinical resistance to SP were not detected in Gabi.
CONCLUSIONS
Although parasites with genotypes associated with the highest levels of resistance to AQ + SP are not yet common in this setting, their importance for deployment of SMC and IPTp dictates that monitoring of these markers of resistance should accompany these interventions. This study also highlights the parasite heterogeneity within a small spatial area and the need to use caution when extrapolating results from surveys of molecular markers of resistance in a single site to inform regional policy decisions.
Journal Article > ResearchFull Text
Trop Med Int Health. 1 November 2004; Volume 9 (Issue 11); 1184-1190.; DOI:10.1111/j.1365-3156.2004.01323.x
Smithuis FM, Shahmanesh M, Kyaw MK, Savran O, Lwin S, et al.
Trop Med Int Health. 1 November 2004; Volume 9 (Issue 11); 1184-1190.; DOI:10.1111/j.1365-3156.2004.01323.x
Multi-drug resistant falciparum malaria is widespread in Asia. In Thailand, Cambodia and Vietnam the national protocols have changed largely to artesunate combined treatment regimens but elsewhere in East and South Asia chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) are still widely recommended by national malaria control programmes. In Kachin State, northern Myanmar, an area of low seasonal malaria transmission, the efficacy of CQ (25 mg base/kg) and SP (1.25/25 mg/kg), the nationally recommended treatments at the time, were compared with mefloquine alone (M; 15 mg base/kg) and mefloquine combined with artesunate (MA; 15:4 mg/kg). An open randomized controlled trial enrolled 316 patients with uncomplicated Plasmodium falciparum malaria, stratified prospectively into three age-groups. Early treatment failures (ETF) occurred in 41% (32/78) of CQ treated patients and in 24% of patients treated with SP (18/75). In young children the ETF rates were 87% after CQ and 35% after SP. Four children (two CQ, two SP) developed symptoms of cerebral malaria within 3 days after treatment. By day 42, failure rates (uncorrected for reinfections) had increased to 79% for CQ and 81% for SP. ETF rates were 2.5% after treatment with M and 3.9% after treatment with MA (P > 0.2). Overall uncorrected treatment failure rates at day 42 following M and MA were 23% and 21%, respectively. Chloroquine and SP are completely ineffective for the treatment of falciparum malaria in northern Myanmar. Mefloquine treatment is much more effective, but three day combination regimens with artesunate will be needed for optimum efficacy and protection against resistance.
Journal Article > ResearchFull Text
Infect Dis Poverty. 25 April 2017; Volume 6 (Issue 1); 76.; DOI:10.1186/s40249-017-0292-4
Nwe TW, Oo T, Wai KT, Zhou SS, van Griensven J, et al.
Infect Dis Poverty. 25 April 2017; Volume 6 (Issue 1); 76.; DOI:10.1186/s40249-017-0292-4
BACKGROUND
This study examined evolving malaria profiles from January, 2010 to December, 2014 to evaluate achievements and challenges of implementing measures to prevent and control spread of artemisinin resistance in Myanmar.
METHODS
Using National Malaria Control Programme (NMCP) data, a cross-sectional descriptive study of 52 townships in artemisinin-resistant containment areas in Myanmar was conducted. Annual program data were analysed, and trends over time are graphically presented.
RESULTS
In the 52 study townships populated by 8.7 million inhabitants, malaria incidence showed a decreasing trend from 10.54 per 1 000 population in 2010 to 2.53 in 2014, and malaria mortalities also decreased from 1.83 per 100 000 population in 2010 to 0.17 in 2014. The proportion of confirmed to total tested malaria cases also decreased from 6 to 1%, while identification of cases improved. All cases from all parasites species, including Plasmodium falciparum, decreased. Coverage of LLIN (long-lasting insecticidal net)/ITN (insecticide-treated mosquito nets) and indoor residual spraying (IRS) was high in targeted areas with at-risk persons, even though the total population was not covered. In addition to passive case detection (PCD), active case detection (ACD) was conducted in hard-to-reach areas and worksites where mobile migrant populations were present. ACD improved in most areas from 2012 to 2014, but continues to need to be strengthened.
CONCLUSIONS
The findings provide useful data on the malaria situation in artemisinin-resistant initiative areas, which may be useful for the NMCP to meet its elimination goal. These profiles could contribute to better planning, implementation, and evaluation of intervention activities.
This study examined evolving malaria profiles from January, 2010 to December, 2014 to evaluate achievements and challenges of implementing measures to prevent and control spread of artemisinin resistance in Myanmar.
METHODS
Using National Malaria Control Programme (NMCP) data, a cross-sectional descriptive study of 52 townships in artemisinin-resistant containment areas in Myanmar was conducted. Annual program data were analysed, and trends over time are graphically presented.
RESULTS
In the 52 study townships populated by 8.7 million inhabitants, malaria incidence showed a decreasing trend from 10.54 per 1 000 population in 2010 to 2.53 in 2014, and malaria mortalities also decreased from 1.83 per 100 000 population in 2010 to 0.17 in 2014. The proportion of confirmed to total tested malaria cases also decreased from 6 to 1%, while identification of cases improved. All cases from all parasites species, including Plasmodium falciparum, decreased. Coverage of LLIN (long-lasting insecticidal net)/ITN (insecticide-treated mosquito nets) and indoor residual spraying (IRS) was high in targeted areas with at-risk persons, even though the total population was not covered. In addition to passive case detection (PCD), active case detection (ACD) was conducted in hard-to-reach areas and worksites where mobile migrant populations were present. ACD improved in most areas from 2012 to 2014, but continues to need to be strengthened.
CONCLUSIONS
The findings provide useful data on the malaria situation in artemisinin-resistant initiative areas, which may be useful for the NMCP to meet its elimination goal. These profiles could contribute to better planning, implementation, and evaluation of intervention activities.
Journal Article > ResearchFull Text
Am J Trop Med Hyg. 21 July 2014; Volume 91 (Issue 4); 833-43.; DOI:10.4269/ajtmh.14-0031
Venkatesan M, Gadalla NB, Stepniewska K, Dahal P, Nsanzabana C, et al.
Am J Trop Med Hyg. 21 July 2014; Volume 91 (Issue 4); 833-43.; DOI:10.4269/ajtmh.14-0031
Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001: were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.
Journal Article > ResearchFull Text
Trans R Soc Trop Med Hyg. 1 November 2021; Volume 115 (Issue 11); 1339-1344.; DOI:10.1093/trstmh/trab116
N'do S, Bandibabone JB, Soma DD, Musaka BZ, Prudhomme J, et al.
Trans R Soc Trop Med Hyg. 1 November 2021; Volume 115 (Issue 11); 1339-1344.; DOI:10.1093/trstmh/trab116
BACKGROUND
Insecticide resistance has become a widespread problem causing a decline in the effectiveness of vector control tools in sub-Saharan Africa. In this situation, ongoing monitoring of vector susceptibility to insecticides is encouraged by the WHO to guide national malaria control programmes. Our study was conducted from April to November 2018 in Tchonka (Sud-Kivu, Democratic Republic of the Congo) and reported primary data on the resistance status of Anopheles funestus and Anopheles gambiae.
METHODS
Insecticide susceptibility bioassays were performed on wild populations of A. funestus and A. gambiae using WHO insecticide-impregnated papers at discriminating concentration. In addition, PCR was performed to identify mosquito species and to detect kdr and ace-1R mutations involved in insecticide resistance.
RESULTS
Bioassay results show resistance to all tested insecticides except pirimiphos-methyl, propoxur, fenitrothion and malathion with a mortality rate ranging from 95.48 to 99.86%. The addition of piperonyl butoxide (PBO) increased the susceptibility of vectors to deltamethrin and alpha-cypermethrin by exhibiting a mortality ranging from 91.50 to 95.86%. The kdr mutation was detected at high frequencies (approximately 0.98) within A. gambiae while ace-1R was not detected.
CONCLUSIONS
This study provides useful data on the insecticide resistance profiles of malaria vector populations to better manage vector control. Our results highlight that, despite the high level of resistance, organophosphorus compounds and pyrethroids + PBO remain effective against the vectors.
Insecticide resistance has become a widespread problem causing a decline in the effectiveness of vector control tools in sub-Saharan Africa. In this situation, ongoing monitoring of vector susceptibility to insecticides is encouraged by the WHO to guide national malaria control programmes. Our study was conducted from April to November 2018 in Tchonka (Sud-Kivu, Democratic Republic of the Congo) and reported primary data on the resistance status of Anopheles funestus and Anopheles gambiae.
METHODS
Insecticide susceptibility bioassays were performed on wild populations of A. funestus and A. gambiae using WHO insecticide-impregnated papers at discriminating concentration. In addition, PCR was performed to identify mosquito species and to detect kdr and ace-1R mutations involved in insecticide resistance.
RESULTS
Bioassay results show resistance to all tested insecticides except pirimiphos-methyl, propoxur, fenitrothion and malathion with a mortality rate ranging from 95.48 to 99.86%. The addition of piperonyl butoxide (PBO) increased the susceptibility of vectors to deltamethrin and alpha-cypermethrin by exhibiting a mortality ranging from 91.50 to 95.86%. The kdr mutation was detected at high frequencies (approximately 0.98) within A. gambiae while ace-1R was not detected.
CONCLUSIONS
This study provides useful data on the insecticide resistance profiles of malaria vector populations to better manage vector control. Our results highlight that, despite the high level of resistance, organophosphorus compounds and pyrethroids + PBO remain effective against the vectors.
Journal Article > ResearchFull Text
Malar J. 5 September 2016; Volume 15 (Issue 1); 452.; DOI:10.1186/s12936-016-1503-3
Otienoburu SD, Maiga-Ascofare O, Schramm B, Jullien V, Jones JJ, et al.
Malar J. 5 September 2016; Volume 15 (Issue 1); 452.; DOI:10.1186/s12936-016-1503-3
BACKGROUND
Plasmodium falciparum uncomplicated malaria can successfully be treated with an artemisinin-based combination therapy (ACT). However resistance is spreading to the different ACT compounds; the artemisinin derivative and the partner drug. Studies of P. falciparum polymorphisms associated with drug resistance can provide a useful tool to track resistance and guide treatment policy as well as an in-depth understanding of the development and spread of resistance.
METHODS
The role of P. falciparum molecular markers in selection of reinfections was assessed in an efficacy trial comparing artesunate-amodiaquine fixed-dose combination with artemether-lumefantrine to treat malaria in Nimba County, Liberia 2008-2009. P. falciparum polymorphisms in pfcrt 76, pfmdr1 86, 184 and 1246, and pfmrp1 876 and 1466 were analysed by PCR-RFLP and pyrosequencing.
RESULTS
High baseline prevalence of pfmdr1 1246Y was found in Nimba county (38 %). Pfmdr1 1246Y and pfmdr1 86+184+1246 haplotypes NYY and YYY were selected in reinfections in the artesunate-amodiaquine arm and pfcrt K76, pfmdr1 N86 and pfmdr1 haplotype NFD were selected in artemether-lumefantrine reinfections. Parasites harbouring pfmdr1 1246Y could reinfect earlier after treatment with artesunate-amodiaquine and parasites carrying pfmdr1 N86 could reinfect at higher lumefantrine concentrations in patients treated with artemether-lumefantrine.
CONCLUSIONS
Although treatment is highly efficacious, selection of molecular markers in reinfections could indicate a decreased sensitivity or tolerance of parasites to the current treatments and the baseline prevalence of molecular markers should be closely monitored. Since individual drug levels and the day of reinfection were demonstrated to be key determinants for selection of reinfections, this data needs to be collected and taken into account for accurate evaluation of molecular markers for anti-malarial treatments.
The protocol for the clinical trial was registered with Current Controlled Trials, under the Identifier Number ISRCTN51688713 on 9 October 2008.
Plasmodium falciparum uncomplicated malaria can successfully be treated with an artemisinin-based combination therapy (ACT). However resistance is spreading to the different ACT compounds; the artemisinin derivative and the partner drug. Studies of P. falciparum polymorphisms associated with drug resistance can provide a useful tool to track resistance and guide treatment policy as well as an in-depth understanding of the development and spread of resistance.
METHODS
The role of P. falciparum molecular markers in selection of reinfections was assessed in an efficacy trial comparing artesunate-amodiaquine fixed-dose combination with artemether-lumefantrine to treat malaria in Nimba County, Liberia 2008-2009. P. falciparum polymorphisms in pfcrt 76, pfmdr1 86, 184 and 1246, and pfmrp1 876 and 1466 were analysed by PCR-RFLP and pyrosequencing.
RESULTS
High baseline prevalence of pfmdr1 1246Y was found in Nimba county (38 %). Pfmdr1 1246Y and pfmdr1 86+184+1246 haplotypes NYY and YYY were selected in reinfections in the artesunate-amodiaquine arm and pfcrt K76, pfmdr1 N86 and pfmdr1 haplotype NFD were selected in artemether-lumefantrine reinfections. Parasites harbouring pfmdr1 1246Y could reinfect earlier after treatment with artesunate-amodiaquine and parasites carrying pfmdr1 N86 could reinfect at higher lumefantrine concentrations in patients treated with artemether-lumefantrine.
CONCLUSIONS
Although treatment is highly efficacious, selection of molecular markers in reinfections could indicate a decreased sensitivity or tolerance of parasites to the current treatments and the baseline prevalence of molecular markers should be closely monitored. Since individual drug levels and the day of reinfection were demonstrated to be key determinants for selection of reinfections, this data needs to be collected and taken into account for accurate evaluation of molecular markers for anti-malarial treatments.
The protocol for the clinical trial was registered with Current Controlled Trials, under the Identifier Number ISRCTN51688713 on 9 October 2008.