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A recent randomized controlled trial, the WANECAM (West African Network for Clinical Trials of Antimalarial Drugs) trial, conducted at seven centers in West Africa, found that artemether-lumefantrine, artesunate-amodiaquine, pyronaridine-artesunate, and dihydroartemisinin-piperaquine all displayed good efficacy. However, artemether-lumefantrine was associated with a shorter interval between clinical episodes than the other regimens. In a further comparison of these therapies, we identified cases of persisting submicroscopic parasitemia by quantitative PCR (qPCR) at 72 h posttreatment among WANECAM participants from 5 sites in Mali and Burkina Faso, and we compared treatment outcomes for this group to those with complete parasite clearance by 72 h. Among 552 evaluable patients, 17.7% had qPCR-detectable parasitemia at 72 h during their first treatment episode. This proportion varied among sites, reflecting differences in malaria transmission intensity, but did not differ among pooled drug treatment groups. However, patients who received artemether-lumefantrine and were qPCR positive at 72 h were significantly more likely to have microscopically detectable recurrent Plasmodium falciparum parasitemia by day 42 than those receiving other regimens and experienced, on average, a shorter interval before the next clinical episode. Haplotypes of pfcrt and pfmdr1 were also evaluated in persisting parasites. These data identify a possible threat to the parasitological efficacy of artemether-lumefantrine in West Africa, over a decade since it was first introduced on a large scale.

Background: Artemether-lumefantrine is a highly effective artemisinin-based combination therapy that was adopted in Mali as first-line treatment for uncomplicated Plasmodium falciparum malaria. This study was designed to measure the efficacy of artemether-lumefantrine and to assess the selection of the P. falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multi-drug resistance 1 (pfmdr1) genotypes that have been associated with drug resistance. Methods: A 28-day follow-up efficacy trial of artemether-lumefantrine was conducted in patients aged 6 months and older suffering from uncomplicated falciparum malaria in four different Malian areas during the 2009 malaria transmission season. The polymorphic genetic markers MSP2, MSP1, and Ca1 were used to distinguish between recrudescence and reinfection. Reinfection and recrudescence were then grouped as recurrent infections and analyzed together by PCR-restriction fragment length polymorphism (RFLP) to identify candidate markers for artemether-lumefantrine tolerance in the P. falciparum chloroquine resistance transporter (pfcrt) gene and the P. falciparum multi-drug resistance 1 (pfmdr1) gene. Results: Clinical outcomes in 326 patients (96.7%) were analyzed and the 28-day uncorrected adequate clinical and parasitological response (ACPR) rate was 73.9%. The total PCR-corrected 28-day ACPR was 97.2%. The pfcrt 76T and pfmdr1 86Y population prevalence decreased from 49.3% and 11.0% at baseline (n = 337) to 38.8% and 0% in patients with recurrent infection (n = 85), p = 0.001), respectively. Conclusion: Parasite populations exposed to artemether-lumefantrine in this study were selected toward chloroquine-sensitivity and showed a promising trend that may warrant future targeted reintroduction of chloroquine or/and amodiaquine.

Background: Previous controlled studies demonstrated seasonal malaria chemoprevention (SMC) reduces malaria morbidity by &gt, 80% in children aged 3&ndash, 59 months. Here, we assessed malaria morbidity after large-scale SMC implementation during a pilot campaign in the health district of Koutiala, Mali. Methods: Starting in August 2012, children received three rounds of SMC with sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ). From July 2013 onward, children received four rounds of SMC. Prevalence of malaria infection, clinical malaria and anemia were assessed during two cross-sectional surveys conducted in August 2012 and June 2014. Investigations involved 20 randomly selected clusters in 2012 against 10 clusters in 2014. Results: Overall, 662 children were included in 2012, and 670 in 2014. Children in 2014 versus those surveyed in 2012 showed reduced proportions of malaria infection (12.4% in 2014 versus 28.7% in 2012 (p = 0.001)), clinical malaria (0.3% versus 4.2%, respectively (p &lt, 0.001)), and anemia (50.1% versus 67.4%, respectively (p = 0.001)). A propensity score approach that accounts for environmental differences showed that SMC conveyed a significant protective effect against malaria infection (IR = 0.01, 95% CI (0.0001, 0.09), clinical malaria (OR = 0.25, 95% CI (0.06, 0.85)), and hemoglobin concentration (&beta, = 1.3, 95% CI (0.69, 1.96)) in 2012 and 2014, respectively. Conclusion: SMC significantly reduced frequency of malaria infection, clinical malaria and anemia two years after SMC scale-up in Koutiala.

Summary Background Artemether–lumefantrine and artesunate–amodiaquine are used as first-line artemisinin-based combination therapies (ACTs) in west Africa. Pyronaridine–artesunate and dihydroartemisinin–piperaquine are potentially useful for diversification of ACTs in this region, but further safety and efficacy data are required on malaria retreatment. Methods We did a randomised, multicentre, open-label, longitudinal, controlled phase 3b/4 clinical trial at seven tertiary centres in Burkina Faso, Guinea, and Mali. Eligible participants for first malaria episode and all retreatment episodes were adults and children aged 6 months and older with microscopically confirmed Plasmodium spp malaria (>0 to

BackgroundWHO recommended seasonal malaria chemoprevention (SMC) in 2012 for Sahel countries in Africa with the aim to reduce malaria among children under 5 years old by using sulphadoxine-pyrimethamine and amodiaquine (SP+AQ). This strategy was scaled up in Mali from 2012. The use of millions of doses of SP+AQ could generate potential Plasmodium falciparum resistance in mutant parasites. The aim of this study was to monitor the prevalence of Pfdhfr +Pfdhps+pfcrt +pfmdr1 mutations in parasites infecting the target population.MethodsTwo cross-sectional surveys were conducted before (August 2012, n=662) and after (June 2014, n=670) a pilot implementation of SMC in the health district of Koutiala. Children aged 3–59 months received 3 and 4 rounds of curative doses of SP+AQ over two malaria seasons in 2012 and 2013, respectively. Genotypes of P. falciparum Pfdhfr codons 51, 59, 108 and 164; Pfdhps codons 437 and 540, Pfcrt codon 76 and Pfmdr1 codon 86 were analysed by PCR on DNA of parasites from SMC population blood samples (after and before) and non-SMC patients aged 7 years or above (November 2014, n=500).ResultsIn the SMC population 191 and 85 children before and after SMC implementation, respectively, were included in’the molecular analysis. In the non-SMC patients, 220 were’successfully PCR analysed. In the SMC population, the’prevalence of the six-mutation Pfcrt [Pfdhfr-dhps quintuple +Pfcrt-76T] genotype increased significantly after SMC implementation, from 0.0% to 7.1% (p=0.0008). The post-intervention prevalence of the six-mutation Pfmdr1 [Pfdhfr-dhps quintuple +Pfmdr1–86Y] and the seven-mutation Pfcrt +Pfmdr1 [Pfdhfr-dhps quintuple +Pfmdr1–86Y+Pfcrt-76T] genotypes were both 1.2% among the SMC population. No six-mutation and seven-mutation genotypes were observed among SMC population at baseline nor in the non-SMC patient population (p=0.30).ConclusionSMC increased the prevalence of the six-mutation Pfcrt genotype of P. falciparum that can lead to resistance in a population exposed to SMC with SP+AQ.

Background Seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine (SP)+amodiaquine (AQ) is being scaled up in countries of the Sahel in West Africa. However, the potential development of Plasmodium falciparum resistance to the respective component drugs is a major concern. Methods Two cross-sectional surveys were conducted before (August 2012) and after (June 2014) a pilot implementation of SMC in Koutiala, Mali. Children aged 3–59 months received 7 rounds of curative doses of SP+AQ over two malaria seasons. Genotypes of P. falciparum dhfr codons 51, 59 and 108; dhps codons 437 and 540, pfcrt codon 76 and pfmdr1codon 86 were analysed by PCR on DNA from samples collected before and after SMC, and in non-SMC controls. Results In the SMC population 191/662 (28.9%) and 85/670 (13.7%) of children were P. falciparum- positive by microscopy and were included in the molecular analysis before (2012) and after SMC implementation (2014), respectively. In the control population 220/310 (71%) were successfully PCR analysed. In the SMC children the prevalence of all molecular markers of SP resistance increased significantly after SMC including the dhfr-dhps quintuple mutant genotype, which was 1.6% before but 7.1% after SMC (p=0.02). The prevalence of Pfmdr1–86Y significantly decreased from 26.7% to 15.3% (p=0.04) while no significant change was seen for pfcrt K76T. In 2014, prevalence of all molecular markers of SP resistance were significantly higher among SMC children compared to the non-SMC control population (p Conclusions SMC increased the prevalence of molecular markers of P. falciparum resistance to SP in the treated children. However, there was no significant flow of these resistance genes into the general parasite population after 2 years and 7 rounds of SMC.

Background Seasonal malaria chemoprevention (SMC) with sulphadoxine-pyrimethamine (SP) plus amodiaquine (AQ) is being scaled up in Sahelian countries of West Africa. However, the potential development of Plasmodium falciparum resistance to the respective component drugs is a major concern. Methods Two cross-sectional surveys were conducted before (August 2012) and after (June 2014) a pilot implementation of SMC in Koutiala, Mali. Children aged 3–59 months received 7 rounds of curative doses of SP plus AQ over two malaria seasons. Genotypes of P. falciparum Pfdhfr codons 51, 59 and 108; Pfdhps codons 437 and 540, Pfcrt codon 76 and Pfmdr1codon 86 were analyzed by PCR on DNA from samples collected before and after SMC, and in non-SMC patient population as controls (November 2014). Results In the SMC population 191/662 (28.9%) and 85/670 (12.7%) of children were P. falciparum positive by microscopy and were included in the molecular analysis before (2012) and after SMC implementation (2014), respectively. In the non-SMC patient population 220/310 (71%) were successfully PCR analyzed. In the SMC children, the prevalence of all molecular markers of SP resistance increased significantly after SMC including the Pfdhfr-dhps quintuple mutant genotype, which was 1.6% before but 7.1% after SMC (p = 0.02). The prevalence of Pfmdr1-86Y significantly decreased from 26.7% to 15.3% (p = 0.04) while no significant change was seen for Pfcrt 76T. In 2014, prevalence of all molecular markers of SP resistance were significantly higher among SMC children compared to the non-SMC population patient (p < 0.01). No Pfdhfr-164 mutation was found neither at baseline nor post SMC. Conclusion SMC increased the prevalence of molecular markers of P. falciparum resistance to SP in the treated children. However, there was no significant increase of these markers of resistance in the general parasite population after 2 years and 7 rounds of SMC.

Serological surveys are essential to quantify immunity in a population but serological cross-reactivity often impairs estimates of the seroprevalence. Here, we show that modeling helps addressing this key challenge by considering the important cross-reactivity between Chikungunya (CHIKV) and O’nyong-nyong virus (ONNV) as a case study. We develop a statistical model to assess the epidemiology of these viruses in Mali. We additionally calibrate the model with paired virus neutralization titers in the French West Indies, a region with known CHIKV circulation but no ONNV. In Mali, the model estimate of ONNV and CHIKV prevalence is 30% and 13%, respectively, versus 27% and 2% in non-adjusted estimates. While a CHIKV infection induces an ONNV response in 80% of cases, an ONNV infection leads to a cross-reactive CHIKV response in only 22% of cases. Our study shows the importance of conducting serological assays on multiple cross-reactive pathogens to estimate levels of virus circulation., O’nyong nyong and Chikungunya virus are arboviruses present in Africa but their prevalence is unknown, partly due to high antibody cross-reactivity with one another. Here, the authors develop a statistical model that accounts for cross-reactivity to characterise circulation of both viruses from seroprevalence surveys.