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Abstract Background Sulphadoxine-pyrimethamine, in combination with artesunate or amodiaquine, is recommended for the treatment of uncomplicated malaria and is being evaluated for intermittent preventive treatment. Yet, limited data is available on pharmacokinetic interactions between these drugs. Methods In a randomized controlled trial, children aged 6-59 months with uncomplicated falciparum malaria, received either one dose of sulphadoxine-pyrimethamine alone (SP), one dose of SP plus three daily doses of amodiaquine (SP+AQ) or one dose of SP plus 3 daily doses of artesunate (SP+AS). Exactly 100 μl of capillary blood was collected onto filter paper before drug administration at day 0 and at days 1, 3, 7, 14, 21 and 28 after drug administration for analysis of sulphadoxine and pyrimethamine pharmacokinetic parameters. Results Fourty, 38 and 31 patients in the SP, SP+AQ and SP+AS arms, respectively were included in this study. The concentrations on day 7 (that are associated with therapeutic efficacy) were similar between the SP, SP+AQ and SP+AS treatment arms for sulphadoxine (median [IQR] 35.25 [27.38-41.70], 34.95 [28.60-40.85] and 33.40 [24.63-44.05] μg/mL) and for pyrimethamine (56.75 [46.40-92.95], 58.75 [43.60-98.60] and 59.60 [42.45-86.63] ng/mL). There were statistically significant differences between the pyrimethamine volumes of distribution (4.65 [3.93-6.40], 4.00 [3.03-5.43] and 5.60 [4.40-7.20] L/kg; p = 0.001) and thus elimination half-life (3.26 [2.74 -3.82], 2.78 [2.24-3.65] and 4.02 [3.05-4.85] days; p < 0.001). This study confirmed the lower SP concentrations previously reported for young children when compared with adult malaria patients. Conclusion Despite slight differences in pyrimethamine volumes of distribution and elimination half-life, these data show similar exposure to SP over the critical initial seven days of treatment and support the current use of SP in combination with either AQ or AS for uncomplicated falciparum malaria treatment in young Malian children.

Abstract Background Resistance to anti-malarial drugs is a widespread problem for control programmes for this devastating disease. Molecular tests are available for many anti-malarial drugs and are useful tools for the surveillance of drug resistance. However, the correlation of treatment outcome and molecular tests with particular parasite markers is not perfect, due in part to individuals who are able to clear genotypically drug-resistant parasites. This study aimed to identify molecular markers in the human genome that correlate with the clearance of malaria parasites after drug treatment, despite the drug resistance profile of the protozoan as predicted by molecular approaches. Methods 3721 samples from five African countries, which were known to contain genotypically drug resistant parasites, were analysed. These parasites were collected from patients who subsequently failed to clear their infection following drug treatment, as expected, but also from patients who successfully cleared their infections with drug-resistant parasites. 67 human polymorphisms (SNPs) on 17 chromosomes were analysed using Sequenom's mass spectrometry iPLEX gold platform, to identify regions of the human genome, which contribute to enhanced clearance of drug resistant parasites. Results An analysis of all data from the five countries revealed significant associations between the phenotype of ability to clear drug-resistant Plasmodium falciparum infection and human immune response loci common to all populations. Overall, three SNPs showed a significant association with clearance of drug-resistant parasites with odds ratios of 0.76 for SNP rs2706384 (95% CI 0.71-0.92, P = 0.005), 0.66 for SNP rs1805015 (95% CI 0.45-0.97, P = 0.03), and 0.67 for SNP rs1128127 (95% CI 0.45-0.99, P = 0.05), after adjustment for possible confounding factors. The first two SNPs (rs2706384 and rs1805015) are within loci involved in pro-inflammatory (interferon-gamma) and anti-inflammatory (IL-4) cytokine responses. The third locus encodes a protein involved in the degradation of misfolded proteins within the endoplasmic reticulum, and its role, if any, in the clearance phenotype is unclear. Conclusions The study showed significant association of three loci in the human genome with the ability of parasite to clear drug-resistant P. falciparum in samples taken from five countries distributed across sub-Saharan Africa. Both SNP rs2706384 and SNP1805015 have previously been reported to be associated with risk of malaria infection in African populations. The loci are involved in the Th1/Th2 balance, and the association of SNPs within these genes suggests a key role for antibody in the clearance of drug-resistant parasites. It is possible that patients able to clear drug-resistant infections have an enhanced ability to control parasite growth.

Abstract Background Artemisinin-based combination therapy (ACT) is currently the most effective medicine for the treatment of uncomplicated malaria. Artemisinin has previously been shown to increase the clearance of Plasmodium falciparum in malaria patients with haemoglobin E trait, but it did not increase parasite inhibition in an in vitro study using haemoglobin AS erythrocytes. The current study describes the efficacy of artemisinin derivatives on P. falciparum clearance in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD), a haemoglobin enzyme deficiency, not yet studied in the same context, but nonetheless is a common in malaria endemic areas, associated with host protection against uncomplicated and severe malaria. The impact of G6PD deficiency on parasite clearance with ACT treatment was compared between G6PD-deficient patients and G6PD-normal group. Methods Blood samples from children and adults participants (1 to 70 years old) with uncomplicated P. falciparum malaria residing in Kambila, Mali were analysed. Study participants were randomly assigned to receive either artemether-lumefantrine (Coartem®) or artesunate plus mefloquine (Artequin™). A restriction-fragment length polymorphism analysis of PCR-amplified DNA samples was used to identify the (A-) allele of the gene mutation responsible for G6PD deficiency (G6PD*A-). 470 blood samples were thus analysed and of these, DNA was extracted from 315 samples using the QIAamp kit for PCR to identify the G6PD*A- gene. Results The DNA amplified from 315 samples using PCR showed that G6PD*A- deficiency was present in 56 participants (17.8%). The distribution of the specific deficiency was 1%, 7% and, 9.8% respectively for homozygous, hemizygous, and heterozygous genotypes. Before treatment, the median parasitaemia and other baseline characteristics (mean haemoglobin, sex and age groups) between G6PD deficiency (hemizygous, heterozygous, and homozygous) and G6PD-normal participants were comparable (p > 0.05). After treatment, parasite clearance did not change significantly whether the participants were G6PD deficient or G6PD normal on day 1 (OR = 1.3; CI = 0.70-2.47; p > 0.05) and on day 2 (OR = 0.859; CI = 0.097-7.61; p > 0.05). Conclusions The presence of G6PD deficiency does not appear to significantly influence the clearance of P. falciparum in the treatment of uncomplicated malaria using ACT.

Abstract Background The use of artemisinin derivative-based combination therapy (ACT) such as artesunate plus amodiaquine is currently recommended for the treatment of uncomplicated Plasmodium falciparum malaria. Fixed-dose combinations are more adapted to patients than regimens involving multiple tablets and improve treatment compliance. A fixed-dose combination of artesunate + amodiaquine (ASAQ) was recently developed. To assess the efficacy and safety of this new combination and to define its optimum dosage regimen (once or twice daily) in the treatment of uncomplicated P. falciparum malaria, a multicentre clinical study was conducted. Methods A multicentre, randomized, controlled, investigator-blinded, parallel-group study was conducted in five African centers in Cameroon, Madagascar, Mali and Senegal from March to December 2006. Efficacy and safety of ASAQ were assessed compared to those of artemether + lumefantrine (AL). The WHO protocol with a 28-day follow-up for assessing the drug therapeutic efficacy was used. Patients suffering from uncomplicated P. falciparum malaria were randomized to receive ASAQ orally once daily (ASAQ1), ASAQ twice daily (ASAQ2) or AL twice daily (AL) for three days. The primary outcome was PCR-corrected parasitological cure rate and clinical response. Results Of 941 patients initially randomized and stratified into two age groups ( Conclusion The non-inferiority of ASAQ compared with AL was demonstrated. The fixed-dose combination artesunate + amodiaquine (ASAQ) is safe and efficacious even in young children under 5 years of age. Whilst administration on a twice-a-day basis does not improve the efficacy of ASAQ significantly, a once-a-day intake of this new combination clearly appears as an effective and safe therapy in the treatment of uncomplicated P. falciparum malaria both in adults and children. Implications of such findings are of primary importance in terms of public health especially in African countries. As most national policies plan to strengthen malaria control to reach the elimination of this disease, anti-malarial drugs such as the artesunate + amodiaquine fixed-dose ACT will play a pivotal role in this process. Trial registration The protocol was registered with the www.clinicaltrials.gov open clinical trial registry under the identifier number NCT00316329.

Abstract Background To update the National Malaria Control Programme of Mali on the efficacy of chloroquine, amodiaquine and sulphadoxine-pyrimethamine in the treatment of uncomplicated falciparum malaria. Methods During the malaria transmission seasons of 2002 and 2003, 455 children – between six and 59 months of age, with uncomplicated malaria in Kolle, Mali, were randomly assigned to one of three treatment arms. In vivo outcomes were assessed using WHO standard protocols. Genotyping of msp1, msp2 and CA1 polymorphisms were used to distinguish reinfection from recrudescent parasites (molecular correction). Results Day 28 adequate clinical and parasitological responses (ACPR) were 14.1%, 62.3% and 88.9% in 2002 and 18.2%, 60% and 85.2% in 2003 for chloroquine, amodiaquine and sulphadoxine-pyrimethamine, respectively. After molecular correction, ACPRs (cACPR) were 63.2%, 88.5% and 98.0% in 2002 and 75.5%, 85.2% and 96.6% in 2003 for CQ, AQ and SP, respectively. Amodiaquine was the most effective on fever. Amodiaquine therapy selected molecular markers for chloroquine resistance, while in the sulphadoxine-pyrimethamine arm the level of dhfr triple mutant and dhfr/dhps quadruple mutant increased from 31.5% and 3.8% in 2002 to 42.9% and 8.9% in 2003, respectively. No infection with dhps 540E was found. Conclusion In this study, treatment with sulphadoxine-pyrimethamine emerged as the most efficacious on uncomplicated falciparum malaria followed by amodiaquine. The study demonstrated that sulphadoxine-pyrimethamine and amodiaquine were appropriate partner drugs that could be associated with artemisinin derivatives in an artemisinin-based combination therapy.

Abstract Background Because of the emergence of chloroquine resistance in Mali, artemether-lumefantrine (AL) or artesunate-amodiaquine (AS+AQ) are recommended as first-line therapy for uncomplicated malaria, but have not been available in Mali until recently because of high costs. Methods From July 2005 to January 2006, a randomized open-label trial of three oral antimalarial combinations, namely AS+AQ, artesunate plus sulphadoxine-pyrimethamine (AS+SP), and amodiaquine plus sulphadoxine-pyrimethamine (AQ+SP), was conducted in Faladje, Mali. Parasite genotyping by polymerase chain reaction (PCR) was used to distinguish new from recrudescent Plasmodium falciparum infections. Results 397 children 6 to 59 months of age with uncomplicated Plasmodium falciparum malaria were enrolled, and followed for 28 days to assess treatment efficacy. Baseline characteristics were similar in all three treatment groups. The uncorrected rates of adequate clinical and parasitologic response (ACPR) were 55.7%, 90.8%, and 97.7% in AS+AQ, AS+SP, and AQ+SP respectively (p < 0.001); after PCR correction ACPR rates were similar among treatment groups: 95.4%, 96.9%, and 99.2% respectively (p = 0.17). Mean haemoglobin concentration increased across all treatment groups from Day 0 (9.82 ± 1.68 g/dL) to Day 28 (10.78 ± 1.49 g/dL) (p < 0.001), with the greatest improvement occurring in children treated with AQ+SP. On Day 2, the prevalence of parasitaemia was significantly greater among children treated with AQ+SP (50.8%) than in children treated with AS+AQ (10.5%) or AS+SP (10.8%) (p < 0.001). No significant difference in gametocyte carriage was found between groups during the follow-up period. Conclusion The combination of AQ+SP provides a potentially low cost alternative for treatment of uncomplicated P. falciparum infection in Mali and appears to have the added value of longer protective effect against new infection.

Background: Artemisinin-based combination therapy (ACT) is the recommended first-line therapy for uncomplicated Plasmodium falciparum malaria worldwide but decreased artemisinin susceptibility, phenotypically characterized as slow parasite clearance time (PCT), has now been reported in Southeast Asia. This makes it all too important to measure the dynamics of parasite clearance in African patients treated with ACT over time, to understand trends and detect changes early enough to intervene Methods: Individual patient data from 27 clinical trials of artesunate-amodiaquine (ASAQ) vs comparators conducted between 1999 and 2009 were analysed for parasite clearance on modified intent-to-treat (ITT) basis. Results: Overall 15,017 patients treated for uncomplicated P. falciparum malaria at 44 sites in 20 sub-Saharan African countries were included in the analysis; 51% (n=7,660) vs 49% (n=7,357) were treated with ASAQ and comparator treatments, respectively. Seventy-seven per cent (77%) were children under six years of age. The proportion of the patients treated with ASAQ with persistent parasitaemia on Day 2 was 8.6%, and 1.5% on Day 3. Risk factor for not clearing parasites on Day 2 and Day 3 calculated by multivariate logistic regression with random effect on site and controlling for treatment were: high parasitaemia before treatment was (adjusted risk ratios (AOR) 2.12, 95% CI 1.91-2.35, AOR 2.43, 95% CI 1.98-3.00, respectively); non-ACT treatment (p=0.001, for all comparisons). Anaemia (p=0.001) was an additional factor for Day 2 and young age (p=0.005) for Day 3. In patients treated with ASAQ in studies who had complete parasitaemia data every 24 hours up to Day 3 and additionally Day 7, the parasite reduction ratio was 93.9% by Day 1 and 99.9% by Day 2. Using the median parasitaemia before treatment (p0=27,125 μL) and a fitted model, the predicted PCT (pPCT = 3.614*ln (p0) – 6.135, r² = 0.94) in ASAQ recipients was 31 hours. Conclusion: Within the period covered by these studies, rapid Plasmodium falciparum clearance continues to be achieved in Sub-Saharan African patients treated with ACT, and in particular with ASAQ. The prediction formula for parasite clearance time could be a pragmatic tool for studies with binary outcomes and once-daily sampling, both for research and monitoring purposes. [ABSTRACT FROM AUTHOR]

Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up., Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive., Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 >5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007., Conclusions: Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.