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Background Artemether–lumefantrine (AL) and artesunate–amodiaquine are first-line treatment for uncomplicated malaria in many endemic countries, including Mali. Dihydroartemisinin–piperaquine (DHA–PQ) is also an alternative first-line artemisinin-based combination therapy, but only few data are available on DHA–PQ efficacy in sub-Saharan Africa. The main aim of this study was to compare clinical efficacy of DHA–PQ versus AL, using the World Health Organization (WHO) 42-day in vivo protocol. Methods The efficacy of three-dose regimens of DHA–PQ was compared to AL combination in a randomized, comparative open label trial using the WHO 42-day follow-up protocol from 2013 to 2015 in Doneguebougou and Torodo, Mali. The primary endpoint was to access the PCR-corrected Adequate Clinical and Parasitological Responses at day 28. Results A total of 317 uncomplicated malaria patients were enrolled, with 159 in DHA–PQ arm and 158 in AL arm. The parasite positivity rate decreased from 68.4% (95% CI 60.5–75.5) on day 1 to 3.8% (95% CI 1.4–8.1) on day 2 for DHA–PQ and 79.8% (95% CI 72.3–85.7) on day 1 to 9.5% (95% CI 5.4–15.2) on day 2 for AL, (p = 0.04). There was a significant difference in the uncorrected ACPR between DHA–PQ and AL, both at 28-day and 42-day follow-up with 97.4% (95% CI 93.5–99.3) in DHA–PQ vs 84.5% (95% CI 77.8–89.8) in AL (p < 0.001) and 94.2% (95% CI 89.3–97.3) in DHA–PQ vs 73.4% (95% CI 65.7–80.2) in AL, respectively (p < 0.001). After molecular correction, there was no significant difference in ACPRc between DHA–PQ and AL, both at the 28-day and 42-day follow-up with 99.4% (95% CI 96.5–100) in DHA–PQ versus 98.1% (95% CI 94.5–99.6) in AL (p = 0.3) and 99.3% (95% CI 96.5–100) in DHA–PQ vs 97.4% (95% CI 93.5–99.3) in AL (p = 0.2). There was no significant difference between DHA–PQ and AL in QTc prolongation 12.1% vs 7%, respectively (p = 0.4). Conclusion The results showed that dihydroartemisinin–piperaquine and artemether–lumefantrine were clinically efficacious on Plasmodium falciparum parasites in Mali.

Background Artemisinin-based combination therapy is the recommended first-line treatment for uncomplicated falciparum malaria worldwide. However, recent studies conducted in Mali showed an increased frequency of recurrent parasitaemia following artemether–lumefantrine (AL) treatment. Methods Study samples were collected during a large WANECAM study. Ex-vivo Plasmodium falciparum sensitivity to artemether and lumefantrine was assessed using the tritiated hypoxanthine-based assay. The prevalence of molecular markers of anti-malarial drug resistance ( pfcrt K76T, pfmdr1 N86Y and K13-propeller) were measured by PCR and/or sequencing. Results Overall 61 samples were successfully analysed in ex vivo studies. Mean IC 50 s increased significantly between baseline and recurrent parasites for both artemether (1.6 nM vs 3.2 nM, p < 0.001) and lumefantrine (1.4 nM vs 3.4 nM, p = 0.004). Wild type Pfmdr1 N86 allele was selected after treatment (71 vs 91%, 112 of 158 vs 95 of 105, p < 0.001) but not the wild type pfcrt K76 variant (23.5 vs 24.8%, 40 of 170 vs 26 of 105, p = 0.9). Three non-synonymous K13-propeller SNPs (A522C, A578S, and G638R) were found with allele frequencies <2%. Conclusion Malian post-AL P. falciparum isolates were less susceptible to artemether and lumefantrine than baseline isolates.

Background Malaria endemic countries need to assess efficacy of anti-malarial treatments on a regular basis. Moreover, resistance to artemisinin that is established across mainland South-East Asia represents today a major threat to global health. Monitoring the efficacy of artemisinin-based combination therapies is of paramount importance to detect as early as possible the emergence of resistance in African countries that toll the highest burden of malaria morbidity and mortality. Methods A WHO standard protocol was used to assess efficacy of the combinations artesunate–amodiaquine (AS–AQ Winthrop ® ), dihydroartemisinin–piperaquine (DHA–PPQ, Eurartesim ® ) and artemether–lumefantrine (AM–LM, Coartem ® ) taken under supervision and respecting pharmaceutical recommendations. The study enrolled for each treatment arm 212 children aged 6–59 months living in Maradi (Niger) and suffering with uncomplicated falciparum malaria. The Kaplan–Meier 42-day PCR-adjusted cure rate was the primary outcome. A standardized parasite clearance estimator was used to assess delayed parasite clearance as surrogate maker of suspected artemisinin resistance. Results No early treatment failures were found in any of the study treatment arms. The day-42 PCR-adjusted cure rate estimates were 99.5, 98.4 and 99.0% in the AS–AQ, DHA–PPQ and AM–LM arms, respectively. The reinfection rate (expressed also as Kaplan–Meier estimates) was higher in the AM–LM arm (32.4%) than in the AS–AQ (13.8%) and the DHA–PPQ arm (24.9%). The parasite clearance rate constant was 0.27, 0.26 and 0.25 per hour for AS–AQ, DHA–PPQ and AM–LM, respectively. Conclusions All the three treatments evaluated largely meet WHO criteria (at least 95% efficacy). AS–AQ and AL–LM may continue to be used and DHA–PPQ may be also recommended as first-line treatment for uncomplicated falciparum malaria in Maradi. The parasite clearance rate were consistent with reference values indicating no suspected artemisinin resistance. Nevertheless, the monitoring of anti-malarial drug efficacy should continue. Trial registration details Registry number at ClinicalTrial.gov: NCT01755559

Background In 2006, the National Malaria Control Program in Mali recommended artemisinin-based combination therapy as the first-line treatment for uncomplicated malaria. Since the introduction of artemisinin-based combination therapy, few reports are available on the level of resistance of Plasmodium falciparum to the most common anti-malarial drugs in Mali. Methods From 2016 to 2017, we assessed the ex-vivo drug sensitivity of P. falciparum isolates in Kéniéroba, a village located in a rural area of southern Mali. We collected P. falciparum isolates from malaria-infected children living in Kéniéroba. The isolates were tested for ex-vivo sensitivity to commonly used anti-malarial drugs, namely chloroquine, quinine, amodiaquine, mefloquine, lumefantrine, dihydroartermisinin, and piperaquine. We used the 50% inhibitory concentration determination method, which is based on the incorporation of SYBR ® Green into the parasite’s genetic material. Results Plasmodium falciparum isolates were found to have a reduced ex-vivo sensitivity to quinine (25.7%), chloroquine (12.2%), amodiaquine (2.7%), and mefloquine (1.3%). In contrast, the isolates were 100% sensitive to lumefantrine, dihydroartermisinin, and piperaquine. A statistically significant correlation was found between 50% inhibitory concentration values of quinine and amodiaquine ( r  = 0.80; p  < 0.0001). Conclusions Plasmodium falciparum isolates were highly sensitive to dihydroartermisinin, lumefantrine, and piperaquine and less sensitive to amodiaquine ( n  = 2), mefloquine ( n  = 1), and quinine ( n  = 19). Therefore, our data support the previously reported increasing trend in chloroquine sensitivity in Mali.

Artemisinin-based combination therapies decrease Plasmodium gametocyte carriage. However, the role of artesunate in monotherapy in vivo, the mechanisms involved, and the utility of gametocyte carriage as a potential tool for the surveillance of antimalarial resistance are poorly understood. In 2010–2011, we conducted an open-label, prospective efficacy study of artesunate as monotherapy in children 1–10 years of age with uncomplicated falciparum malaria in Bougoula-Hameau, Mali. Standard oral doses of artesunate were administered for 7 days and patients were followed up for 28 days. The data were compared to a similar study conducted in 2002–2004. Of 100 children enrolled in the 2010–2011 study, 92 were analyzed and compared to 217 children enrolled in the 2002–2004 study. The proportion of gametocyte carriers was unchanged at the end of treatment (23% at baseline vs. 24% on day 7, p = 1.0) and did not significantly decline until day 21 of follow-up (23% vs. 6%, p = 0.003). The mean gametocyte density at inclusion remained unchanged at the end of treatment (12 gametocytes/μL vs. 16 gametocytes/μL, p = 0.6). Overall, 46% of the 71 initial non-carriers had gametocytes detected by day 7. Similar results were found in the 2002–2004 study. In both studies, although gametocyte carriage significantly decreased by the end of the 28-day follow-up, artesunate did not clear mature gametocytes during treatment and did not prevent the appearance of new stage V gametocytes as assessed by light microscopy. Baseline gametocyte carriage was significantly higher 6 years after the deployment of artemisinin-based combination therapies in this setting. Les combinaisons thérapeutiques à base d’artémisinine diminuent la prévalence de la gamétocytémie. Cependant, le rôle de l’artésunate en monothérapie, les mécanismes impliqués et l’utilité du portage de gamétocytes comme un outil potentiel pour la surveillance de la chimiorésistance à ces antipaludiques sont mal compris. En 2010-2011, nous avons mené une étude prospective ouverte de l’efficacité de l’artésunate en monothérapie chez des enfants âgés de 1 à 10 ans et atteints de paludisme simple à Plasmodium falciparum à Bougoula-Hameau, au Mali. Des doses standards d’artésunate ont été administrées per os et les patients ont été suivis pendant 28 jours. Les données ont été comparées à celles d’une étude similaire menée en 2002-2004. Sur les 100 enfants inscrits dans l’étude en 2010-2011, 92 ont été analysés et comparés à 217 enfants inclus dans l’étude de 2002-2004. La proportion de porteurs de gamétocytes était inchangée à la fin du traitement (23 % au départ contre 24 % au jour 7, p = 1.0) et n’a diminué de façon significative qu’au 21e jour de suivi (23 % vs 6 %, p = 0.003). La densité (moyenne géométrique) des gamétocytes à l’inclusion est restée inchangée à la fin du traitement (12 gamétocytes/μL vs 16 gamétocytes/μL, p = 0.6). Globalement, 46 % des 71 patients non-porteurs initiaux avait des gamétocytes détectés entre le début du traitement et le jour 7. Des résultats similaires ont été obtenus lors de l’étude de 2002-2004. Lors de ces deux études, bien que le portage des gamétocytes ait considérablement diminué à la fin des 28 jours de suivi, l’artésunate n’avait ni éliminé les gamétocytes matures pendant le traitement ni empêché l’apparition de nouveaux gamétocytes de stade V, selon les observations de microscopie optique. Le taux de base de portage de gamétocytes était significativement plus élevé six années après l’introduction des combinaisons thérapeutiques à base d’artémisinine dans cette localité.

Background Intermittent preventive treatment in infants (IPTi) with sulphadoxine-pyrimethamine (SP) given during routine vaccinations is efficacious in preventing malaria disease and shows no interaction with the vaccines. However, there is a fear that IPTi may result in a rapid increase of parasite resistance to SP. Methods To evaluate the impact of IPTi on SP-resistance point mutations, the 22 health sub-districts in the district of Kolokani, Mali, were randomized in a 1:1 ratio and starting in December 2006, IPTi with SP was implemented in 11 health sub-districts (intervention zone), while the other 11 health sub-districts served as the control (non-intervention zone). Blood smears and blood dots on filter paper were obtained from children aged 0-5 years, randomly selected in each of heath sub-districts during two cross-sectional surveys. The first survey was conducted in May 2007 before the start of the transmission season to collect baseline prevalence of the molecular markers of resistance to SP and the second in December 2007 after the end of the transmission season and one year after implementation of IPTi. A total of 427 and 923 randomly selected blood samples from the first and second surveys respectively were analysed by PCR for dhfr and dhps mutations. Results Each of the three dhfr mutations at codons 51, 59 and 108 was present in 35% and 57% of the samples during the two surveys with no significant differences between the two zones. Dhps mutations at codons 437 and 540 were present respectively in about 20% and 1% of the children during the two surveys in both zones at similar proportion. The prevalence of quadruple mutants (triple dhfr -mutants + dhps -437G) associated with in-vivo resistance to SP in Mali after one year implementation of IPTi was also similar between the two zones (11.6% versus 11.2%, p = 0.90) and to those obtained at baseline survey (10.3% versus 8.1%). Conclusion This study shows no increase in the frequency of molecular markers of SP resistance in areas where IPTi with SP was implemented for one year.

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.

Seasonal Malaria Chemoprevention (SMC) has been implemented in Moissala Health District, southern Chad, since 2013 using the standard regimen of sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ). Although not the sole determinant, SMC can play an important role in generating parasite drug resistance. Three studies spanning a ten-year period were conducted to monitor evolving trends of molecular markers of resistance to SP and AQ in implementation areas. In 2014, 2021, and 2023, a total of 136, 256, and 219 blood samples, respectively, were collected from children with clinical malaria residing in eight health zones. Samples were analysed for known molecular mutations associated with emerging Plasmodium falciparum resistance to SP (dhfr N51I, C59R, and S108N; dhps A437G and K540E) and to AQ (pfcrt K76T and pfmdr-1 N86Y). The proportion of triple dhfr mutants was very high in 2014 and 2021 (100% and 96.9%, respectively), but significantly lower in 2023 (83.9%, p < 0.001). The proportion of quadruple mutants (triple dhfr + dhps A437G) significantly increased from 28.0% in 2014 to 41.0% in 2021 and 47.9% in 2023 (p < 0.001). The proportion of quintuple mutants (triple dhfr + double dhps) was low and did not significantly increase over the years studied (7.6%, 2.8%, and 5.9% in 2014, 2021, and 2023, respectively). The proportion of samples with the pfcrt K76T mutation decreased from 44.6% in 2014 to approximately 11% in 2021 and 2023, while the proportion of samples with the pfmdr-1 N86Y mutation remained consistently low across all three studies. One sample in 2014 exhibited all seven point-mutations investigated, while none were detected in samples in 2021 or 2023. Surveillance of molecular markers of resistance conducted over a ten-year period in Moissala Health District indicates that SP and AQ remain effective despite prolonged use. However, the rise in quadruple mutants-linked to partial SP resistance-is concerning, and monitoring is needed to detect any increase in quintuple mutants, which confer stronger resistance. These findings underscore the importance of sustained molecular surveillance to guide policy decisions and enable timely adaptations of SMC strategies as resistance patterns evolve.

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. 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 <200 000 parasites per μL of blood) and fever or history of fever in the previous 24 h. Individuals with severe or complicated malaria, an alanine aminotransferase concentration of more than twice the upper limit of normal, or a QTc greater than 450 ms were excluded. Using a randomisation list for each site, masked using sealed envelopes, participants were assigned to either pyronaridine–artesunate or dihydroartemisinin–piperaquine versus either artesunate–amodiaquine or artemether–lumefantrine. Block sizes were two or four if two treatments were allocated, and three or six if three treatments were allocated. Microscopists doing the parasitological assessments were masked to treatment allocation. All treatments were once-daily or twice-daily tablets or granules given orally and dosed by bodyweight over 3 days at the study centre. Patients were followed up as outpatients up to day 42, receiving clinical assessments on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42. Two primary outcomes were compared for non-inferiority: the 2-year incidence rate of all microscopically confirmed, complicated and uncomplicated malaria episodes in patients in the intention-to-treat population (ITT; non-inferiority margin 20%); and adequate clinical and parasitological response (ACPR) in uncomplicated malaria across all episodes (unadjusted and PCR-adjusted for Plasmodium falciparum and unadjusted for other Plasmodium spp) in the per-protocol population on days 28 and 42 (non-inferiority margin 5%). Safety was assessed in all participants who received one dose of study drug. This study is registered at the Pan African Clinical Trials Registry (PACTR201105000286876). Between Oct 24, 2011, and Feb 1, 2016, we assigned 4710 eligible participants to the different treatment strategies: 1342 to pyronaridine–artesunate, 967 to artemether–lumefantrine, 1061 to artesunate–amodiaquine, and 1340 to dihydroartemisinin–piperaquine. The 2-year malaria incidence rate in the ITT population was non-inferior for pyronaridine–artesunate versus artemether–lumefantrine (1·77, 95% CI 1·63–1·93 vs 1·87, 1·72–2·03; rate ratio [RR] 1·05, 95% CI 0·94–1·17); and versus artesunate–amodiaquine (1·39, 95% CI 1·22–1·59 vs 1·35, 1·18–1·54; RR 0·97, 0·87–1·07). Similarly, this endpoint was non-inferior for dihydroartemisinin–piperaquine versus artemether–lumefantrine (1·16, 95% CI 1·01–1·34 vs 1·42 1·25–1·62; RR 1·22, 95% CI 1·06–1·41) and versus artesunate–amodiaquine (1·35, 1·21–1·51 vs 1·68, 1·51–1·88; RR 1·25, 1·02–1·50). For uncomplicated P falciparum malaria, PCR-adjusted ACPR was greater than 99·5% at day 28 and greater than 98·6% at day 42 for all ACTs; unadjusted ACPR was higher for pyronaridine–artesunate versus comparators at day 28 (96·9% vs 82·3% for artemether–lumefantrine and 95·6% vs 89·0% for artesunate–amodiaquine) and for dihydroartemisinin-piperaquine versus comparators (99·5% vs 81·6% for artemether–lumefantrine and 99·0% vs 89·0% for artesunate–amodiaquine). For non-falciparum species, unadjusted ACPR was greater than 98% for all study drugs at day 28 and at day 42 was greater than 83% except for artemether–lumefantrine against Plasmodium ovale (in ten [62·5%] of 16 patients) and against Plasmodium malariae (in nine [75·0%] of 12 patients). Nine deaths occurred during the study, none of which were related to the study treatment. Mostly mild transient elevations in transaminases occurred with pyronaridine–artesunate versus comparators, and mild QTcF prolongation with dihydroartemisinin-piperaquine versus comparators. Pyronaridine–artesunate and dihydroartemisinin–piperaquine treatment and retreatment of malaria were well tolerated with efficacy that was non-inferior to first-line ACTs. Greater access to these efficacious treatments in west Africa is justified. The European and Developing Countries Clinical Trial Partnership, Medicines for Malaria Venture (Geneva, Switzerland), the UK Medical Research Council, the Swedish International Development Cooperation Agency, German Ministry for Education and Research, University Claude Bernard (Lyon, France), University of Science, Techniques and Technologies of Bamako (Bamako, Mali), the Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso), Institut de Recherche en Sciences de la Santé (Bobo-Dioulasso, Burkina Faso), and Centre National de Formation et de Recherche en Santé Rurale (Republic of Guinea).

Background. The mechanism of Plasmodium falciparum resistance to quinine is not known. In vitro quantitative trait loci mapping suggests involvement of a predicted P. falciparum sodium-hydrogen exchanger (pfnhe-1) on chromosome 13. Methods. We conducted prospective quinine efficacy studies in 2 villages, Kollé and Faladié, Mali. Cases of clinical malaria requiring intravenous therapy were treated with standard doses of quinine and followed for 28 days. Treatment outcomes were classified using modified World Health Organization protocols. Molecular markers of parasite polymorphisms were used to distinguish recrudescent parasites from new infections. The prevalence of pfnhe-1 ms4760-1 among parasites before versus after quinine treatment was determined by direct sequencing. Results. Overall, 163 patients were enrolled and successfully followed. Without molecular correction, the mean adequate clinical and parasitological response (ACPR) was 50.3% (n = 163). After polymerase chain reaction correction to account for new infections, the corrected ACPR was 100%. The prevalence of ms4760-1 increased significantly, from 26.2% (n= 107) before quinine treatment to 46.3% (n = 54) after therapy (P = .01). In a control sulfadoxine-pyrimethamine study, the prevalence of ms4760-l was similar before and after treatment. Conclusions. This study supports a role for pfnhe-l in decreased susceptibility of P. falciparum to quinine in the field.