Plasmodium falciparum clearance time in Malawian children with cerebral malaria: a retrospective cohort study

Background Standard treatment for both uncomplicated and severe malaria is artemisinin derivatives. Delayed parasite clearance times preceded the appearance of artemisinin treatment failures in Southeast Asia. Most worldwide malaria cases are in sub-Saharan Africa (SSA), where clinically significant artemisinin resistance or treatment failure has not yet been detected. The recent emergence of a resistance-conferring genetic mutation in the Plasmodium falciparum parasite in Africa warrants continued monitoring throughout the continent. Methods An analysis was performed on data from a retrospective cohort study of Malawian children with cerebral malaria admitted between 2010 and 2019 to a public referral hospital, ascertaining parasite clearance times across years. Data were collected from patients treated for severe malaria with quinine or artesunate, an artemisinin derivative. Parasite density was determined at admission and every subsequent 6 h until parasitaemia was below 1000 parasites/µl.The mean parasite clearance time in all children admitted in any one year was compared to the parasite clearance time in 2014, the first year of artesunate use in Malawi. Results The median population parasite clearance time was slower from 2010 to 2013 (quinine-treated patients) compared to 2014, the first year of artesunate use in Malawi (30 h (95% CI: 30–30) vs 18 h (95% CI: 18–24)). After adjustment for admission parasite count, there was no statistically significant difference in the median population parasite clearance time when comparing 2014 with any subsequent year. Conclusion Malaria parasite clearance times in Malawian children with cerebral malaria remained constant between 2014 and 2019, arguing against evolving artemisinin resistance in parasites in this region.

OC 8459 ASSESSMENT OF PARASITE CLEARANCE AFTER REPEATED TREATMENT WITH ARTESUNATE AMODIAQUINE, DIHYDROARTEMISININ-PIPERAQUINE, PYRONARIDINE-ARTESUNATE IN MALARIA PATIENTS IN BURKINA FASO

BackgroundReports from Southeast Asia showed delayed parasite clearance after treatment with known artemisinin-based combination therapies (ACTs), the first-line treatment for malaria. We then carried out a study in the framework of the WANECAM clinical trial to assess comparatively the parasite clearance time and rate from P. falciparum malaria patients repeatedly treated with the artesunate-amodiaquine (ASAQ), dihydroartemisinin-piperaquine (DHA-PQ) and artesunate-pyronaridine (PYR).MethodsA randomised, phase III/IV comparative, multicentre, open-label, parallel 3-arms trial was conducted in Banfora Health District area comparing the efficacy of a three-day regimen of DHA-PQ, PYR with ASAQ for the treatment of children (above 6 months) and adults with uncomplicated falciparum malaria. From August 2012 to December 2013, each randomised patient was followed up for 42 days over a period of two years. Treatment was directly observed, and blood smear samples were collected twice daily (12 hour±2 hour) until parasite clearance.The endpoints of the present sub-study were parasite clearance rate and time. The secondary endpoints included PCR-corrected and uncorrected cure rates.ResultsOut of 2843 screened patients, 763 were recruited for parasite clearance endpoint analyses. The median parasite clearance time (PCT) was 24.1 hour (2-sided 95% CI, 24.0 to 24.2 hour), 23.9 hour (2-sided 95% CI, 23.8 to 24.0 hour) and 24.2 hour (2-sided 95% CI, 24.1 to 24.5 hour), in PYR and DHA-PQ, respectively. The PCR-corrected efficacy rates were estimated at 99.8%; 99.7%; 99.9%, at day 28% and 99.3%; 99.7%–99.9% in PYR, ASAQ and DHA-PQ, respectively.ConclusionThe parasite clearance times were comparable among the three ACT arms of treatment and their efficacy was comparable and higher than 99%. There was no delay in parasite clearance time (PCT ≥72 hour).

Delayed Parasite Clearance after Treatment with Dihydroartemisinin-Piperaquine in Plasmodium falciparum Malaria Patients in Central Vietnam

ABSTRACTReduced susceptibility ofPlasmodium falciparumtoward artemisinin derivatives has been reported from the Thai-Cambodian and Thai-Myanmar borders. Following increasing reports from central Vietnam of delayed parasite clearance after treatment with dihydroartemisinin-piperaquine (DHA-PPQ), the current first-line treatment, we carried out a study on the efficacy of this treatment. Between September 2012 and February 2013, we conducted a 42-dayin vivoandin vitroefficacy study in Quang Nam Province. Treatment was directly observed, and blood samples were collected twice daily until parasite clearance. In addition, genotyping, quantitative PCR (qPCR), andin vitrosensitivity testing of isolates was performed. The primary endpoints were parasite clearance rate and time. The secondary endpoints included PCR-corrected and uncorrected cure rates, qPCR clearance profiles,in vitrosensitivity results (for chloroquine, dihydroartemisinin, and piperaquine), and genotyping for mutations in the Kelch 13 propeller domain. Out of 672 screened patients, 95 were recruited and 89 available for primary endpoint analyses. The median parasite clearance time (PCT) was 61.7 h (interquartile range [IQR], 47.6 to 83.2 h), and the median parasite clearance rate had a slope half-life of 6.2 h (IQR, 4.4 to 7.5 h). The PCR-corrected efficacy rates were estimated at 100% at day 28 and 97.7% (95% confidence interval, 91.2% to 99.4%) at day 42. At day 3, theP. falciparumprevalence by qPCR was 2.5 times higher than that by microscopy. The 50% inhibitory concentrations (IC50s) of isolates with delayed clearance times (≥72 h) were significantly higher than those with normal clearance times for all three drugs. Delayed parasite clearance (PCT, ≥72 h) was significantly higher among day 0 samples carrying the 543 mutant allele (47.8%) than those carrying the wild-type allele (1.8%;P= 0.048). In central Vietnam, the efficacy of DHA-PPQ is still satisfactory, but the parasite clearance time and rate are indicative of emerging artemisinin resistance. (This study has been registered at ClinicalTrials.gov under registration no. NCT01775592.)

Therapeutic responses to different anti-Trypanosoma cruzidrugs in experimental infection by benznidazole-resistant parasite stock

SUMMARYThis study describes the role of parasite clearance time induced by benznidazole, fexinidazole and posaconazole treatments upon mice infection with a benznidazole-resistantTrypanosoma cruzistrain in the pathological outcomes.Trypanosoma cruzi-infected mice were treated with different drugs and parasite clearance time was detected by blood and tissue qPCR, to determine the dynamic relationship between the efficacy of the treatments and the intensity of heart lesion/serum inflammatory mediators. Our results indicate that anti-T. cruzitreatments were able to reduce parasite replication and consequently induce immunomodulatory effects, where the degree of the immunopathology prevention was related to the time of parasite clearance induced by different treatments. Nevertheless, in benznidazole and posaconazole treatments, parasite rebounding was detected with parasitism reaching levels similar to infected and non-treated mice; the time for parasitic rebound being earlier among benznidazole-treated mice. In parallel, an increase of cardiac lesions and plasma chemokine levels was also detected and was more accentuated in benznidazole-treated animals. Interestingly, in the presence of parasitological cure (fexinidazole treatment), basal levels of these inflammatory mediators were evidenced as well as an absence of cardiac inflammation or fibrosis. Overall, our data indicate that all treatments have positive effects on the clinical evolution ofT. cruziinfection, with success in preventing cardiac alterations being drug-dependent.

Efficacy of artemether-lumefantrine and artesunate-amodiaquine for treating uncomplicated falciparum malaria in children

Background Artesunate-amodiaquine (ASAQ) has been usedas a firsdine treatment for uncomplicated faldparum malariain Indonesia since 2004. Its efficacy depends on amodiaquineresistance of the infecting parasites. Artemether-lumefantrine(AL) has been shown to be highly efficacious in treatinguncomplicated faldparum malaria in several countries. However,there have been few studies on these anti-malarial medicationsin Indonesia.Objective To compare the efficacy of AL to ASAQ for treatinguncomplicated faldparum malaria in children.Methods An open, randomized, controlled trial wasconducted in school-aged children in the Mandailing NatalRegency, North Sumatera Province, Indonesia, from Octoberto December 2010. A total of 280 pediatric, uncomplicatedfalciparum malaria patients were randomly assigned to receiveeither AL or ASAQ for 3 days. Participants were followed-up ondays 1,2,3,7, 14, 28 and 42 following the first medication dose.The outcomes noted were adequate clinical and parasitologicalresponse (ACPR), parasite reduction, parasite clearance time,fever clearance time and adverse events. Analysis was basedon intention-to-treat.Results In this study, ACPRs on day 42 were 86.4% and 90.7%for the ASAQ and AL groups, respectively (p=0.260). On days 7and 14, the AL group had higher cure rates than that of the ASAQgroup (P<0.05). Early treatment failure, late treatment failure andparasitological failure for both groups were similar. We also foundfaster parasite clearance time and higher parasite reduction in theAL group than in the ASAQ group. However, fever clearancetime was shorter in the ASAQ group. The incidence of adverseevents such as nausea, vomiting, malaise, and pruritus were similarbetween the two groups (P=0.441).Conclusion AL had higher efficacy than ASAQ for the treatment of uncomplicated falciparum malaria in children.[Paediatr rndones. 2012;52:260-6].