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Abstract Background HIV-infected individuals on antiretroviral therapy (ART) require treatment with artemisinin-based combination therapy (ACT) when infected with malaria. Artemether–lumefantrine (AL) is the most commonly used ACT for treatment of falciparum malaria in Africa but there is limited evidence on the safety and efficacy of AL in HIV-infected individuals on ART, among whom drug–drug interactions are expected. Day-42 adequate clinical and parasitological response (ACPR) and incidence of adverse events was assessed in HIV-infected individuals on efavirenz-based ART with uncomplicated falciparum malaria treated with AL. Methods A prospective, open label, non-randomized, interventional clinical trial was conducted at St Paul’s Hospital in northern Zambia, involving 152 patients aged 15–65 years with uncomplicated falciparum malaria, who were on efavirenz-based ART. They received a 3-day directly observed standard treatment of AL and were followed up until day 63. Day-42 polymerase chain reaction (PCR)-corrected ACPRs (95% confidence interval [CI]) were calculated for the intention-to-treat population. Results Enrolled patients had a baseline geometric mean (95% CI) parasite density of 1108 (841–1463) parasites/µL; 16.4% (25/152) of the participants had a recurrent malaria episode by day 42. However, PCR data was available for 17 out of the 25 patients who had malaria recurrence. Among all the 17 patients, PCR findings demonstrated malaria re-infection, making the PCR-adjusted day-42 ACPR 100% in the 144 patients who could be evaluated. Even when eight patients with missing PCR data were considered very conservatively as failures, the day-42 ACPR was over 94%. None of the participants, disease or treatment characteristics, including day-7 lumefantrine concentrations, predicted the risk of malaria recurrence by day 42. AL was well tolerated following administration. There were only two cases of grade 3 neutropaenia and one serious adverse event of lobar pneumonia, none of which was judged as probably related to intake of AL. Conclusions AL was well tolerated and efficacious in treating uncomplicated falciparum malaria in HIV co-infected adults on efavirenz-based ART. However, a higher than anticipated proportion of participants experienced malaria re-infection, which highlights the need for additional malaria prevention measures in this sub-population after treatment with AL. Trial registration Pan African Clinical Trials Registry (PACTR): PACTR201311000659400. Registered on 4 October 2013. https://pactr.samrc.ac.za/Search.aspx

Abstract Background The World Health Organization recommends regular therapeutic efficacy studies (TES) to monitor the performance of first and second-line anti-malarials. In 2016, efficacy and safety of artemether-lumefantrine (AL) for the treatment of uncomplicated falciparum malaria were assessed through a TES conducted between April and October 2016 at four sentinel sites of Kibaha, Mkuzi, Mlimba, and Ujiji in Tanzania. The study also assessed molecular markers of artemisinin and lumefantrine (partner drug) resistance. Methods Eligible patients were enrolled at the four sites, treated with standard doses of AL, and monitored for 28 days with clinical and laboratory assessments. The main outcomes were PCR corrected cure rates, day 3 positivity rates, safety of AL, and prevalence of single nucleotide polymorphisms in Plasmodium falciparum kelch 13 (Pfk13) (codon positions: 440–600) and P. falciparum multi-drug resistance 1 (Pfmdr1) genes (codons: N86Y, Y184F and D1246Y), markers of artemisinin and lumefantrine resistance, respectively. Results Of 344 patients enrolled, three withdrew, six were lost to follow-up; and results were analysed for 335 (97.4%) patients. Two patients had treatment failure (one early treatment failure and one recrudescent infection) after PCR correction, yielding an adequate clinical and parasitological response of > 98%. Day 3 positivity rates ranged from 0 to 5.7%. Common adverse events included cough, abdominal pain, vomiting, and diarrhoea. Two patients had serious adverse events; one died after the first dose of AL and another required hospitalization after the second dose of AL (on day 0) but recovered completely. Of 344 samples collected at enrolment (day 0), 92.7% and 100% were successfully sequenced for Pfk13 and Pfmdr1 genes, respectively. Six (1.9%) had non-synonymous mutations in Pfk13, none of which had been previously associated with artemisinin resistance. For Pfmdr1, the NFD haplotype (codons N86, 184F and D1246) was detected in 134 (39.0%) samples; ranging from 33.0% in Mlimba to 45.5% at Mkuzi. The difference among the four sites was not significant (p = 0.578). All samples had a single copy of the Pfmdr1 gene. Conclusion The study indicated high efficacy of AL and the safety profile was consistent with previous reports. There were no known artemisinin-resistance Pfk13 mutations, but there was a high prevalence of a Pfmdr1 haplotype associated with reduced sensitivity to lumefantrine (but no reduced efficacy was observed in the subjects). Continued TES and monitoring of markers of resistance to artemisinin and partner drugs is critical for early detection of resistant parasites and to inform evidence-based malaria treatment policies. Trial Registration ClinicalTrials.gov NCT03387631

Toussaint Rouamba,1,2 Paul Sondo,2 Isidore W Yerbanga,2 Adelaide Compaore,2 Maminata Traore-Coulibaly,2 Franck S Hien,2 Nassirou A Diande,2 Daniel Valia,2 Innocent Valea,2 Patricia Akweongo,3 Rita Baiden,4 Fred Binka,4 Fati Kirakoya-Samadoulougou,1 Halidou Tinto2 1Center for Research in Epidemiology, Biostatistics and Clinical Research, School of Public Health, Université libre de Bruxelles (ULB), Brussels, Belgium; 2Clinical Research Unit of Nanoro, Institute for Research in Health Sciences, National Center for Scientific and Technological Research, Ouagadougou, Burkina Faso; 3Epidemiology and Disease Control Department, University of Ghana, Accra, Ghana; 4INDEPTH-Network, Accra, Ghana Purpose: In 2005, Burkina Faso changed its first-line treatment for uncomplicated malaria from chloroquine to artemisinin-based combination therapies (ACTs). Patient adherence to ACTs regimen is a keystone to achieve the expected therapeutic outcome and prevent the emergence and spread of parasite resistance. Eleven years after the introduction of ACTs in the health system, this study aimed to measure adherence level of patients in rural settlement and investigate the determinants of nonadherence.Patients and methods: The study was carried out at public peripheral health facilities from May 2017 to August 2017 in Nanoro health district, Burkina Faso. An electronic semi-structured questionnaire was used for data collection from patients with an ACT prescription at their medical consultation exit visit and during home visit at day 5±2. Adherence level was measured through self-report and pill counts. Logistic regression was performed to identify factors for nonadherence.Results: The analysis was conducted on 199 outpatients who received ACT as prescription. About 92.5% of ACT prescriptions included artemether-lumefantrine tablets. Adherence level was measured in 97.0% of included patients at day 5±2. Of these, 86.0% were classified as “complete adherent” and 14.0% as “nonadherent”. In univariate analysis, patients/caregivers who considered that affordability of ACTs was easy seemed to be less adherent to the treatment regimen (OR: 0.26; 95% CI: 0.07–0.70). In univariate and multivariable analyses, patients/caregivers who did not receive advices from health care workers (HCWs) were more likely to be nonadherent to the prescribed ACTs (adjusted OR: 3.21; 95% CI: 1.13–9.12).Conclusion: This study demonstrates that majority of those who get an ACT prescription comply with the recommended regimen. This emphasizes that in rural settings where ACTs are provided free of charge or at a subsidized price, patient adherence to ACTs is high, thus minimizing the risk of subtherapeutic concentrations of the drug in blood which is known to increase resistance and susceptibility to new infections. Therefore, to address the problem of patient nonadherence, strategy to strengthen communication between HCWs and patients should be given greater consideration. Keywords: malaria, hyperendemic area, drug prescription, artemether-lumefantrine, amodiaquine-artesunate

Background: The current first-line treatments for uncomplicated malaria recommended by the National Malaria Control Programme in Mali are artemether–lumefantrine (AL) and artesunate–amodiaquine (ASAQ). From 2015 to 2016, an in vivo study was carried out to assess the clinical and parasitological responses to AL and ASAQ in Sélingué, Mali. Methods: Children between 6 and 59 months of age with uncomplicated Plasmodium falciparum infection and 2000–200,000 asexual parasites/μL of blood were enrolled, randomly assigned to either AL or ASAQ, and followed up for 42 days. Uncorrected and PCR-corrected efficacy results at days 28 and 42. were calculated. Known markers of resistance in the Pfk13, Pfmdr1, and Pfcrt genes were assessed using Sanger sequencing. Results: A total of 449 patients were enrolled: 225 in the AL group and 224 in the ASAQ group. Uncorrected efficacy at day 28 was 83.4% (95% CI 78.5–88.4%) in the AL arm and 93.1% (95% CI 89.7–96.5%) in the ASAQ arm. The per protocol PCR-corrected efficacy at day 28 was 91.0% (86.0–95.9%) in the AL arm and 97.1% (93.6–100%) in the ASAQ arm. ASAQ was significantly (p < 0.05) better than AL for each of the aforementioned efficacy outcomes. No mutations associated with artemisinin resistance were identified in the Pfk13 gene. Overall, for Pfmdr1, the N86 allele and the NFD haplotype were the most common. The NFD haplotype was significantly more prevalent in the post-treatment than in the pre-treatment isolates in the AL arm (p < 0.01) but not in the ASAQ arm. For Pfcrt, the CVIET haplotype was the most common. Conclusions: The findings indicate that both AL and ASAQ remain effective for the treatment of uncomplicated malaria in Sélingué, Mali. [ABSTRACT FROM AUTHOR]

Background: Malaria is a major public health problem in India and accounts for about 88% of malaria burden in South-East Asia. India alone accounted for 2% of total malaria cases globally. Anti-malarial drug resistance is one of the major problems for malaria control and elimination programme. Artemether-lumefantrine (AL) is the first-line treatment of uncomplicated Plasmodium falciparum in north eastern states of India since 2013 after confirming the resistance against sulfadoxine-pyrimethamine. In the present study, therapeutic efficacy of artemether-lumefantrine and k13 polymorphism was assessed in uncomplicated P. falciparum malaria. Methods: This study was conducted at four community health centres located in Koraput district of Odisha, Bastar district of Chhattisgarh, Balaghat district of Madhya Pradesh and Gondia district of Maharashtra state. Patients with uncomplicated P. falciparum malaria were administered with fixed dose combination (6 doses) of artemether-lumefantrine for 3 days and clinical and parasitological response was recorded up to 28 days as per World Health Organization protocol. Nucleotide sequencing of msp1 and msp2 gene was performed to differentiate between recrudescence and reinfection. Amplification and sequencing of k13 propeller gene region covering codon 450–680 was also carried out to identify the polymorphism. Results: A total 376 malaria patients who fulfilled the enrolment criteria as well as consented for the study were enrolled. Total 356 patients were followed up successfully up to 28 days. Overall, the adequate clinical and parasitological response was 98.9% and 99.4% with and without PCR correction respectively. No case of early treatment failure was observed. However, four cases (1.1%) of late parasitological failure were found from the Bastar district of Chhattisgarh. Genotyping of msp1 and msp2 confirmed 2 cases each of recrudescence and reinfection, respectively. Mutation analysis of k13 propeller gene showed one non-synonymous mutation Q613H in one isolate from Bastar. Conclusions: The study results showed that artemether-lumefantrine is highly effective in the treatment of uncomplicated P. falciparum malaria among all age groups. No functional mutation in k13 was found in the study area. The data from this study will be helpful in implementation of artemether-lumefantrine in case of treatment failure by artesunate plus sulfadoxine-pyrimethamine. [ABSTRACT FROM AUTHOR]

Background: Artemether/lumefantrine (AL), sold under the brand name Coartem, is the most common artemisinin-based combination therapy for the treatment of malaria. Drug-induced oculogyric crisis is a neurological disorder characterized by frequent upward deviations of the eye. In the literature, no cases of Coartem-induced oculogyric crisis have been reported in Ghana. Case presentation: A 19-year-old male patient, who presented fever measuring 37.9 °C, general body pains, and weakness was prescribed with antimalarial therapy artemether/lumefantrine, Coartem®, from a local pharmacy. Just after initiation of treatment, the patient complained of double vision, involuntary upward eye deviation, and inability to close both eyes. The patient was diagnosed with Coartem-induced oculogyric crisis and was treated with the cessation of the causing agent and intramuscular injection of promethazine hydrochloride. Conclusions: When a patient exhibits a neurological disorder, such as oculogyric crisis, with normal conscious state and normal vital signs, special attention should be given to obtaining a history of recently administered medications. Clinicians should recognize adverse reactions to drugs based on a thorough patient history and examination. The goal of this report was to present Coartem-induced oculogyric crisis. [ABSTRACT FROM AUTHOR]

Background: Regular monitoring of anti-malarial drug efficacy is vital for establishing rational malaria treatment guidelines and ensuring adequate treatment outcomes. This study aimed to synthesize the available evidence on the efficacy of artemether–lumefantrine for the management of uncomplicated falciparum malaria in Ethiopia. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Relevant published studies were searched from the databases (PubMed, Google Scholar and Clinical trial registry) on published artemether–lumefantrine therapeutic efficacy studies conducted in Ethiopia from 2004 to 2020. The retrieved studies were assessed for quality using the modified Newcastle Ottawa Scale for observational studies and modified Jadad scale for interventional studies. Risk of bias was also assessed by using ROBINS-I tool. OpenMeta-Analyst software was used for the statistical analysis. The review protocol is registered in PROSPERO, number CRD42020201859. Results: Fifteen studies (1523 participants) were included in the final analysis. The overall PCR-uncorrected pooled proportion of treatment success of artemether–lumefantrine therapy for uncomplicated falciparum malaria was 98.4% (95%CI 97.6–99.1). A random-effects model was used because of considerable heterogeneity [χ2 = 20.48, df (14), P = 0.011 and I2 = 31.65]. PCR-corrected pooled proportion of treatment success of artemether–lumefantrine therapy was 98.7% (95% CI 97.7–99.6). A random-effects model was used [χ2 = 7.37, df(6), P = 0.287 and I2 = 18.69]. Most studies included in the present review achieved a rapid reduction of fevers and parasitaemia between D0 and D3 of assessment. Adverse events were mostly mild and only two cases were reported as serious, but were not directly attributed to the drug. Conclusion: The present meta-analysis suggests that artemether–lumefantrine therapy is efficacious and safe in treating uncomplicated falciparum malaria in Ethiopia. However, owing to the high risk of bias in the included studies, strong conclusions cannot be drawn. Further high-quality RCTs assessing anti-malarial efficacy and safety should be performed to demonstrates strong evidence of changes in parasite sensitivity to artemether–lumefantrine in Ethiopia. [ABSTRACT FROM AUTHOR]

Background: The emergence of artemisinin resistance in Southeast Asia and Plasmodium falciparum kelch13 propeller gene mutations in sub-Saharan African pose the greatest threat to global efforts to control malaria. This is a critical concern in Uganda, where artemisinin-based combination therapy (ACT) is the first-line treatment for uncomplicated falciparum. The objective of this study was to compare the efficacy and safety of dihydroartemisinin–piperaquine (DHA–PQ) and artemether–lumefantrine (AL) for the treatment of uncomplicated falciparum malaria in Ugandan children. Methods: A search of PubMed and the Cochrane Central Register of Controlled Trials for retrieving randomized controlled trials comparing the efficacy and safety of DHA–PQ and AL for treatment of uncomplicated falciparum malaria in Ugandan children was done. The search was performed up to 31 August 2020. The data extracted from eligible studies and pooled as risk ratio (RR) with a 95% confidence interval (CI), using Rev Man Software (5.4). The protocol was registered in PROSPERO, ID: CRD42020182354. Results: Eleven trials were included in this review and two of them only included under safety outcome. Total 3798 participants were enrolled. The PCR unadjusted treatment failure was significantly lower with DHA–PQ at day 28 (RR 0.30, 95% CI 0.19–0.49; participants = 7863; studies = 5; I2 = 93%, low quality evidence) and at day 42 (RR 0.53, 95% CI 0.38–0.76; participants = 1618; studies = 4; I2 = 79%, moderate quality of evidence). The PCR adjusted treatment failure at day 42 was significantly lower with DHA–PQ treatment group (RR 0.45, 95% CI 0.28 to 0.72; participants = 1370; studies = 5, high quality of evidence), and it was below 5% in both arms at day 28 (moderate quality of evidence). AL showed a longer prophylactic effect on new infections which may last for up to 63 days (PCR-adjusted treatment failure: RR 2.04, 95% CI 1.13–3.70; participants = 1311; studies = 2, moderate quality of evidence). Compared to AL, DHA–PQ was associated with a slightly higher frequency of cough (RR 1.07, 95% CI 1.01 to 1.13; 2575 participants; six studies; high quality of evidence). In both treatment groups, the risk of recurrent parasitaemia due to possible recrudescence was less than 5% at day 28. The appearance of gametocyte between 29 and 42 days was also significantly lower in DHA–PQ than AL (RR 0.26, 95% CI 0.12 to 0.56; participants = 623; studies = 2; I2 = 0%). Conclusion: Compared to AL, DHA–PQ appeared to reduce treatment failure and gametocyte carriage in Ugandan children. This may trigger DHA–PQ to become the first-line treatment option. Both treatments were safe and well-tolerated. [ABSTRACT FROM AUTHOR]

Background: The use of pyronaridine-artesunate (PA) has been associated with scarce transaminitis in patients. This analysis aimed to evaluate the hepatic safety profile of repeated treatment with PA versus artemether-lumefantrine (AL) in patients with consecutive uncomplicated malaria episodes in Bobo-Dioulasso, Burkina Faso. Methods: This study analysed data from a clinical trial conducted from 2012 to 2015, in which participants with uncomplicated malaria were assigned to either PA or AL arms and followed up to 42 days. Subsequent malaria episodes within a 2-years follow up period were also treated with the same ACT initially allocated. Transaminases (AST/ALT), alkaline phosphatase (ALP), total and direct bilirubin were measured at days 0 (baseline), 3, 7, 28 and on some unscheduled days if required. The proportions of non-clinical hepatic adverse events (AEs) following first and repeated treatments with PA and AL were compared within study arms. The association of these AEs with retreatment in each arm was also determined using a logistic regression model. Results: A total of 1379 malaria episodes were included in the intention to treat analysis with 60% of all cases occurring in the AL arm. Overall, 179 non-clinical hepatic AEs were recorded in the AL arm versus 145 in the PA arm. Elevated ALT was noted in 3.05% of treated malaria episodes, elevated AST 3.34%, elevated ALP 1.81%, and elevated total and direct bilirubin in 7.90% and 7.40% respectively. Retreated participants were less likely to experience elevated ALT and AST than first episode treated participants in both arms. One case of Hy's law condition was recorded in a first treated participant of the PA arm. Participants from the retreatment group were 76% and 84% less likely to have elevated ALT and AST, respectively, in the AL arm and 68% less likely to present elevated ALT in the PA arm. In contrast, they were almost 2 times more likely to experience elevated total bilirubin in both arms. Conclusions: Pyronaridine-artesunate and artemether-lumefantrine showed similar hepatic safety when used repeatedly in participants with uncomplicated malaria. Pyronaridine-artesunate represents therefore a suitable alternative to the current first line anti-malarial drugs in use in endemic areas. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization recommends regularly assessing the efficacy of artemisinin-based combination therapy (ACT), which is a critical tool in the fight against malaria. This study evaluated the efficacy of two artemisinin-based combinations recommended to treat uncomplicated Plasmodium falciparum malaria in Burkina Faso in three sites: Niangoloko, Nanoro, and Gourcy. Methods: This was a two-arm randomized control trial of the efficacy of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP). Children aged 6–59 months old were monitored for 42 days. The primary outcomes of the study were uncorrected and PCR-corrected efficacies to day 28 for AL and 42 for DP. Molecular markers of resistance to artemisinin derivatives and partner drugs were also analysed. Results: Of 720 children enrolled, 672 reached study endpoints at day 28, 333 in the AL arm and 339 in the DP arm. PCR-corrected 28-day per protocol efficacy in the AL arm was 74% (64–83%) in Nanoro, 76% (66–83%) in Gourcy, and 92% (84–96%) in Niangoloko. The PCR-corrected 42-day per protocol efficacy in the DP arm was 84% (75–89%) in Gourcy, 89% (81–94%) in Nanoro, and 97% (92–99%) in Niangoloko. No Pfk13 mutation previously associated with artemisinin-resistance was observed. No statistically significant association was found between treatment outcome and presence of the 86Y mutation in the Pfmdr1 gene. There was also no association observed between treatment outcome and Pfpm2 or Pfmdr1 copy number variation. Conclusion: The results of this study indicate evidence of inadequate efficacy of AL at day 28 and DP at day 42 in the same two sites. A change of first-line ACT may be warranted in Burkina Faso. Trial Registry Pan African Clinical Trial Registry Identifier: PACTR201708002499311. Date of registration: 8/3/2017 https://pactr.samrc.ac.za/Search.aspx [ABSTRACT FROM AUTHOR]

Background: In clinical trials of therapy for uncomplicated Plasmodium falciparum, there are usually some patients who fail treatment even in the absence of drug resistance. Treatment failures, which can be due to recrudescence or re-infection, are categorized as 'clinical' or 'parasitological' failures, the former indicating that symptoms have returned. Asymptomatic recrudescence has public health implications for continued malaria transmission and may be important for the spread of drug-resistant malaria. As the number of recrudescences in an individual trial is often low, it is difficult to assess how commonplace asymptomatic recrudescence is, and with what factors it is associated. Methods: A systematic literature review was carried out on clinical trials of artemether-lumefantrine (AL) in patients seeking treatment for symptomatic uncomplicated falciparum malaria, and information on symptoms during treatment failure was recorded. Only treatment failures examined by polymerase chain reaction (PCR) were included, so as to exclude re-infections. A multivariable Bayesian regression model was used to explore factors potentially explaining the proportion of recrudescent infections which are symptomatic across the trials included in the study. Results: Across 60 published trials, including 9137 malaria patients, 37.8% [95% CIs (26.6–49.4%)] of recrudescences were symptomatic. A positive association was found between transmission intensity and the observed proportion of recrudescences that were asymptomatic. Symptoms were more likely to return in trials that only enrolled children aged < 72 months [odds ratio = 1.62, 95% CIs (1.01, 2.59)]. However, 84 studies had to be excluded from this analysis, as recrudescences were not specified as symptomatic or asymptomatic. Conclusions: AL, the most widely used treatment for uncomplicated P. falciparum in Africa, remains a highly efficacious drug in most endemic countries. However in the small proportion of patients where AL does not clear parasitaemia, the majority of patients do not develop symptoms again and thus would be unlikely to seek another course of treatment. This continued asymptomatic parasite carriage in patients who have been treated may have implications for drug-resistant parasites being introduced into high-transmissions settings. [ABSTRACT FROM AUTHOR]

Introduction: Artemether-Lumefantrine (A-L) remains the drug of choice for the treatment of uncomplicated malaria in Ghana. However, the pharmaco-activity of A-L has not been assessed on various Plasmodium falciparum Kelch 13 and Pfmdr1 genes. Therefore, this study sought to determine the therapeutic efficacy of A-L on P. falciparum parasites isolated from Ghana. Methods: The clinical study was done in Ga West Municipality, Ghana, where 78 uncomplicated malaria patients were recruited with prior consent. The patients were treated orally with A-L according to national treatment guidelines. Baseline parasitaemia was determined before treatment and 8-hourly parasitaemia posttreatment were determined till initial clearance of parasitaemia and at days 7, 14, 21, and 28. Kelch 13 and Pfmdr1 genes were genotyped by sequencing using baseline samples. Parasite clearance characteristics were determined using Parasite Clearance Estimator beta 0.9 application. Results: Five Kelch 13 (F446I, S466N, R539I, A578S, and A676S) and three Pfmdr1 mutations (N86Y, Y184F and D1246Y) were identified in 78 infected samples. About 8% of the samples contained two Pfmdr1 double mutations (N86Y & D1246Y and Y184F & N86Y). Additionally, three samples (3.8%) were found to contain both Kelch 13 mutations and Pfmdr1 wild type genes. In all patients, parasitaemia persisted within the first 24 h of A-L therapy. However, at hour 40, only two patients were parasitaemic while all patients were aparasitaemic at hour 48. The genotypic profiles of the two persistent parasites at hour 40 were F446I and D1246Y, and R539I, Y184F, and N86Y. The slope half-life of the former was 6.4 h while the latter was 6.9 h and their respective PCT99 were 47.9 h and 49.2 h as well as a clearance rate constants of 0.109 and 0.092 respectively. Conclusion: This study reports the effectiveness of A-L on various P. falciparum mutant alleles. However, continuous surveillance of Kelch 13 mutations and Pfmdr1 gene in Ghana and regular assessment of the therapeutic efficacy of A-L and other artemisinin derivatives is recommended.

A documented side-effect of artemisinin therapy is post-artemisinin delayed hemolysis (PADH), primarily occurring after parenteral treatment for severe P. falciparum infections. PADH has been infrequently reported after oral therapy and is rarely severe enough to require hospitalization and blood transfusions. A 24 year old man was diagnosed with P. falciparum, prompting initiation of oral artemether-lumefantrine (AL). Further work-up demonstrated that he met WHO criteria for severe malaria infection on the basis of high parasitemia and his regimen was switched to intravenous quinidine and oral doxycycline. He was transitioned back to AL after 4 days and was discharged on hospital day six. Five days later, he was readmitted for hemolytic anemia. His peripheral blood was absent of malaria parasites and he was diagnosed with PADH, ultimately requiring multiple blood transfusions. Severe hemolytic anemia requiring blood transfusions after oral artemisinin therapy is rare and may be associated with higher parasite loads. This case demonstrates the importance of close reassessment and consideration of PADH in patients treated with oral therapies, particularly in the setting of severe malarial infections.

Abstract Background In 2009, the Papua New Guinea (PNG) Department of Health adopted artemether–lumefantrine (AL) and dihydroartemisinin–piperaquine (DHA-PPQ) as the first- and second-line treatments for uncomplicated malaria, respectively. This study was conducted to assess the efficacy of both drugs following adoption of the new policy. Methods Between June 2012 and September 2014, a therapeutic efficacy study was conducted in East Sepik and Milne Bay Provinces of PNG in accordance with the standard World Health Organization (WHO) protocol for surveillance of anti-malarial drug efficacy. Patients ≥ 6 months of age with microscopy confirmed Plasmodium falciparum or Plasmodium vivax mono-infections were enrolled, treated with AL or DHA-PPQ, and followed up for 42 days. Study endpoints were adequate clinical and parasitological response (ACPR) on days 28 and 42. The in vitro efficacy of anti-malarials and the prevalence of selected molecular markers of resistance were also determined. Results A total of 274 P. falciparum and 70 P. vivax cases were enrolled. The day-42 PCR-corrected ACPR for P. falciparum was 98.1% (104/106) for AL and 100% (135/135) for DHA-PPQ. The day-42 PCR-corrected ACPR for P. vivax was 79.0% (15/19) for AL and 92.3% (36/39) for DHA-PPQ. Day 3 parasite clearance of P. falciparum was 99.2% with AL and 100% with DHA-PPQ. In vitro testing of 96 samples revealed low susceptibility to chloroquine (34% of samples above IC50 threshold) but not to lumefantrine (0%). Molecular markers assessed in a sub-set of the study population indicated high rates of chloroquine resistance in P. falciparum (pfcrt SVMNT: 94.2%, n = 104) and in P. vivax (pvmdr1 Y976F: 64.8%, n = 54). Conclusions AL and DHA-PPQ were efficacious as first- and second-line treatments for uncomplicated malaria in PNG. Continued in vivo efficacy monitoring is warranted considering the threat of resistance to artemisinin and partner drugs in the region and scale-up of artemisinin-based combination therapy in PNG.

Daudi Omari Simba,1 Deodatus Kakoko,2 Tumaini Nyamhanga,3 Zakayo Mrango,4 Phare Mujinja2 1Department of Community Health, School of Public Health and Social Sciences, Muhimbili University of Health and Allied Sciences, Dar-es Salaam, Tanzania; 2Department of Behavioural Sciences, School of Public Health and Social Sciences, Muhimbili University of Health and Allied Sciences, Dar-es Salaam, Tanzania; 3Department of Development Studies, School of Public Health and Social Sciences, Muhimbili University of Health and Allied Sciences, Dar-es Salaam, Tanzania; 4National Institute for Medical Research, Kilosa Station, Kilosa, Tanzania Purpose: Improving access to malaria treatment in rural remote areas remains a major challenge facing innovative strategies, such as Accredited Drug Dispensing Outlets (ADDOs) and Community Health Workers (CHWs) programs in Tanzania. This study tested the effectiveness of a financial benefit approach to motivate CHWs to improve prompt access to malaria treatment. Patients and methods: We applied a quasi-experimental study design in rural-remote areas in Kilosa district, Tanzania. Febrile children in selected intervention areas were provided access to malaria diagnostic and treatment at a minimal fee to CHWs and compared with non-intervention areas. We measured impact using difference in differences (DID) analysis. Results: At baseline, 870 children

Abstract Background The national treatment guidelines of Nepal have adopted Artemisinin Combination Therapies (ACTs) for the treatment of uncomplicated falciparum malaria since 2004. Emergence of Artemisinin resistance in the Greater Mekong Sub-region (GMS) and beyond may become a threat for Nepal as well. The main objective of this study was to assess the therapeutic efficacy of antimalarial drug artemether-lumefantrine in uncomplicated P. falciparum infected patients at health centers/hospitals treated over the period of 2 years (2013–2014). Methods Giemsa stained thick and thin smears, prepared from uncomplicated falciparum malaria patients who visited the selected sentinel sites in Nepal during 2013 to 2014 and met the inclusion criteria that included parasitemia (1000–10,000 /μL of blood), were evaluated until 28 days after ACTs treatment, following a World Health Organization (WHO) therapeutic efficacy protocol. Based on the re-occurrence of fever and resurge in parasitemia, the study patients were classified as resistant or susceptible. Blood specimens on filter papers were further analyzed by Polymerase Chain Reaction (PCR), specifically for the K13 propeller gene mutation (a recently identified molecular marker for ACT resistance). Results A total of 56,013 suspected malaria cases were screened for this study. Of which, 120 (0.21%) were infected with falciparum malaria. Out of 120, 28 cases of P. falciparum (28/120; 23.33%) were enrolled in the study, of which 24 cases completed the post-treatment follow up for 28 days. Only one case out of 24 (4%) was identified as a late treatment failure (LTF). K13 mutation, a proxy indicator for ACT resistance in parasites, was not detected on the day 1, which indicates resistance had not yet reached the molecular level. Conclusion Only one case of late treatment failure was identified in this study. ACT combination using artemether-lumefantrine was still effective for the treatment of uncomplicated falciparum malaria in Nepal. A close monitoring and supervision for ACT resistance is essential for future malaria treatment in Nepal.

Abstract Background Artemether–lumefantrine (AL) is the recommended first-line artemisinin-based combination therapy (ACT) for the treatment of uncomplicated falciparum malaria in most of the malaria-endemic countries, including Tanzania. Recently, dihydroartemisinin–piperaquine (DP) has been recommended as the alternative anti-malarial to ensure effective case management in Tanzania. This study assessed the parasite clearance rate and efficacy of AL and DP among patients aged 6 months to 10 years with uncomplicated falciparum malaria in two sites with different malaria transmission intensity. Methods This was an open-label, randomized trial that was conducted at two sites of Muheza Designated District Hospital and Ujiji Health Centre in Tanga and Kigoma regions, respectively. Patients meeting inclusion criteria were enrolled, treated with either AL or DP and followed up for 28 (extended to 42) and 42 (63) days for AL and DP, respectively. Parasite clearance time was monitored in the first 72 h post treatment and the clearance rate constant and half-life were calculated using an established parasite clearance estimator. The primary outcome was parasitological cure on days 28 and 42 for AL and DP, respectively, while secondary outcome was extended parasitological cure on days 42 and 63 for AL and DP, respectively. Results Of the 509 children enrolled (192 at Muheza and 317 at Ujiji), there was no early treatment failure and PCR uncorrected cure rates on day 28 in the AL group were 77.2 and 71.2% at Muheza and Ujiji, respectively. In the DP arm, the PCR uncorrected cure rate on day 42 was 73.6% at Muheza and 72.5% at Ujiji. With extended follow-up (to day 42 for AL and 63 for DP) cure rates were lower at Ujiji compared to Muheza (AL: 60.2 and 46.1%, p = 0.063; DP: 57.6 and 40.3% in Muheza and Ujiji, respectively, p = 0.021). The PCR corrected cure rate ranged from 94.6 to 100% for all the treatment groups at both sites. Parasite clearance rate constant was similar in the two groups and at both sites (

Abstract Background Artemisinin resistance in Plasmodium falciparum has emerged and spread in Southeast Asia. In areas where resistance is established longer courses of artemisinin-based combination therapy have improved cure rates. Methods The standard 3-day course of artemether–lumefantrine (AL) was compared with an extended 5-day regimen for the treatment of uncomplicated falciparum malaria in Kayin state in South-East Myanmar, an area of emerging artemisinin resistance. Late parasite clearance dynamics were described by microscopy and quantitative ultra-sensitive PCR. Patients were followed up for 42 days. Results Of 154 patients recruited (105 adults and 49 children

Abstract Background The spread of SP resistance may compromise the effectiveness of intermittent preventive treatment of malaria in pregnancy (MiP) with sulfadoxine–pyrimethamine (IPTp-SP) across Africa. However, there is no recommended alternative medicine for IPTp or alternative strategy for prevention of MiP. This poses problems for the prevention of MiP. This study investigated, whether screening with a rapid diagnostic test for malaria at routine antenatal clinic attendances and treatment of only those who are positive (intermittent screening and treatment) with artemether–lumefantrine is as effective and safe as IPTp-SP in pregnant women. Methods During antenatal clinic sessions at the General Hospital Calabar, Nigeria, held between October 2013 and November 2014, 459 pregnant women were randomized into either the current standard IPTp-SP or intermittent screening and treatment with artemether–lumefantrine (ISTp-AL). All women received a long-lasting insecticide-treated net at enrolment. Study women had a maximum of four scheduled visits following enrolment. Haemoglobin concentration and peripheral parasitaemia were assessed in the third trimester (36–40 weeks of gestation). Birth weight was documented at delivery or within a week for babies delivered at home. Results In the third trimester, the overall prevalence of severe anaemia (Hb

Abstract Background Artemisinin-based combinations differ in their impact on gametocyte prevalence and density. This study assessed female and male gametocyte dynamics after treating children with uncomplicated Plasmodium falciparum malaria with either pyronaridine–artesunate (PA) or artemether–lumefantrine (AL). Methods Kenyan children with uncomplicated Plasmodium falciparum malaria were included and randomly assigned to PA or AL treatment. Filter paper blood samples were collected as a source of RNA for quantitative reverse-transcription PCR (qRT-PCR) and nucleic acid sequence based amplification (QT-NASBA) to detect female gametocytes (targeting Pfs25 mRNA). Male gametocytes were detected by qRT-PCR (targeting PfMGET mRNA). Duration of gametocyte carriage, the female and male gametocyte response and the agreement between qRT-PCR and QT-NASBA were determined. Results The mean duration of female gametocyte carriage was significantly longer for PA (4.9 days) than for AL (3.8 days) as estimated by QT-NASBA (P = 0.036), but this difference was less clear when determined by Pfs25 qRT-PCR (4.5 days for PA and 3.7 for AL, P = 0.166). qRT-PCR based female gametocyte prevalence decreased from 100% (75/75) at baseline to 6.06% (4/66) at day 14 in the AL group and from 97.7% (83/85) to 13.9% (11/79) in the PA group. Male gametocyte prevalence decreased from 41.3% (31/75) at baseline to 19.7% (13/66) at day 14 in the AL group and from 35.3% (30/85) to 22.8% (18/79) in the PA group. There was good agreement between Pfs25 qRT-PCR and QT-NASBA female gametocyte prevalence (0.85, 95% CI 0.82–0.87). Conclusions This study indicates that female gametocyte clearance may be slightly faster after AL compared to PA. Male gametocytes showed similar post-treatment clearance between study arms. Future studies should further address potential differences between the post-treatment transmission potential after PA compared to AL. Trial registration This study is registered at clinicaltrials.gov under NCT02411994. Registration date: 8 April 2015. https://clinicaltrials.gov/ct2/show/NCT02411994?term=pyronaridine-artesunate&cond=Malaria&cntry=KE&rank=1

Abstract Background Prompt, effective treatment of confirmed malaria cases with artemisinin-based combination therapy (ACT) is a cornerstone of malaria control. Maximizing adherence to ACT medicines is key to ensuring treatment effectiveness. Methods This open-label, randomized trial evaluated caregiver adherence to co-formulated artemether–lumefantrine (AL) and fixed-dose amodiaquine–artesunate (AQAS) in Sierra Leone. Children aged 6–59 months diagnosed with malaria were recruited from two public clinics, randomized to receive AL or AQAS, and visited at home the day after completing treatment. Analyses were stratified by site, due to differences in participant characteristics and outcomes. Results Of the 784 randomized children, 680 (85.6%) were included in the final per-protocol analysis (340 AL, 340 AQAS). Definite adherence (self-reported adherence plus empty package) was higher for AL than AQAS at both sites (Site 1: 79.4% AL vs 63.4% AQAS, odds ratio [OR] 2.16, compared to probable adherence plus probable or definite non-adherence, 95% confidence interval [CI] 1.34–3.49; p = 0.001; Site 2: 52.1% AL vs 37.5% AQAS, OR 1.53, 95% CI 1.00–2.33, p = 0.049). However, self-reported adherence (ignoring drug package inspection) was higher for both regimens at both sites and there was no strong evidence of variation by treatment (Site 1: 96.6% AL vs 95.9% AQAS, OR 1.19, 95% CI 0.39–3.63, p = 0.753; Site 2: 91.5% AL vs 96.4% AQAS, OR 0.40, 95% CI 0.15–1.07, p = 0.067). In Site 2, correct treatment (correct dose + timing + duration) was lower for AL than AQAS (75.8% vs 88.1%, OR 0.42, 95% CI 0.23–0.76, p = 0.004). In both sites, more caregivers in the AQAS arm reported adverse events (Site 1: 3.4% AL vs 15.7% AQAS, p

Abstract Background Pyronaridine–artesunate is a novel artemisinin-based combination therapy. The efficacy and safety of pyronaridine–artesunate were compared with artemether–lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in children. Methods This phase III open-label randomized controlled non-inferiority trial was conducted in Western Kenya. Children aged 6 months to ≤ 12 years with a bodyweight > 5 kg and microscopically confirmed P. falciparum malaria were randomly assigned in a 1:1 ratio to orally receive pyronaridine–artesunate or artemether–lumefantrine, dosed according to bodyweight, for 3 days. Results Of 197 participants, 101 received pyronaridine–artesunate and 96 received artemether–lumefantrine. The day-28 adequate clinical and parasitological response in the per-protocol population, PCR-corrected for reinfections, was 98.9% (93/94, 95% CI 94.2–99.8) for pyronaridine–artesunate and 96.4% (81/84, 95% CI 90.0–98.8) for artemether–lumefantrine. Pyronaridine–artesunate was found to be non-inferior to artemether–lumefantrine: the treatment difference was 2.5% (95% CI − 2.8 to 9.0). Adverse events occurred in 41.6% (42/101) and 34.4% (33/96) of patients in the pyronaridine–artesunate group and the artemether–lumefantrine group, respectively. No participants were found to have alanine or aspartate aminotransferase levels > 3 times the upper limit of normal. Conclusions Pyronaridine–artesunate was well tolerated, efficacious and non-inferior to artemether–lumefantrine for the treatment of uncomplicated P. falciparum malaria in Kenyan children. Results are in line with previous reports and inclusion of pyronaridine–artesunate in paediatric malaria treatment programmes should be considered. This study is registered at clinicaltrials.gov under NCT02411994. Registration date: 8 April 2015. https://clinicaltrials.gov/ct2/show/NCT02411994?term=pyronaridine–artesunate&cond=Malaria&cntry=KE&rank=1

Context: Malarial remains a leading course of death in developing countries. Current treatment protocol involves the use of artemisinin-based combination therapy. In endemic areas, cost of treatment is a concern hence generic prescription is on the high. It is therefore necessary to investigate how equivalent or otherwise the generics are to the innovator brand Coatem®. Aims: To compare the physicochemical properties and in vivo bioavailability of a locally manufactured generic artemether-lumefantrine tablet formulation and that of the innovator brand sold on the Kumasi market, Ghana. Methods: The most used locally manufactured generic and the innovator brands were sampled from retail pharmacies. The samples were confirmed by colorimetry. Pharmaceutical equivalence of the brands was determined using compendial tests. In vivo bioavailability study on the two brands was done using a two-period, single dose, cross-over design involving 20 healthy rabbits. Pharmacokinetic parameters (AUC0-72, AUC0-∞, and Cmax) for both brands derived from the study were analysed statistically. Results: Both the generic and innovator brands passed the physicochemical tests. The artemether component of both brands complied with the pharmacopoeia specification for dissolution testing while the lumefantrine did not. Average bioequivalence was demonstrated per the FDA criterion with the geometric mean ratios and corresponding 90% confidence intervals falling within the acceptable limits of 0.80 – 1.25. Conclusions: Based on the similarity demonstrated between the two brands, evidence have been shown to support substitutability of the often-expensive innovator brand with the affordable locally produced brand.

Abstract Background The Angolan government recommends three artemisinin-based combinations for the treatment of uncomplicated Plasmodium falciparum malaria: artemether–lumefantrine (AL), artesunate–amodiaquine (ASAQ), and dihydroartemisinin–piperaquine (DP). Due to the threat of emerging anti-malarial drug resistance, it is important to periodically monitor the efficacy of artemisinin-based combination therapy (ACT). This study evaluated these medications’ therapeutic efficacy in Benguela, Lunda Sul, and Zaire Provinces. Methods Enrollment occurred between March and July 2017. Study participants were children with P. falciparum monoinfection from each provincial capital. Participants received a 3-day course of a quality-assured artemisinin-based combination and were monitored for 28 (AL and ASAQ arms) or 42 days (DP arm). Each ACT was assessed in two provinces. The primary study endpoints were: (1) follow-up without complications and (2) failure to respond to treatment or development of recurrent P. falciparum infection. Parasites from each patient experiencing recurrent infection were genotyped to differentiate new infection from recrudescence of persistent parasitaemia. These parasites were also analysed for molecular markers associated with ACT resistance. Results Of 608 children enrolled in the study, 540 (89%) reached a primary study endpoint. Parasitaemia was cleared within 3 days of medication administration in all participants, and no early treatment failures were observed. After exclusion of reinfections, the corrected efficacy of AL was 96% (91–100%, 95% confidence interval) in Zaire and 97% (93–100%) in Lunda Sul. The corrected efficacy of ASAQ was 100% (97–100%) in Benguela and 93% (88–99%) in Zaire. The corrected efficacy of DP was 100% (96–100%) in Benguela and 100% in Lunda Sul. No mutations associated with artemisinin resistance were identified in the pfk13 gene in the 38 cases of recurrent P. falciparum infection. All 33 treatment failures in the AL and ASAQ arms carried pfmdr1 or pfcrt mutations associated with lumefantrine and amodiaquine resistance, respectively, on day of failure. Conclusions AL, ASAQ, and DP continue to be efficacious against P. falciparum malaria in these provinces of Angola. Rapid parasite clearance and the absence of genetic evidence of artemisinin resistance are consistent with full susceptibility to artemisinin derivatives. Periodic monitoring of in vivo drug efficacy remains a priority routine activity for Angola.

Abstract Background Adherence to anti-malarial medication is highly variable but frequently suboptimal. Numerous interventions with a variety of methodological approaches have been implemented to address the problem. A recently conducted, randomized, controlled trial in western Kenya evaluated the effects of short message service (SMS) reminders on paediatric adherence to artemether–lumefantrine (AL) and found over 97% adherence rates in both intervention and control arms. The current study was undertaken to explore participants’ experiences in the trial and identify the factors contributing to the high adherence rates. Methods In July 2016, 5 months after the trial completion, focus group discussions (FGDs) were undertaken with caregivers of children who had been treated in the intervention (n = 2) or control (n = 2) arms and who, post-trial, had received malaria treatment from the same facilities. The FGDs explored similarities and differences in perceptions and experiences of the care they received during and after the trial. Results Intervention-arm participants reported that SMS messages were effective dosing reminders. Participants from both arms reported that trial instructions to keep empty AL packs for verification during a home visit by a health worker affected their dosing and adherence practices. Differences between trial and post-trial treatment experiences included: administration of the first AL dose by health workers with demonstration of dispersible tablets dilution; advice on what to do if a child vomited; clear instructions on timing of dosing with efforts made to ensure understanding; and, information that dose completion was necessary with explanation provided. Participants reported that after the trial AL was not available at facilities, constraining their ability to adhere to recommended malaria treatment. They emphasized receiving respectful and personal treatment from trial health workers contributing to perceptions of high quality care and enhanced readiness to adhere to dosing instructions. Conclusions This study highlights the complex range of factors that influence AL adherence. The results suggest that in addition to standardized definitions and measurement of adherence, and the influence of enrolment procedures, AL adherence trials need to take account of how intervention impact can be influenced by differences in the quality of care received under trial and routine conditions.

Abstract Background Blackwater fever is a complication of malaria infection consisting of a syndrome of febrile intra-vascular haemolysis with severe anaemia and intermittent passage of dark-red to black colour urine. Despite numerous reports and studies of this condition, its pathogenesis remains incompletely understood. Case presentation This report describes a case of classic blackwater fever in a returning traveller, without prior history of malaria infection nor usage of anti-malarial prophylaxis, treated with two courses of oral artemether–lumefantrine combination therapy. Unusual persistence of submicroscopic Plasmodium falciparum parasitaemia was detected by PCR for 18 days after initiation of treatment. Conclusion To the authors’ knowledge this is the first reported occurrence of a case of blackwater fever associated with prolonged submicroscopic parasitaemia. This unusual case challenges the current knowledge of the pathogenesis of this condition and opens questions that may have important diagnostic and treatment implications.

Background: Single nucleotide polymorphisms occurring in the Plasmodium falciparum multidrug resistant gene 1 (pfmdr1) are known to be associated with aminoquinoline resistance and, therefore, represent key P. falciparum markers for monitoring resistance both in susceptible groups (children under 5 years old and pregnant women) and in the general population. This study aimed to determine prevalence and factors associated with the carriage of pfmdr1 N86Y, Y184F and D1246Y polymorphisms among pregnant women in a setting of high malaria transmission in Burkina Faso. Methods: Plasmodium falciparum isolates were collected at the first antenatal care visit (ANC-1) as well as at delivery from pregnant women participating in the COSMIC trial (NTC01941264), which assessed malaria preventive interventions during pregnancy in the Nanoro Health District. Here, pregnant women received intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) and malaria infections and/or diseases were treated using artemether-lumefantrine (AL) during the trial. Parasite DNA was extracted from dried blood spots and the presence of pfmdr1 mutations at positions 86, 184 and 1246 was determined using nested PCR, followed by restriction fragment length polymorphism (RFLP) analysis. Results: A prevalence of 13.2% (20/151) and 12.1% (14/116) of the pfmdr1 86Y mutant allele was found at ANC-1 and at delivery, respectively, while no mutant allele was observed for Y184F and D1246Y codons at both ANC-1 and at delivery. There were no significant factors associated with pfmdr1 86Y mutant allele carriage at ANC-1. However, malaria infections at delivery with a parasite density above the median (2237.2 (IQR: 613.5–11,425.7) parasites/µl) was associated with an increase risk of pfmdr1 86Y mutant allele carriage (AOR = 5.5 (95% CI 1.07–28.0); P = 0.04). In contrast, both three or more IPTp-SP doses (AOR = 0.25 (95% CI 0.07–0.92); P = 0.04) and one or more AL treatment (AOR = 0.25 (95% CI 0.07–0.89); P = 0.03) during pregnancy were associated with a significant reduce risk of pfmdr1 86Y mutant allele carriage at delivery. Conclusion: These findings suggest that both high coverage of IPTp-SP and the use of AL for the treatment of malaria infection/disease during pregnancy select for pfmdr1 N86 wild-type allele at delivery. [ABSTRACT FROM AUTHOR]

Background: Extended artemisinin-based combination therapy (ACT) for treatment of uncomplicated Plasmodium falciparum malaria with already existing drug regimens, such as artemether-lumefantrine, might be effective in tackling the emerging ACT resistance. However, given the history of cardiotoxicity among anti-malarial drugs structurally similar to lumefantrine, the potential effect of extended artemether-lumefantrine treatment on the electrocardiographic (ECG) QTc interval is of high concern. Methods: Male and non-pregnant females aged 1–65 years, diagnosed with uncomplicated P. falciparum malaria in Bagamoyo district, Tanzania, were randomized into two arms. The intervention arm received an extended, i.e. 6-day, course of artemether-lumefantrine and an additional single low-dose primaquine (0.25 mg/kg) administered together with the last artemether-lumefantrine dose. The control arm received the standard weight-based 3-day course. ECGs were performed at day 0 and 4–5 h after the last dose at day 5. QT intervals were read manually using the tangent method and automatically. Bazett's (QTcB) and Fridericia's (QTcF) formulae were used for correction for heart rate. Descriptive statistics were used to calculate baseline characteristics and the number of supra-thresholds QTc intervals (QTc prolongation > 500, change in QTc interval (ΔQTc) > 60 ms). The mean change in QTc interval in and between the two arms was compared using the paired t-test and independent samples t-test, respectively. Results: A total of 195 patients were enrolled, 103 and 92 in the intervention and control arm, respectively. No patient experienced QTc intervals > 500 ms on day 5 by both formulae. Patients with ΔQTc > 60 ms, for QTcF were 6/103 (5.8%) vs 2/92 (2.2%) and for QTcB 2/103 (1.9%) vs 1/92 (1.1%) in the intervention and control arms, respectively. The mean difference in ΔQTc interval was statistically significant between the two arms with both correction formulae, 11.4 ms (95% CI 2.7–20.0, p = 0.010) and 13.4 ms (95% CI 5.3–21.5, p = 0.001), for QTcB and QTcF, respectively. Conclusion: The extended 6-day course of artemether-lumefantrine did not reveal clinically relevant QTc prolonging effects. However, significant QTcF prolongation and presence of patients with supra-threshold QTc values observed in the intervention arm underscore the importance of further monitoring of QTc parameters in extended artemether-lumefantrine treatment. Trial registration ClinicalTrials.gov, NCT03241901. Registered July 27, 2017. https://clinicaltrials.gov/show/NCT03241901 [ABSTRACT FROM AUTHOR]

Background: The efficacy of artemether-lumefantrine (AL) for treatment of uncomplicated Plasmodium falciparum malaria in south-western Ethiopia is poorly documented. Regular monitoring of drug efficacy is an important tool for supporting national treatment policies and practice. This study investigated the therapeutic efficacy of AL for the treatment of P. falciparum malaria in Ethiopia. Methods: The study was a one-arm, prospective, evaluation of the clinical and parasitological, responses to directly observed treatment with AL among participants 6 months and older with uncomplicated P. falciparum malaria. Real-time polymerase chain reaction (PCR) and nested PCR reaction methods were used to quantify and genotype P. falciparum. A modified protocol based on the World Health Organization 2009 recommendations for the surveillance of anti-malarial drug efficacy was used for the study with primary outcomes, clinical and parasitological cure rates at day-28. Secondary outcomes assessed included patterns of fever and parasite clearance. Cure rate on day-28 was assessed by intention to treat (ITT) and per protocol (PP) analysis. Parasite genotyping was also performed at baseline and at the time of recurrence of parasitaemia to differentiate between recrudescence and new infection. Results: Of the 80 study participants enrolled, 75 completed the follow-up at day-28 with ACPR. For per protocol (PP) analysis, PCR-uncorrected and-corrected cure rate of AL among the study participants was 94.7% (95% CI 87.1–98.5) and 96% (95% CI 88.8–99.2), respectively. For intention to treat (ITT) analysis, the cure rate was 90% (95% CI 88.8–99.2). Based on Kaplan–Meier survival estimate, the cumulative incidence of failure rate of AL was 3.8% (95% CI 1.3–11.4). Only three participants 3.8% (95% CI 0.8–10.6) of the 80 enrolled participants were found to be positive on day-3. The day three-positive participants were followed up to day 28 and did not correspond to treatment failures observed during follow-up. Only 7.5% (6/80) of the participants were gametocyte-positive on enrollment and gametocytaemia was absent on day-2 following treatment with AL. Conclusions: The therapeutic efficacy of AL is considerably high (above 90%). AL remained highly efficacious in the treatment of uncomplicated malaria in the study area resulted in rapid fever and parasite clearance as well as low gametocyte carriage rates despite the use of this combination for more than 15 years. [ABSTRACT FROM AUTHOR]

Background: Anti-malarial resistance is a threat to recent gains in malaria control. This study aimed to assess the efficacy and safety of artesunate–amodiaquine (ASAQ) and artemether–lumefantrine (AL) in the management of uncomplicated malaria and to measure the prevalence of molecular markers of resistance of Plasmodium falciparum in sentinel sites in Maferinyah and Labé Health Districts in Guinea in 2016. Methods: This was a two-arm randomised controlled trial of the efficacy of AL and ASAQ among children aged 6–59 months with uncomplicated Plasmodium falciparum malaria in two sites. Children were followed for 28 days to assess clinical and parasitological response. The primary outcome was the Kaplan–Meier estimate of Day 28 (D28) efficacy after correction by microsatellite-genotyping. Pre-treatment (D0) and day of failure samples were assayed for molecular markers of resistance in the pfk13 and pfmdr1 genes. Results: A total of 421 participants were included with 211 participants in the Maferinyah site and 210 in Labé. No early treatment failure was observed in any study arms. However, 22 (5.3%) participants developed a late treatment failure (8 in the ASAQ arm and 14 in the AL arm), which were further classified as 2 recrudescences and 20 reinfections. The Kaplan–Meier estimate of the corrected efficacy at D28 was 100% for both AL and ASAQ in Maferinyah site and 99% (95% Confidence Interval: 97.2–100%) for ASAQ and 99% (97.1–100%) for AL in Labé. The majority of successfully analysed D0 (98%, 380/389) and all day of failure (100%, 22/22) samples were wild type for pfk13. All 9 observed pfk13 mutations were polymorphisms not associated with artemisinin resistance. The NFD haplotype was the predominant haplotype in both D0 (197/362, 54%) and day of failure samples (11/18, 61%) successfully analysed for pfmdr1. Conclusion: This study observed high efficacy and safety of both ASAQ and AL in Guinea, providing evidence for their continued use to treat uncomplicated malaria. Continued monitoring of ACT efficacy and safety and molecular makers of resistance in Guinea is important to detect emergence of parasite resistance and to inform evidence-based malaria treatment policies. [ABSTRACT FROM AUTHOR]

Background: Artemisinin-based combination therapy (ACT) resistant Plasmodium falciparum represents an increasing threat to Africa. Extended ACT regimens from standard 3 to 6 days may represent a means to prevent its development and potential spread in Africa. Methods: Standard 3-day treatment with artemether–lumefantrine (control) was compared to extended 6-day treatment and single low-dose primaquine (intervention); in a randomized controlled, parallel group, superiority clinical trial of patients aged 1–65 years with microscopy confirmed uncomplicated P. falciparum malaria, enrolled in Bagamoyo district, Tanzania. The study evaluated parasite clearance, including proportion of PCR detectable P. falciparum on days 5 and 7 (primary endpoint), cure rate, post-treatment prophylaxis, safety and tolerability. Clinical, and laboratory assessments, including ECG were conducted during 42 days of follow-up. Blood samples were collected for parasite detection (by microscopy and PCR), molecular genotyping and pharmacokinetic analyses. Kaplan–Meier survival analyses were done for both parasite clearance and recurrence. Results: A total of 280 patients were enrolled, 141 and 139 in the control and intervention arm, respectively, of whom 121 completed 42 days follow-up in each arm. There was no difference in proportion of PCR positivity across the arms at day 5 (80/130 (61.5%) vs 89/134 (66.4%), p = 0.44), or day 7 (71/129 (55.0%) vs 70/134 (52.2%), p = 0.71). Day 42 microscopy determined cure rates (PCR adjusted) were 97.4% (100/103) and 98.3% (110/112), p = 0.65, in the control and intervention arm, respectively. Microscopy determined crude recurrent parasitaemia during follow-up was 21/121 (17.4%) in the control and 14/121 (11.6%) in the intervention arm, p = 0.20, and it took 34 days and 42 days in the respective arms for 90% of the patients to remain without recurrent parasitaemia. Lumefantrine exposure was significantly higher in intervention arm from D3 to D42, but cardiac, biochemical and haematological safety was high and similar in both arms. Conclusion: Extended 6-day artemether–lumefantrine treatment and a single low-dose of primaquine was not superior to standard 3-day treatment for ACT sensitive P. falciparum infections but, importantly, equally efficacious and safe. Thus, extended artemether–lumefantrine treatment may be considered as a future treatment regimen for ACT resistant P. falciparum, to prolong the therapeutic lifespan of ACT in Africa. Trial registration ClinicalTrials.gov, NCT03241901. Registered July 27, 2017 https://clinicaltrials.gov/show/NCT03241901 [ABSTRACT FROM AUTHOR]

Background: The spread of artemisinin resistance in the Greater Mekong Subregion of Southeast Asia poses a significant threat for current anti-malarial treatment guidelines globally. The aim of this study was to assess the current prevalence of molecular markers of drug resistance in Plasmodium falciparum in the four provinces with the highest malaria burden in Pakistan, after introducing artemether–lumefantrine as first-line treatment in 2017. Methods: Samples were collected during routine malaria surveillance in Punjab, Sindh, Baluchistan, and Khyber Pakhtunkhwa provinces of Pakistan between January 2018 and February 2019. Plasmodium falciparum infections were confirmed by rapid diagnostic test or microscopy. Plasmodium falciparum positive isolates (n = 179) were screened by Sanger sequencing for single nucleotide polymorphisms (SNPs) in the P. falciparum kelch 13 (pfk13) propeller domain and in P. falciparum coronin (pfcoronin). SNPs in P. falciparum multidrug resistance 1 (pfmdr1) N86Y, Y184F, D1246Y and P. falciparum chloroquine resistance transporter (pfcrt) K76T were genotyped by PCR-restriction fragment length polymorphism. Results: No artemisinin resistance associated SNPs were identified in the pfk13 propeller domain or in pfcoronin. The pfmdr1 N86, 184F, D1246 and pfcrt K76 alleles associated with reduced lumefantrine sensitivity were present in 83.8% (150/179), 16.9% (29/172), 100.0% (173/173), and 8.4% (15/179) of all infections, respectively. The chloroquine resistance associated pfcrt 76T allele was present in 98.3% (176/179) of infections. Conclusion: This study provides an update on the current prevalence of molecular markers associated with reduced P. falciparum sensitivity to artemether and/or lumefantrine in Pakistan, including a first baseline assessment of polymorphisms in pfcoronin. No mutations associated with artemisinin resistance were observed in pfk13 or pfcoronin. However, the prevalence of the pfmdr1 N86 and D1246 alleles, that have been associated with decreased susceptibility to lumefantrine, remain high. Although clinical and molecular data suggest that the current malaria treatment guidelines for P. falciparum are presently effective in Pakistan, close monitoring for artemisinin and lumefantrine resistance will be critical to ensure early detection and enhanced containment of emerging ACT resistance spreading across from Southeast Asia. [ABSTRACT FROM AUTHOR]

Background: Day 7 plasma lumefantrine concentration is suggested as a predictor for malaria treatment outcomes and a cut-off of ≥ 200 ng/ml is associated with day 28 cure rate in the general population. However, day 7 lumefantrine plasma concentration can be affected by age, the extent of fever, baseline parasitaemia, and bodyweight. Therefore, this study assessed the usefulness of day 7 lumefantrine plasma concentration as a predictor of malaria treatment outcome in under-fives children treated with generic or innovator drug-containing artemether-lumefantrine (ALu) in Tanzania. Methods: This study was nested in an equivalence prospective study that aimed at determining the effectiveness of a generic ALu (Artefan®) in comparison with the innovator's product (Coartem®). Children with uncomplicated malaria aged 6–59 months were recruited and randomized to receive either generic or innovator's product. Children were treated with ALu as per World Health Organization recommendations. The clinical and parasitological outcomes were assessed after 28 days of follow up. PCR was performed to distinguish recrudescence and re-infections among children with recurrent malaria. Analysis of day 7 lumefantrine plasma concentration was carried out using a high-performance liquid chromatographic method with UV detection. Results: The PCR corrected cure rates were 98.7% for children treated with generic and 98.6% for those treated with the innovator product (p = 1.00). The geometric mean (± SD) of day 7 plasma lumefantrine concentration was 159.3 (± 2.4) ng/ml for the generic and 164 (± 2.5) ng/ml for the innovator groups, p = 0.87. Geometric mean (± SD) day 7 lumefantrine plasma concentration between cured and recurrent malaria was not statistically different in both treatment arms [158.5 (± 2.4) vs 100.0 (± 1.5) ng/ml, (p = 0.28) for generic arm and 158.5 (± 2.3) vs 251.2 (± 4.2) ng/ml, (p = 0.24) for innovator arm]. Nutritional status was found to be a determinant of recurrent malaria (adjusted hazardous ratio (95% confidence interval) = 3(1.1–8.2), p = 0.029. Conclusion: Using the recommended cut-off point of ≥ 200 ng/ml, day 7 plasma lumefantrine concentration failed to predict malaria treatment outcome in children treated with ALu in Tanzania. Further studies are recommended to establish the day 7 plasma lumefantrine concentration cut-off point to predict malaria treatment outcome in children. [ABSTRACT FROM AUTHOR]

Background: Primaquine is an important gametocytocidal drug that is combined with conventional malaria treatment for prevention of Plasmodium falciparum malaria transmission. Primaquine has been administered together on the first or the last day of conventional treatment but the impact of primaquine timing has never been examined. This study aimed to assess safety, efficacy and optimal timing of single full-dose (0.75 mg/kg) primaquine when added to a standard 6-dose regimen of artemether–lumefantrine (AL). Methods: In an individual-level randomized controlled trial, enrolled participants who were G6PD normal and had uncomplicated P. falciparum malaria were randomly assigned to receive: AL only; AL and a single 0.75 mg/kg primaquine dose on the first day of AL (day 1); or AL and single 0.75 mg//kg primaquine on the last day of AL (day 3). On days 2, 3, 4, 8, 11 and 15, gametocytes were assessed and quantified by microscope and quantitative nuclear acid sequence based quantification (QT-NASBA). Results: Overall, 111 participants aged between 3 and 17 years were randomly allocated to receive AL only (36) or combined with primaquine on day 1 (38), or primaquine on day 3 (37). Day 4 gametocyte prevalence in AL + day 1 primaquine was half the level seen in either AL + day 3 primaquine or AL only arm (11% [4/35] vs 26% [8/31] and 27% [8/30], respectively) albeit not statistically significant. A similar trend of lower gametocyte in the AL + day 1 primaquine verses AL + day 3 primaquine or AL only arm was observed in mean gametocyte density. Mean (sd) haemoglobin level in AL + day 3 primaquine arm recovered from -0.42(1.2) g/dl on day 2 to 0.35 (1.5) g/dl on day 15 of follow up. This was not the case in AL only and AL + day 1 primaquine arms during the same follow-up period, although the difference was not statistically significant (p = 318). No serious adverse events reported in the study. Across arms, 23% (26/111) of participants reported a total of 31 mild adverse events and the difference was not statistically significant (p = 0.477). Conclusion: Primaquine administration on the first day of AL is well tolerated and as safe as later administration. Whilst the World Health Organization currently recommends a lower dose of primaquine (0.25 mg/kg), the findings are supportive of early primaquine administration when combined with artemisinin-combination therapy. ClinicalTrials.gov Registration NCT01906788 [ABSTRACT FROM AUTHOR]

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Background: Malaria remains a major public health problem, affecting mainly low-and middle-income countries. The management of this parasitic disease is challenged by ever increasing drug resistance. This study, investigated the therapeutic efficacy, tolerability and safety of artemether–lumefantrine (AL) and artesunate–amodiaquine (AS–AQ), used as first-line drugs to treat uncomplicated malaria in Lambaréné, Gabon. Methods: A non-randomized clinical trial was conducted between October 2017 and March 2018 to assess safety, clinical and parasitological efficacy of fixed-doses of AL and AS–AQ administered to treat uncomplicated Plasmodium falciparum malaria in children aged from 6 months to 12 years. After 50 children were treated with AL, another 50 children received ASAQ. The 2009 World Health Organization protocol for monitoring of the efficacy of anti‑malarial drugs was followed. Molecular markers msp1 and msp2 were used to differentiate recrudescence and reinfection. For the investigation of artemisinin resistant markers, gene mutations in Pfk13 were screened. Results: Per-protocol analysis on day 28 showed a PCR corrected cure rate of 97% (95% CI 86–100) and 95% (95% CI 84–99) for AL and AS–AQ, respectively. The most frequent adverse event in both groups was asthenia. No mutations in the kelch-13 gene associated with artemisinin resistance were identified. All participants had completed microscopic parasite clearance by day 3 post-treatment. Conclusion: This study showed that AL and AS–AQ remain efficacious, well-tolerated, and are safe to treat uncomplicated malaria in children from Lambaréné. However, a regular monitoring of efficacy and a study of molecular markers of drug resistance to artemisinin in field isolates is essential. Trial registration ANZCTR, ACTRN12616001600437. Registered 18 November, http://www.anzctr.org.au/TrialSearch.aspx?searchTxt=ACTRN12616001600437p&isBasic=True [ABSTRACT FROM AUTHOR]

Plasmodium falciparum and P. vivax co-exist at different endemicity levels across Ethiopia. For over two decades Artemether-Lumefantrine (AL) is the first line treatment for uncomplicated P. falciparum, while chloroquine (CQ) is still used to treat P. vivax. It is currently unclear whether a shift from CQ to AL for P. falciparum treatment has implications for AL efficacy and results in a reversal of mutations in genes associated to CQ resistance, given the high co-endemicity of the two species and the continued availability of CQ for the treatment of P. vivax. This study thus assessed the prevalence of Pfcrt -K76T and Pfmdr1 -N86Y point mutations in P. falciparum. 18S RNA gene based nested PCR confirmed P. falciparum samples (N = 183) collected through community and health facility targeted cross-sectional surveys from settings with varying P. vivax and P. falciparum endemicity were used. The proportion of Plasmodium infections that were P. vivax was 62.2% in Adama, 41.4% in Babile, 30.0% in Benishangul-Gumuz to 6.9% in Gambella. The Pfcrt- 76T mutant haplotype was observed more from samples with higher endemicity of P. vivax as being 98.4% (61/62), 100% (31/31), 65.2% (15/23) and 41.5% (22/53) in samples from Adama, Babile, Benishangul-Gumuz and Gambella, respectively. However, a relatively higher proportion of Pfmdr1 -N86 allele (77.3–100%) were maintained in all sites. The observed high level of the mutant Pfcrt- 76T allele in P. vivax co-endemic sites might require that utilization of CQ needs to be re-evaluated in settings co-endemic for the two species. A country-wide assessment is recommended to clarify the implication of the observed level of variation in drug resistance markers on the efficacy of AL-based treatment against uncomplicated P. falciparum malaria. Image 1 [ABSTRACT FROM AUTHOR]

BackgroundSince the late 1980s a series of malaria epidemics has occurred in western Kenya highlands. Among the possible factors that may contribute to the highland malaria epidemics, parasite resistance to antimalarials has not been well investigated.MethodsUsing parasites from highland and lowland areas of western Kenya, we examined key mutations associated with Plasmodium falciparum resistance to sulfadoxine – pyrimethamine and chloroquine, including dihydrofolate reductase (pfdhfr) and dihydropteroate synthetase (pfdhps), chloroquine resistance transporter gene (pfcrt), and multi-drug resistance gene 1 (pfmdr1).ResultsWe found that >70% of samples harbored 76T pfcrt mutations and over 80% of samples harbored quintuple mutations (51I/59R/108N pfdhfr and 437G/540E pfdhps) in both highland and lowland samples. Further, we did not detect significant difference in the frequencies of these mutations between symptomatic and asymptomatic malaria volunteers, and between highland and lowland samples.ConclusionThese findings suggest that drug resistance of malaria parasites in the highlands could be contributed by the mutations and their high frequencies as found in the lowland. The results are discussed in terms of the role of drug resistance as a driving force for malaria outbreaks in the highlands.

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.

Abstract Background As Ethiopia is one of the sub-Saharan countries with a great burden of malaria the effectiveness of first line anti-malarial drugs is the major concern. The aim of this study was to synthesize the available evidence on the efficacy of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Ethiopia. This was done by performing a meta-analysis of recent studies conducted in the country on this topic. Methods Studies published between January 2010 and January 2017 that reported on the efficacy of artemether-lumefantrine in the treatment of P. falciparum malaria in Ethiopian patients were searched for using the PubMed and Google Scholar databases. Ten prospective single-arm cohort studies that followed patients for 28–42 days were included in this analysis. All of the included studies were deemed to be of high quality. Results Ten studies involving 1179 patients that were eligible for meta-analysis were identified. At recruitment, the average parasite count per patient was 1 2981/μl of blood. On the third day of treatment, 96.7% and 98.5% of the study subjects become fever-free and parasite-free, respectively. Based on the per protocol analysis, the cure rate after use of artemether-lumefantrine was 98.2% (polymerase chain reaction corrected) and 97.01% (polymerase chain reaction uncorrected) after 28 days of follow-up. The reinfection rate within 28 days was 1.1% and the recrudescence rate was 1.9%. Conclusions This review found that the cure rate for uncomplicated P. falciparum malaria using artemether-lumefantrine in Ethiopia is still high enough to recommend the drug as a first-line agent. There should be careful periodic monitoring of the efficacy of this drug, as treatment failure may occur due to resistance, sub-therapeutic levels that may occur due to non-adherence, or inadequate absorption.

Abstract Background A recent randomized trial showed that artemisinin–naphthoquine (AN) was non-inferior to artemether–lumefantrine (AL) for falciparum malaria and superior for vivax malaria in young Papua New Guinean children. The aim of this study was to compare the cost-effectiveness of these two regimens. Methods An incremental cost-effectiveness analysis was performed using data from 231 children with Plasmodium falciparum and/or Plasmodium vivax infections in an open-label, randomized, parallel-group trial. Recruited children were randomized 1:1 to receive once daily AN for 3 days with water or twice daily AL for 3 days given with fat. World Health Organisation (WHO) definitions were used to determine clinical/parasitological outcomes. The cost of transport between the home and clinic, plus direct health-care costs, served as a basis for determining each regimen’s incremental cost per incremental treatment success relative to AL by Day 42 and its cost per life year saved. Results In the usual care setting, AN was more effective for the treatment of uncomplicated malaria in children aged 0.5–5.9 years. AL and AN were equally efficacious for the treatment of falciparum malaria, however AN had increased anti-malarial treatment costs per patient of $10.46, compared with AL. AN was the most effective regimen for treatment of vivax malaria, but had increased treatment costs of $14.83 per treatment success compared with AL. Conclusions Whilst AN has superior overall efficacy for the treatment of uncomplicated malaria in PNG children, AL was the less costly regimen. An indicative extrapolation estimated the cost per life year saved by using AN instead of AL to treat uncomplicated malaria to be $12,165 for girls and $12,469 for boys (discounted), which means AN may not be cost-effective and affordable for PNG at current cost. However, AN may become acceptable should it become WHO prequalified and/or should donated/subsidized drug supply become available.

Abstract Malaria treatment performance is potentially influenced by pharmacogenetic factors. This study reports an association study between the ABCB1 c.3435C>T, CYP3A4*1B (g.-392A>G), CYP3A5*3 (g.6986A>G) SNPs and artemether + lumefantrine treatment outcome in 103 uncomplicated malaria patients from Angola. No significant associations with the CYP3A4*1B and CYP3A5*3 were observed, while a significant predominance of the ABCB1 c.3435CC genotype was found among the recurrent infection-free patients (p

Abstract Background Early detection of febrile illnesses at community level is essential for improved malaria case management and control. Currently, mobile phone-based technology has been commonly used to collect and transfer health information and services in different settings. This study assessed the applicability of mobile phone-based technology in real-time reporting of fever cases and management of malaria by village health workers (VHWs) in north-eastern Tanzania. Methods The community mobile phone-based disease surveillance and treatment for malaria (ComDSTM) platform, combined with mobile phones and web applications, was developed and implemented in three villages and one dispensary in Muheza district from November 2013 to October 2014. A baseline census was conducted in May 2013. The data were uploaded on a web-based database and updated during follow-up home visits by VHWs. Active and passive case detection (ACD, PCD) of febrile cases were done by VHWs and cases found positive by malaria rapid diagnostic test (RDT) were given the first dose of artemether–lumefantrine (AL) at the dispensary. Each patient was visited at home by VHWs daily for the first 3 days to supervise intake of anti-malarial and on day 7 to monitor the recovery process. The data were captured and transmitted to the database using mobile phones. Results The baseline population in the three villages was 2934 in 678 households. A total of 1907 febrile cases were recorded by VHWs and 1828 (95.9%) were captured using mobile phones. At the dispensary, 1778 (93.2%) febrile cases were registered and of these, 84.2% were captured through PCD. Positivity rates were 48.2 and 45.8% by RDT and microscopy, respectively. Nine cases had treatment failure reported on day 7 post-treatment and adherence to treatment was 98%. One patient with severe febrile illness was referred to Muheza district hospital. Conclusion The study showed that mobile phone-based technology can be successfully used by VHWs in surveillance and timely reporting of fever episodes and monitoring of treatment failure in remote areas. Further optimization and scaling-up will be required to utilize the tools for improved malaria case management and drug resistance surveillance.

Tekalign Deressa,1 Mengistu Endris Seid,1 Wubet Birhan,1 Yetemwork Aleka,1 Biniam Mathewos Tebeje1,2 1School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; 2Molecular Parasitology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia Background: Artemether–lumefantrine (AL) has been used as a first-line treatment for uncomplicated Plasmodium falciparum malaria in Ethiopia since 2004. Antimalarial drug resistance is one of the major obstacles for malaria control and curtails the lifespan of several drugs. Thus, continued monitoring of the efficacy of AL is of great public health importance in malaria endemic areas. Objective: This study aimed to investigate the therapeutic efficacy and safety of AL for the treatment of uncomplicated P. falciparum malaria in the Dembia district, northwest Ethiopia. Methods: A prospective study was conducted from April 2015 to February 2016 at Kola Diba Health Center (KHC) in the Dembia district to determine the therapeutic efficacy and safety of AL for the treatment of uncomplicated P. falciparum monoinfection. Patients were treated with the six-dose regimen of AL over 3 days and followed up for 28 days as per the World Health Organization protocol. Results: Of the total 80 patients enrolled in the AL efficacy study, 75 patients completed the 28 days follow-up. None of the participants reported major adverse events. No early treatment failure or late clinical failure were observed during the study, but there were 6 (8.0%) late parasitological failures. The uncorrected per protocol cure rate of AL was 92.0 (95% CI: 85.7–98.3). Treatment with AL cleared parasitemia and fever in >95% of the patients by day 3. Conclusion: This study showed that AL is well tolerated and remains efficacious for treatment of uncomplicated P. falciparum malaria in northwest Ethiopia. However, the observed late parasitological failures in this study are of a concern and warrant continued monitoring of drug efficacy as per the World Health Organization recommendations. Keywords: artemether–lumefantrine, uncomplicated Plasmodium falciparum, Ethiopia, malaria, antimalarial efficacy

Abstract Artemisinin-based combination therapy (ACT) is recommended by the World Health Organization for the treatment of uncomplicated malaria. Currently, there appears to be a downward trend in the efficacy of ACT in some parts of sub-Saharan Africa because some patients have been positive for Plasmodium parasite 3 days after artemether-lumefantrine treatment. We reported three cases of possible parasite resistance to artemether-lumefantrine therapy. All subjects had complete parasite clearance when treated with other antimalarial drugs. This observation necessitates the urgent need to re-evaluate artemether-lumefantrine medication in Nigeria since it is one of the most commonly used ACT drug.

Background: Artemisinin-based combination therapy (ACT) has been effective in the supervised treatment of uncomplicated malaria in Ghana. Since ACT usage is primarily unsupervised, this study aimed to determine the effectiveness of artemether-lumefantrine (AL) for treating malaria patients in two transmission settings in Ghana., Methods: Eighty-four individuals with uncomplicated Plasmodium falciparum malaria were recruited from Lekma Hospital (LH) in Accra (low-transmission area; N = 28), southern Ghana, and King's Medical Centre (KMC) in Kumbungu (high-transmission area; N = 56), northern Ghana. Participants were followed up for 28 days after unsupervised treatment with AL. The presence of asexual parasites was determined by microscopic examination of Giemsa-stained blood smears. Plasmodium species identification was confirmed using species-specific primers targeting the 18S rRNA gene. Parasite recrudescence or reinfection was determined by genotyping the Pfmsp 1 and Pfmsp 2 genes., Results: After AL treatment, 3.6% (2/56) of the patients from KMC were parasitaemic on day 3 compared to none from the LH patients. One patient from KMC with delayed parasite clearance on day 3 remained parasite-positive by microscopy on day 7 but was parasite-free by day 14. While none of the patients from LH experienced parasite recurrence during the 28-day follow-up, three and two patients from KMC had recurrent parasitaemia on days 21 and 28, respectively. Percentage reduction in parasite densities from day 1, 2, and 3 for participants from the KMC was 63.2%, 89.5%, and 84.5%. Parasite densities for participants from the LH reduced from 98.2%, 99.8% on day 1, and 2 to 100% on day 3. The 28-day cumulative incidence rate of treatment failure for KMC was 12.8% (95% confidence interval: 1.9-23.7%), while the per-protocol effectiveness of AL in KMC was 89.47%. All recurrent cases were assigned to recrudescence after parasite genotyping by Pfmsp 1 and Pfmsp 2., Conclusion: While AL is efficacious in treating uncomplicated malaria in Ghana, when taken under unsupervised conditions, it showed an 89.4% PCR-corrected cure rate in northern Ghana, which is slightly below the WHO-defined threshold., (© 2024. The Author(s).)

The combinations of artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) are used as first-line treatments for uncomplicated malaria in the Ivory Coast. Different studies document the efficacy of two artemisinin-based combination therapies (ACTs) (AL and ASAQ) in the Ivory Coast. However, there is no meta-analysis examining the data set of these studies. The purpose of this work was to determine the prevalence of malaria treatment failure cases in randomized control trials with two artemisinin-based combination therapies (AL versus ASAQ) in the Ivory Coast between 2009 to 2016. This study is a meta-analysis of data from the results of four previous multicenter, open-label, randomized clinical trial studies evaluating the clinical and parasitological efficacy of artemether-lumefantrine and artesunate-amodiaquine conducted between 2009 and 2016 following World Health Organization (WHO) protocol at sentinel sites in the Ivory Coast. These drug efficacy data collected between 2009 and 2016 were analyzed. During these studies, to distinguish between recrudescence and new infection, molecular genotyping of genes encoding merozoite surface protein 1 and 2 was carried out using nested polymerase chain reaction (PCR). A total of 1575 patients enrolled in the four studies, including 768 in the AL arm and 762 in the ASAQ arm, which were fully followed either for 28 days or 42 days according to WHO protocol. The adequate clinical and parasitological response (ACPR) was higher than 95% in the two groups (intention to treat (ITT): AL = 96.59% and ASAQ = 96.81; Per Protocol (PP): AL = 99.48% and ASAQ = 99.61%) after PCR correction at day 28. Aggregate data analysis (2009-2016) showed that at day 28, the proportions of patients with recurrent infection was higher in the AL group (ITT: 3.79%, PP: 3.9%) than in the ASAQ group (ITT: 2.17%, PP: 2.23%). After PCR correction, most treatment failures were classified as new infections (AL group (ITT: 0.13%, PP: 0.13%); ASAQ group (ITT: 0.39%, PP: 0.39%). The recrudescent infections rate was high, at 0.39% compared to 0.13% for ASAQ and AL, respectively, for both ITT and PP, no significant difference. However, the Kaplan-Meier curve of cumulative treatment success showed a significant difference between the two groups after PCR from 2012-2013 ( p = 0.032). Overall, ASAQ and AL have been shown to be effective drugs for the treatment of uncomplicated P. falciparum malaria in the study areas, 14 years after deployment of these drugs.