Artemisinin-based Combination Treatments Research Articles

Availability of antimalarial medicines and inventory management at the community level: a case study of Bugesera district in Rwanda

BackgroundMalaria is a public health hazard globally, with Sub-Saharan Africa accounting for more than 90% of malaria deaths, primarily affecting children under the age of five. In Rwanda, malaria interventions include the availability of antimalarial medications, notably Artemisinin-based combination treatments (ACTs) and quick diagnostic test kits (RDTs). However, the availability of antimalarial medicines and its related inventory management at community level in Rwanda has yet to be identified.MethodsThe study was conducted using a descriptive cross-sectional research design. The study involved the Community Health Workers (CHWs) in Bugesera District, working as a team of one male-female pair called Binômes. CHWs provide Integrated Community Case Management (iCCM) and treatment of Malaria in the villages. The sample size was 295 and respondents were selected using convenient random sampling from 15 sectors of Bugesera District, each cell being represented. A structured research questionnaire was used to collect data. The questionnaires were filled by CHWs who were available for this study at the time of data collection. Collected data were exported to SPSS version 26 for coding and analysis.ResultsThe CHWs reported to be actively involved in managing the antimalarial medicines inventory. Overall, 64.1% of CHWs indicated that the population could easily obtain antimalarial medicines from community health workers and 31.2% attested that people could also obtain antimalarial medicines from the health centers. Majority of respondents 78% confirmed that the CHWs had the appropriate storage conditions for antimalarial medicines, while the overall stock out recorded was 3.20%. Furthermore, CHWs described some challenges, including but not limited to, lack of appropriate or dependable transportation and inappropriate medicines storage. Transportation was reported as a critical barrier for accessing antimalarial medicines. The majority, 70,85% travel on foot while 25.4% reported that CHWs walk for a distance between 1 and 2 h for resupply of antimalarial medicines.ConclusionThis study investigated the availability of antimalarial medicines and inventory management challenges at community level in Rwanda. Addressing these challenges will reduce the rate of stockout and increase the availability of antimalarial medicine at community level. Appropriate storage, and reduction of stock out rate, will serve to strengthen the current CHWs system, and provide critical guidance for the evolution of CHWs’ systems in Rwanda.

Situational Analysis of Malaria Incidence Under Integrated Malaria Service in Hotspot Township - Minbya Township, Rakhine State, Myanmar, 2017-2020.

Malaria is a significant public health concern and tropical disease, particularly affecting Myanmar within the Greater Mekong Subregion. The annual parasite index (API) exceeds 1 per 10,000 population in the northern seven townships of Rakhine State, with Minbya Township designated as a high-burden area for malaria by the World Health Organization (WHO) Myanmar and the National Malaria Control Programme (NMCP). Since 2017, the Malaria reduction intensification plan has been in place in this township to combat the high disease transmission rates. This study aims to assess the malaria epidemiology in Minbya Township from 2017 to 2020 under the intensification plan for elimination, as well as to evaluate the effectiveness of the integrated strategy in reducing cases in hotspot areas. The study utilized a surveillance study design to collect secondary data from the Malaria surveillance system (MSS) and the epidemiologic monitoring dashboard of Minbya Township, Maruk-U District, located in Rakhine State. Since 2017, the Malaria prevention and control (P&C) Program in Minbya Township has successfully decreased malaria morbidity, eliminated malaria-related deaths, and bolstered malaria testing capabilities through the participation of village health volunteers (VHVs). Approximately 87% of malaria prevention and control services are executed by the township's malaria elimination and disease control programs, with additional support from stakeholders. The API dropped from 13 in 2017 to 2.5 in 2020, with Plasmodium vivax being the most prevalent malaria species, accounting for 55% of cases. The study suggests that early diagnosis and promotion of artemisinin-based combination treatment (ACT), along with strategic planning including expanding active case detection in rural health centers and implementing a community-based integrated healthcare approach, are effective and efficient strategies for malaria elimination.

Efficacy and safety of pyronaridine-artesunate (PYRAMAX) for the treatment of P. falciparum uncomplicated malaria in African pregnant women (PYRAPREG): study protocol for a phase 3, non-inferiority, randomised open-label clinical trial

IntroductionMalaria infection during pregnancy increases the risk of low birth weight and infant mortality and should be prevented and treated. Artemisinin-based combination treatments are generally well tolerated, safe and effective;...

Efficacy of Plasmoquine for the Treatment of Plasmodium Vivax and Plasmodium Falciparum

This study is a response to the challenge of malaria infections, which remain a major public health in South Africa. Reports of malarial outbreaks in the country have been predominant in KwaZulu-Natal, Mpumalanga, and Limpopo provinces. Currently, combination therapy referred to artemisinin-based combination treatments (ACTs) has been recommended both by the World Health Organization and the National Department of Health of South Africa. However, due to widespread reports of artemisinin resistance, other alternative treatment options were explored. The aim of the study was thus to establish the efficacy of plasmoquine as an alternative treatment option among malaria patients in Johannesburg, the economic capital of South Africa, found in the Gauteng Province. The study adopted a quantitative approach, and a purposive retrospective investigation was adopted. Patient data from 2018-2022 was analyzed to determine the incidence of malaria in the study location and the efficacy of treatment with plasmoquine. The results of this study, therefore, indicate that P. falciparum is still the main cause of malaria in the study area. A total of 322 patient files were included in the study, with P. falciparum determined to be the main cause of infection over the four-year data assessed. Furthermore, plasmoquine was determined to be effective in treating malaria among 298 of the study population, with only 24 (7.5%) experiencing the development of vomiting after the treatment course. The findings of the study offer government makes policymakers the opportunity to develop policies that enhance the re-introduction of plasmoquine to combat malaria in South Africa. Keywords: Artemisinin-based combination treatments; Artemisinin resistance, Malaria; Plasmoquine.

Blood-stage antiplasmodial activity and oocyst formation-blockage of metallo copper-cinchonine complex.

In the fight against malaria, the key is early treatment with antimalarial chemotherapy, such as artemisinin-based combination treatments (ACTs). However, Plasmodium has acquired multidrug resistance, including the emergence of P. falciparum strains with resistance to ACT. The development of novel antimalarial molecules, that are capable of interfering in the asexual and sexual blood stages, is important to slow down the transmission in endemic areas. In this work, we studied the ability of the mettalo copper-cinchonine complex to interfere in the sexual and asexual stages of Plasmodium. The tested compound in the in vitro assay was a cinchonine derivative, named CinCu (Bis[Cinchoninium Tetrachlorocuprate(II)]trihydrate). Its biological functions were assessed by antiplasmodial activity in vitro against chloroquine-resistant P. falciparum W2 strain. The mice model of P. berghei ANKA infection was used to analyze the antimalarial activity of CinCu and chloroquine and their acute toxicity. The oocyst formation-blocking assay was performed by experimental infection of Anopheles aquasalis with P. vivax infected blood, which was treated with different concentrations of CinCu, cinchonine, and primaquine. We found that CinCu was able to suppress as high as 81.58% of parasitemia in vitro, being considered a molecule with high antiplasmodial activity and low toxicity. The in vivo analysis showed that CinCu suppressed parasitemia at 34% up to 87.19%, being a partially active molecule against the blood-stage forms of P. berghei ANKA, without inducing severe clinical signs in the treated groups. The transmission-blocking assay revealed that both cinchonine and primaquine were able to reduce the infection intensity of P. vivax in A. aquasalis, leading to a decrease in the number of oocysts recovered from the mosquitoes' midgut. Regarding the effect of CinCu, the copper-complex was not able to induce inhibition of P. vivax infection; however, it was able to induce an important reduction in the intensity of oocyst formation by about 2.4 times. It is plausible that the metallo-compound also be able to interfere with the differentiation of parasite stages and/or ookinete-secreted chitinase into the peritrophic matrix of mosquitoes, promoting a reduction in the number of oocysts formed. Taken together, the results suggest that this compound is promising as a prototype for the development of new antimalarial drugs. Furthermore, our study can draw a new pathway for repositioning already-known antimalarial drugs by editing their chemical structure to improve the antimalarial activity against the asexual and sexual stages of the parasite.

Plasmodium falciparum merozoite invasion ligands, linked antimalarial resistance loci and ex vivo responses to antimalarials in The Gambia.

Artemether/lumefantrine is the most commonly used artemisinin-based combination treatment (ACT) for malaria in sub-Saharan Africa. Drug resistance to ACT components is a major threat to malaria elimination efforts. Therefore, rigorous monitoring of drug efficacy is required for adequate management of malaria and to sustain the effectiveness of ACTs. This study identified and described genomic loci that correlate with differences in ex vivo responses of natural Plasmodium falciparum isolates from The Gambia to antimalarial drugs. Natural P. falciparum isolates from The Gambia were assayed for IC50 responses to four antimalarial drugs (artemether, dihydroartemisinin, amodiaquine and lumefantrine). Genome-wide SNPs from 56 of these P. falciparum isolates were applied to mixed-model regression and network analyses to determine linked loci correlating with drug responses. Genomic regions of shared haplotypes and positive selection within and between Gambian and Cambodian P. falciparum isolates were mapped by identity-by-descent (IBD) analysis of 209 genomes. SNPs in 71 genes, mostly involved in stress and drug resistance mechanisms correlated with drug responses. Additionally, erythrocyte invasion and permeability loci, including merozoite surface proteins (Pfdblmsp, Pfsurfin), and high-molecular-weight rhoptry protein 2 (Pfrhops2) were correlated with responses to multiple drugs. Haplotypes of pfdblmsp2 and known drug resistance loci (pfaat1, pfcrt and pfdhfr) from The Gambia showed high IBD with those from Cambodia, indicating co-ancestry, with significant linkage disequilibrium between their alleles. Multiple linked genic loci correlating with drug response phenotypes suggest a genomic backbone may be under selection by antimalarials. This calls for further analysis of molecular pathways to drug resistance in African P. falciparum.

Antimalarial Drug Predictions Using Molecular Descriptors and Machine Learning against Plasmodium Falciparum.

Malaria remains by far one of the most threatening and dangerous illnesses caused by the plasmodium falciparum parasite. Chloroquine (CQ) and first-line artemisinin-based combination treatment (ACT) have long been the drug of choice for the treatment and controlling of malaria; however, the emergence of CQ-resistant and artemisinin resistance parasites is now present in most areas where malaria is endemic. In this work, we developed five machine learning models to predict antimalarial bioactivities of a drug against plasmodium falciparum from the features (i.e., molecular descriptors values) obtained from PaDEL software from SMILES of compounds and compare the machine learning models by experiments with our collected data of 4794 instances. As a consequence, we found that three models amongst the five, namely artificial neural network (ANN), extreme gradient boost (XGB), and random forest (RF), outperform the others in terms of accuracy while observing that, using roughly a quarter of the promising descriptors picked by the feature selection algorithm, the five models achieved equivalent and comparable performance. Nevertheless, the contribution of all molecular descriptors in the models was investigated through the comparison of their rank values by the feature selection algorithm and found that the most potent and relevant descriptors which come from the ‘Autocorrelation’ module contributed more while the ‘Atom type electrotopological state’ contributed the least to the model.

Molecular Surveillance and Burden of Plasmodium falciparum Isolate to the Resistance of Artemisinin and Mefloquine-based Therapy among Febrile Subjects in Ilorin Metropolis, North-Central Nigeria

Introduction: Artemisinin-based combination treatments (ACTs) such as Artemisinin and mefloquine are generally accepted as the best forms of therapy for uncomplicated falciparum malaria and usually exceed more than 90% effectiveness. However, the problem of resistance to the target parasites remains a great challenge especially within the northcentral Nigeria. Therefore this study aimed to assess the burden of resistance of Plasmodium falciparum to artemisinin and Mefloquine from the blood smear febrile patients attending tertiary health facility in Ilorin, Nigeria.
 Methodology: The study was carried among two hundred and one (201) consented febrile individuals age ranged 1-46 years (Mean=22.7 years; M=39; F=61) between May and August 2019. Blood samples collected were subjected to Microscopy using Giemsa staining technique and Rapid diagnostic test (RDT) using (SD BIOLINE Malaria Ag P.f/Pv, South Korea) kit to detect the presence of P. falciparum A semi-structured questionnaire was used to capture demographic and other relevant information while data was analysed with SPSS version 21.
 Results: Of the 201 samples tested, 113 (56.5%) were positive for Microscopy and RDT. Fifty of the positive samples for Microscopy and RDT were further subjected to PCR technique for the presence of Plasmodium falciparum and amplification of Kelch13 and FR1gene mutation of which one (2.0%) showed amplification for the PfKelch13 gene mutation for artemisinin while none was recorded for FR1 gene mutation in case of Mefloquine.
 Conclusion: This study reported a high rate of detection for Plasmodium falciparum using microscopy and RDT but moderately low rate of resistance to amplification for the PfKelch13 gene mutation for artemisinin but none for FR1 gene mutation for mefloquine by PCR. This suggests a clue for further monitoring of the artemisinin and Mefloquine resistance by detection of some molecular markers in k13 and FRI genes of Plasmodium in our communities in Nigeria.

Polymorphisms in Plasmodium falciparum chloroquine resistance transporter (Pfcrt) and multidrug-resistant gene 1 (Pfmdr-1) in Nigerian children 10 years post-adoption of artemisinin-based combination treatments

The emergence and spread of Plasmodium falciparum parasites resistant to artemisinin derivatives and their partners in southeastern Asia threatens malaria control and elimination efforts, and heightens the need for an alternative therapy. We have explored the distribution of P. falciparum chloroquine resistance transporter (Pfcrt) and multidrug-resistant gene 1 (Pfmdr-1) haplotypes 10 years following adoption of artemisinin-based combination therapies in a bid to investigate the possible re-emergence of Chloroquine-sensitive parasites in Nigeria, and investigated the effect of these P. falciparum haplotypes on treatment outcomes of patients treated with artemisinin-based combination therapies. A total of 271 children aged <5 years with uncomplicated falciparum malaria were included in this study. Polymorphisms on codons 72–76 of the Pfcrt gene and codon 86 and 184 of Pfmdr-1 were determined using the high resolution melting assay. Of 240 (88.6%) samples successfully genotyped with HRM for Pfcrt, wildtype C72M74N75K76 (42.9%) and mutant C72I74E75T76 (53.8%) were observed. Also, wildtype N86Y184 (62.9%) and mutant N86F184 (21.1%), Y86Y184 (6.4%), and Y86F184 (0.4%) haplotypes of Pfmdr-1 were observed. Measures of responsiveness to ACTs were similar in children infected with P. falciparum crt haplotypes (C72I74E75T76 and C72M74N75K76) and major mdr-1 haplotypes (N86Y184, N86F184 and Y86Y184). Despite a 10 year gap since the malaria treatment policy changed to ACTs, over 50% of the P. falciparum parasites investigated in this study harboured the Chloroquine-resistant C72I74E75T76 haplotype, however this did not compromise the efficacy of artemisinin-based combination therapies. Should complete artemisinin resistance emerge from or spread to Nigeria, chloroquine might not be a good alternative therapy.

Reticulocyte count changes in paediatric patients with uncomplicated malaria treated with artemisinin combination therapy

Background: Acute malaria is associated with reticulocyte count depression, and artemisinin derivatives have also been shown to cause reversible count changesin patients with severe malaria. However, there has been no report on the effect of artemisinin on reticulocytecountwhen used in combination with other antimalarials, or the effect of artemisinin-based treatment on reticulocyte count changes in patients with uncomplicated malaria. Objective: This study reports the effects of artemisinin-based antimalarial treatments on reticulocytes among paediatric patients with uncomplicated malaria. Methods: The reticulocyte counts, haemoglobin, and platelet counts of children with uncomplicated malaria treated with artesunate-amodiaquine (116), artemether-lumefantrine (90), or amodiaquine (17) were measured before treatment (day 0) and then on days 3, 7, 14, and 28. Results: The fractional changes in reticulocyte counts were higher in the artesunate-amodiaquine and artemether-lumefantrine groups during the initial stages of treatment. However, the overall fractional reticulocyte change between acute illness and pre-illness levels was higher in the amodiaquine treated group. There was a negative correlation between haemoglobin and reticulocyte counts before treatment (day 0 ) and on all the follow up days. Conclusion: Treatment of uncomplicated malaria in children with artesunate-amodiaquine or artemether-lumefantrine was associated with less profound reticulocyte count changes compared with children treated with amodiaquine alone. These changes were most likely due to the rapid parasite clearance by the two artemisinin-based combination treatment regimens.

Reticulocyte count changes in paediatric patients with uncomplicated malaria treated with artemisinin combination therapy

Background: Acute malaria is associated with reticulocyte count depression, and artemisinin derivatives have also been shown to cause reversible count changes in patients with severe malaria. However, there has been no report on the effect of artemisinin on reticulocyte count when used in combination with other antimalarials, or the effect of artemisinin-based treatment on reticulocyte count changes in patients with uncomplicated malaria. Objective:This study reports the effects of artemisinin-based antimalarial treatments on reticulocytes among paediatric patients with uncomplicated malaria. Methods: The reticulocyte counts, haemoglobin, and platelet counts of children with uncomplicated malaria treated with artesunate-amodiaquine (116), artemether-lumefantrine (90), or amodiaquine (17) were measured before treatment (day 0) and then on days 3, 7, 14, and 28. Results: The fractional changes in reticulocyte counts were higher in the artesunate-amodiaquine and artemether-lumefantrine groups during the initial stages of treatment. However, the overall fractional reticulocyte change between acute illness and pre-illness levels was higher in the amodiaquine treated group. There was a negative correlation between haemoglobin and reticulocyte counts before treatment (day0) and on all the follow up days. Conclusion: Treatment of uncomplicated malaria in children with artesunate-amodiaquine or artemether-lumefantrine was associated with less profound reticulocyte count changes compared with children treated with amodiaquine alone. These changes were most likely due to the rapid parasite clearance by the two artemisinin-based combination treatment regimens

Declining responsiveness of childhood Plasmodium falciparum infections to artemisinin-based combination treatments ten years following deployment as first-line antimalarials in Nigeria

BackgroundThe development and spread of artemisinin-resistant Plasmodium falciparum malaria in Greater Mekong Subregion has created impetus for continuing global monitoring of efficacy of artemisinin-based combination therapies (ACTs). This post analyses is aimed to evaluate changes in early treatment response markers 10 years after the adoption of ACTs as first-line treatments of uncomplicated falciparum malaria in Nigeria.MethodsAt 14 sentinel sites in six geographical areas of Nigeria, we evaluated treatment responses in 1341 children under 5 years and in additional 360 children under 16 years with uncomplicated malaria enrolled in randomized trials of artemether-lumefantrine versus artesunate-amodiaquine at 5-year interval in 2009–2010 and 2014–2015 and at 2-year interval in 2009–2010 and 2012–2015, respectively after deployment in 2005.ResultsAsexual parasite positivity 1 day after treatment initiation (APPD1) rose from 54 to 62% and 2 days after treatment initiation from 5 to 26% in 2009–2010 to 2014–2015 (P = 0.002 and P < 0.0001, respectively). Parasite clearance time increased significantly from 1.6 days (95% confidence interval [CI]: 1.55–1.64) to 1.9 days (95% CI, 1.9–2.0) and geometric mean parasite reduction ratio 2 days after treatment initiation decreased significantly from 11 000 to 4700 within the same time period (P < 0.0001 for each). Enrolment parasitaemia > 75 000 μl− 1, haematocrit > 27% 1 day post-treatment initiation, treatment with artemether-lumefantrine and enrolment in 2014–2015 independently predicted APPD1. In parallel, Kaplan-Meier estimated risk of recurrent infections by day 28 rose from 8 to 14% (P = 0.005) and from 9 to 15% (P = 0.02) with artemether-lumefantrine and artesunate-amodiaquine, respectively. Mean asexual parasitaemia half-life increased significantly from 1.1 h to 1.3 h within 2 years (P < 0.0001).ConclusionsThese data indicate declining parasitological responses through time to the two ACTs may be due to emergence of parasites with reduced susceptibility or decrease in immunity to the infections in these children.Trial registrationPan African Clinical Trial Registration PACTR201508001188143, 3 July 2015; PACTR201508001191898, 7 July 2015 and PACTR201508001193368, 8 July 2015 PACTR201510001189370, 3 July 2015; PACTR201709002064150, 1 March 2017; https://www.pactr.samrca.ac.za

Safety and tolerability of single low-dose primaquine in a low-intensity transmission area in South Africa: an open-label, randomized controlled trial

BackgroundTo reduce onward falciparum malaria transmission, the World Health Organization recommends adding single low-dose (SLD) primaquine to artemisinin-based combination treatment in low transmission areas. However, uptake of this recommendation has been relatively slow given concerns about whether individual risks justify potential community benefit. This study was undertaken to generate comprehensive local data on the risk–benefit profile of SLD primaquine deployment in a pre-elimination area in South Africa.MethodsThis randomized, controlled open-label trial investigated adding a single low primaquine dose on day 3 to standard artemether–lumefantrine treatment for uncomplicated falciparum malaria. Efficacy, safety and tolerability of artemether–lumefantrine and primaquine treatment were assessed on days 3, 7, 14, 28 and 42. Lumefantrine concentrations were assayed from dried blood spot samples collected on day 7.ResultsOf 217 patients screened, 166 were enrolled with 140 randomized on day 3, 70 to each study arm (primaquine and no primaquine). No gametocytes were detected by either microscopy or PCR in any of the follow-up samples collected after randomization on day 3, precluding assessment of primaquine efficacy. Prevalence of the CYP2D6*4, CYP2D6*10 and CYP2D6*17 mutant alleles was low with allelic frequencies of 0.02, 0.11 and 0.16, respectively; none had the CYP2D6*4/*4 variant associated with null activity. Among 172 RDT-positive patients G6PD-genotyped, 24 (14%) carried the G6PD deficient (A−) variant. Median haemoglobin concentrations were similar between treatment arms throughout follow-up. A third of participants had a haemoglobin drop > 2 g/dL; this was not associated with primaquine treatment but may be associated with G6PD genotype [52.9% (9/17) with A− genotype vs. 31% (36/116) with other genotypes (p = 0.075)]. Day 7 lumefantrine concentrations and the number and nature of adverse events were similar between study arms; only one serious adverse event occurred (renal impairment in the no primaquine arm). The artemether–lumefantrine PCR-corrected adequate clinical and parasitological response rate was 100%, with only one re-infection found among the 128 patients who completed 42-day follow-up.ConclusionsSafety, tolerability, CYP2D6 and G6PD variant data from this study support the deployment of the WHO-recommended SLD primaquine without G6PD testing to advance malaria elimination in South African districts with low-intensity residual transmission.Trial registration Pan African Clinical Trial Registry, PACTR201611001859416. Registered 11 November 2016, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=1859

Malaria care-seeking behaviour among HIV-infected patients receiving antiretroviral treatment in South-Eastern Nigeria: A cross-sectional study.

This study assesses malaria prevention and treatment behaviour among people living with HIV/AIDS (PLWHA) in Owerri, South Eastern Nigeria. Although Nigeria bears one of the world’s largest burdens of both malaria and HIV, there is almost no research studying how co-infected patients manage their care. We systematically sampled 398 PLWHA receiving care at Imo State Specialist Hospital and the Federal Medical Centre in Owerri to complete a structured, pre-tested questionnaire on malaria care-seeking behaviour. Descriptive statistics were reported and chi-square tests and multivariate logistic regressions were also used. The majority of HIV-infected patients (78.9%) reported having had an episode of suspected malaria quarterly or more often. There was a large variation in care-seeking patterns: on suspicion of malaria, 29.1% of participants engaged in self-medication; 39.2% went to drug shops, and only 22.6% visited HIV/AIDS care centres. Almost 40% waited more than 24 hours before initiating treatment. Most (60.3%), reported taking recommended artemisinin-based combination treatments (ACT) but a significant minority took only paracetamol (25.6%) or herbal remedies (3.5%). Most (80%) finished their chosen course of treatment; and completion of treatment was significantly associated with the frequency of suspected malaria occurrence (p = 0.03). Most (62.8%) did not take anti-malaria medication while taking antiretroviral treatment (ART) and almost all (87.6%) reported taking an ACT regimen that could potentially interact with Nigeria’s first-line ART regimen. Our findings suggest the need to pay more attention to malaria prevention and control as a crucial element in HIV/AIDS management in this part of Nigeria and other areas where malaria and HIV/AIDS are co-endemic. Also, more research on ART-ACT interactions, better outreach to community-level drug shops and other private sector stakeholders, and clearer guidelines for clinicians and patients on preventing and managing co-infection may be needed. This will require improved collaboration between programmes for both diseases.

Patients experiences on the use of dihydroartemisinin piperaquine as an alternative first line artemisinin-based combination treatment for uncomplicated malaria in Northern Ghana

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Three different artemisinin-based combination therapies (ACTs) namely; artesunate-amodiaquine, artemether-lumefantrine and dihydroartemisinin-piperaquine (being the latest to be introduced) are concurrently being used for the treatment of &lt;em&gt;falciparum&lt;/em&gt; malaria in Ghana. This study assessed patients’ experience, perceptions and willingness to use dihydroartemisinin-piperaquine, brand name duo-cotecxin as an alternative first line ACT for the treatment of &lt;em&gt;falciparum&lt;/em&gt; malaria in Northern Ghana.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; This was a qualitative study using phenomenology approach where sixty in-depth interviews were conducted with two groups; thirty patients who were given duo-cotecxin, one group and thirty interviews with patients who were given other ACTs (artesunate-amodiaquine, artemether-lumefantrine) as another group. The interviews were conducted between August and November, 2015 Purposive sampling technique was used to select study participants. The interviews were transcribed and coded into themes using QSR NVivo 11 software for thematic content analysis.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; All patients who used duo-cotecxin reported that the drug was very good in treating uncomplicated malaria compared to other ACTs they had used in the past. Some of the patients who used other ACTs could not complete their doses because of the side effects. However, none of the patients who used duo-cotecxin reported side effects. The findings revealed high acceptance and preference to use duo-cotecxin to treat uncomplicated malaria compared with other ACTs. All the participants were also willing to recommend duo-cotexcin to their relatives and friends to use.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Duo-cotecxin as an alternative first line ACT for treatment of uncomplicated malaria is highly accepted, preferred and there was willingness to use it compared with other first line recommended ACTs.&lt;/p&gt;

PO 8542 CLINICAL ILLNESS AND OUTCOMES IN NIGERIAN CHILDREN WITH PERSISTENT EARLY-APPEARING ANAEMIA FOLLOWING ARTEMISININ-BASED COMBINATION TREATMENTS OF UNCOMPLICATEDPLASMODIUM FALCIPARUMMALARIA

BackgroundEarly-appearing anaemia (EAA) is not uncommon in malarious children following artemisinin-based combination treatments (ACTs) of uncomplicated infections and it may become persistent (PEAA). There is little evaluation of the factors contributing to and the kinetics of the resolution of haemoglobin deficit characteristic of ACT-related PEAA.MethodsPEAA was defined as haemoglobin concen„tration &lt;10 g/dL for at least 1 week after treatment initiation with artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ) or dihydroartemisinin-piperaquine (DP) in malarious children with haemoglobin ≥10 g/dL pre-treatment. Drug-attributable fall in haemoglobin (DAFHb) was defined as the difference between pre-treatment and the lowest recorded haemoglobin value in the first week after treatment initiation. Stepwise multiple logistic regression model was used to evaluate independent predictors of PEAA. Time course of deficits in haemoglobin from baseline was used to estimate the disposition kinetics of haemoglobin deficits using a one compartment model.ResultsAsymptomatic PEAA occurred in 46 of 540 children. A duration of illness ≤3 days before presentation, haemoglobin &lt;11.7 g/dL pre-treatment and 8.3 g/dL 1 day after treatment initiation. DAFHb ≥2 g/dL and treatment with DP independently predicted PEAA. Time to 90% reduction in haemoglobin deficit was significantly longer in AL-treated children compared with other treatments. Declines in haemoglobin deficits were monoexponential with the following overall estimated parameters: Cmax 2.6 g/dL (95% CI 2.3–2.9), Tmax 3.2 days (95% CI 2.2–4.1), AUC 31.9 g.dL-1.day (95% CI 25–38.8), Kel0.3 day-1(95% CI 0.3–0,4), t1/23.9 days (95% CI 2.6–5.1), CLp 0.6L.day-1(95% CI 0.5–0.7), and Vd 2.4L (95% CI 1.7–3). Overall, mean anaemia recovery time of 17.9 days (95% CI 15.5–20.2, n=39) was equivalent to 5 multiples of half-time of haemoglobin deficit on Bland-Altman analysis. Eight children, after recovery from PEAA progressed to asymptomatic late-appearing anaemia (LAA).ConclusionAsymptomatic PEAA, which may progress to LAA, is not uncommon in young children following ACTs. Its occurrence, and progression to LAA, may have implications for case management and control efforts for ACT-related anaemia in sub-Saharan Africa.

Role of 2-Dimensional Autocorrelation Descriptors in Predicting Antimalarial Activity of Artemisinin and its Aanalogues: A QSAR Study.

Malaria, one of the World's biggest billers' is on the schedule for biomedical research and public health policies. The introduction of the artemisinin, a Chinese traditional drug from Artemisia annua is a revolution in the treatment of malaria. Artemisinin-based combination treatment (ACT) is considered to be the best strategy for uncomplicated Falciparum malaria. The presence of 1,2,4-trioxane system in artemisinin is responsible for its antimalarial activity. In this study, twenty-nine analogues of artemisinin were taken into account for QSAR studies along with artemisinin. The most active analogue of artemisinin 21 was energy minimized. All the structures were prepared from the active conformer 21 and energy was minimized to the stable state using MMFF94 force field using ChemBioDraw-12. Genetic Algorithm is used to decide the descriptors best required for the model generation. The test set and training set division were done by using hierarchal clustering module available with NCSS statistical software. The antimalarial activity of the artemisinin and its substituted analogues has been analyzed through the multiple linear regression (MLR) using various physiochemical and structural descriptors obtained from PADEL software. The models were prepared using the Sigma Plot version 11. The calculated 2D autocorrelation descriptors and the MLR model suggest that artemisinin and its analogues hold the scope in the optimization of antimalarial activity.

Clinical illness and outcomes in Nigerian children with persistent early-appearing anaemia following initiation of artemisinin-based combination treatments of uncomplicated falciparum malaria.

In non-anaemic children with malaria, early-appearing anaemia (EAA) is common following artemisinin-based combination treatments (ACTs) and it may become persistent (PEAA). The factors contributing to and kinetics of resolution of the deficit in haematocrit from baseline (DIHFB) characteristic of ACTs-related PEAA were evaluated in 540 consecutive children with malaria treated with artemether-lumefantrine, artesunate-amodiaquine or dihydroartemisinin-piperaquine. Asymptomatic PEAA occurred in 62 children. In a multiple logistic regression model, a duration of illness ≤3 days before presentation, haematocrit <35% before and <25% one day after treatment initiation, drug attributable fall in haematocrit ≥6%, and treatment with dihydroartemisinin-piperaquine independently predicted PEAA. Overall, mean DIHFB was 5.7% (95% CI 4.8–6.6) 7 days after treatment initiation and was similar for all treatments. Time to 90% reduction in DIHFB was significantly longer in artemether-lumefantrine-treated children compared with other treatments. In a one compartment model, declines in DIHFB were monoexponential with overall mean estimated half-time of 3.9 days (95% CI 2.6–5.1), Cmax of 7.6% (95% CI 6.7–8.4), and Vd of 0.17 L/kg (95% CI 0.04–0.95). In Bland-Altman analyses, overall mean anaemia recovery time (AnRT) of 17.4 days (95% CI 15.5–19.4) showed insignificant bias with 4, 5 or 6 multiples of half-time of DIHFB. Ten children after recovery from PEAA progressed to late-appearing anaemia (LAA). Progression was associated with female gender and artesunate-amodiaquine treatment. Asymptomatic PEAA is common following ACTs. PEAA or its progression to LAA may have implications for case and community management of anaemia and for anaemia control efforts in sub-Saharan Africa where ACTs have become first-line antimalarials.Trial registration: Pan Africa Clinical Trial Registration PACTR201709002064150, 1 March 2017 http://www.pactr.org

Artemisinin resistance: Cause for worry?

Background: Artemisinin resistance is being reported from certain regions of the world. Globally, the scientific community is engaged in tracing the epidemiology of this resistance while also working on possible interventions to curb the spread. Aim: We reviewed the epidemiology of antimalarial drug resistance, especially artemisinin resistance both globally and in India, and report the possible ways forward. Literature Search: Resistance to all antimalarial drugs developed initially in South East Asia and thereafter spread globally. Artemisinin-based combination treatment (ACT) was formally recommended by the World Health Organisation (WHO) in 2005 to achieve an enhanced barrier to drug resistance. However in 2008, resistance to artemisinin was first reported from Western Cambodia/Thailand. Subsequently, P falciparum chromosome 13 ('kelch' motif or K13) (Pfk 13) was implicated with slow in vivo parasite clearance. As of 2019, artemisinin resistance has been confirmed in six countries of the Greater Mekong Sub-region. The North east states of India have been the portal for entry of anti-malarial drug resistance over the past decades. Though in vitro testing have not shown evidence of decreased artemisinin sensitivity, however, Pfk13 mutations have been reported from India, thus sounding a note of caution and indicating the need for continued genetic, clinical and public health surveillance. Conclusion: Though clinical cure in falciparum malaria infection continues to be elicited through use of ACT even in the countries reporting artemisinin resistance, however a comprehensive framework for combating the resistance has already been put into action by the WHO.

A barcode of multilocus nuclear DNA identifies genetic relatedness in pre- and post-Artemether/Lumefantrine treated Plasmodium falciparum in Nigeria

BackgroundThe decline in the efficacy of artemisinin-based combination treatment (ACT) in some endemic regions threatens the progress towards global elimination of malaria. Molecular surveillance of drug resistance in malaria-endemic regions is vital to detect the emergence and spread of mutant strains.MethodsWe observed 89 malaria patients for the efficacy of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum infections in Lagos, Nigeria and determined the prevalence of drug resistant strains in the population. Parasite clearance rates were determined by microscopy and the highly sensitive var gene acidic terminal sequence (varATS) polymerase chain reaction for 65 patients with samples on days 0, 1, 3, 7, 14, 21 and 28 after commencement of treatment. The genomic finger print of parasite DNA from pre- and post-treatment samples were determined using 24 nuclear single nucleotide polymorphisms (SNP) barcode for P. falciparum. Drug resistance associated alleles in chloroquine resistance transporter gene (crt-76), multidrug resistance genes (mdr1–86 and mdr1–184), dihydropteroate synthase (dhps-540), dihydrofolate reductase (dhfr-108) and kelch domain (K-13580) were genotyped by high resolution melt analysis of polymerase chain reaction (PCR) fragments.ResultsBy varATS qPCR, 12 (18.5%) of the participants had detectable parasite DNA in their blood three days after treatment, while eight (12.3%) individuals presented with genotypable day 28 parasitaemia. Complexity of infection (CoI) was 1.30 on day 0 and 1.34 on day 28, the mean expected heterozygosity (HE) values across all barcodes were 0.50 ± 0.05 and 0.56 ± 0.05 on days 0 and 28 respectively. Barcode (π) pairwise comparisons showed high genetic relatedness of day 0 and day 28 parasite isolates in three (37.5%) of the eight individuals who presented with re-appearing infections. Crt-76 mutant allele was present in 38 (58.5%) isolates. The mdr1–86 mutant allele was found in 56 (86.2%) isolates. No mutation in the K-13580 was observed.ConclusionsPersistence of DNA-detectable parasitaemia in more than 18% of cases after treatment and indications of genetic relatedness between pre- and post-treatment infections warrants further investigation of a larger population for signs of reduced ACT efficacy in Nigeria.