Therapeutic efficacy of artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria treatment in Metehara, Central-east Ethiopia

Therapeutic efficacy of artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria treatment in Metehara, Central-east Ethiopia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Therapeutic efficacy of artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria treatment in Metehara, Central-east Ethiopia Mahelet Tesfaye, Ashenafi Assefa, Hassen Mamo This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3936178/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Malaria drug resistance presents a significant challenge to malaria control and elimination efforts. Therefore, it is crucial to conduct regular surveillance to assess the therapeutic efficacy of first-line antimalarial drugs, which informs policy decisions to manage this threat. This study aimed to evaluate the therapeutic efficacy of artemether-lumefantrine (AL), which is the first-line treatment for uncomplicated malaria in Ethiopia since 2004, for uncomplicated Plasmodium falciparum malaria in Metehara, central-east Ethiopia. Using a one-arm prospective evaluation design, the study assessed the clinical and parasitological responses of patients with uncomplicated P. falciparum malaria. Initially, 80 patients (50 males and 30 females) were screened, and a total of 73 participants (44 males, 29 females) successfully completed the follow-up. The results indicated rapid parasite clearance and resolution of clinical symptoms, with all patients achieving complete recovery from asexual parasitemia and fever by day 3. The prevalence of gametocytes decreased from 6.3% on day zero to 2.5% on days two, three, seven, and ultimately achieving complete clearance afterwards. The overall cure rate for AL treatment, without a polymerase chain reaction correction, was 100%, demonstrating its high efficacy in effectively eliminating the malaria parasite in patients. Importantly, no serious adverse events related to AL treatment were reported during the study, suggesting its safety and tolerability among the participants. These findings confirm that, even 20 years after its introduction in Ethiopia, AL remains an effective treatment for uncomplicated P. falciparum malaria in the study site. Plasmodium falciparum therapeutic efficacy artemether-lumefantrine Metehara Figures Figure 1 Figure 2 Introduction Globally, there were approximately 249 million cases and 608,000 deaths due to malaria in 2022 [ 1 ]. This is higher compared to the respective numbers 244 million and 610,000 in 2021 after the COVID-19 interruption. Socio-economic factors such as unemployment, low income, and inadequate housing construction act as barriers to effectively mitigating malaria [ 2 ]. Furthermore, land use, urbanization and climate change are contributing to an increased risk of malaria in sub-Saharan African countries. Urbanization leads to deforestation for various purposes, including accommodating the growing urban population, which in turn alters the distribution of vector species. These changes result in spatial and temporal variations in temperature, humidity, and precipitation, all of which impact the ecology and biology of the vectors and increase the risk of disease transmission [ 3 , 4 ]. Case management using artemisinin combination therapies (ACTs) is among the cornerstones of malaria control. ACTs are the recommended first-line treatment for the deadliest malaria parasite, Plasmodium falciparum , and the most commonly used ACT is the combination of artemether-lumefantrine (AL) [ 5 ]. However, the emergence and rapid spread of drug-resistant parasite strains pose a continuous threat. Resistance to AL has been observed in Southeast Asia [ 6 ], and recent reports from Rwanda [ 7 ], Uganda [ 8 ], Ethiopia [ 9 , 10 ] and Eritrea [ 11 ] suggest a similar trend in sub-Saharan Africa. To combat drug resistance, surveillance systems have been established to monitor its spread and assess the effectiveness of antimalarial treatments. The efficacy of national first- and second-line anti-malarial treatments should be assessed at least once every two years, following the guidelines outlined in the WHO standard protocol for monitoring drug efficacy [ 12 ]. Regular malaria efficacy testing provides valuable data for updating and refining treatment guidelines. It helps determine which antimalarial drugs are most effective in specific regions and against certain strains of the malaria parasite. This information enables healthcare professionals to make informed decisions about which drugs to prescribe and helps ensure that patients receive the most appropriate and effective treatment. Effective malaria control and elimination programs rely on accurate information about drug efficacy. Regular testing helps identify areas where drug resistance is prevalent, allowing public health authorities to develop targeted interventions. It also aids in evaluating the impact of interventions such as the introduction of new drugs or combination therapies. Monitoring drug efficacy is essential for the safety and well-being of individual patients. If a drug is no longer effective against malaria parasites in a particular region, using it as a treatment option can lead to treatment failure, prolonged illness, and increased morbidity and mortality. Regular efficacy testing helps ensure that patients receive the most appropriate and effective treatment, improving their chances of recovery. Understanding the efficacy of existing antimalarial drugs provides valuable insights for the development of new and more effective treatments. By tracking drug resistance patterns and evaluating the effectiveness of different drugs, potential targets for new antimalarial drugs and improve treatment options for malaria can be identified. In summary, regular malaria drug efficacy testing is necessary for monitoring drug resistance, optimizing treatment guidelines, supporting public health strategies, ensuring patient safety, and facilitating the development of new antimalarial drugs. It plays a crucial role in combating malaria and improving the effectiveness of malaria control and elimination efforts. In alignment with the global effort, Ethiopia has been closely monitoring AL efficacy through nationwide sentinel sites since its introduction in 2004. This study serves as an extension of the national AL therapeutic efficacy studies conducted in one of the multiple sentinel sites located in central-east Ethiopia. The nation’s malaria strategic plan 2021–2025, extended to 2030, is currently underway following a malaria program review in anticipation of malaria elimination in certain low transmission settings with a combination of the available malaria control tools [ 13 ]. Methods Study site Metehara is a town located in the Oromia Region of Ethiopia, situated about 200km southeast of the capital city, Addis Ababa. It is positioned along the main highway that connects Addis Ababa with the eastern parts of the country, making it an important transportation hub. Geographically, Metehara is situated in the Great Rift Valley, which is a geological trench that extends from the Middle East to Mozambique. The town is located between the eastern escarpment of the Rift Valley and the Awash River, which flows nearby. The surrounding landscape is characterized by vast plains, scattered hills, and volcanic formations. In terms of climate, Metehara experiences a semi-arid climate with hot and dry conditions. The town lies in a lowland region, resulting in high temperatures throughout the year. The average annual temperature ranges from 24 to 30 o C. The hottest months are typically from March to May, with temperatures often exceeding 35 o C. The coolest months are from November to February, with average temperatures of 18-24 o C. Metehara receives most of its rainfall during the wet season, which typically occurs from June to September. The average annual precipitation is around 600-800mm. The vegetation in and around Metehara is mainly characterized by savannah grasslands and scattered acacia trees. The Awash River and its surrounding areas support a diverse ecosystem with various bird species. Metehara is also known for its proximity to the Awash National Park, which is located about 50km east of the town. Overall, Metehara's location in the Great Rift Valley, coupled with its semi-arid climate and diverse wildlife, makes it an interesting and unique area in Ethiopia. Metehara town and its surrounding is recognized for its malaria transmission, which persists throughout the year but varies in intensity, as the town health record system show. The study was conducted between November 2020 and March 2021, aligning with the continuous transmission of malaria in the area. Study population and design The study enrolled patients who visited the outpatient department of the Metehara Health Centre (MHC) and met the inclusion criteria established by the WHO for evaluating and monitoring the effectiveness of antimalarial drugs [ 12 ]. The inclusion criteria comprised presence of fever, age ≥ 6 months, mono-infection with P. falciparum , ability to swallow an oral medication, and willingness to adhere to the study protocol. Exclusion criteria encompassed severe malaria, infection with mixed or non-falciparum plasmodium, severe malnutrition, other febrile conditions, acknowledged chronic or severe diseases, hypersensitivity to the study drugs, and pregnancy or breastfeeding. The sample size was determined following the above same WHO guidelines [ 12 ] for assessing therapeutic efficacy of antimalarial drugs, requiring a minimum of 73 patients to estimate the efficacy of the study drug. To accommodate for potential attrition and withdrawals, a total of 80 patients were selected from the population. The study employed a one-arm prospective evaluation design, in which patients receiving AL were followed for 28 consecutive days to evaluate treatment effectiveness and identify instances of therapeutic failure. Data collection and analysis Data were gathered at the baseline and throughout the follow-up period. During the baseline, a physical examination was conducted, and sociodemographic data, medical history, and capillary blood samples were obtained. The follow-up visits consisted of regular check-ups, as well as clinical and laboratory examinations. The blood samples were utilized to create thick and thin blood films in order to detect, identify and measure parasitemia. Hemoglobin (Hb) and hematocrit levels were recorded at baseline only due to shortage of supplies. The data analysis encompassed double data entry, descriptive statistics, and the utilization of statistical tests such as independent t-tests to compare continuous variables. Results Baseline population A total of 2,332 individuals (1,187 males and 1,145 females) suspected of having malaria visited MHC for malaria diagnosis between November 26, 2020 and March 24, 2021. Among them, 178(7.6%) tested positive for malaria. Out of these 178 positive cases, 102(57.3%) were initially identified as P. falciparum mono-infections, while 76(42.7%) were identified as P. vivax infections. Among the 102 individuals with P. falciparum infections, 89 were eligible for the study, but 9 refused to participate due to their mobile working arrangements. Therefore, at baseline (day 0) there were 80 patients, 50 males and 30 females. The mean age of the population was 17.7±14.24, with 15 under-five, 26 between 5-15 years and 39 over 15. The minimum age was 8 months and the maximum 65 years. While the overall mean bodyweight was 36.8±19.9kg, it was 10.9±3.08, 23.1±6.72, 55.4±9.75 for the 15 age groups respectively. Twenty-nine (36.3%) participants reported a previous history of clinical malaria, and 38(47.5%) confirmed the availability of a bed net, but only 27(33.8%) reported using it regularly (Table 1). At the baseline, individuals with body temperature of ≥37.5°C were 29(36.3%) and the result had self-reported fever in the past 24-hour. The mean baseline body temperatures were 37.7±1.3 for the under-five, 37.7±1.34 for 5-15, and 35.8±5.9 for over 15 with overall mean of 36.8 o C. The range of body temperature was 32.5-40.2°C, and 39(48.7%) patients complained of headache, 6(7.5) nausea and 2(2.5%) dizziness without sign of general danger or severe P. falciparum or complicated malaria. The mean baseline Hb was 8.3±2.16g/dL, 9.7±2.0g/dL and 11.4±1.5g/dL for the 15 age groups respectively, and the overall mean Hb level was 10.41±2.1. During enrollment, 42(52.5%) patients were anemic (14(33.3%) severe (Hb<8 g/dL), 16(38.1%) moderate (Hb 8-10 g/dL), and 12(28.5%) mild (Hb 10 g/dL). Of these, 23(54.8%) were male and 19(45.2%) were female. The highest anemia (40.5%) recorded among 5-15 age group, 31.0% among 15(28.5%). The total mean parasitemia at baseline was 10,627±20,736.7 asexual parasites/μl of blood. There were 41 severely parasitemic patients (≥10,000 parasites/µl) and 39 moderately parasitemic patients (1000-9,999 parasites/µl). There was a significant variation in mean parasitemia between children below 5 years old (3,754.62±4,435.472 parasites/μl) and those between 5 and 15 years old (14,278.08±27,981.34 parasites/μl). Three patients had a parasitemia level exceeding 50,000 parasites/μl, maximum 98,235 parasites/μl. The gametocyte prevalence at baseline was 6.3% (5/80), with gametocyte numbers ranging from 80 to 5,320 sexual parasites/μl of blood. Follow-up Protocol violations including loss-to-follow-up The baseline participant number was reduced to 79, 78, 77, 74, and 73, respectively, on days 1, 7, 14, 21, 28. Because there was one loss-to-follow-up (LTFU) on each of days 1, 7, 14, 21, and 28. Additionally, there were two cases of mixed infection with P. vivax (involuntary protocol violations) on day 21, a 5-year girl and a 50-year man. All of the LTFU were males and their ages of those lost on days 1, 7, 14, 21 and 28 were 28, 32, 28, 10 and 29 years respectively. Primary Endpoint Adequate clinical and parasitological response (ACPR) was recorded for the patients. The ACPR rate was 100% (Table 2), and Kaplan-Meier analyses indicated no early treatment failures (ETF), late treatment failures (LTF), or late parasitological failures (LPF) (Fig. 1, Fig. 2). Secondary Endpoint Parasite and fever clearance At the baseline, 41(51.3%) of the study participants had a severe parasitic load (≥10,000 asexual parasites/μl). Following AL administration, the parasite count decreased to 0 by day 2 and afterwards no asexual parasites were microscopically detected. Parasite clearance was achieved before day 3 and remained so until day 28. At enrollment (n=80), 29(36.3%) individuals had an axillary temperature of ≥37.5°C. This percentage decreased to 10.1% (8 out of 79) on day one, reached 0 on day two, and was at 1.3% (1 out of 79) on day three, considering the loss-to-follow-up (LTF) of one participant on day one. The overall findings of the study indicate that a standard six-dose treatment of AL achieved a 100% cure rate for uncomplicated P. falciparum malaria over a 28-day period, without polymerase chain reaction (PCR) correction. Fever and parasitemia were rapidly eliminated within the first three days of treatment, although there was one individual who experienced fever on day seven for reasons that remain unidentified. Gametocytemia clearance At the baseline, gametocytes were detected in 5 participants, representing a prevalence of 6.3%. Among these 5 individuals with gametocytes, 11.5% (3 out of 26) were aged 5-15 years, 5.1% (2 out of 39) were above 15 years, and 6.7% (1 out of 15) were below 5 years of age. The proportion of participants with gametocyte carriage declined from 6.3% on day 0 to 2.5% on days two, three, and day 7, with complete disappearance thereafter. Adverse Events At baseline, the patients reported common signs and symptoms typically associated with malaria, with the majority (48.9%) experiencing headaches. After the administration of AL treatment, possible signs and symptoms that could be attributed to the medication were noticed on days three and seven, with one report each. On day 14, two signs were reported, and on days 21 and 28, one sign each was reported. However, there were no signs of illness reported on days one and two. It is important to note that all of these signs and symptoms were not serious, and no participant was withdrawn from the study due to these reasons. Discussion In our retrospective assessment of the past four-year duration (2018–2023), there was a continuous increase in malaria prevalence in the study area (data not shown). Although P. falciparum accounted for the highest number of cases, among the two species observed, the number of P. vivax is also sizable. This could be attributed to various factors such as resource constraints, ineffective preventive measures, and the development of insecticide resistance, highlighting the need for scale up of control interventions. The presence of parasitemia on day 3 is a key indicator for suspected artemisinin resistance [ 14 ]. However, in this study, the baseline mean parasitemia was 10,627 ± 20,736.7, which decreased to zero on day 3. Artemether, being a potent anti-malarial drug that is rapidly absorbed, leads to a rapid reduction in parasite biomass, prompt symptomatic improvement, and rapid elimination [15]. Consequently, the absence of ETF confirms the non-existence of artemisinin-resistant P. falciparum strains among the study population although this may not be ruled out from the study areas as a whole. Similarly, the study did not observe LTF or LPF. The adjusted cure rate at day 28 was found to be 100% for children under five, as well as for the age groups of 5–15 and over 15. High levels of parasitemia in the bloodstream can contribute to severe fever. Fever is a response by the body's immune system to fight off the infection and also indicates high replication and development of the parasite [ 16 ]. Although high fever and parasitemia were recorded at enrollment, the administration of the drug resulted in the elimination of parasitemia by day 2 and a decline in fever to the normal range by day 1. This demonstrates that AL rapidly clears parasites, prevents disease progression, resolves symptoms quickly, and reduces the risk of complicated malaria. AL primarily targets the asexual stage of the malaria parasite to decrease and clear it, but it also exhibits gametocidal activity, which interrupts the transmission cycle between the mosquito vector and the human host. A study using membrane-feeding Anopheles mosquitoes demonstrated a reduction in malaria transmission following the six-dose regimen of AL [ 17 ]. The authors reported that gametocyte clearance was observed by day 2, with one case persisting until day 3 and completely disappearing by day 7 and onwards. Similarly, in the current study, gametocyte carriage at day 0 decreased over and disappeared after day 7. Similar high efficacy findings have been reported in other parts of Ethiopia and sub-Saharan Africa [ 18 ]. A meta-analysis of anti-malarial treatment outcomes in Ethiopia, based on 21 publications, reported an average efficacy of 98.1% [ 19 ], which is almost consistent with the findings of the present study. In contrast to results from Southeast Asian nations where delayed fever clearance was observed with AL, the rapid fever-resolving ability of AL has been consistently observed in efficacy tests conducted in Ethiopia. Malaria can cause anemia, which is characterized by a decrease in Hb levels. However, the effect of different malaria treatments on Hb levels can vary. Some studies have shown that certain antimalarial treatments can lead to an improvement in Hb levels. For example, effective treatment of malaria with antimalarial drugs can help clear the infection, allowing the body to recover and restore Hb levels [ 20 , 21 ]. This improvement in Hb levels is often seen in individuals who receive prompt and appropriate treatment. On the other hand, there have been reports of antimalarial drugs causing a decrease in Hb levels or exacerbating anemia in some individuals [ 22 , 23 ]. For example, certain medications, such as primaquine, used for the treatment of P. vivax malaria and nowadays against P. falciparum gametocytes, may cause hemolysis, leading to a drop in Hb levels [ 24 ]. No serious adverse events were noted, and the majority of the reported reactions were already recognized by the manufacturer as common adverse reactions and documented with the Food and Drug Administration. These reactions included joint discomfort, weakness, headache, cough, anorexia, and stomach ache. Once the parasites were cleared, these minor symptoms quickly resolved except one or incidents around the end of the study whose causes could not be established. The results of other studies in Ethiopia [ 26 , 27 ] align with the absence of major adverse events following AL treatment in the current investigation. Nevertheless, this study has certain limitations. In fact, these limitations are limitations of most other similar malaria drug efficacy studies. The study focuses on a specific study area, and the findings may not be representative of the entire region or other geographical locations. The prevalence of malaria and the effectiveness of treatment may vary in different settings. The study's duration is days 28 days. Assessing the sustainability of the observed trends and treatment efficacy over a longer period would provide more robust conclusions. Sample size appears the minimum and the method of participant selection is nonrandom, it is convenience sampling. A small sample size or biased selection process could affect the generalizability and validity of the study's findings. Potential confounding factors that could influence the study outcomes are not rigorously considered. Factors such as socio-economic status, access to healthcare, and individual behaviors might have influenced the prevalence of malaria and treatment outcomes. Moreover, while the study documented no serious adverse events, comprehensive information on adverse events or their frequency was not obtainable. A more detailed analysis of adverse events would provide a better understanding of the safety profile of the treatment. The study did not utilize molecular analysis to confirm the absence of artemisinin-resistant P. falciparum strains. Molecular analysis is crucial for detecting resistance markers and assessing the potential spread of resistant strains. Financial limitations prevented the provision of fatty food alongside AL administration. This may have influenced the drug's bioavailability and potentially affected treatment outcomes, although there was no phenotypic treatment failure and microscopically, highlighting a limitation in the study design. Moreover, most malaria drug efficacy studies don not measure drug blood concentration, and do not use molecular methods to detect submicroscopic low level parasitemia. One of the key aspects in assessing the efficacy of a malaria drug is determining the concentration of the drug in the bloodstream. Measuring drug blood concentration helps to understand how much of the drug is present in the body, which can directly impact its effectiveness in eliminating the malaria parasite. Without measuring drug blood concentration, it becomes difficult to establish a clear relationship between drug dosage and treatment outcomes. Additionally, variations in drug metabolism or drug interactions may affect drug blood concentration, and without this measurement, it is challenging to determine the reasons behind treatment failures or successes accurately. Moreover, this study has its own specific limitations that should be considered. Firstly, there was a lack of measurement of Hb levels during the follow-up period, which made it impossible to determine the participants' anemia status and assess the potential impact of the treatment on this parameter. Additionally, the exclusion of seven participants during the follow-up period resulted in a reduction in the sample size, which is just the minimum threshold of 73 participants set by the WHO. This reduction in sample size may have affected the statistical power and generalizability of the study findings. These limitations underscore the need for improvements in adherence to the study protocol and the inclusion of a larger sample size from the outset. Addressing these issues in future studies will enhance the validity, reliability, and generalizability of findings in this area. Conclusion Notwithstanding the above limitations, this study found no evidence of artemisinin-resistant P. falciparum strains among the study population although recent studies detected the parasite’s partial mutation in the AL resistance genes. The administration of AL resulted in rapid clearance of parasitemia and a decline in fever, indicating that AL effectively clears parasites, prevents disease progression, and resolves symptoms quickly some 20 years after its introduction. AL also exhibits gametocidal activity, which interrupts the transmission cycle of malaria. Overall, the study demonstrated the high efficacy of AL in the study area during the study period and can serve as a valuable source of information for policy decision. Abbreviations ACPR: adequate clinical and parasitological response, ACTs: artemisinin combination therapies, AL: artemether-lumefantrine, ETF: early treatment failure, FMoH: Federal Ministry of Health, LCF: late clinical failure, LPF: late parasitological failure, LTFU: loss-to-follow-up, PV: protocol violation, WHO: World Health Organization Declarations Ethical approval and consent of participants The study received approval from the College of Natural and Computational Sciences Institutional Review Board at Addis Ababa University. The Ethical Review Committee of Ethiopian Public Health Institution, Ethiopia also approved the protocol. Informed consent was obtained from adult participants and assent of parental/guardians were collected for minors. Consent to Publication Not applicable. Availability of Data and Materials All data generated and analyzed in the study are included in this manuscript. Conflict of Interests The authors declare that there is no conflict of interest. Funding The study did not have a specific funding source. Authors' Contributions MT performed the field study and data entry, analyzed and interpreted the results, AA conceptualized the study supervised the field work and interpreted the results, HM supervised the field work, contributed to the interpretation of results and prepared the manuscript. All authors read and approved the final manuscript. Acknowledgments The authors would like to acknowledge Metehara health center officials for their administrative support, health workers for their technical support and the study participants for their kind participation. Author's Details 1 Department of Microbial, Cellular and Molecular Biology, College of Natural and Computational Sciences, Addis Ababa University, Addis Ababa, ET 2 Ethiopian Public Health Institute, Addis Ababa, ET References WHO 2023. World malaria report 2023. World Health Organization, Geneva, Switzerland. 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Tables Table 1. Mean or number (proportion) of baseline characteristics of the study participants at Metehara Health Centre, Central-east Ethiopia Variables Age Category 15 (n=39) Overall (n = 80) Age, years 3±1.2 9±2.24 30±11.9 18±14.6 Gender Male, no.(%) 8(53.3) 16(61.5) 26(66.7) 50(62.5) Female, no.(%) 7(46.7) 10(38.5) 13(33.3) 30(37.5) Body temp., ºC±SD 37.7±1.3 37.7±1.38 36.7±0.92 37.2±1.25 Bodyweight ±SD 10.9±3.08 23.1±6.72 55.4±9.75 36.8±19.9 Hb, g/dL±SD 8.6±2.18 9.88±2.01 11.6±1.42 10.5±2.14 Parasitemia per μl±SD 3754.62±4435.472 14278.08±27981.343 10679.03±18193.26 10,627±20,736.7 Gametocyte pos., no.(%) 1(7.7) 3(12.6) 2(5.8) 6(8.4) Bed net use, no.(%) Yes, no.(%) 5(33.3) 7(26.9) 19(48.7) 30(37.5) No, no.(%) 10(66.7) 19(73.1) 20(51.3) 50(62.5) Past malaria, no.(%) Yes, no.(%) 4(26.7) 9(34.6) 21(53.8) 34(42.5) No, no.(%) 11(73.3) 17(65.4) 18(46.2) 46(57.5) no.: number, %: per cent, ºC: degree Celsius, SD: standard deviation, g/dL: gram per deciliter Table 2. Treatment outcomes based on Per Protocol analysis among patients treated with artemether-lumefantrine at Metehara Health Centre, Central-east Ethiopia Description Frequency in each age (year) category 15 (n = 39) Overall ACPR 14(93.3%) 25(96.2%) 34(87.2%) 73(100) ETF 0(0) 0(0) 0(0) 0(0) LTF 0(0) 0(0) 0(0) 0(0) LPF 0(0) 0(0) 0(0) 0(0) LFU 0(0) 1(28.6%) 4(71.4%) 5(10.9%) PV 1 0 1 2 W 0(0) 0(0) 0(0) 0(0) ACPR - adequate clinical and parasitological response, ETF - early treatment failure, LTF - late treatment failure, LPF - late parasitological failure, LFU - loss-to-follow-up, PV - protocol violation, W - withdrawal Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 31 Mar, 2024 Reviews received at journal 27 Mar, 2024 Reviewers agreed at journal 05 Mar, 2024 Reviewers invited by journal 03 Mar, 2024 Editor assigned by journal 07 Feb, 2024 Submission checks completed at journal 07 Feb, 2024 First submitted to journal 07 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3936178","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":271755249,"identity":"19965d49-a986-4cdf-995d-09978b1b8b8e","order_by":0,"name":"Mahelet Tesfaye","email":"","orcid":"","institution":"Addis Ababa University","correspondingAuthor":false,"prefix":"","firstName":"Mahelet","middleName":"","lastName":"Tesfaye","suffix":""},{"id":271755250,"identity":"16e42efe-757e-41e0-9170-cb28114fc9fd","order_by":1,"name":"Ashenafi Assefa","email":"","orcid":"","institution":"Ethiopian Public Health Institute","correspondingAuthor":false,"prefix":"","firstName":"Ashenafi","middleName":"","lastName":"Assefa","suffix":""},{"id":271755251,"identity":"d9393e22-02ea-4406-91dc-c97f3c6f7199","order_by":2,"name":"Hassen Mamo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuElEQVRIiWNgGAWjYBACA2YILcfAwEOiFmMStEDpxAaitZiz8x7d8DPHJn3D8bMHH3xgsJPTbSCgxbKZL+1m77a03A1n8pINZzAkG5sdIOSwwzxmN3i3Hc7dcCDHTJqH4UDiNmK03Py77XC6wfk3JGi5DbQlweAGsbZYNgO1yG5LM5x5442x4QwDIvxizn/G7ObbbTbyfOdzDB98qLCTI6gFDhTAKg0IqEIB8g2kqB4Fo2AUjIIRBQDFKkKGFmgbCAAAAABJRU5ErkJggg==","orcid":"","institution":"Addis Ababa University","correspondingAuthor":true,"prefix":"","firstName":"Hassen","middleName":"","lastName":"Mamo","suffix":""}],"badges":[],"createdAt":"2024-02-07 08:14:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3936178/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3936178/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51020259,"identity":"81042a27-c3b5-4cf2-a27a-848b038de257","added_by":"auto","created_at":"2024-02-12 19:44:13","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":40877,"visible":true,"origin":"","legend":"\u003cp\u003eScreening, enrollment, follow-up and treatment outcomes of \u003cem\u003eP. falciparum\u003c/em\u003e malaria patients in Metehara Health Centre, Central-east Ethiopia [ACPR - adequate clinical and parasitological response, ETF - early treatment failure, LCF - late clinical failure, LPF - late parasitological failure, IPV - involuntary protocol violation, LTFU - loss-to-follow-up]\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3936178/v1/8249866cd978a4a687ef017b.png"},{"id":51020258,"identity":"21c005ee-d697-4ffd-860b-73afdf483b3b","added_by":"auto","created_at":"2024-02-12 19:44:13","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":66630,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival analysis of 28-day cure rate of \u003cem\u003eP. falciparum\u003c/em\u003e for artemether-lumefantrine, Metehara Health Centre, Central.east Ethiopia\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3936178/v1/eb05dfcebfab0a6c0034d521.png"},{"id":51021040,"identity":"a592c76e-67ab-47ef-9532-bcfa2fc0ceb6","added_by":"auto","created_at":"2024-02-12 19:52:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":419963,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3936178/v1/77bb14f9-e5e1-4ae1-a54c-cb26d2f1bfd3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Therapeutic efficacy of artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria treatment in Metehara, Central-east Ethiopia","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGlobally, there were approximately 249\u0026nbsp;million cases and 608,000 deaths due to malaria in 2022 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This is higher compared to the respective numbers 244\u0026nbsp;million and 610,000 in 2021 after the COVID-19 interruption. Socio-economic factors such as unemployment, low income, and inadequate housing construction act as barriers to effectively mitigating malaria [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Furthermore, land use, urbanization and climate change are contributing to an increased risk of malaria in sub-Saharan African countries. Urbanization leads to deforestation for various purposes, including accommodating the growing urban population, which in turn alters the distribution of vector species. These changes result in spatial and temporal variations in temperature, humidity, and precipitation, all of which impact the ecology and biology of the vectors and increase the risk of disease transmission [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCase management using artemisinin combination therapies (ACTs) is among the cornerstones of malaria control. ACTs are the recommended first-line treatment for the deadliest malaria parasite, \u003cem\u003ePlasmodium falciparum\u003c/em\u003e, and the most commonly used ACT is the combination of artemether-lumefantrine (AL) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, the emergence and rapid spread of drug-resistant parasite strains pose a continuous threat. Resistance to AL has been observed in Southeast Asia [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], and recent reports from Rwanda [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], Uganda [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], Ethiopia [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] and Eritrea [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] suggest a similar trend in sub-Saharan Africa.\u003c/p\u003e \u003cp\u003eTo combat drug resistance, surveillance systems have been established to monitor its spread and assess the effectiveness of antimalarial treatments. The efficacy of national first- and second-line anti-malarial treatments should be assessed at least once every two years, following the guidelines outlined in the WHO standard protocol for monitoring drug efficacy [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Regular malaria efficacy testing provides valuable data for updating and refining treatment guidelines. It helps determine which antimalarial drugs are most effective in specific regions and against certain strains of the malaria parasite. This information enables healthcare professionals to make informed decisions about which drugs to prescribe and helps ensure that patients receive the most appropriate and effective treatment.\u003c/p\u003e \u003cp\u003eEffective malaria control and elimination programs rely on accurate information about drug efficacy. Regular testing helps identify areas where drug resistance is prevalent, allowing public health authorities to develop targeted interventions. It also aids in evaluating the impact of interventions such as the introduction of new drugs or combination therapies. Monitoring drug efficacy is essential for the safety and well-being of individual patients. If a drug is no longer effective against malaria parasites in a particular region, using it as a treatment option can lead to treatment failure, prolonged illness, and increased morbidity and mortality. Regular efficacy testing helps ensure that patients receive the most appropriate and effective treatment, improving their chances of recovery. Understanding the efficacy of existing antimalarial drugs provides valuable insights for the development of new and more effective treatments. By tracking drug resistance patterns and evaluating the effectiveness of different drugs, potential targets for new antimalarial drugs and improve treatment options for malaria can be identified.\u003c/p\u003e \u003cp\u003e In summary, regular malaria drug efficacy testing is necessary for monitoring drug resistance, optimizing treatment guidelines, supporting public health strategies, ensuring patient safety, and facilitating the development of new antimalarial drugs. It plays a crucial role in combating malaria and improving the effectiveness of malaria control and elimination efforts.\u003c/p\u003e \u003cp\u003eIn alignment with the global effort, Ethiopia has been closely monitoring AL efficacy through nationwide sentinel sites since its introduction in 2004. This study serves as an extension of the national AL therapeutic efficacy studies conducted in one of the multiple sentinel sites located in central-east Ethiopia. The nation\u0026rsquo;s malaria strategic plan 2021\u0026ndash;2025, extended to 2030, is currently underway following a malaria program review in anticipation of malaria elimination in certain low transmission settings with a combination of the available malaria control tools [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy site\u003c/h2\u003e \u003cp\u003eMetehara is a town located in the Oromia Region of Ethiopia, situated about 200km southeast of the capital city, Addis Ababa. It is positioned along the main highway that connects Addis Ababa with the eastern parts of the country, making it an important transportation hub. Geographically, Metehara is situated in the Great Rift Valley, which is a geological trench that extends from the Middle East to Mozambique. The town is located between the eastern escarpment of the Rift Valley and the Awash River, which flows nearby. The surrounding landscape is characterized by vast plains, scattered hills, and volcanic formations. In terms of climate, Metehara experiences a semi-arid climate with hot and dry conditions. The town lies in a lowland region, resulting in high temperatures throughout the year. The average annual temperature ranges from 24 to 30\u003csup\u003eo\u003c/sup\u003eC. The hottest months are typically from March to May, with temperatures often exceeding 35\u003csup\u003eo\u003c/sup\u003eC. The coolest months are from November to February, with average temperatures of 18-24\u003csup\u003eo\u003c/sup\u003eC.\u003c/p\u003e \u003cp\u003eMetehara receives most of its rainfall during the wet season, which typically occurs from June to September. The average annual precipitation is around 600-800mm. The vegetation in and around Metehara is mainly characterized by savannah grasslands and scattered acacia trees. The Awash River and its surrounding areas support a diverse ecosystem with various bird species. Metehara is also known for its proximity to the Awash National Park, which is located about 50km east of the town. Overall, Metehara's location in the Great Rift Valley, coupled with its semi-arid climate and diverse wildlife, makes it an interesting and unique area in Ethiopia. Metehara town and its surrounding is recognized for its malaria transmission, which persists throughout the year but varies in intensity, as the town health record system show. The study was conducted between November 2020 and March 2021, aligning with the continuous transmission of malaria in the area.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy population and design\u003c/h2\u003e \u003cp\u003eThe study enrolled patients who visited the outpatient department of the Metehara Health Centre (MHC) and met the inclusion criteria established by the WHO for evaluating and monitoring the effectiveness of antimalarial drugs [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The inclusion criteria comprised presence of fever, age\u0026thinsp;\u0026ge;\u0026thinsp;6 months, mono-infection with \u003cem\u003eP. falciparum\u003c/em\u003e, ability to swallow an oral medication, and willingness to adhere to the study protocol. Exclusion criteria encompassed severe malaria, infection with mixed or non-falciparum plasmodium, severe malnutrition, other febrile conditions, acknowledged chronic or severe diseases, hypersensitivity to the study drugs, and pregnancy or breastfeeding.\u003c/p\u003e \u003cp\u003eThe sample size was determined following the above same WHO guidelines [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] for assessing therapeutic efficacy of antimalarial drugs, requiring a minimum of 73 patients to estimate the efficacy of the study drug. To accommodate for potential attrition and withdrawals, a total of 80 patients were selected from the population. The study employed a one-arm prospective evaluation design, in which patients receiving AL were followed for 28 consecutive days to evaluate treatment effectiveness and identify instances of therapeutic failure.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData collection and analysis\u003c/h2\u003e \u003cp\u003eData were gathered at the baseline and throughout the follow-up period. During the baseline, a physical examination was conducted, and sociodemographic data, medical history, and capillary blood samples were obtained. The follow-up visits consisted of regular check-ups, as well as clinical and laboratory examinations. The blood samples were utilized to create thick and thin blood films in order to detect, identify and measure parasitemia. Hemoglobin (Hb) and hematocrit levels were recorded at baseline only due to shortage of supplies. The data analysis encompassed double data entry, descriptive statistics, and the utilization of statistical tests such as independent t-tests to compare continuous variables.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eBaseline population\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 2,332 individuals (1,187 males and 1,145 females) suspected of having malaria visited MHC for malaria diagnosis between November 26, 2020 and March 24, 2021. Among them, 178(7.6%) tested positive for malaria. Out of these 178 positive cases, 102(57.3%) were initially identified as P. falciparum mono-infections, while 76(42.7%) were identified as P. vivax infections. Among the 102 individuals with P. falciparum infections, 89 were eligible for the study, but 9 refused to participate due to their mobile working arrangements. Therefore, at baseline (day 0) there were 80 patients, 50 males and 30 females.\u003c/p\u003e\n\u003cp\u003eThe mean age of the population was 17.7\u0026plusmn;14.24, with 15 under-five, 26 between 5-15 years and 39 over 15. The minimum age was 8 months and the maximum 65 years. While the overall mean bodyweight was 36.8\u0026plusmn;19.9kg, it was 10.9\u0026plusmn;3.08, 23.1\u0026plusmn;6.72, 55.4\u0026plusmn;9.75 for the \u0026lt;5, 5-15 and \u0026gt;15 age groups respectively. Twenty-nine (36.3%) participants reported a previous history of clinical malaria, and 38(47.5%) confirmed the availability of a bed net, but only 27(33.8%) reported using it regularly (Table 1).\u003c/p\u003e\n\u003cp\u003eAt the baseline, individuals with body temperature of \u0026ge;37.5\u0026deg;C were 29(36.3%) and the result had self-reported fever in the past 24-hour. The mean baseline body temperatures were 37.7\u0026plusmn;1.3 for the under-five, 37.7\u0026plusmn;1.34 for 5-15, and 35.8\u0026plusmn;5.9 for over 15 with overall mean of 36.8\u003csup\u003eo\u003c/sup\u003eC. The range of body temperature was 32.5-40.2\u0026deg;C, and 39(48.7%) patients complained of headache, 6(7.5) nausea and 2(2.5%) dizziness without sign of general danger or severe P. falciparum or complicated malaria.\u003c/p\u003e\n\u003cp\u003eThe mean baseline Hb was 8.3\u0026plusmn;2.16g/dL, 9.7\u0026plusmn;2.0g/dL and 11.4\u0026plusmn;1.5g/dL for the \u0026lt;5, 5-15 and \u0026gt;15 age groups respectively, and the overall mean Hb level was 10.41\u0026plusmn;2.1. During enrollment, 42(52.5%) patients were anemic (14(33.3%) severe (Hb\u0026lt;8 g/dL), 16(38.1%) moderate (Hb 8-10 g/dL), and 12(28.5%) mild (Hb 10 g/dL). Of these, 23(54.8%) were male and 19(45.2%) were female. The highest anemia (40.5%) recorded among 5-15 age group, 31.0% among \u0026lt;5-year and \u0026gt;15(28.5%).\u003c/p\u003e\n\u003cp\u003eThe total mean parasitemia at baseline was 10,627\u0026plusmn;20,736.7 asexual parasites/\u0026mu;l of blood. There were 41 severely parasitemic patients (\u0026ge;10,000 parasites/\u0026micro;l) and 39 moderately parasitemic patients (1000-9,999 parasites/\u0026micro;l). There was a significant variation in mean parasitemia between children below 5 years old (3,754.62\u0026plusmn;4,435.472 parasites/\u0026mu;l) and those between 5 and 15 years old (14,278.08\u0026plusmn;27,981.34 parasites/\u0026mu;l). Three patients had a parasitemia level exceeding 50,000 parasites/\u0026mu;l, maximum 98,235 parasites/\u0026mu;l. The gametocyte prevalence at baseline was 6.3% (5/80), with gametocyte numbers ranging from 80 to 5,320 sexual parasites/\u0026mu;l of blood.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProtocol violations including loss-to-follow-up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe baseline participant number was reduced to 79, 78, 77, 74, and 73, respectively, on days 1, 7, 14, 21, 28. Because there was one loss-to-follow-up (LTFU) on each of days 1, 7, 14, 21, and 28. Additionally, there were two cases of mixed infection with P. vivax\u0026nbsp;(involuntary protocol violations) on day 21, a 5-year girl and a 50-year man. All of the LTFU were males and their ages of those lost on days 1, 7, 14, 21 and 28 were 28, 32, 28, 10 and 29 years respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary Endpoint\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdequate clinical and parasitological response (ACPR) was recorded for the patients. The ACPR rate was 100% (Table 2), and Kaplan-Meier analyses indicated no early treatment failures (ETF), late treatment failures (LTF), or late parasitological failures (LPF) (Fig. 1, Fig. 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary Endpoint\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParasite and fever clearance\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt the baseline, 41(51.3%) of the study participants had a severe parasitic load (\u0026ge;10,000 asexual parasites/\u0026mu;l). Following AL administration, the parasite count decreased to 0 by day 2 and afterwards no asexual parasites were microscopically detected. Parasite clearance was achieved before day 3 and remained so until day 28. At enrollment (n=80), 29(36.3%) individuals had an axillary temperature of \u0026ge;37.5\u0026deg;C. This percentage decreased to 10.1% (8 out of 79) on day one, reached 0 on day two, and was at 1.3% (1 out of 79) on day three, considering the loss-to-follow-up (LTF) of one participant on day one.\u003c/p\u003e\n\u003cp\u003eThe overall findings of the study indicate that a standard six-dose treatment of AL achieved a 100% cure rate for uncomplicated P. falciparum malaria over a 28-day period, without polymerase chain reaction (PCR) correction. Fever and parasitemia were rapidly eliminated within the first three days of treatment, although there was one individual who experienced fever on day seven for reasons that remain unidentified.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGametocytemia clearance\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt the baseline, gametocytes were detected in 5 participants, representing a prevalence of 6.3%. Among these 5 individuals with gametocytes, 11.5% (3 out of 26) were aged 5-15 years, 5.1% (2 out of 39) were above 15 years, and 6.7% (1 out of 15) were below 5 years of age. The proportion of participants with gametocyte carriage declined from 6.3% on day 0 to 2.5% on days two, three, and day 7, with complete disappearance thereafter.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse Events\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt baseline, the patients reported common signs and symptoms typically associated with malaria, with the majority (48.9%) experiencing headaches. After the administration of AL treatment, possible signs and symptoms that could be attributed to the medication were noticed on days three and seven, with one report each. On day 14, two signs were reported, and on days 21 and 28, one sign each was reported. However, there were no signs of illness reported on days one and two. It is important to note that all of these signs and symptoms were not serious, and no participant was withdrawn from the study due to these reasons.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our retrospective assessment of the past four-year duration (2018\u0026ndash;2023), there was a continuous increase in malaria prevalence in the study area (data not shown). Although \u003cem\u003eP. falciparum\u003c/em\u003e accounted for the highest number of cases, among the two species observed, the number of \u003cem\u003eP. vivax\u003c/em\u003e is also sizable. This could be attributed to various factors such as resource constraints, ineffective preventive measures, and the development of insecticide resistance, highlighting the need for scale up of control interventions.\u003c/p\u003e \u003cp\u003eThe presence of parasitemia on day 3 is a key indicator for suspected artemisinin resistance [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, in this study, the baseline mean parasitemia was 10,627\u0026thinsp;\u0026plusmn;\u0026thinsp;20,736.7, which decreased to zero on day 3. Artemether, being a potent anti-malarial drug that is rapidly absorbed, leads to a rapid reduction in parasite biomass, prompt symptomatic improvement, and rapid elimination [15]. Consequently, the absence of ETF confirms the non-existence of artemisinin-resistant \u003cem\u003eP. falciparum\u003c/em\u003e strains among the study population although this may not be ruled out from the study areas as a whole. Similarly, the study did not observe LTF or LPF. The adjusted cure rate at day 28 was found to be 100% for children under five, as well as for the age groups of 5\u0026ndash;15 and over 15. High levels of parasitemia in the bloodstream can contribute to severe fever. Fever is a response by the body's immune system to fight off the infection and also indicates high replication and development of the parasite [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough high fever and parasitemia were recorded at enrollment, the administration of the drug resulted in the elimination of parasitemia by day 2 and a decline in fever to the normal range by day 1. This demonstrates that AL rapidly clears parasites, prevents disease progression, resolves symptoms quickly, and reduces the risk of complicated malaria. AL primarily targets the asexual stage of the malaria parasite to decrease and clear it, but it also exhibits gametocidal activity, which interrupts the transmission cycle between the mosquito vector and the human host. A study using membrane-feeding Anopheles mosquitoes demonstrated a reduction in malaria transmission following the six-dose regimen of AL [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The authors reported that gametocyte clearance was observed by day 2, with one case persisting until day 3 and completely disappearing by day 7 and onwards. Similarly, in the current study, gametocyte carriage at day 0 decreased over and disappeared after day 7.\u003c/p\u003e \u003cp\u003eSimilar high efficacy findings have been reported in other parts of Ethiopia and sub-Saharan Africa [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. A meta-analysis of anti-malarial treatment outcomes in Ethiopia, based on 21 publications, reported an average efficacy of 98.1% [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e19\u003c/span\u003e], which is almost consistent with the findings of the present study. In contrast to results from Southeast Asian nations where delayed fever clearance was observed with AL, the rapid fever-resolving ability of AL has been consistently observed in efficacy tests conducted in Ethiopia.\u003c/p\u003e \u003cp\u003eMalaria can cause anemia, which is characterized by a decrease in Hb levels. However, the effect of different malaria treatments on Hb levels can vary. Some studies have shown that certain antimalarial treatments can lead to an improvement in Hb levels. For example, effective treatment of malaria with antimalarial drugs can help clear the infection, allowing the body to recover and restore Hb levels [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This improvement in Hb levels is often seen in individuals who receive prompt and appropriate treatment. On the other hand, there have been reports of antimalarial drugs causing a decrease in Hb levels or exacerbating anemia in some individuals [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. For example, certain medications, such as primaquine, used for the treatment of \u003cem\u003eP. vivax\u003c/em\u003e malaria and nowadays against \u003cem\u003eP. falciparum\u003c/em\u003e gametocytes, may cause hemolysis, leading to a drop in Hb levels [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNo serious adverse events were noted, and the majority of the reported reactions were already recognized by the manufacturer as common adverse reactions and documented with the Food and Drug Administration. These reactions included joint discomfort, weakness, headache, cough, anorexia, and stomach ache. Once the parasites were cleared, these minor symptoms quickly resolved except one or incidents around the end of the study whose causes could not be established. The results of other studies in Ethiopia [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e27\u003c/span\u003e] align with the absence of major adverse events following AL treatment in the current investigation.\u003c/p\u003e \u003cp\u003eNevertheless, this study has certain limitations. In fact, these limitations are limitations of most other similar malaria drug efficacy studies. The study focuses on a specific study area, and the findings may not be representative of the entire region or other geographical locations. The prevalence of malaria and the effectiveness of treatment may vary in different settings. The study's duration is days 28 days. Assessing the sustainability of the observed trends and treatment efficacy over a longer period would provide more robust conclusions. Sample size appears the minimum and the method of participant selection is nonrandom, it is convenience sampling. A small sample size or biased selection process could affect the generalizability and validity of the study's findings. Potential confounding factors that could influence the study outcomes are not rigorously considered. Factors such as socio-economic status, access to healthcare, and individual behaviors might have influenced the prevalence of malaria and treatment outcomes.\u003c/p\u003e \u003cp\u003eMoreover, while the study documented no serious adverse events, comprehensive information on adverse events or their frequency was not obtainable. A more detailed analysis of adverse events would provide a better understanding of the safety profile of the treatment. The study did not utilize molecular analysis to confirm the absence of artemisinin-resistant \u003cem\u003eP. falciparum\u003c/em\u003e strains. Molecular analysis is crucial for detecting resistance markers and assessing the potential spread of resistant strains.\u003c/p\u003e \u003cp\u003eFinancial limitations prevented the provision of fatty food alongside AL administration. This may have influenced the drug's bioavailability and potentially affected treatment outcomes, although there was no phenotypic treatment failure and microscopically, highlighting a limitation in the study design.\u003c/p\u003e \u003cp\u003eMoreover, most malaria drug efficacy studies don not measure drug blood concentration, and do not use molecular methods to detect submicroscopic low level parasitemia. One of the key aspects in assessing the efficacy of a malaria drug is determining the concentration of the drug in the bloodstream. Measuring drug blood concentration helps to understand how much of the drug is present in the body, which can directly impact its effectiveness in eliminating the malaria parasite. Without measuring drug blood concentration, it becomes difficult to establish a clear relationship between drug dosage and treatment outcomes. Additionally, variations in drug metabolism or drug interactions may affect drug blood concentration, and without this measurement, it is challenging to determine the reasons behind treatment failures or successes accurately.\u003c/p\u003e \u003cp\u003eMoreover, this study has its own specific limitations that should be considered. Firstly, there was a lack of measurement of Hb levels during the follow-up period, which made it impossible to determine the participants' anemia status and assess the potential impact of the treatment on this parameter. Additionally, the exclusion of seven participants during the follow-up period resulted in a reduction in the sample size, which is just the minimum threshold of 73 participants set by the WHO. This reduction in sample size may have affected the statistical power and generalizability of the study findings.\u003c/p\u003e \u003cp\u003eThese limitations underscore the need for improvements in adherence to the study protocol and the inclusion of a larger sample size from the outset. Addressing these issues in future studies will enhance the validity, reliability, and generalizability of findings in this area.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eNotwithstanding the above limitations, this study found no evidence of artemisinin-resistant \u003cem\u003eP. falciparum\u003c/em\u003e strains among the study population although recent studies detected the parasite\u0026rsquo;s partial mutation in the AL resistance genes. The administration of AL resulted in rapid clearance of parasitemia and a decline in fever, indicating that AL effectively clears parasites, prevents disease progression, and resolves symptoms quickly some 20 years after its introduction. AL also exhibits gametocidal activity, which interrupts the transmission cycle of malaria. Overall, the study demonstrated the high efficacy of AL in the study area during the study period and can serve as a valuable source of information for policy decision.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACPR: \u0026nbsp;adequate clinical and parasitological response, ACTs: artemisinin combination therapies, AL: artemether-lumefantrine, ETF: early treatment failure, FMoH: Federal Ministry of Health, LCF: late clinical failure, LPF: late parasitological failure, LTFU: loss-to-follow-up, PV: protocol violation, WHO: World Health Organization\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;and consent of participants\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study received approval from the College of Natural and Computational Sciences Institutional Review Board at Addis Ababa University. The Ethical Review Committee of Ethiopian Public Health Institution, Ethiopia also approved the protocol. Informed consent was obtained from adult participants and assent of parental/guardians were collected for minors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated and analyzed in the study are included in this manuscript.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that there is no conflict of interest.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study did not have a specific funding source.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMT performed the field study and data entry, analyzed and interpreted the results, AA conceptualized the study supervised the field work and interpreted the results, HM supervised the field work, contributed to the interpretation of results and prepared the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to acknowledge Metehara health center officials for their administrative support, health workers for their technical support and the study participants for their kind participation.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026apos;s Details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment\u003csup\u003e\u0026nbsp;\u003c/sup\u003eof Microbial, Cellular and Molecular Biology, College of Natural and Computational Sciences, Addis Ababa University, Addis Ababa, ET \u003csup\u003e2\u003c/sup\u003eEthiopian Public Health Institute, Addis Ababa, ET\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWHO 2023. World malaria report 2023. 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Nat Med 26:1602-1608. \u003c/li\u003e\n\u003cli\u003eConrad MD, Asua V, Garg S, Giesbrecht D, Niar\u0026eacute; K, Smith S, Namuganga JF, Katairo T, Legac J, Crudale RM, Tumwebaze PK, Nsobya SL, Cooper RA, Kamya MR, Dorsey G, Bailey JA, Rosenthal PJ 2023. Evolution of partial resistance to artemisinins in malaria parasites in Uganda. N Engl J Med 389:722-732.\u003c/li\u003e\n\u003cli\u003eFeleke SM, Reichert EN, Aydemir O, Mohammed H, Brhane BG, Mamo H, Petros B, Solomon H, Abate E, Hennelly C, Denton M, Meshnick SR, Juliano JJ, Bailey JA, Cunningham J, Parr JB 2021. Plasmodium falciparum is evolving to escape malaria rapid diagnostic tests in Ethiopia. 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Malar J 13:358. \u003c/li\u003e\n\u003cli\u003eDe Nardo P, Oliva A, Giancola ML, Ghirga P, Mencarini P, Bibas M, Nicastri E, Antinori A, Corpolongo A 2013. Haemolytic anaemia after oral artemether-lumefantrine treatment in a patient affected by severe imported falciparum malaria. Infect 41:863-865.\u003c/li\u003e\n\u003cli\u003eCorpolongo A, De Nardo P, Ghirga P, Gentilotti E, Bellagamba R, Tommasi C, Paglia MG, Nicastri E, Narciso P 2012. Haemolytic anaemia in an HIV-infected patient with severe falciparum malaria after treatment with oral artemether-lumefantrine. Malar J 11:91.\u003c/li\u003e\n\u003cli\u003eTylor WRJ, Kheng S, Muth S, Tor P, Kim S, Bjorge S, Topps N, Kosal K, Sotheal KSouy P, Char MP, Vanna C, Ly P, Khieu V, Christophel E, Kerlengue A, Pantaleo A, Mukaka M, Menard D, Baird KJ 2019. Hemolytic dynamics of weekly primaquine antirelapse therapy among Cambodians with acute \u003cem\u003ePlasmodium vivax\u003c/em\u003e malaria with or without glucose-6-phosphate dehydrogenase deficiency. J Infect Dis 220(11):1750-1760. \u003c/li\u003e\n\u003cli\u003eWhite NJ 2002. The assessment of antimalarial drug efficacy. Tren Parasitol 18(10):458-464. \u003c/li\u003e\n\u003cli\u003eNega D, Assefa A, Mohamed H, Solomon H, Woyessa A, Assefa Y, Kebede A, Kassa M, Therapeutic efficacy of artemether-lumefantrine (coartem\u0026reg;) in treating uncomplicated \u003cem\u003eP. falciparum \u003c/em\u003emalaria in Metehara, eastern Ethiopia: Regulatory clinical study. PLoS One 11(4): e0154618.\u003c/li\u003e\n\u003cli\u003eTeklemariam M, Assefa A, Kassa M, Mohammed H, Mamo H 2017. Therapeutic efficacy of artemether-lumefantrine against uncomplicated \u003cem\u003eP. falciparum\u003c/em\u003e malaria in a high-transmission area in northwest Ethiopia. PLoS One 12(4):e0176004.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Mean or number (proportion) of baseline characteristics of the study participants at Metehara Health Centre, Central-east Ethiopia\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge Category\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u0026lt;5 (n= 15) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;5-15 (n=26) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026gt;15 \u0026nbsp;(n=39) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Overall (n = 80)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.742268041237114%\" valign=\"top\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e3\u0026plusmn;1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e9\u0026plusmn;2.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003e30\u0026plusmn;11.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e18\u0026plusmn;14.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.742268041237114%\" valign=\"top\"\u003e\n \u003cp\u003eGender\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.742268041237114%\" valign=\"top\"\u003e\n \u003cp\u003eMale, no.(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e8(53.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e16(61.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003e26(66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e50(62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.742268041237114%\" valign=\"top\"\u003e\n \u003cp\u003eFemale, no.(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e7(46.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e10(38.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003e13(33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e30(37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.742268041237114%\" valign=\"top\"\u003e\n \u003cp\u003eBody temp., \u0026ordm;C\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e37.7\u0026plusmn;1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e37.7\u0026plusmn;1.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003e36.7\u0026plusmn;0.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e37.2\u0026plusmn;1.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.742268041237114%\" valign=\"top\"\u003e\n \u003cp\u003eBodyweight \u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e10.9\u0026plusmn;3.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e23.1\u0026plusmn;6.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003e55.4\u0026plusmn;9.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e36.8\u0026plusmn;19.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.742268041237114%\" valign=\"top\"\u003e\n \u003cp\u003eHb, g/dL\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e8.6\u0026plusmn;2.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e9.88\u0026plusmn;2.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003e11.6\u0026plusmn;1.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e10.5\u0026plusmn;2.14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.742268041237114%\" valign=\"top\"\u003e\n \u003cp\u003eParasitemia per \u0026mu;l\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e3754.62\u0026plusmn;4435.472\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e14278.08\u0026plusmn;27981.343\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003e10679.03\u0026plusmn;18193.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e10,627\u0026plusmn;20,736.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.742268041237114%\" valign=\"top\"\u003e\n \u003cp\u003eGametocyte pos., no.(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e1(7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e3(12.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003e2(5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e6(8.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.742268041237114%\" valign=\"top\"\u003e\n \u003cp\u003eBed net use, no.(%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.742268041237114%\" valign=\"top\"\u003e\n \u003cp\u003eYes, no.(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e5(33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e7(26.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003e19(48.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e30(37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.742268041237114%\" valign=\"top\"\u003e\n \u003cp\u003eNo, no.(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e10(66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e19(73.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003e20(51.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e50(62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.742268041237114%\" valign=\"top\"\u003e\n \u003cp\u003ePast malaria, no.(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.742268041237114%\" valign=\"top\"\u003e\n \u003cp\u003eYes, no.(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e4(26.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e9(34.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003e21(53.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e34(42.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.742268041237114%\" valign=\"top\"\u003e\n \u003cp\u003eNo, no.(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e11(73.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e17(65.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003e18(46.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e46(57.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eno.: number, %: per cent, \u0026ordm;C: degree Celsius, SD: standard deviation, g/dL: gram per deciliter\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Treatment outcomes based on Per Protocol analysis among patients treated with artemether-lumefantrine at Metehara Health Centre, Central-east Ethiopia\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.35353535353536%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDescription\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"64.64646464646465%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFrequency in each age (year) category\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.4375%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;5 (n = 15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e5-15 (n = 26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.4375%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026gt;15 (n = 39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.125%\" valign=\"top\"\u003e\n \u003cp\u003eOverall\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.35353535353536%\" valign=\"top\"\u003e\n \u003cp\u003eACPR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003e14(93.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.161616161616163%\" valign=\"top\"\u003e\n \u003cp\u003e25(96.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003e34(87.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.181818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;73(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.35353535353536%\" valign=\"top\"\u003e\n \u003cp\u003eETF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.161616161616163%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.181818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.35353535353536%\" valign=\"top\"\u003e\n \u003cp\u003eLTF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.161616161616163%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.181818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.35353535353536%\" valign=\"top\"\u003e\n \u003cp\u003eLPF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.161616161616163%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.181818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.35353535353536%\" valign=\"top\"\u003e\n \u003cp\u003eLFU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.161616161616163%\" valign=\"top\"\u003e\n \u003cp\u003e1(28.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003e4(71.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.181818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e5(10.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.35353535353536%\" valign=\"top\"\u003e\n \u003cp\u003ePV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.161616161616163%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.181818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.35353535353536%\" valign=\"top\"\u003e\n \u003cp\u003eW\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.161616161616163%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.181818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eACPR - adequate clinical and parasitological response, ETF - early treatment failure, LTF - late treatment failure, LPF - late parasitological failure, LFU - loss-to-follow-up, PV - protocol violation, W - withdrawal\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"malaria-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"malj","sideBox":"Learn more about [Malaria Journal](http://malariajournal.biomedcentral.com/)","snPcode":"12936","submissionUrl":"https://submission.nature.com/new-submission/12936/3","title":"Malaria Journal","twitterHandle":"@malariajournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Plasmodium falciparum, therapeutic efficacy, artemether-lumefantrine, Metehara","lastPublishedDoi":"10.21203/rs.3.rs-3936178/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3936178/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMalaria drug resistance presents a significant challenge to malaria control and elimination efforts. Therefore, it is crucial to conduct regular surveillance to assess the therapeutic efficacy of first-line antimalarial drugs, which informs policy decisions to manage this threat. This study aimed to evaluate the therapeutic efficacy of artemether-lumefantrine (AL), which is the first-line treatment for uncomplicated malaria in Ethiopia since 2004, for uncomplicated \u003cem\u003ePlasmodium falciparum\u003c/em\u003e malaria in Metehara, central-east Ethiopia. Using a one-arm prospective evaluation design, the study assessed the clinical and parasitological responses of patients with uncomplicated \u003cem\u003eP. falciparum\u003c/em\u003e malaria. Initially, 80 patients (50 males and 30 females) were screened, and a total of 73 participants (44 males, 29 females) successfully completed the follow-up. The results indicated rapid parasite clearance and resolution of clinical symptoms, with all patients achieving complete recovery from asexual parasitemia and fever by day 3. The prevalence of gametocytes decreased from 6.3% on day zero to 2.5% on days two, three, seven, and ultimately achieving complete clearance afterwards. The overall cure rate for AL treatment, without a polymerase chain reaction correction, was 100%, demonstrating its high efficacy in effectively eliminating the malaria parasite in patients. Importantly, no serious adverse events related to AL treatment were reported during the study, suggesting its safety and tolerability among the participants. These findings confirm that, even 20 years after its introduction in Ethiopia, AL remains an effective treatment for uncomplicated \u003cem\u003eP. falciparum\u003c/em\u003e malaria in the study site.\u003c/p\u003e","manuscriptTitle":"Therapeutic efficacy of artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria treatment in Metehara, Central-east Ethiopia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-12 19:44:08","doi":"10.21203/rs.3.rs-3936178/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-04-01T03:52:03+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-27T06:52:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"37f5d349-70f6-4a16-8530-88e4af894ff5","date":"2024-03-05T10:03:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-03T09:43:41+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-08T04:43:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-02-08T04:43:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Malaria Journal","date":"2024-02-07T08:02:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"malaria-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"malj","sideBox":"Learn more about [Malaria Journal](http://malariajournal.biomedcentral.com/)","snPcode":"12936","submissionUrl":"https://submission.nature.com/new-submission/12936/3","title":"Malaria Journal","twitterHandle":"@malariajournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"261a56fa-70d1-47ff-b9c6-389e642c1cc9","owner":[],"postedDate":"February 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-05-14T06:52:01+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-12 19:44:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3936178","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3936178","identity":"rs-3936178","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}