Abstract
Background
Artemether–lumefantrine (AL) is currently the first-line treatment for uncomplicated Plasmodium falciparum malaria in Liberia. To ensure antimalarial treatments are effective, the World Health Organization (WHO) recommends routinely testing the efficacy of oral artemisinin-based combination therapy (ACT) for uncomplicated malaria using therapeutic efficacy studies (TES) every two years. The most recent TES in Liberia conducted from December 2017 to May 2018 reported a PCR-corrected adequate clinical and parasitological response (ACPR) of 90.2% in Bensonville and 92.7% in Saclepea for artesunate–amodiaquine (ASAQ), and 100% in Kakata and Sinje for AL. Due to these findings AL was prioritized over ASAQ as the first-line ACT in Liberia. However, ASAQ is commonly available in Liberia and remains highly efficacious in other West African countries.
Methods
The therapeutic efficacy of AL and ASAQ were evaluated using the standard WHO TES protocol in Saclepea and Sinje, Liberia, from August 2022 to July 2023. Eligible children aged 6 – 59 months with uncomplicated P. falciparum malaria infection (2,000—200,000 asexual parasites/μL) were recruited, treated with AL or ASAQ at each site, and monitored clinically and parasitologically for 28 days.
Results
A total of 1,630 children were screened for eligibility and 305 were enrolled. Among enrolled children, 152 were treated with AL (78 in Sacleapea and 74 in Sinje) and 153 were treated with ASAQ (77 in Sacleapea and 76 in Sinje). Of the enrolled children, 299 (98%) reached a study endpoint or completed the 28 days of follow up. No adverse events were reported for either AL or ASAQ during the study period. The proportion of participants with parasitaemia on day 3 of follow up was 1.3% (2/153) for ASAQ, and 0% (0/151) treated with AL. The PCR-corrected ACPR at day 28 was 100% in Saclepea and 95.9% (95CI 88.0%-98.7%) in Sinje for AL, and 100% in Saclepea and 94.4% (95CI 85.9%-97.9%) in Sinje for ASAQ.
Conclusion
The PCR-corrected ACPR efficacy greater than the 90% WHO threshold, and day 3 slide positivity rate demonstrate that AL and ASAQ are both effective treatments for uncomplicated malaria in Liberia.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12936-025-05576-3.
Background
In 2023, there were an estimated 263 million cases of malaria in 85 malaria endemic countries, an increase by 11 million cases from 2022, of which the World Health Organization (WHO) Africa Region accounted for 94% of cases globally [1]. Malaria control relies on the scale-up of interventions such as long-lasting insecticidal nets (LLIN), indoor residual spraying (IRS), and effective case management including accurate malaria rapid diagnostic tests (RDT) and effective oral artemisinin-based combination therapy (ACT) for uncomplicated malaria [2]. ACT combines a potent short half-life artemisinin derivative with a long half-life partner drug and include artemether–lumefantrine (AL), artesunate–amodiaquine (ASAQ), artesunate–mefloquine (ASMQ), dihydroartemisinin–piperaquine (DP), artesunate–sulfadoxine/pyrimethamine (ASSP) and artesunate–pyronaridine (ASPY) for the treatment of uncomplicated Plasmodium falciparum malaria [2]. AL is the most used ACT in Africa and makes up approximately 85% of all procured artemisinin-based combinations [3].
There are numerous biological threats to malaria control and elimination [4]. Antimalarial drug resistance has implications for the effectiveness of case management in both preventing deaths and reducing the infectious reservoir [5]. To characterize and mitigate the risks associated with antimalarial drug resistance, the WHO recommends monitoring of antimalarial drug efficacy and resistance in endemic countries using a standardized therapeutic efficacy study (TES) protocol at least every 2 years [6]. These TES are prospective evaluations of the expected adequate clinical and parasitological responses (ACPR) to treatment of uncomplicated malaria and are the gold standard for generating evidence for national treatment guidelines.
Artemisinin partial resistance has been confirmed in four countries in East Africa [7–13]. While AL is the most commonly used ACT in Africa, ASAQ is commonly used in West and Central Africa and thus evaluated more often in TES resulting in more efficacy data, compared to AL which has been nearly exclusively used in the Eastern and Southern Africa region [6]. In general, AL and ASAQ remain highly effective in West Africa [14–17], though there is increasing concern that AL efficacy is waning in East, Central and some countries in West Africa[18]. Given ASAQ remains highly efficacious in East Africa, [6, 19] with some data suggesting transitions from AL to ASAQ for first line ACT in Tanzania [20]. Data from TES in these different regions are also key to the implementation of a new strategy to respond to antimalarial drug resistance of using multiple first line therapies (MFT), where artemisinin-based combinations are rotated or stratified to specific populations or geographic regions [3].
While TES offer valuable insights to inform existing and novel strategies, inconsistencies in implementation across countries and even across TES within countries can impact comparability of findings. Careful determination of whether parasite detection is due to recrudescence (prior infection) or reinfection (new infection) after treatment is critical [21].
In Liberia, malaria transmission is perennial with an estimated 614,000 cases and 3,541 deaths in 2023 [1]. Per the most recent Malaria Indicator Survey (MIS) conducted in 2022, approximately 10% and 18% of children aged 6–59 months were found to be positive for malaria by microscopy and RDT, respectively [22]. This MIS suggested subnational heterogeneity in malaria infections, with 13.3% of children positive by microscopy and 22.2% by RDT in the North Central Region, and 11.5% of children positive by microscopy and 19.5% by RDT in the North Western Region [22]. In 2008–2009, both AL and ASAQ had a PCR-corrected ACPR above 97% [23]. However, the most recent TES conducted from December 2017 to May 2018 demonstrated a decline in ASAQ efficacy, with a PCR-corrected ACPR of 90.2% (95% CI 78.6–96.7%) in Bensonville and 92.7% (95% CI 83.4.8–96.5%) in Saclepea [24]. In contrast, the same TES found that AL remained highly effective, with an ACPR of 100% in both Kakata and Sinje [24], even as other neighbouring countries in West Africa continue to report high efficacy of both AL and ASAQ [14–17, 25]. This finding prompted the Liberian Ministry of Health (MOH) National Malaria Control Programme (NMCP) to prioritize AL as the first-line drug of choice rather than ASAQ [14–17, 25, 26]. To provide updated evidence for national malaria policy the clinical and parasitological efficacy of AL and ASAQ were evaluated as per WHO recommendations [21].
Methods
Study sites and study design
Study participants were recruited from two health facilities in different geographic locations: Saclepea Comprehensive Health Center, Saclepea District, Nimba County; and Sinje Health Center, Garwula District, Grand Cape Mount County (Fig. 1), both of which were included in the 2017–2018 TES. The present study adopted an open-label, parallel-arm design which alternated treatment with either AL or ASAQ for enrolled participants at each site. Enrolled participants were then monitored clinically and parasitologically for 28 days according to the standard 2009 WHO TES protocol [21]. To calculate the necessary sample size, the treatment failure rate was assumed to be 5% for both ASAQ and AL. A minimum of 73 patients per drug per site with a valid endpoint were needed to achieve a precision of 5% around the point estimate with a confidence level of 95%. To allow for 20% loss to follow-up or withdrawal, the study targeted 88 participants per arm per site, for a total of 176 patients per health facility, and 352 children overall.
Fig. 1.
Map of Liberia showing Therapeutic Efficacy Study site locations and drugs tested. AL: Artemether lumefantrine; ASAQ: Artesunate amodiaquine
Recruitment, treatment, and follow-up
Children who presented to the study sites between August 2022 and July 2023 were screened for the following inclusion criteria; age 6 to 59 months, weight > 5 kg, axillary temperature ≥ 37.5 °C and/or history of reported fever in the past 24 h, haemoglobin (Hb) ≥ 8 g/dL (Hemocue AB, Ängelholm, Sweden), with uncomplicated malaria mono-infection (2000–200,000 asexual parasites/μL) diagnosed by thick and thin blood smear microscopy. Other required inclusion criteria included living within the catchment area during the study, ability to take oral medications, willingness to comply with the required follow-up visits, and informed consent of the parents or guardians. Exclusion criteria included the presence of general danger signs or signs of severe falciparum malaria, mixed or mono-infection with non-falciparum species, severe malnutrition (weight for age < 3 SD), AL or ASAQ hypersensitivity, any treatment with antimalarials or antibiotics with antimalarial activity in the past two weeks, other concomitant infection, a plan to travel or leave the study area in the next three months, and febrile conditions due to co-infections at the time of presentation. Patients excluded from the study received appropriate care and treatment according to Liberian MOH national guidelines.
AL was given twice daily for three days according to the recommended dosing schedule (0, 8, 24, 36, 48, and 60 h) and weight bands: one tablet for those weighing 5–14 kg and two tablets for 15–24 kg. Children treated with ASAQ received treatment for 3 days according to the recommended dosing schedule (0, 24, and 48 h) and weight bands: one tablet of 25 mg artesunate + 67.5 mg amodiaquine for 4.5 to < 9 kg body weight, one tablet of 50 mg artesunate + 135 mg amodiaquine for 9 to < 18 kg body weight, and one tablet of 100 mg artesunate + 270 mg amodiaquine for 18 to < 36 kg body weight. The artesunate dose target was 4 mg/kg (range 2–10 mg/kg) + amodiaquine 10 mg/kg (range 7.5–15 mg/kg) body weight once daily for three days. All morning doses of AL or ASAQ were administered under direct observation by the study staff, and patients were observed for 60 min post-administration. AL was given at the facilities with milk or fatty meal, and upon leaving, participants were given three packages of biscuits and told to take evening doses with biscuits, a fatty meal, or milk at home. Evening doses of AL were not directly observed. Full doses were readministered to children who vomited within 30 min and half doses were administered to children who vomited between 31 and 60 min of administration. If vomiting recurred, the patient was given an artesunate injection according to national guidelines and the patient was withdrawn from the study. Patients with treatment failure were treated with quinine 10 mg/kg three times a day for seven days per MOH treatment guidelines. Prequalified ASAQ (manufactured by Sanofi with batch number 20E009), and AL (manufactured by Novartis with batch number KAY04) were obtained from the Liberia MOH NMCP. Study children were followed for up to 28 days at scheduled visits on days 0, 1, 2, 3, 7, 14, 21, and 28, and at any unscheduled sick visit where symptoms worsened or recurred. The allowable time window for the weekly follow-up was ± 1 day. A clinical history, physical exam, and parasitological examination by blood smear microscopy (except day 1) were performed at each visit. Community Health Volunteers (CHVs) in the study areas were engaged and trained to trace patients if they did not show up for the scheduled appointments.
Laboratory investigation
Thick and thin blood smears collected on the day of recruitment (day 0) and follow-up days were stained with Giemsa and asexual parasites were counted against the number of white blood cells (WBC) in the thick blood smear using the WHO procedure [2]. Assuming a WBC count of 6000 WBCs/μL, parasite density (asexual parasites per μL of blood) was calculated by dividing the number of asexual parasites by the number of WBCs and then multiplying by 6000 WBCs/μL. Two microscopists independently read all thick and thin blood smears. During onsite supervision visits, a third expert microscopist re-examined the blood smears with discordant results (species diagnosis, parasite density of > 50%, or presence of parasites), and a subset of randomly selected blood smears (> 10% of smears prepared since the last visit) to verify results. The final parasite density was calculated by taking the average of the two closest counts. Per the WHO protocol, a blood smear was declared negative if no asexual parasites were observed after examination of 1,000 WBCs. Dried blood spots were collected on Whatman 903 filter paper from each patient at all visits, stored at room temperature in sealed individual plastic bags with desiccant and protected from light, moisture, and extreme temperature for future molecular analysis. Recrudescence versus re-infection was determined using capillary electrophoresis fragment analysis of polymorphic genes msp1, msp2, and poly-A, and both the “3/3”, also known as the 2007/2008 WHO algorithm, and the “2/3” algorithm were used comparing samples at day 0 and day of failure [27].
Outcomes measures
Antimalarial drug efficacy was assessed by standardized, predefined clinical and parasitological outcomes; early treatment failure (ETF), late treatment failure (LTF), which included late clinical failure (LCF), and late parasitological failure (LPF), and adequate clinical and parasitological response (ACPR) (Supplement Table S1) [21]. The primary outcome for each arm was the proportion of all patients followed up to 28 days that were classified as having an PCR-corrected ACPR. Follow-up was complete when a participant met one of the four classification criteria (Supplement Table S1), withdrew from the study, or was lost to follow up. The secondary outcome of interest was day 3 blood smear positivity. The per-protocol analysis was performed excluding patients who discontinued treatment, withdrawn, or had new infections during follow-up. Kaplan–Meier survival analysis was used to calculate the cumulative risk of treatment failure over time, where all LTF were assumed to be recrudescent infections, and the data for those lost to follow-up or excluded during the study were included with right-censoring. PCR correction was performed on paired day 0 and day of failure samples that met quality control standards at the CDC Malaria Laboratory in Atlanta, Georgia. All analyses were conducted in R Studio version 2023.12.1.
Ethical considerations
Ethical approval for the study protocol was obtained from the University of Liberia Pacific Institute for Research and Evaluation (UL-PIRE) Institutional Review Board (IRB) and was determined as a non-research activity within the U.S. Centers for Disease Control and Prevention (CDC) (0900f3eb81e634a9). The study was registered on the US NIH Clinical Trials website (ClinicalTrials.gov ID NCT06300970) [28]. Parents/guardians were informed of the study procedure, its benefits, and potential risks, and provided written informed consent for their children to participate in the study prior to enrollment (see Table 1).
Table 1.
Study inclusion and exclusion criteria
| Inclusion criteria | Exclusion criteria |
|---|---|
| 1. Age 6–59 months of age |
1. Presence of severe malaria or danger signs, including prostration, alteration in level of consciousness, respiratory distress, convulsions, or jaundice |
| 2. Weight > 5.0 kg |
2. Severe malnutrition according to WHO child growth standards (weight for age < 3 standard deviations) |
| 3. Axillary temp ≥ 37.5°C or history of fever in the past 24 h | 3. Known hypersensitivity to AL or ASAQ |
| 4. Hemoglobin ≥ 8 g/deciliter at enrolment |
4. Use of antimalarials or other drugs with antimalarial activity in the last 2 weeks |
|
5. Slide-confirmed mono-infection with Plasmodium falciparum and asexual parasitemia between 2,000 and 200,000 parasites/μL |
5. General clinical condition necessitates hospitalization |
|
6. Live within the catchment area of the study site (10 km radius) |
6. Evidence of concomitant infections at the time of presentation |
| 7. Able to swallow oral medication | 7. Plan to travel or leave the area within the next 3 months |
|
8. Able and willing to comply with the protocol for the duration of the study |
8. Previously enrolled in this study |
|
9. Able and willing to comply with the study visit schedule on days 2, 3, 7, 14, 21, and 28 |
|
| 10. Written informed consent provided by parent or guardian |
AL: Artemether lumefantrine; ASAQ: Artesunate amodiaquine
Results
A total of 1630 children were screened for eligibility and 305 were enrolled. Among enrolled children, 152 were treated with AL (78 in Sacleapea and 74 in Sinje) and 153 were treated with ASAQ (77 in Sacleapea and 76 in Sinje) (Fig. 2). Screening, enrollment, and participant characteristics at baseline are described in Table 2. Only five children were lost to follow-up, and one was excluded on day 3 for signs of a severe infection in the absence of parasitaemia. Of the enrolled children, 299 (98%) reached a treatment outcome or completed the 28 days of follow-up. No adverse events were reported for either AL or ASAQ during the study period. Both treatments resulted in rapid parasite clearance, with two children in the ASAQ arm at Sinje remaining parasitaemic on day 3, and one other child that met ETF classification based on clinical criteria (Table 2). On day 3, 3% (2/72) of patients who received ASAQ in Sinje were parasitaemic, while rest of study patients cleared their parasites. There were five LTFs in the AL arm and five LTFs in the ASAQ arm, all of which were at the Sinje site. The PCR-uncorrected ACPR by Kaplan–Meier (KM) analysis at day 28 was 100% in Saclepea and 93.2% (95%CI 87.8–99.1%) in Sinje for AL, and 100% in Saclepea and 91.8% (95%CI 85.8–98.3%) in Sinje for ASAQ (Table 3).
Fig. 2.
Flow diagram describing participant enrollment by study arm. AL: Artemether lumefantrine; ASAQ: Artesunate amodiaquine. *Participant excluded for signs of severe infection in absence of parasitemia on day 3
Table 2.
Number of participants screened, enrolled, and finishing follow-up and characteristics at baseline as part of the therapeutic efficacy monitoring in Liberia, 2022–2023
| Saclepea | Sinje | |||
|---|---|---|---|---|
| Parameter | AL | ASAQ | AL | ASAQ |
| No. of participants screened | 334 | 299 | 498 | 499 |
| No. total enrolled | 78 | 77 | 74 | 76 |
| No. loss to follow up, n (%) | 1 (1%) | 1 (1%) | 0 (0%) | 3 (4%) |
| Excluded, n (%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 (1%) |
| No. reached study endpoint, n (%) | 77 (99%) | 76 (99%) | 74 (100%) | 72 (95%) |
| Participant characteristics at baseline | ||||
| Median Age (yrs) (range months) | 3.0 (6–59) | 1.9 (6–59) | 2.7 (6–59) | 3.0 (8–59) |
| Median weight (kg) (range) | 12 (5–20) | 10 (6–19) | 12 (6–25) | 11 (6–20) |
| % Female | 35% | 49% | 47% | 50% |
| Day 0 hemoglobin (g/dl), med (range) | 10.9 (8.4–13.2) | 10.9 (8.6–15.2) | 10.4 (8.1–14) | 10.4 (8.0–14) |
| Day 0 parasitemia (p/ul), med (range) |
39,112 (4666–170,014) |
29,336 (2039–148,354) |
28,678 (2228–131,007) |
28,027 (2471–121,450) |
APCR: Adequate Clinical and Parasitological Response
AL: Artemether lumefantrine; ASAQ: Artesunate amodiaquine
*Confidence intervals are undefined
Table 3.
Treatment outcomes and efficacy of first line antimalarials for participants finishing follow-up as part of therapeutic efficacy monitoring in Saclepea and Sinje, Liberia, 2022–2023
| Saclepea | Sinje | |||
|---|---|---|---|---|
| Study Arm | AL (n = 77) | ASAQ (n = 76) | AL (n = 74) | ASAQ (n = 72) |
| Day 2 slide negativity, % (95% CI) | 100% (94–100%) | 100% (94–100%) | 99% (92–100%) | 96% (88–99%) |
| Day 3 slide negativity, % (95% CI) | 100% (94–100%) | 100% (94–100%) | 100% (94–100%) | 97% (90–100%) |
| Treatment Failures | 0 | 0 | 5 (7%) | 6 (8%) |
| Early Treatment Failure | 0 | 0 | 0 | 1 (1%) |
| Late Treatment Failure (LCF or LPF) | ||||
| Day 7 | 0 | 0 | 0 | 0 |
| Day 14 | 0 | 0 | 0 | 1 (1%) |
| Day 21 | 0 | 0 | 2 (3%) | 3 (4%) |
| Day 28 | 0 | 0 | 3 (4%) | 1 (1%) |
| Adequate Clinical and Parasitological Response | 77 (100%) | 76 (100%) | 69 (93%) | 66 (92%) |
| PCR uncorrected Kaplan–Meier ACPR Estimate | 100%* | 100%* | 93.2% (95CI 84.5–97.1%) | 91.7% (95CI 82.4–96.2%) |
| PCR corrected Kaplan–Meier ACRP Estimate | 100%* | 100%* | 95.9% (95CI 88.0–98.7%) | 94.4% (95CI 85.9–97.9%) |
APCR: Adequate Clinical and Parasitological Response; AL: Artemether lumefantrine; ASAQ: Artesunate amodiaquine; LCF: Late Clinical Failure; LPF: Late Parasitological Failure
*Confidence intervals are undefined
Of the 10 LTFs, only four pairs of DBS met the CDC quality assurance standards due to mold growth due to high humidity conditions in Liberia or were missing. All four LTFs that were analyzed were found to be reinfections by both the “3/3”, also known as the 2007/2008 WHO algorithm, and the “2/3” algorithm. The PCR-corrected ACPR by KM analysis at 28 days was 100% in Saclepea and 95.9% (95CI 88–98.7%) in Sinje for AL, and 100% in Saclepea and 94.4% (95CI 85.9–97.9%) in Sinje for ASAQ (Table 3).
Discussion
Using the WHO-recommended TES protocol, the current study conducted between August 2022 and July 2023, approximately 4 years after the prior TES, showed cure rates above the 90% WHO-recommended threshold for both AL and ASAQ. In the current study, parasite genotyping to distinguish between reinfection and recrudescence (true failures) was not completed due to the small number of treatment failures. The PCR uncorrected ACPRs provide a worst-case scenario, assuming that all treatment failures were recrudescent infections. The ACPRs for both AL and ASAQ were 100%, and there were no participants with day 3 parasitaemia at the Saclepea site, demonstrating that both AL and ASAQ remained highly efficacious at this location. In Sinje, the PCR uncorrected ACPR for AL was 93.2% (95%CI: 87.8–99.1%), and for ASAQ was 91.8% (95%CI: 85.8%-98.3%). Two participants in the ASAQ arm still had microscopically detected parasites on day 3. It is unclear if the geographic location of Sinje, in the North Western Region, has a slightly higher level of ACT resistance or if the lower ACPRs reflect an increased incidence of re-infections at this site. However, data from the MIS conducted in 2022 indicated the prevalence of malaria among children aged 5 to 59 months were similar in the North Central and North Western Regions, with a P. falciparum prevalence of 22.5% by RDT and 13.3% by microscopy in North Central Region, and 19.5% by RDT and 11.5% by microscopy in North Western Region[22]. The WHO-recommended PCR-correction of the ACPRs at the Sinje site would increase the ACPR estimates if any treatment failures were re-classified as re-infections rather than recrudescences [27]. Thus, the PCR uncorrected ACPRs in this study are likely an underestimate of the true efficacy of both AL and ASAQ. The PCR corrected ACPRs support this as the four samples that were able to be analysed by fragment analysis were all classified as reinfections, increasing the ACPR estimate to approximately 96% for AL and 94% ASAQ in Sinje.
Both AL and ASAQ utilize an artemisinin derivative and partner drug, lumefantrine and amodiaquine (AQ), respectively. AQ is a 4-aminoquinoline with a longer half-life than lumefantrine, which helps clear residual parasites and prevents recrudescence and has greater prophylactic effect preventing new infections [29]. AQ is rapidly absorbed and extensively metabolized in the liver to its active metabolite, desethylamodiaquine (DEAQ). The parent compound, amodiaquine, has a relatively short elimination half-life of approximately 5 h, however, DEAQ has a much longer half-life, ranging from 6 to 18 days [30]. In contrast, lumefantrine exhibits a terminal elimination half-life ranging from approximately 3 to 6 days in patients with malaria [31, 32]. Thus, ASAQ likely has a much longer ability to clear residual parasites and prevent recrudescence, so that theoretically, ASAQ should have higher uncorrected efficacies just due to the longer protection of AQ. However, in this TES the PCR-corrected ACPR for AL was 95.9% (95CI 88.0–98.7%), and for ASAQ was 94.4% (95CI 85.9–97.9%) at the Sinje site, essentially equal given the overlapping 95% confidence intervals. The Sinje site screened more participants to achieve the required sample size suggesting a lower malaria incidence rate compared to the Saclepea site, this would suggest that the uncorrected failure rate should have been higher at the Saclepea site. Interestingly, this was the opposite, fewer recurrent infections were seen at the site with presumed higher transmission. This may have been due to higher LLIN use after enrollment in the TES or other community-based prevention measures.
Limitations and operational challenges of this study include the prolonged length of time to recruit the required sample size at each site, approximately 11 months. This is becoming more common for TES studies as community case management with community health workers (CHW) becomes more robust in highly malaria endemic countries [2]. More often febrile uncomplicated P. falciparum malaria patients are being treated by CHWs in the community and do not present to public facilities where they could be encountered for enrollment in a TES. The study did attempt to refer some patients to the TES sites if they were interested in participating. This could be further expanded more formally by utilizing CHWs in future TES to recruit participants meeting general inclusion criteria based on symptoms and age. Lastly, this TES did not ensure direct observed therapy for the evening doses of AL. Guardians were reminded of the evening AL doses, but some missed doses could have happened. However, compliance was likely very good given the high efficacy in the AL arms. Lastly, improved DBS storage conditions and early DNA extraction from samples could have allowed all LTF samples to be analyzed.
This TES provides reassuring evidence to the Liberian MOH and NMCP that both AL and ASAQ remain highly efficacious. In the current study, parasites were cleared by day 3 in all but two patients, which, together with the absence of the Pfkelch13 mutations known to be associated with artemisinin resistance from the prior TES [24], continue to suggest the likely absence of artemisinin resistance in Liberia. The results of this study support both the use of AL and ASAQ as first-line treatment for uncomplicated malaria infections in Liberia.
Conclusions
The uncorrected ACPR efficacy results greater than the 90% WHO threshold and day 3 microscopy results suggest that AL and ASAQ are likely still effective treatments for uncomplicated malaria infections in Liberia. However, to characterize and mitigate the risks associated with antimalarial drug resistance in Africa, the NMCP should continue to conduct TES every two years [2].
Supplementary Information
Additional file 1. Supplement Table 1: Classification of responses to treatment with AL or ASAQ.
Acknowledgements
We express our gratitude to the children who participated in the study and their parents and guardians.
Author contributions
VSK and JS designed the study, wrote the protocol, and manuscript preparation. LS designed the data collection tools, data cleaning, and data management. OK, TW, MD, JK, UI, GP, VL, JZ, BG, WH, MP assisted in study design, study implementation, data collection, and study supervision. ZZ analyzed the paired DBS samples. JS performed data analysis and manuscript preparation.
Funding
This study was funded by the U.S. President’s Malaria Initiative (PMI).
Data availability
The datasets used and/or analyzed during the current study will be made available upon request from the Liberian Ministry of Health's National Malaria Control Program.
Declarations
Ethics approval and consent to participate
Ethical approval for the study protocol was obtained from the University of Liberia Pacific Institute for Research and Evaluation (UL-PIRE) Institutional Review Board (ULIRB) and was determined as non-research activity within the U.S. Centers for Disease Control and Prevention (CDC) (0900f3eb81e634a9). The study was registered on the US NIH Clinical Trials website (ClinicalTrials.gov ID NCT06300970). Parents/guardians were informed of the study procedure, its benefits, potential risks, and gave written informed consent for their children to participate in the study prior to enrollment.
Consent for publication
All co-authors consent for the publication of the included results.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Victor S. Koko, Email: victorskoko82@gmail.com
Jonathan S. Schultz, Email: rix1@cdc.gov
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Additional file 1. Supplement Table 1: Classification of responses to treatment with AL or ASAQ.
Data Availability Statement
The datasets used and/or analyzed during the current study will be made available upon request from the Liberian Ministry of Health's National Malaria Control Program.