Plasmodium falciparum is resistant to most antimalarial drugs, including artemisinin derivatives. Regular monitoring of the efficacy of these drugs is crucial for detecting early changes in P. falciparum susceptibility [1]. The chemoresistance of P. falciparum poses a significant threat to malaria elimination efforts. Consequently, the World Health Organization (WHO) recommends routine monitoring through Therapeutic Efficacy Studies (TESs), which track clinical and parasitological outcomes in individuals receiving antimalarial treatment [2]. The results of TES are essential for countries to determine or review their national treatment policies [2].

In Côte d’Ivoire, the incidence of malaria was 266 per 1000 in the general population and 844 per 1000 in children under 5 years of age in 2022 [3]. This parasitic disease accounts for 33% of all outpatient visits and one-third of reported deaths in healthcare facilities [4]. This country, along with 28 other sub-Saharan countries, accounted for 96% of malaria cases and deaths globally in 2022 [2]. Since 2005, uncomplicated cases of malaria have been treated with Artemisinin-based Combination Therapies (ACTs) [5]. Artesunate–amodiaquine (AS + AQ) as a first-line treatment and artemether–lumefantrine (AL) as a second-line treatment were the ACTs recommended by the National Malaria Control Program (NMCP). Based on TES results indicating the same high efficacy rate for both combinations, the NMCP adopted both regimens as first-line treatments in 2013 [6]. In 2018, dihydroartemisinin–piperaquine (DHA-P) was introduced into the therapeutic arsenal as a first-line treatment, similarly to AS + AQ and AL [7]. Since 2022, the therapeutic management of uncomplicated cases of malaria recommended by NMCP is AS + AQ, AL, DHA-P, or artesunate–pyronaridine, all as first-line treatment [8]. However, only AS + AQ and AL combinations are administered free of charge in public healthcare centers, which is why they are assessed using TESs. Other recommended ACTs are available in the private health sector.

Recent reports on mutations in the Plasmodium falciparum Kelch propeller domain 13 (pfk13) gene linked to artemisinin resistance in Rwanda and Tanzania [9,10,11] provide evidence to reinforce the surveillance of these antimalarial drugs, which remain a last resort in the treatment of malaria.

The first study, which assessed the efficacy of ACT in Côte d’Ivoire, was conducted in 2009 [12]. Since then, six nationwide TESs, including both published and unpublished data, have been carried out at sentinel sites across the country [12,13,14,15,16,17]. These studies consistently reported that AS + AQ and AL remain effective and well-tolerated treatments for uncomplicated malaria in Côte d’Ivoire. However, no studies have compared the evolution of cure rates at the same site using the same antimalarial drugs over time. Since its addition to the list of sentinel sites, the site of Bouna has hosted only two TESs in 2019 and 2023. This study aimed to report the temporal dynamics of AL efficacy in managing uncomplicated malaria cases at Bouna, in Côte d’Ivoire.

A total of 60 and 88 patients were included in the 2019 and 2023 evaluations, respectively. The inclusion rates were 1.9% (60/3192) and 27.8% (317/88) in 2019 and 2023 surveys, respectively. A 28-day follow-up was achieved for 57 patients in 2019 and 87 patients in 2023. The trial profiles are presented in Figure 1 and Figure 2.

Females were predominant (51.7%; sex ratio, 0.94 in 2019; 54.5%; sex ratio, 0.83 in 2023). Their mean age was 6.3 years (SD = 6.8; range: 0.50–32) in the 2019 survey and 4.7 years (SD = 2.4; range: 0.80–12) in 2023. The infection rate among children under five years old was 60% (2019) and 60.2% (2023) in the two surveys. The geometric mean parasitemia was 65187.8 parasites/μL (SD = 55,251) (range: 116–41,2461) in 2019 and 41,340.8 parasites/μL (SD = 42,196.9) (range: 2486–198,478) in 2023. The baseline characteristics of the patients included in each survey are shown in Table 1.

The analyses were performed in ITT and PP on day 28 for both surveys and on day 42 only for the 2019 evaluation. On day 28, the PCR-adjusted cure rates were higher in 2023 than in 2019, both in the ITT analysis (96.6% versus 90.0%) and in the PP analysis (97.7% versus 94.7%). On day 42, the PCR-adjusted cure rates were 88.3% and 93.0% following ITT and PP analyses, respectively.

After 28 days of follow-up, more failures (23) were observed in 2023 than in 2019 (9).

On day 28, four of nine failure cases were classified as late clinical failure (LCF), whereas the other five were described as late parasitological failure (LPF) in the 2019 survey. In 2023, 14 cases of LCF and nine cases of LPF were observed. After 42 days of follow-up in the 2019 survey, 10 failures were observed. Five of these ten cases were LCF, while the other five were LPF. Overall, none of the patients experienced an early treatment failure (ETF).

After PCR adjustment, nearly all cases were reinfections. In 2019, three cases of recurrence and six cases of new infections were observed. In 2023, two recurrence events and 21 new infections were observed. The single case of failure observed between days 28 and 42 in the 2019 survey was classified as a recrudescence case. However, no significant differences were observed between the two surveys.

In addition, no patient presented with parasites on day 3 in either survey.

Treatment outcomes are summarized in Table 2.

Overall, a similar evolution in the proportion of patients with parasitic infections was observed during follow-up in both surveys. In both surveys, AL facilitated rapid parasite clearance (Figure 3).

A decrease in fever during follow-up was noticed in both surveys, but it was faster in 2013 than in 2019 (Figure 4).

At the clinical level, seven cases of adverse events were detected in 2019: two cases of vomiting, one of nausea, one of asthenia, one of diarrhea, one of abdominal pain, and one of abdominal distension. No adverse events were reported in 2023.

Therapeutic Efficacy Studies (TESs) are crucial for detecting early changes in P. falciparum susceptibility to antimalarial drugs and are useful for countries to best determine or review their national treatment policies [2]. Since the beginning of TESs in Côte d’Ivoire, only two TESs have been carried out at the sentinel site of Bouna. This study presents the results of the two TESs. This study compared the evolution of cure rates observed after AL administration for the management of uncomplicated malaria cases in Bouna.

In Côte d’Ivoire, malaria occurs more frequently among vulnerable populations, such as pregnant women and children under the age of five [4]. In the present study, children under five years old were more likely to be infected in the two surveys. This age group is more frequently infected because of their immature immune system and increased exposure to malaria parasites [26].

Artemether–lumefantrine (AL) and AS + AQ are ACTs administered free of charge in public-sector healthcare establishments. In most health facilities in Côte d’Ivoire, AL is prescribed at higher rates than ASAQ because of patients’ complaints following the use of the latter [27]. Globally, AL is also the most widely used ACT, followed by AS + AQ [28].

Overall, the efficacy of AL remained relatively unchanged over time, with 94.7% PCR-corrected efficacy in 2019 and 97.7% in 2023 after 28 days of follow-up. The therapeutic efficacy of AL in the two surveys was well above the 90% threshold recommended by the WHO [18]. This result is in line with previous studies conducted in Côte d’Ivoire [13,14,15] and other African countries [29,30]. In addition, prompt parasite clearance was observed during the early days. Delayed parasite clearance at 72 h is an in vivo predictor of subsequent treatment failure with ACTs and an indicator of choice for routine monitoring of suspected artemisinin resistance in P. falciparum. The proportion of patients with persistent parasitemia on day 3 after ACTs is a useful indicator as a simple and readily measurable marker in the setting of drug efficacy surveillance studies [31]. In the current study, none of the patients presented with parasites on day 3, as observed previously in the country [16], indicating rapid parasite clearance from patients following artemether–lumefantrine in Bouna. These results should encourage the PNLP to maintain AL as the first-line treatment for uncomplicated malaria in Bouna and Côte d’Ivoire.

Despite the high cure rates, concerns remain. Indeed, a high level of failure was observed in 2023 compared with 2019. Antimalarial treatment failure is a useful indicator for assessing ACT resistance [1] and may be caused by many factors other than the intrinsic susceptibility of P. falciparum to the drug being tested [32]. Crude failure rates are higher in 2023. Several studies that compared AL with ACT regimens consisting of longer-acting partner drugs demonstrated a shorter time to reinfection for AL. The mean protection provided by AL is estimated at 13.8 days . In most health facilities in Côte d’Ivoire, AL is prescribed more than AS + AQ because of patient complaints following the use of the latter [27].

After PCR correction, most cases of failure were classified as new infections in both surveys, showing a high level of exposure of patients to malaria. The number of new infestations is expected to increase by 2023. This result may be attributed to the study period. In 2019, the survey was conducted mainly during the dry season (February, March, April, and May), unlike in 2023, when the survey was conducted at the beginning of the rainy season, when transmission was high in the country. Populations are more exposed to mosquito bites during the rainy season, posing a high risk of infection in vulnerable populations if no preventive tools are adopted. This result demonstrates the importance of reinforcing community mobilization and behavioral change mechanisms, which could be significant for the success of all malaria prevention activities implemented in the country [33].

As reported in most studies [13,14,15,34,35,36], prompt fever clearance was observed during the early days of treatment with AL.

In addition, AL is well tolerated without serious adverse events, as usually reported [13,14,15,35,36]. At the clinical level, seven cases of adverse events were detected between 2019 and 2023. This gap could be explained by the fact that in 2019, people aged up to 65 years were included, contrary to 2023, where patients aged no more than 12 years were included, expressing less concern about the effects experienced.

A limitation of this study is the non-availability of 42 days of follow-up data from the 2023 survey, causing a lack of comparison of the long-lasting protective action of partner drugs in ACTs.

AL remains effective and well-tolerated for the therapeutic management of uncomplicated malaria in Bouna, Côte d’Ivoire. Furthermore, the increase in new infections suggests the need to strengthen preventive measures at this sentinel site. In any case, monitoring ACTs should remain a high priority at the national level.