Background
Malaria, caused by infection with
Plasmodium protozoan parasites, threatens over half the world’s population [
1]. Despite concerted efforts, which have considerably reduced the burden of mortality and morbidity in recent years, malaria remains a major public health threat [
2,
3]. In 2017, over 219 million cases and 435,000 deaths were reported [
2]. Approximately 92% of the cases and 93% of the deaths were from sub-Saharan Africa [
2]. Between 2000 and 2015, the widespread adoption of artemisinin-based combination therapy (ACT), the increased use of insecticide-treated nets (ITNs) and indoor residual spraying (IRS) against the
Anopheles mosquito vector, decreased the global number of malaria deaths by an estimated 37% [
4]. Recently, these fragile gains are, jeopardized by the emergence and spread of drug resistance in the parasite and insecticide resistance in the mosquito vector [
5].
Ethiopia is also one of the many malaria epidemic-prone countries in Africa [
6]. The trends in malaria over the past five years have also shown a decline in malaria cases and reduced epidemics [
7]. In 2014/2015, Ethiopia reported 2,174,707 malaria cases and 662 reported malaria deaths among all age groups which is 98% reduction compared to 41,000 estimated deaths in 2006 [
7,
8]. The key interventions which have been contributing to such significant decline includes: introduction of prompt and effective treatment with artemisinin-based combinations to treat uncomplicated
Plasmodium falciparum malaria, the distribution of long-lasting insecticidal nets (LLINs), indoor residual spraying (IRS); and to a lesser extent environmental management [
7‐
9]. Following this, Ethiopia has also set a goal to eliminate the disease by 2030 [
10,
11].
ACT is the first-line treatment for uncomplicated
P. falciparum malaria and has been instrumental in reducing malaria burden [
12,
13]. As yet the majority of endemic prone areas have little or no drug resistance to ACT, and its high efficacy (~ 95%) at clearing parasitaemia has been extensively demonstrated from clinical trials [
14,
15]. However, there is limited information on ACT effectiveness in routine health care when treatment is not monitored.
Resistance of
Plasmodium species to artemisinin has been reported from eastern and southern Asian countries which threatens malaria control and elimination efforts worldwide [
16‐
18]. For the purpose of ensuring good performance and detection of emergence of resistance of anti-malarial drugs, especially those used as a first-line and second-line treatment in a country, the World Health Organization (WHO) recommends regular monitoring of their efficacy at least every two years in malaria-endemic countries [
19].
Early diagnosis and prompt treatment is one of the main strategies in malaria prevention and control and it is also the key to reducing morbidity and preventing mortality in Ethiopia [
6]. According to the President’s malaria initiative Ethiopia malaria operational plan fiscal year 2018, 60–70% of the total projected numbers of malaria cases are due to
P. falciparum and to be treated with AL from year 2017–2019 [
7]. The emergence and spread of both artemisinin and partner drug resistance threatens the efficacy of ACT and subsequently undermines the treatment of uncomplicated falciparum malaria, which is to eliminate all parasites from the body and prevent progression to severe disease [
12,
21]. It is, therefore, necessary to generate continuous data on the therapeutic efficacy of first-line ACT to ensure real-time evidence-based review of national treatment policies as and when necessary. Since the introduction of ACT in Ethiopia in 2004, there have been few studies on therapeutic efficacy of AL [
22‐
24]. This paper presents data on the therapeutic efficacy of AL for the treatment of uncomplicated falciparum malaria, the prevalence of day three parasitaemia, which has previously been used as a surrogate for artemisinin (partial) resistance and patterns of fever and parasite clearance.
Discussion
In this study, the PCR-corrected cure rate 96% (95% CI 88.8–99.2), which showed the high therapeutic efficacy of AL since its introduction for the treatment of uncomplicated falciparum malaria in the study area, meeting the WHO recommendation that cure rates for falciparum malaria should be at least 90% [
20]. The observed PCR corrected cure rate in this study is comparable with what was documented in other parts of Ethiopia by Nega et al. Mekonnen et al. and Getnet et al. in which PCR-corrected ACPR of 97.8, 98.8 and 95% respectively, were observed after 28 days follow following treatment with AL [
22‐
24]. The observed high AL cure rate is comparable with other findings in other parts of Africa in which PCR-corrected ACPR of 95% in Ghana by Abuaku et al
. and 99.3% in Tanzania by Ishengoma et al. were demonstrated [
33,
34]. Most of these results are well within the confidence intervals of this study and minor differences may be attributable to host nutritional and immune status, initial parasitaemia level, pharmacokinetics and pharmacodynamics may influence the therapeutic efficacy of a drug apart from inherent parasite susceptibility [
35].
Early treatment failure was not observed in this study, whereas three LPF were 3.9% (95% CI 0.8–11.1) in PCR uncorrected and 4% (95% CI 0.8–11.2) treatment failure was observed in PCR corrected data. Several studies [
36‐
39] in which therapeutic efficacy tests were combined with sampling of plasma or whole blood for drug concentration measurements at various times during follow-up have shown that cured patients have higher drug concentrations than those in whom treatment failed. There are two possible explanations for the latter finding. First, failures are associated with inadequate drug concentrations rather than resistance-this could be the case in our findings of treatment failure of 4%; secondly, when drug resistance emerges, there is a higher likelihood that a resistant strain will emerge if the drug is present at a suboptimal concentration.
According to the Kaplan Meier PP survival analysis in the current study, the PCR-corrected AL failure rate was 3.8% (95% CI 1.3–11.4) and the cumulative incidence of success rate of AL among study participants was 96.2% (95% CI 88.6–98.7) (Fig.
2). The AL treatment failure rates observed is below the WHO threshold of 10%, and, therefore, suggests that lumefantrine was not failing as partner drug in AL use in the study area, with no change in the national treatment policy [
20]. Inadequate drug absorption resulting in suboptimal serum drug concentrations can cause treatment failure. Artemether is rapidly absorbed and eliminated (half-life of a few hours), whereas lumefantrine was variably absorbed and more slowly eliminated [
12]. Lumefantrine is a lipophilic compound with erratic bioavailability unless administered with a small fatty meal [
40], and for this reason, guidelines recommend administration of AL with a fatty meal such as milk or a small biscuit. In the case of our study, we were unable to confirm adequate serum concentrations of lumefantrine; however, all participants received a complete course of treatment and all the doses were supervised in the health Centre and administered with a milk biscuit to ensure good absorption. Nevertheless, considerable inter-individual variation exists in lumefantrine exposure, and these participants may have had relatively low concentrations.
Day-3 parasitaemia may be a poor predictor of patient outcomes on day 28 because the supplemental drug may still clear the infection. However, determining the presence of day 3 parasitaemia has been suggested as a surrogate for assessing artemisinin resistance e.g. in mobile populations [
41]. In the present study, the parasitaemia on day 3 following treatment with AL was only 3.8% (95% CI 0.8–10.6) on day-3 and Day-3 parasitaemia did not correspond to failures observed during follow-up. This may indicate absence of resistant strains of P. falciparum to artemisinin in study area. This is in line with the WHO 2009 anti-malarial protocol, that if 10% of the study participants have peripheral parasitaemia on day 3, it is an indicator of emergence of artemisinin resistance to Plasmodium species [
20,
42]. The overall rate of day-3 positivity observed in this study are consistent with the 3–5% background rate of day-3 positivity that might be expected in the absence of resistance to artemisinin, but also the 3–10% range which in the past has been seen as appropriate window for initiating containment activities [
43].
Episodes of recurrent parasitaemia following treatment may be due to recrudescence of the initial infection, reflecting failure of the drug to clear the infection; or, they may be due to new infections that occurred during the follow-up period [
44]. In areas of high endemicity recurrent infections are common although PCR analysis of
msp1 and
msp2 gene markers estimated that three cases were recrudescence and a single case of re-infections are observed in this study. The recrudescent parasitaemia resolved quickly after initiated re-treatment in all cases.
AL showed rapid parasite and fever clearance during the first 3 days of controlled supervised follow-up period. Over all prevalence of parasite and fever declined by 96.2 and 97.5% on day 3 respectively. Gametocytaemia was absent on day 3 following treatment with AL. These findings suggest that AL remains effective in rapidly clearing asexual parasites and fever as well as reducing gametocyte carriage rates in study Ethiopia [
22‐
24]. The high parasite and fever clearance rates could be explained by the fast act of artemether to clear parasite biomass leading to rapid resolution of clinical manifestations [
12,
45].
This study also showed that AL had a safety profile comparable to previous studies and was well tolerated with minimal adverse events. Studies conducted in other African countries [
46‐
48] reported similar safety profiles of AL when used for the treatment of uncomplicated falciparum malaria. A high number of cases reporting cough at the study site could be attributed to weather conditions, which were relatively cold and rainy at the time of the study.
The relative bioavailability of artemether and lumefantrine increases by 2–3 times and 16 times, respectively, when administered after a high-fat meal [
49]. The limitation of this study is the lack of pharmacokinetic data to better explain the recrudescence observed. The cure rates for AL may therefore be higher than the rates observed in this study.
Acknowledgements
The authors would like to express their appreciation to study participants and their parents or guardians, local health officials and all health personnel involved on the study. Special thanks go to Dr.Abebe Genetu Bayih, Dr. Aline Lamien-Meda, Kalab Eskinder, Ms. Ikram Es-sbata, Ms. Nada Lafkih, and Mr. Tarik Lakhlifi for their technical assistance and help. Support for the development of the manuscript was provided through Jimma University, DAAD In-Country/In-Region scholarship and MOUNAF Intra-African Mobility Project.
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