Malaria still represents a major public health issue in the tropics, with an estimated 228 million cases and 405,000 deaths in 2018[1, 2]. Approximately 92% of the cases and 93% of the deaths were from sub-Saharan Africa [1], and the only tool for treatment is a small arsenal of anti-malarial drugs [1, 2]. The pivotal losses of two key drugs (chloroquine and pyrimethamine) during the last few decades have led to millions of deaths [2]. The lost clinical efficacy of these compounds is suspected to have contributed to millions of additional malaria deaths in young African children in the 1980s [4].Since 2001, the World Health Organization (WHO) has recommended artemisinin based combination therapy (ACT) for uncomplicated malaria treatment in all endemic countries [4]. Five ACT recommended by WHO for treatment of uncomplicated P .falciparum malaria are: artemether-lumefantrine(AL), artesunate-amodiaquine(ASAQ), artesunate mefloquine(ASMQ), artesunate plus sulfadoxine-pyrimethamine(ASSP) and dihydroartemisinin-piperaquine(DHP) [6, 7]. Nearly all countries in sub-Saharan Africa recommend AL, ASAQ, or either of these regimens for the treatment of uncomplicated malaria [3, 7]. The Ethiopian Federal Ministry of Health (EFMoH) adopted AL as the first-line treatment of uncomplicated P. falciparum malaria in 2004 [8]. A 3-day AL treatment regime will cover three erythrocytic cycles with adequate concentration of the artemisinin component to kill parasites demonstrating a delayed clearance. Moreover, EFMoH and the World Health Organization (WHO) recommends use of single low-dose primaquine (0.25 mg/kg), a P. falciparum gametocytocidal drug; for blocking transmission in low-transmission areas in combination with ACT irrespective of glucose-6-phosphate dehydrogenase enzyme status [6, 7, 8].
Unfortunately, artemisinin resistance (ART-R), characterized by delayed P. falciparum clearance following treatment with artemisinin monotherapy or an ACT [9, 10], is now wide-spread in the Greater Mekong subregion (GMS), which consists of Cambodia, Thailand, Vietnam, Myanmar and Laos [11, 12].Mutations in the propeller domain of a kelch gene on chromosome 13 (PF3D7_1343700, K13 gene) constitute the primary determinant of ART-R [9, 13]. These mutations are suspected to reduce Pfkelch13 function, which is required for parasite-mediated endocytosis of host hemoglobin in the newly invaded intra-erythrocytic ring stages [14, 15]. The artemisinin agents are rapidly acting and significantly reduce the biomass of sensitive parasites corresponding to a single cycle of a sexual blood stage of P. falciparum in 48 h.The use of short acting artemisinin (half-life < 1 h) and long-lasting partnerdrug (lumefantrine, amodiaquine, or piperaquine) in ACT, has contributed to an estimated 30% reduction in global rate of malaria associated mortality in the past decade [1, 2, 3]. Pfkelch13 C580Y is the most widespread allele in Southeast Asia (SEA) [12, 16] and has recently been detected in Guyana [17] and Papua New Guinea [18]. Non-synonymous Pfkelch13mutations associated with delayed parasite clearance or day 3 positivity (day 3+) in the GMS (F446I, Y493H, R539T, I543T, P553L, R561H, P574L, C580Y, A675V) that are associated with elevated ring-stage survival rates in vitro and long parasite clearance half-lives (> 5 h), have only been rarely reported, if at all, in Africa[ 19, 20]. Resistance to the partner drugs piperaquine and mefloquine is also now common in the GMS, causing high rates of ACT treatment failure. Resistance selection might be less likely in Africa compared with other areas because of the high level of immunity in African populations, the high level of complexity of African infections, and other factors, which limit the emergence of relatively unfit resistant strains [21]. Nonetheless, resistance to multiple classes of antimalarial drugs has spread to Africa, and as transmission decreases in some areas, the likelihood of emergence of resistance might increase. Hence, monitoring the efficacy of anti-malarial drugs is a key component of malaria control and subsequent elimination.
Recent report from Rwanda showed that Pfkelch13R561H mutation was identified in 7.4% patients in Masaka. This study provides evidence for the de novo emergence of Pfkelch13-mediated artemisinin resistance in Rwanda, potentially compromising the continued success of antimalarial chemotherapy in Africa [22]. Besides,several case reports have described failed therapy with ACT in individuals who have returned to other countries after acquiring malaria in Africa; A Chinese man presented in 2013 with P falciparum malaria in China about 6 weeks after returning from Equatorial Guinea, where he was treated for malaria six times over 20 months[23]. The patient was treated with directly observed DHP, and had persistence of parasitaemia on day 3 after initiation, but clearance by day 7; the infecting parasite had a K13 mutation; a switch from a methionine to an isoleucine at amino acid position 579 (M579I). Four patients in Sweden treated with AL in 2012-15[24], four patients in the UK treated with AL in 2015-16[25], and two patients in Italy treated with DHP in 2014-16[26, 27]; all with uncomplicated P falciparum malaria acquired in Africa, experienced late treatment failures. Most of these patients were non-immune European individuals, compliance with treatment regimens was uncertain, and all infecting parasites had wild-type K13PD sequences. Considering these case reports, treatment failures are of concern in Africa.
There have been some reports of delayed parasite clearance during routine therapeutic efficacy studies of ACT in Africa. However, these reports have not been consistent over time [28]. A study from the coast of Kenya in year 2005–2008 showed decreased rates of parasite clearance and increased recrudescence over time after treatment with AL or DHP. These results might suggest decreases in drug efficacy, but a more likely explanation is a decrease in antimalarial immunity in a region with decreasing malaria transmission intensity over this time frame [29]. In Uganda, among 78 children diagnosed with severe malaria, three had isolates with the Ala578Ser K13PD mutation, and parasite clearance was delayed in these children compared with the full cohort [30]. In a 2013 trial comparing AL and DHP for uncomplicated malaria, genotype-corrected recrudescence at 28 days was reported in 12% of children treated with AL in Zaire Province with cure rate of 88.1% (81–95) AL efficacy [31].A pooled analysis involving 1179 subjects in 2017 in Ethiopia also showed efficacy rates of AL, which are the first-line drug for uncomplicated falciparum malaria, was 97.1% (PCR corrected) [8]. Considering that the referred pooled-analysis data wasover the last three years, recent data are needed to update the understanding of the current efficacy of AL in Ethiopia according to WHO recommendations [28, 32, 33].
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 [28]. In Ethiopia, the Federal ministry of Health (FMOH), in collaboration with its partners, including President’s Malaria Initiative (PMI), research institutions, universities, WHO country office and Global fund, have been conducting regular therapeutic efficacy studies (TESs). The efforts of the FMOH to ensure regular TESs have also been complemented by TESs conducted by independent researchers. Thus, regular implementation of TESs is one of the priority activities of the FMOH, which provides useful data for monitoring the efficacy of AL for falciparum malaria and detecting emergence of drug tolerance/resistance to these and other anti-malarials used in the country. The findings of these studies have been used to guide the FMOH in reviewing and changing anti-malarial drug policy in the past [32, 33]
Although there are several studies that were conducted to assess the efficacy of malaria treatment agents yielding different success rates in Ethiopia, there has been no up-to-date systematic review and/or meta-analysis conducted that organized the available evidence about the outcome of malaria treatment. The present paper reviewed the implementation of in-vivo efficacy testing in Ethiopia after deployment of AL in order to monitor the efficacy of AL for the treatment of uncomplicated P. falciparum malaria. The paper compares the cure rates, parasite clearance and fever clearance times and safety data reported in efficacy study involving AL in Ethiopia that where published between 2004 and 2020. It provides updates on country-specific performance of AL after its wide scale deployment for treating uncomplicated falciparum malaria and provides evidence-based guidance for monitoring the early signs of artemisinin resistance and effective case management that will be critical in optimizing malaria control and containment efforts