Efficacy of artemether–lumefantrine therapy for the treatment of uncomplicated Plasmodium falciparum malaria in Southwestern Ethiopia

Mekonnen et al. Malar J (2015) 14:317 DOI 10.1186/s12936-015-0826-9 Open Access RESEARCH Efficacy of artemether–lumefantrine therapy for the treatment of uncomplicated Plasmodium falciparum malaria in Southwestern Ethiopia Seleshi Kebede Mekonnen1,3* , Girmay Medhin2, Nega Berhe2,5, Ronald M Clouse4 and Abraham Aseffa3 Abstract Background: The development and spread of chloroquine-resistant Plasmodium falciparum threatens the health of millions of people and poses a major challenge to the control of malaria. Monitoring drug efficacy in 2-year intervals is an important tool for establishing rational anti-malarial drug policies. This study addresses the therapeutic efficacy of artemether-lumefantrine (AL) for the treatment of Plasmodium falciparum in southwestern Ethiopia. Methods: A 28-day in vivo therapeutic efficacy study was conducted from September to December, 2011, in southwestern Ethiopia. Participants were selected for the study if they were older than 6 months, weighed more than 5 kg, symptomatic, and had microscopically confirmed, uncomplicated P. falciparum. All 93 eligible patients were treated with AL and followed for 28 days. For each patient, recurrence of parasitaemia, the clinical condition, and the presence of gametoytes were assessed on each visit during the follow-up period. PCR was conducted to differentiate re-infection from recrudescence. Results: Seventy-four (83.1 %) of the study subjects cleared fever by day 1, but five (5.6 %) had fever at day 2. All study subjects cleared fever by day 3. Seventy-nine (88.8 %) of the study subjects cleared the parasite by day 1, seven (7.9 %) were blood-smear positive by day 1, and three (3.4 %) were positive by day 2. In five patients (5.6 %), parasitaemia reappeared during the 28-day follow-up period. From these five, one (1.1 %) was a late clinical failure, and four (4.5 %) were a late parasitological failure. On the day of recurrent parasitaemia, the level of chloroquine/desethylchloroquine (CQ-DCQ) was above the minimum effective concentration (>100 ng/ml) in one patient. There were 84 (94.4 %) adequate clinical and parasitological responses. The 28-day, PCR-uncorrected (unadjusted by genotyping) cure rate was 84 (94.4 %), whereas the 28-day, PCR-corrected cure rate was 87 (97.8 %). Of the three re-infections, two (2.2 %) were due to P. falciparum and one (1.1 %) was due to P. vivax. From 89 study subjects, 12 (13.5 %) carried P. falciparum gametocytes at day 0, whereas the 28-day gametocyte carriage rate was 2 (2.2 %). Conclusions: Years after the introduction of AL in Ethiopia, the finding of this study is that AL has been highly effective in the treatment of uncomplicated P. falciparum malaria and reducing gametocyte carriage in southwestern Ethiopia. Keywords: Artemesinin combination therapy, Treatment failure *Correspondence: 1 College of Health Siences, Jimma University, Jimma, Ethiopia Full list of author information is available at the end of the article © 2015 Mekonnen et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Mekonnen et al. Malar J (2015) 14:317 Background Although there have been encouraging reports of declining of morbidity and mortality from malaria in most endemic countries [1], it remains an overwhelming public health problem. At present, approximately 198 million people have malaria worldwide, leading to 5,84,000 deaths per year. Ninety percent of these deaths are in Africa, and approximately 453,000 of those are children under five children [2]. In Ethiopia 75 % of the area is malarious, and approximately 52 million people live in high-risk areas, mainly at altitudes below 2,000 metres [3]. Plasmodium falciparum and P. vivax are the two dominant parasite species, with relative frequencies of about 60 and 40 %, respectively (although thosevary by location and season). Still, Plasmodium falciparum is the dominant parasite species, causing severe and complicated manifestations and is responsible for most malarial deaths [4]. Early diagnosis and effective treatment are essential elements for the control of malaria. However, one of the obstacles to controlling malaria is the capability of the parasites to evolve resistance to various anti-malarial drugs. Plasmodium falciparum has an extraordinary ability to do this, creating a major challenge for the control efforts and increasing the number of deaths in sub-Saharan Africa [5, 6]. In Ethiopia, resistance of P. falciparum to a standard triple-dose of chloroquine (25 mg base/kg) [7], and a report from Debre Zeit of chloroquine (CQ) treatment failure for P. falciparum and P. vivax, brought a policy change, and sulfadoxine-pyrimetamine (SP) has been used as an affordable alternative treatment of uncomplicated malaria cases since 1998 [8]. Unfortunately, unlike chloroquine, SP was used extensively, and parasites developed resistance within a short time [9]. Moreover, earlier studies reported widespread and high rates of therapeutic failure to SP for the treatment of P. falciparum [10]. As a result, in 2001, WHO recommended a shift to artemisinin-based combination therapy (ACT) for the treatment of P. falciparum malaria for all countries experiencing resistance to monotherapies in 2001 [11]. Accordingly, Ethiopia replaced SP by artemether– lumefantrine (AL), which showed no treatment failure and no significant after a follow-up period of 14 days in 2004 [12]. Replacing ineffective anti-malarial drugs with ACT has reduced the morbidity and mortality associated with malaria. SP is still used, however, as intermittent preventive therapy for pregnant women in Ethiopia [13]. ACT was designed to attack malaria parasites with different mechanisms of action simultaneously. It reduces the emergence of drug resistance, and it gives a faster relief from clinical symptoms and parasite clearance [14]. Artemether is quickly hydrolyzed to dihydroartemisinin Page 2 of 8 (DHA), its main active metabolite, and absorbed rapidly. Artemether and DHA reduce asexual parasite mass by 10,000-fold per reproductive cycle. The partner drug, lumefantrine, is absorbed and cleared more slowly, acting to eliminate the remaining parasites and thus prevent recrudescence [15]. Twice-daily dosing of AL for 3 days maintains artemether and DHA concentrations at supratherapeutic levels [16]. To insure timely changes to treatment policy, WHO recommended therapeutic efficacy studies of the drug every 2 years [5]. Accordingly, a study of AL was co (...truncated)