Efficacy of artemether-lumefantrine and artesunate-amodiaquine as first line therapy of uncomplicated malaria in Burkina Faso, 11 years after policy change

Introduction Artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) are the first line therapy of uncomplicated malaria in Burkina Faso. We assessed the treatment efficacy, tolerability of these drugs 11 years following its adoption as first line treatment. Methods In this opened randomized controlled trial carried out in 2016, participants with age over 6 months who consented to participate were randomly assigned treatment with artemether-lumefantrine or artesunate-amodiaquine and followed up for 28 days. Primary endpoint was the treatment efficacy over 28 days of follow up unadjusted by Polymerase chain reaction (PCR). Results Two hundred and eighty-one (281) participants were enrolled and the completion rate was 92.9%. No early treatment failure was found. Adequate clinical and parasitological responses were significantly higher in artesunate-amodiaquine group (97% versus 85.2%, p = 0.0008). On day 28, the risk of failure was 4 times higher in AL group 20.14%, 95% CI (13-30.47) against 5.16%, 95% CI (1.91-13.54) in ASAQ group. All treatments had a similar and good tolerability profile. Conclusion Eleven years following artemether-lumefantrine and artesunate-amodiaquine adoption as first line therapy for uncomplicated malaria in Burkina Faso, artemether-lumefantrine retained fairly good efficacy even though its efficacy fell below WHO threshold of 90% considering uncorrected outcome.


Introduction
The cornestone of malaria treatment has been since the last fithteen years the artemisinin based combination therapy (ACTs) mainly artemether-lumefantrine and artesunate-amodiaquine. Procurement of ACTs faced severe shorted during the first five to ten years of its adoption. Currently, the procurement market has improved and ACTs This situation inevitably sustains the use of the ACTs and thus the increase in drug pressure to the used drugs (artemether-lumefantrine and artesunate-amodiaquine). As drug pressure is known to contribute to the alteration of drug efficacy [11] , this continuous ACT use over 11 years warrants the investigation of this first line therapy efficacy; the present report is intented to provide updated efficacy data for artemether-lumefantrine and artesunate-amodiaquine in Burkina Faso to guide the national malaria control program.

Methods
Study site: the study was carried out in two peripheral health facilities, Colsama and Sakaby during the transmission season between June and December 2016. Each health facility was staffed by two to three nurses and one midwife. They were equipped with one outpatient department and one inpatient wall. All sites were located in Bobo-Dioulasso the second capital city of Burkina Faso at 365 km from Ouagadougou. Transmission of malaria is long but seasonal occurring over 6 months and containing at least 60-80% of clinical cases.
Study participants: subjects presenting to the study health facilities with fever (axillary temperature ≥ 37.5°C) or history of fever in the previous 24 hours were screened against the following inclusion criterias in accordance with WHO guideline 2015: age at least 6 months, weight at least 5 kg, no evidence of concomitant illness, the provision of informed consent by the parents and the ability to participate in 28 days follow up, no history of antimalarial treatment within the last two weeks, no danger sign or evidence of severe malaria, P.falciparum mono infection, parasite density of 2000-200 000 parasites per µl of blood and hemoglobin ≥ 5 g/dL. During the screening process, participants satisfying the above criterias were enrolled while those who were excluded were referred to the health facility staff for standard care.
Evaluation at entry and randomization: potential participants were assigned a number (ID), interviewed on past medical history, examined and then referred to the study nurses dedicated only to treatment allocation. Participants were randomly allocated to oral three days treatments based on a computer generated code provided by a staff not involving in the patient's evaluation. The treatment was either artemether-lumefantrine or artesunate-amodiaquine. The dosage was given on weight basis as per national malaria control program recommendation as this study is intented to evaluate the efficacy of first line treatments of malaria as implemented by the national malaria control program: (a) Artemether-lumefantrine (Coartem® Novartis administrated in tablet containing 20 mg of artemether plus 120 mg of lumefantrine); (b) artesunate-amodiaquine as given as tablet containing 67.5 mg plus 25mg respectively). The study as per its objectives is to inform straight away, it was not blinded to the study staff and patient. The treatment was administrated as DOT (directly observed treatment) and participants were retained for 30 minutes and in case of vomiting within this time period, a replacement dose was given. Any repeated vomiting led to the participant exclusion from further follow up and referral to health facility staff for standard care. Children presenting with hemoglobin less than 10 g/dL were treated according to the Integrated management of childhood Illness guidelines with ferrous sulfate for 14 days and anthelmintic treatment, if appropriate.
Follow up and classification of treatment outcome: patients were asked to return to the study clinics on day 1,2,3,7,14,21 & 28 and at any time they were feel illness. Field workers visited those who failed to return to the clinics and each visit consisted on standard case report completion, physical examination, a finger pick for thin and thick blood smear. Blood smears were read to assess the parasite density and gametocytes. Patients were followed up for 28 days and Gametocytes were recorded as present or absent. Hemoglobin level was measured from finger prick blood sample using a portable photo spectrophotometer (HemoCue).
Statistical analysis: the study was designed to check the efficacy of first line treatment of malaria in Burkina Faso, artemetgherlumefantrin and artesunate-amodiaquine. We anticipated that 136 participants will be needed in each group to assess the efficacy of artemether-lumefantrin versus artesunate-amodiaquine assuming 90% uncorrected cure rate in artesunate-amodiaquine group (detecting a difference of 15%) with 80% and significance level of 0.05 accounting for 20% of lost to follow up. Baseline characteristics of enrolled participants will be summarized; participants in each category (anemic or not) will be presented as proportion and compared between drug regimen. Categorical variables will be compared dosing chi square test while continuous are compared using either independent or dependant t-test. Kaplan Meyer estimate will be used to calculate the risk of treatment failure using strick formula and patient were censored the day they left the study.

Results
Baseline characteristics of enrolled participants: a total of 281 children were enrolled over the study period and treated with either AL or ASAQ for three days. About 43% of the participants treated with AL and 56.7% of those treated with ASAQ were male. Children 5-9 years were more represented. Mean hemoglobin was 10.82±1,2 g/dL and 10.92±1,85 g/DL respectively in AL and ASAQ groups. Other characteristics are described in Table 1 and Figure 1.
Treatment efficacy: we did not record any early treatment failure over the 28 days follow up period in all treatment groups. Late clinical failures were recorded in all groups: 5 cases 3.9% in AL and 1.5% in ASAQ group meaning that patients treated with AL were 2.6 more likely to have late clinical failure compared to patients treated with ASAQ (p = 0.2). All cases were above 59 months except the failure in the AL group which occurred in 16 months old boy. On the other hand, late parasitological failures were more common, 10.9% and 1.5% respectively in AL and ASAQ groups; patients treated with AL were almost 8 times likely to experience late parasitological failure than those treated with ASAQ (p = 0.0016). Finally, treatment was significantly successful in ASAQ group (  (Table 3 and Figure 2).
Clinical symptoms: clinical symptoms were common at entry for all two drugs regimen. Weakness was observed in approximately 58% of participants in each arm but vomiting was more frequently observed with ASAQ (78.83% versus 65.94%, p = 0.1) ( Table 4).
Treatment tolerability: over the study period, we found no serious adverse event. The registered adverse events were mild to moderate and none required active treatment or intervention's discontinuation.
Common adverse events were weakness in either group. No pruritus or nausea were found (Table 5).

Discussion
This clinical trial was a study that is part of routine monitoring of first Thus, we can expect these drugs to retain some efficacy for a while.
In this study, all treatments doses were directly observed and this may have contributed to reach such high efficacy level.

What this study adds
 Overall these drugs remain effective even though the uncorrected efficacy is below the threshold of more than 90% recommended by the WHO;  This study rises the discussion around the Polymerase Chain Reaction correction to consider the drug efficacy in real life.

Competing interests
The authors declare no competing interests.

Acknowledgments
This research was conducted as part of the routine National Malaria Control Program Monitoring and Evaluation of first line therapy efficacy. We thank the nurses and the laboratory technicians who collected the data. We thank also the administration of the health district of Do and health facility of Colsama and Sakaby for their strong collaboration. We are grateful for all parents and children who participated in this study.             almost all patients were apyretic on day 2 and 3 for artemether-lumefantrine treated participants and very few remained on day 3