Treatment of Uncomplicated Malaria among Under-Five Children: A Systematic Review

Most uncomplicated malaria dominated countries have embraced the recommended first-line treatment of uncomplicated malaria. Artemisinin-based combination therapies such as Artemether-Lumefantrine, Artesunate + Amodiaquine and Dihydroartemisinin-Piperaquine have shown to be effective with Artemether-Lumefantrine and considered the most effective and approved by WHO. The study collected and reviewed recent randomized controlled trials for the treatment of uncomplicated malaria under five children. Eligibility criteria for the selected studies were based on the use of tools such as PICO (T) and data extraction tools such as REPOSE guidelines, PRISMA statement and eligibility criteria. This study includes only RCTs on the treatment of uncomplicated malaria under 5 s. Data was analyzed through comparative-narrative analysis. This study found 8 studies. Selected studies had a total of 10,682 participants within the age range of 0 - 59 months with the diagnosis of uncomplicated malaria and an MCP range of 2000 - 200,000 treated with different antimalarial drugs. Artesunate + Amodiaquine and Dihydroartemisinin-Piperaquine and Artemether-Lumefantrine drugs were found to be consistent in the treatment of uncomplicated malaria under 5 s within three days. Findings show that Artemether-Lumefantrine, Artesunate + Amodiaquine and Dihydroartemisinin-Piperaquine were the best drugs of choice due to their fast rate in fever reduction and parasite clearance. The efficacy of Artesunate + Amodiaquine and Dihydroartemisinin-Piperaquine is comparable to Dihydroartemisinin-Piperaquine. The study concludes that Artesunate + Amodiaquine and Dihydroartemisinin-Piperaquine can also be drugs of choice along with the well-known and utilized Artemether-Lumefantrine combination because of the fever reduction and parasite clearance within the first three days duration.


Background of Study
Malaria constitutes a global public health challenge despite the availability and affordability of its treatment and preventive measures. The World Health Organisation (WHO) [1] report revealed that malaria was responsible for an estimated 660,000 people morbidity and mortality comprised mostly of children under-five years in Sub-Saharan Africa. In another report (WHO) [2] report, Nigeria and the Republic of Congo accounted for over 40% of the estimated global malaria deaths. The Federal Ministry of Health (FMH) [3] suggests that malaria accounts for one quarter of all death cases in Africa and one of the world's highest malaria associated death rate with one in six children dying from malaria related illness before their fifth birthday. It is, pertinent to state that it is difficult to attribute the cause of death of under-five children in these countries to malaria alone without considering other existing conditions such as malnutrition, diarrhoea, respiratory tract infections (WHO) [4]. According to the National Population Commission [5], the endemic nature of malaria in Nigeria is very high with nearly 110 million cases diagnosed clinically annually with 25%, 11% and 30% of infant mortality, maternal mortality and under-five mortality respectively associated with malaria. It is important to state that the incidence of uncomplicated malaria in Sub-Sahara Africa always coexists with malnutrition which is a public health challenge [6] [7].
Following the birth of programs from International Organisations like Roll back malaria, Global Fund, UNICEF and non-profit international agencies, much emphasis is being directed towards the treatment of uncomplicated malaria in under-five [8]. Consequently, these bodies are faced with serious challenge of combating ACTs (Artemisinin-based combination therapies) resistance [9]. ACTs such as Artemether-Lumefantrine and Artesunate + Amodiaquine combinations continue to top the list in the multiple first-line treatment [10].
According to WHO [11] "the therapeutic efficacy studies are prospective evaluation of patients clinical and parasitological responses to directly observe treatment of uncomplicated malaria". WHO further recommends that all national malaria control programs (NMCP) should adopt antimalarial medicines with a parasitological cure rate of over 95%. WHO [11], however stated that there should be a change in the national treatment policy if the total treatment failure proposition is ≥ 10%. This policy statement thus initiated the establishment of a global surveillance system to monitor the emergence of resistance to antimalarial agents [11]. WHO, therefore continues to steer the driving wheel in the treatment of uncomplicated malaria through the development of drug policies in all WHO regions. Such policies have contributed to the withdrawal of some drugs for the treatment of malaria. The objective of this study was thus aimed at reviewing randomised controlled trials (RCTs) published studies on the treatment of uncomplicated malaria.

Materials and Methods
A systematic review design was used to identify, collect and analyse RCTs. Data for this study were from RCTs sourced from biographic database and the following search engines: Biomed central, Discover, Embase, Cochrane Library, and Science Direct. Only data from studies published in reputable and peer-reviewed journals were used. RCTs were restricted to those published or transcribed in English on the treatment of uncomplicated malaria in under-five children [12].

Study Protocol
Uncomplicated malaria is complex especially in under-five children. This is because children cannot verbalise the signs and symptoms they experience. The study protocol as shown on Figure 1 adopted and carried out in six stages according to the Cochrane's protocol format [13] as shown below.

Study Selection
The process of identifying RCTs with the aim to answer the research question is rigorous. However, the selection was done by the authors using the Cochrane's tool of assessing bias and the PRISMA checklist as a guide [14] [15] and the CONSORT recommendation selection process. The RCTs for this study was on studies examining the treatment of uncomplicated malaria in under-five children [16].

Sampling Technique
A purposive sampling technique guided by Cochrane's tool for assessing bias was employed for the study since a purposive sampling technique is a nonprobability sampling tool usually based on the author's judgement even though it is highly inflicted by the author's bias [17]. The sampling technique was done after Figure 1. Systematic review protocol for the study adopted from Higgins et al. [13].

Data Collection
Data source triangulation was the primary means of data collection. Data was collected through electronic means from databases, search engines and manually from the [18] [19]. Data extraction was based on the eligibility criteria as shown on Table 1, study design, age of participants; intervention, attrition and detection bias [20]. Randomization was assessed in relation to allocation, concealment, blinding, reporting of outcomes and follow ups that helped in removing bias and missing data [21].

Data Extraction
To achieve the aims and objective of the study, data was extracted using some data extraction tools such as PRISMA statement, REPOSE guidelines, PICOT, eligibility criteria, report characteristics of each included study like language, publication and year [27] [28]. This process of data extraction helped re-extract individual studies that were skipped during the first data collection. Data extraction was done solely by the authors. However, data extraction was done in duplicates to identify errors and minimise subjectivity from interpreting data [12].

Ethical Consideration
The ethical consideration of systematic reviews is authorship which is of different types: falsification, fabrication and plagiarism of RCTs. Considering the fact that systematic reviews integrity is highly threatened by these aforementioned [29] [30] this study maintained high degree of transparency as stated in the Cochrane's ethics of publishable reviews [31].

Description of Included Studies
A total of 6 electronic databases and search engines where searched. An aggregate of 6315 studies on the treatment of malaria was found ( Figure 2 & Table 2)

Analysis
With the use of Cochrane's tool for assessing bias, 8 studies were identified and analysed. All studies must have less than 15% drop out rate Inconsistencies in the dropout rate in each study [22] [23] NB: the method of randomizing subjects and form of blinding played a major role in the inclusion criteria [24]. In appraising the inclusion criteria for the study, the Cochrane's tool for assessing bias was used [25]. The rationale for this is because studies assessed with this tool reports low risks of bias [16] [26].

Characteristics of Included Studies
A total of 8 studies from 31 full-text studies were included in this review. The total numbers of participants in this review were 10,682 with an average of 1335 participants per study. However, the study with the highest number of participants had 4116 participants [32] while the least number of participants were 218 participants [33]. The age distributions of participants across the studies were 0 -  HIV exposure is not a complication of malaria neither is malaria a complication of HIV hence the study was included in this study. A brief description of the characteristics of the included study includes: Artesunate + Mefloquine versus Arthemeter-Lumefantrine [35]; No chemoprevention versus Sulphadoxine-Pyrimethamine versus Trimethoprim-Sulphamethoxazole versus Dihydroartemisin-Piperaquine [34]; Sulphadoxine-Pyrimethamine + Artesunate versus Sulphadoxine-Pyrimethamine + Amodiaquine versus Sulphadoxine-Pyrimethamine [36], Dihydroartemisin-Piperaquine versus Artemether-Lumefantrine [37]; Artesunate + Amodiaquine versus Artemether-Lumefantrine [38] and Artesunate + Amodiaquine versus Dihydroartemisin-Piperaquine versus Arthemeter-Lumefantrine versus Chroproguanil-daspone + Amodiaquine [32]. Other studies in this review include Amodiaquine versus Sulphadoxine-Pyrimethamine versus Sulphadoxine-Pyrimethamine + Amodiaquine [39]; and Quinine versus Arthemeter-Lumefantrine versus Dihydroartemisin-Piperaquine [33]. The studies were carried in a total of 3 -6 weeks. Majority of the studies (75%) were carried out in malarial) in this review is 13 (Table 2).

Quality of Included Studies (Risk of Bias)
The Cochrane's tool for assessing bias was used to determine the quality of the included studies [25] the quality of the included studies generally was high except in the areas of blinding of outcome of assessment with 40% high risk of bias as reported in Table 3, Figure 3 and Figure 4 respectively. Graphical and tabular representations of the quality of the included studies are displayed on Figure   3, Figure 4 and Table 2. All studies randomised the participants in their study.
Similarly, all included studies (100%) used random sequencing generation in allocating participants into various study groups however, 75% of the studies concealed their random sequencing generation while 25% were unclear about their allocation concealment [32] [34]. Therefore, for studies with unclear allocation concealment, there was insufficient knowledge to ascertain if they were or were not conducted properly ( Figure 3 and Figure 4). In the aspect of blinding of participants, only 2 studies (25%) Maiga et al. [36] Schramm et al. [38] used blinding technique for their participants. Thus 50% and 25% had unclear risks and high risk of bias respectively.
According to Higgins and Green [14], different types of people can be blinded in the course of conducting a study. Poor blinding of participants and/or healthcare providers introduces bias which may affect the end point (result) of the study. However, there are studies which describe the type of randomisation in a "blind" or "double-blinded" of either or both participants and personnel.   Yet in empirical studies, poor blinding exaggerates estimated intervention by 9% when measured on odds ratio. Hence the RCTs in this review reveal both subjective and objective outcomes (plasmodium clearance and elimination of fever after treatment).
Blinding of outcome assessment in this study occurred in 3 studies (38%) [36] [37] [38] while 38% and 25% were unclear and had high risk bias respectively. Often times, when outcomes are made known, subjective data are difficult to obtain as such data seeks to favour the study's expected outcome. All studies (100%) stated the number of participants and analysed the number that was present for follow-up. Conversely, all studies had few numbers of dropouts (missing data due to attrition). In all cases of missing data, either death or absence of participants and their parents/guidance were the cause of attrition [39] [40] [41]. It is important to note that concerns over bias from incomplete data are often left for theoretical considerations. Previous studies on the relationship between missing data and the magnitude of effects of potential bias found that there is no clear evidence of bias [42] [43]. Furthermore, 5 studies (63%) did not employ selective reporting while analysing their studies. However, 2 studies had unclear risk of bias, as one study had a high risk of bias for selective reporting [33]. Other forms of bias seen in this study was in one study (12%) [34]. While other studies showed no sign of other bias. These combine to present a high methodology for the included studies as seen on Figure 3, Figure 4 and Table 4.
The inclusion of the studies was determined by their quality as seen on Table  3.

Review of Findings from Included Studies
According to The 4ABC Study Group (2011), the efficacy can be summarised as   Pyrimethamine monotherapy group and none in Sulphadoxine-Pyrimethamine + Artesunate and Sulphadoxine-Pyrimethamine + Amodiaquine groups. There was rapid reduction in fever in all groups as 1.7%, 2.6% and 5.9% of Sulphadoxine-Pyrimethamine + Artesunate, Sulphadoxine-Pyrimethamine + Amodiaquine and SP treatment groups had the parasite on Day 3. Gametocyte carriage decreased between baseline and on Day 28 in Sulphadoxine-Pyrimethamine + Artesunate and Sulphadoxine-Pyrimethamine + Amodiaquine with no decrease found in the SP treatment monotherapy group. On Day 28, there was no reduction in the prevalence of malaria in all the groups. Hence the non-ACTs like Sulphadoxine-Pyrimethamine + Amodiaquine was as efficacious as

Adverse Events (Complications from the Study)
All studies reported adverse events. Most of the adverse events were related to the prognosis of the severity of malaria especially in studies that reported death of participants [32], however, finding was not stated in Sulphadox-

Discussion
This study analysed 8 RCTs on the treatment of uncomplicated malaria in under 5 children. The studies involved a total of 10,682 participants with an average of 1335 participants per study. The study used different pharmaceutical antimalarial agents approved for the treatment of malaria in humans. All studies had similar study objectives, baseline demographic characteristics and study popula-tion but different antimalarial agents.
Two common objectives among the studies were: reduction of fever and parasite clearance. According to the findings, all antimalarial in this study were effective in reducing fever parasite clearance. Although Arthemeter-Lumefantrine was often the drug of choice, it was not the only medication found to be effective from analysis. Artesunate + Amodiaquine and Dihydroartemisin-Piperaquine were also effective in the early reduction of fever and parasite clearance. Based on these findings, it is important to note that the use of single antimalarial monotherapy (Quinine, Amodiaquine and Sulphadoxine-Pyrimethamine) had records of failures compared to antimalarial combination therapies. Previously, monotherapy had been effective in the treatment of uncomplicated malaria until there was report of resistance to antimalarial monotherapy medications. Sodahlon and colleagues [44] study report supported this assertion on the low quality in the efficacy of Quinine and Amodiaquine in children whose indication has been diminished with the production of Arthemeter-Lumefantrine, Artesunate + Amodiaquine and other antimalarial combination therapies [45]. From the analysis, Artesunate + Amodiaquine showed faster fever clearance than AL due to the antipyretic properties of Artesunate. This is in agreement with studies by Gbotosho et al. [46] [47] which state that Artesunate + Amodiaquine has antipyretic properties that act in fever clearance thus their high recommendation for its use in the treatment of uncomplicated Malaria especially among under 5 s.
This evidence is supported by the approval of Arthemeter-Lumefantrine as the first line drug of choice in the treatment of malaria by WHO [48] in Africa. The findings also revealed that fever elimination was quicker in children treated with Artesunate + Amodiaquine and Arthemeter-Lumefantrine than other antimalarial as reported by Oguche and colleagues [49] study. This review observed that both ACTs and Non-ACTs use resulted in the elimination of the malaria parasites by the spleen. This is in agreement with Chotwanich et al. [50] and Gbotosho et al. [51] studies who opined that antimalarial combination therapies eliminate parasites more than monotherapies. It also observed that there was haemoglobin improvement to a normal level after the treatment with the above drugs of choice. Anaemia due to destruction red blood cells was thus significantly reduced after treatment compared with baseline level prior to the commencement of the trials. This finding was supported by Oguche and colleagues [49] study stating that effective use of antimalarial results in improvement of haemoglobin. The analysis showed that reduction in haemoglobin level from the use of AL, Artesunate + Amodiaquine and Dihydroartemisin-Piperaquine were faster compared with other antimalarial. Nevertheless, the disparities of the adverse events reported in the studies were not different from the signs and symptoms of uncomplicated malaria thus the result of withdrawal from the studies by participants were minimal as all studies had under 15% withdrawal rate. Although differentiating the side effects from signs and symptoms of uncomplicated malaria is difficult, measuring the severity can be de-termined through prolonged/resistance to treatment. Studies involving Arthemeter-Lumefantrine, Artesunate + Amodiaquine and Dihydroartemisin-Piperaquine, reported participants' tolerance of these drugs more than other drugs may be due to the high fever and parasite clearance. Studies suggest that compliance and tolerance to antimalarial agents results in increased efficacy in the treatment of uncomplicated malaria in children [52] [53].

Conclusion
This study systematically reviewed studies involving different antimalarial used in the treatment of uncomplicated malaria under 5 s children. A total of 8 RCTs were reviewed with above average low risk bias in qualities of studies. The rate of low risk of bias was high among the studies used thus considering this study to be of high quality. Findings showed that Arthemeter-Lumefantrine, Artesunate + Amodiaquine and Dihydroartemisin-Piperaquine were best drugs of choice due to their fast fever rate reduction and parasite clearance. No difference was observed in the efficacy of Arthemeter-Lumefantrine when compared to Artesunate + Amodiaquine and Dihydroartemisin-Piperaquine in the treatment of uncomplicated malaria. It is suggested that due to the faster rate of fever reduction in participants when treated with Artesunate + Amodiaquine and Dihydroartemisin-Piperaquine, there is need to classify Arthemeter-Lumefantrine, Artesunate + Amodiaquine and Dihydroartemisin-Piperaquine among the first line drugs in the treatment of uncomplicated and resistant malaria respectively.