Trans R Soc Trop Med Hyg 2016; 00: 111

doi:10.1093/trstmh/trw077

Efcacy and safety of artesunate-meoquine therapy for treating

uncomplicated Plasmodium falciparum malaria: systematic
review and meta-analysis

REVIEW
Henry Maia Peixotoa,b,c,*, Paola Barbosa Marchesinid and Maria Regina Fernandes de Oliveiraa,c

a
Centre for Tropical Medicine, University of Braslia, Braslia, Federal District, Brazil; bUniversity Centre of Braslia, Braslia,
Federal District, Brazil; cNational Institute for Science and Technology for Health Technology Assessment (IATS/CNPq), Porto

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Alegre, Rio Grande do Sul, Brazil; dMinistry of Health, Secretariat of Health Surveillance, Brazil

*Corresponding author: E-mail: [email protected]

Received 14 September 2016; revised 7 November 2016; editorial decision 30 November 2016; accepted 1 December 2016

Introduction: The present study is a systematic review of the literature on the efcacy and safety of the treat-
ment of uncomplicated Plasmodium falciparum infections with artesunate-meoquine (ASMQ) compared to
other artemisinin-based combination therapies (ACTs), designed to assist decision makers in Brazil.
Methods: Twenty-four randomized controlled trials (RCTs) were selected in four electronic databases and in
complementary sources. Meta-analyses were performed to evaluate the efcacy expressed by relative risks
(RR) obtained from treatment failure conrmed by the PCR.
Results: Due primarily to the presence of measurement bias in the selected studies, the quality of the evi-
dence was considered predominantly moderate. Statistically signicant associations were not observed when
ASMQ was compared to artemether-lumefentrine and dihydroartemisinin-piperaquine. The results of studies
performed in areas with a history of use of ASMQ, regardless of the intensity of transmission, were not statis-
tically different from those presented in the meta-analyses. For comparisons with artesunate-amodiaquine
and artesunate+sulfadoxine-pyrimethamine, the results were favourable to ASMQ. No deaths were attributed
to ASMQ, severe adverse events were rare and some studies indicate a higher frequency of mild adverse
events.
Conclusions: The use of ASMQ it is recommended to Brazil as rst line treatment of uncomplicated P. falciparum
infections.

Keywords: Artesunate-meoquine, Artemisinin-based combination therapy, Efcacy, Malaria, Plasmodium falciparum, Treatment

Introduction has a lower viability due to the inuence of technical and oper-
Malaria is a major cause of illness and death among adults and ational factors such as scarcity in health-care, the increased
children worldwide. It is estimated that 3.2 billion people are transmission caused by substantial cross-border populational
residing in countries and territories with malaria risk.1 According movements, political instability and poor management.3
to WHO, only in 2015, 214 million cases and 438 000 deaths Even though P. falciparum is responsible for most of the compli-
attributed to malaria occurred worldwide.1 cations and malaria deaths worldwide, the mortality rate due to
Although malaria persists as one of the major public health the disease has been reducing each year,1 potentially due to the
problems in the world, in the past years the efforts destined to control strategies adopted by malaria control programs, based
its control have shown successful results, leading some regions especially on appropriate diagnosis, treatment with effective
to discuss the possibility of its elimination.2 In that respect, drugs, mass drug administration, the use of long-lasting insecti-
Tatem et al. showed that endemic countries in America and cide-treated nets and insecticide spraying.46
Asia present a great potential for the elimination of Plasmodium Bhatt and collaborators, when analysing the control strat-
falciparum, for Central and West Africa countries, elimination egies used in Africa between 2000 and 2015, indicated that

The Author 2016. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved.
For permissions, please e-mail: [email protected].

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the large-scale implementation of immediate treatment with with potential positive repercussions, both from a technical
artemisinin-based combination therapy (ACT) signicantly reduced point of view by standardizing and adopting a more effective
the number of severe malaria cases and deaths, besides contribut- and safe treatment and from the operational point of view,
ing to the reduction of disease incidence.7 facilitating the training, the use, the acquisition and the distribu-
Treatment of uncomplicated malaria should target the rapid tion of the medication in the country (unpublished data).
elimination of all parasites from the body, the prevention of In Brazil, the Ministry of Health recommends the therapy and
severe disease complications and the prevention of transmis- provides antimalarial medicines for all the country. The choice of
sion.8 WHO recommends that treatment of uncomplicated mal- malaria treatment is made by the Subcommittee of Malaria
aria, caused by P. falciparum, should be founded on therapeutic Therapy of the PNCM, composed of researchers, professors and
regimens based on ACT and indicates the following combina- health professionals of renowned reputation in the area, based
tions: artemether-lumefentrine (AL); artesunate-amodiaquine on the best scientic evidence available16 and the recommen-
(AA); artesunate-meoquine (ASMQ); artesunate+sulfadoxine- dations of WHO.8
pyrimethamine (ASP); dihydroartemisinin-piperaquine (DP).8 Based on this background, the present study was demanded

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ACTs have been strongly recommended based on high quality by the Ministry of Health in order to assist in the decision about
evidence of very good efcacy besides the reduction of the risk of the possibility of recommendation of treatment with the same
drug resistance.8,9 Nevertheless, the continuous monitoring of derivate of artemisinin for the whole country. This study con-
therapeutic efcacy of ACT for P. falciparum is recommended and ducted a systematic literature review, the objective of which
the efcacy of the medication should be considered by the was to collect scientic evidence related to the efcacy and
national malaria control programs when dening the most appro- safety of uncomplicated P. falciparum treatment with ASMQ
priate ACT.8 Recently published studies have shown different combination compared to treatment with other ACTs.
results in different regions. The study conducted by Ladeia-
Andrade et al. in Acre, Brazilian Amazon, demonstrated an excel-
lent therapeutic performance of ASMQ, besides not identifying
Methods
evidence of drug resistance.10 On the other hand, Phyo et al. indi-
cated a potential increase in treatment failure with ASMQ on the The present systematic literature review selected indexed arti-
Thailand-Myanmar border.11 The spread of the resistance of cles in the databases of EBSCOhost Research Databases
P. falciparum to artemisinin has caused concern worldwide due to (EBSCO), MEDLINE, Latin American and Caribbean Literature on
the potential impact on the efciency of ACTs. Regarding this, Health Sciences (LILACS) and Cochrane Central Register of
Mnard et al. report that this resistance is restricted to Southeast Controlled Trials (CENTRAL). The searches were organized from a
Asia and China.12 Ashley et al. inform that despite the spread of set of descriptors and MeSH terms presented in Box 1.
resistance to artemisinin in Southeast Asia, the ACTs remain highly The eligibility criteria included studies published in the last 15
effective.13 years, between January 2001 and December 2015. Only original
Recently, Banek and collaborators presented a systematic lit- studies were considered, resulting from controlled and rando-
erature review evaluating adherence to four different ACTs, indi- mized clinical trials that evaluated the efcacy and/or safety of
cating, from evidence from several prospective studies conducted P. falciparum infection treatments with the ASMQ combination,
in different countries, that adherence varied as follows: ASMQ whose diagnosis were made by microscopy, rapid test or PCR
between 94 and 95.5%, AL between 39 and 99.3%, AA between and which used one of the following ACTs for comparison: AL,
48 and 94% and ASP between 39 and 75%.14 Santelli et al., AA, ASP and DP. Articles and documents according to the follow-
when assessing ASMQ in a region of the state of Acre in the ing criteria were excluded: whose objective was not the treat-
Brazilian Amazon, demonstrated that the continuous use of the ment of P. falciparum infections with the combination ASMQ,
therapeutic regimen reduced the incidence and hospitalizations developed with children under six months and pregnant
due to P. falciparum, besides not identifying severe adverse women. Additional articles were obtained from the tracking of
events.15 the references cited in reviewed articles and from the selected
In Brazil, two ACTs are indicated for uncomplicated P. falcip- original studies, besides research on grey literature.
arum treatment: AL, mainly used in the Brazilian Amazon Each abstract identied was read by the researcher and
region; and ASMQ, especially used in the other regions.16,17 Both supervised by a second one. The abstracts were classied
regimens are administered orally for three days, the ASMQ com- according to the dened criteria of inclusion and exclusion.
bination in a single daily dose and the AL in two daily doses, Those that met the inclusion criteria and did not show any of
thus, requiring a larger quantity of tablets.16 the exclusion ones were selected for full reading. Those which
According to WHO, every country must choose the most did not meet the inclusion criteria or that met the exclusion
appropriate ACT, taking into account aspects related to adher- ones were excluded from the full reading phase and the
ence, safety and efcacy.8 In this scope, further clarication on abstracts that did not allow conclusions about meeting the cri-
the efcacy of the ASMQ regimen, and security-related aspects, teria were also selected for full reading.
can assist the decision-making process regarding the recom- The selected articles were evaluated on the quality of the
mendation of a unique rst line regimen to treat uncomplicated evidence and the degree of recommendation using the meth-
P. falciparum infections in all Brazilian regions, what, according ods and instruments described below. The tool proposed by the
to the Subcommittee of Malaria Therapy of the National Cochrane Collaboration guided the evaluation of quality, in
Programme of Prevention and Control of Malaria (PNCM), would terms of bias risks of the randomized controlled clinical trials
provide a better standardization of the treatment in the country, (RCTs) selected. Six areas were evaluated: randomization

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Box 1. Descriptors and MeSH terms used for literature search.

MEDLINE: ((artesunate[Supplementary Concept] OR artesunate[All Fields]) AND (meoquine[MeSH Terms] OR meoquine[All Fields]))
AND ((treatment outcome[MeSH Terms] OR (treatment[All Fields] AND outcome[All Fields]) OR treatment outcome[All Fields]) OR
(therapy[Subheading] OR therapy[All Fields] OR treatment[All Fields] OR therapeutics[MeSH Terms] OR therapeutics[All Fields]) OR
(therapy[Subheading] OR therapy[All Fields] OR therapeutics[MeSH Terms] OR therapeutics[All Fields]) OR (therapeutics[MeSH Terms]
OR therapeutics[All Fields]) OR ((therapy[Subheading] OR therapy[All Fields] OR treatment[All Fields] OR therapeutics[MeSH Terms]
OR therapeutics[All Fields]) AND success[All Fields]) OR (treatment failure[MeSH Terms] OR (treatment[All Fields] AND failure[All Fields])
OR treatment failure[All Fields]) OR efcacy[All Fields] OR effectiveness[All Fields] OR (safety[MeSH Terms] OR safety[All Fields]) OR toler-
ability[All Fields] OR (drug resistance[MeSH Terms] OR (drug[All Fields] AND resistance[All Fields]) OR drug resistance[All Fields])) AND
((malaria[MeSH Terms] OR malaria[All Fields]) OR (plasmodium falciparum[MeSH Terms] OR (plasmodium[All Fields] AND
falciparum[All Fields]) OR plasmodium falciparum[All Fields]) OR falciparum[All Fields]) AND ((clinical trial[Publication Type] OR clinical

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trials as topic[MeSH Terms] OR clinical trial[All Fields]) OR (randomized controlled trial[Publication Type] OR randomized controlled trials
as topic[MeSH Terms] OR randomized controlled trial[All Fields] OR randomised controlled trial[All Fields]) OR ((random allocation[MeSH
Terms] OR (random[All Fields] AND allocation[All Fields]) OR random allocation[All Fields] OR randomized[All Fields]) AND
(Trials[Journal] OR trials[All Fields]))) AND (humans[MeSH Terms] OR humans[All Fields])
EBSCO: (Artesunate and meoquine) AND (Treatment Outcome OR Treatment OR therapy OR treatment success OR treatment failure OR ther-
apeutics OR efcacy OR effectiveness or safety OR tolerability OR drug resistance) AND (malaria OR Plasmodium falciparum) AND (Clinical Trial
OR randomized controlled trial OR randomized trials) AND (humans)
LILACS: (Artesunate and meoquine) AND (malaria OR Plasmodium falciparum)
CENTRAL: (Artesunate and meoquine) AND (Treatment Outcome OR Treatment OR therapy OR therapeutics OR treatment success OR treat-
ment failure OR efcacy OR effectiveness OR safety OR tolerability OR drug resistance) AND (malaria OR Plasmodium falciparum) AND (Clinical
Trial OR randomized controlled trial OR randomized trials) AND (humans)

CENTRAL: Cochrane Central Register of Controlled Trials; EBSCO: EBSCOhost Research Databases; LILACS: Latin American and Caribbean
Literature on Health Sciences.

(selection bias occurred during the generation of the sequence The outcomes related to efcacy, for which more than one
of the randomization); allocation concealment (selection bias study was identied, were combined according to the medicines
due to inadequate concealment of the allocation); blinding being compared and the moment when the outcomes were
(measurement bias due to prior knowledge of interventions by evaluated (28, 42 and 63 days). The RevMan software (Review
patients and professionals); incomplete outcome (attrition bias Manager 5.3; Cochrane Collaboration, London, UK) subsidized
due to the amount, nature or manipulation of data expressing the combination of the relative risks and the estimation of
incomplete results); and selective reporting (information bias condence intervals at 95%. A homogeneity statistical test at
due to selective outcome report). The results were categorised decision level of 5% was performed. The xed effect model was
into high risk of bias, low risk of bias and unclear.18 The method- used in most of the analyses, however, the random effects
ology proposed by the Grading of Recommendations Assess- model was used when the test for homogeneity presented
ment, Development and Evaluation Guidelines (GRADE) guided the p value lower than 0.5 or the I statistic was higher than
the quality evaluation of the set of evidence and recommenda- 50%.
tion. The outcomes that evaluated the treatment failure after The results related to security were synthesised qualitatively
63 days of follow-up were considered critical for recommenda- from the individual analysis of the selected studies regarding
tion, that is, of greatest importance. The results obtained after deaths and adverse events.
28 or 42 days were considered important, but not critical, since
they may have underestimated the treatment failure.
The efcacy was evaluated by the outcome treatment failure
adjusted according to the PCR results for 28, 42 and 63 days, Results
allowing the differentiation between recrudescence and reinfec-
tion. Meta-analyses were performed according to the intention- Selecting the evidence base
to-treat analysis (ITT) and the per-protocol analysis (PP). In the Figure 1 describes the ow of information in the different review
ITT, the patients who presented recrudescence conrmed by stages. Initially, 326 studies were found, 319 from the system-
the PCR, follow-up losses and inconclusive tests results (inconclu- atic search in the databases and seven from other sources con-
sive or missing PCR) were considered as treatment failure. New sidered complementary. After the evaluation of duplication, 198
infections were excluded from the analysis. In the PP, patients articles remained, of which 155 were excluded after reading the
who presented recrudescence conrmed by PCR were considered title and abstract for not meeting the inclusion criteria. Forty-
as treatment failure. The losses of follow-up, the results of incon- three studies were selected for full reading, but only 24 were
clusive tests (inconclusive or missing PCR) and the new infections included in the qualitative synthesis, of which two did not com-
were excluded from the analysis. pose the quantitative synthesis since their data on efcacy were

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Figure 1. Fluxogram of the selection process for the evidence on efcacy and safety of artesunate-meoquine in the treatment of Plasmodium
falciparum malaria.

dealt with in the multicentre study published by Valecha et al., The results were organized and are presented in Table 3 and
also included in this review.19 Figures 2 and 3.
Table 3 summarizes the main results, organizing them
according to the considered comparison, it presents the quality
Main characteristics and quality of the evidence evaluation and the importance of the set of evidences selected,
in terms of risk of bias in each analysis, for the formulation of the recommendation.
The studies presented at least one serious risk of bias, they
In Table 1 the main characteristics of the 24 selected RCTs are
were considered free of indirect evidence for having been per-
described. The identication of studies conducted in 12 coun-
formed, preponderantly, with children, adolescents and adults
tries is observed, predominating those developed in Asia, fol-
living in areas with different levels of transmission, besides
lowed by Africa and South America, in areas with different
having been held in different continents. Figures 2 and 3 dem-
patterns of transmission. Regarding the participants, 17 trials
onstrate that the majority of the combined studies presented
selected children, adolescents and adults, three selected only
similar results and were homogeneous in the level of statistical
teenagers and adults, two only children and two only adults.
decision at 5%. The combinations were precise in most of the
The therapeutic regimens compared to ASMQ were more fre-
analyses.
quently AL and DP, whose follow-up time varied between 28, 42
The results evidence that in the comparison between ASMQ
and 63 days.
and AL regimens, the treatment with ASMQ showed a better
In Table 2 the evaluation of the risk of bias of the 24 selected
efcacy for all the outcomes considered critical for recommen-
articles according to the tool proposed by the Cochrane
dation, although they were not statistically signicant in the
Collaboration18 is presented. Although only RCTs have been
decision level at 5% or did not present specic values that
included, all of them presented at least one major risk of bias,
express elevated effects.
with a highlight to the measurement bias related to the
The comparison between ASMQ and DP demonstrated, in the
absence of blinding, since all studies were open label trials, fol-
ITT analysis for the follow-up of 63 days, favourable effects to
lowed by the lack of detailing about the randomization
ASMQ; the PP analysis was favourable to DP, although neither
sequence present in 14 studies.
were statistically signicant at the 5% decision level or did not
present a high magnitude of effect.
To compare ASMQ and AA, relative risks favourable and
Efcacy and safety of the artesunate-meoquine statistically signicant to ASMQ were identied, with high mag-
therapy nitudes of effect for the outcome treatment failure adjusted
Analyses were performed from the comparison between the by the PCR on the 63rd day, with RR=0.17 (ITT) and RR=0.02
ASMQ combination and the other ACTs considered in the study. (PP). However, only one study was considered in the analysis,

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Table 1. Main characteristics of the randomized controlled trials included in a review to evaluate the efcacy of artesunate-meoquine (ASMQ)
in treating uncomplicated Plasmodium falciparum malaria

Study country and reference Participants ACTs compared Transmission of P. falciparam Follow-up
to ASMQ

Senegal20 Children, adolescents and adults AL, AA, ASP Moderate 28 days
Senegal21 Children AL Without description 28 days
Thailand22 Children, adolescents and adults AL Low 42 days
Thailand23 Adolescents and adults AL Without description 28 days
Laos24 Children, adolescents and adults AL High 42 days
Mali25 Children, adolescents and adults AL High 28 days

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India26 Children, adolescents and adults AL, ASP High 42 days
Myanmar27 Children, adolescents and adults AL, DP, AA Without description 63 days
Laos28 Children, adolescents and adults AL High 42 days
Senegal29 Adults AL High 63 days
Rpublique de Cte dIvoire30 Children AL High 28 days
Bangladesh31 Children, adolescents and adults AL High 42 days
Colombia32 Adolescents and adults AL Without description 42 days
Thailand33 Children, adolescents and adults DP Low 63 days
Thailand34 Children, adolescents and adults DP Low 63 days
Peru35 Children, adolescents and adults DP Low 63 days
Cambodia36 Children, adolescents and adults DP Low 63 days
Laos37 Children, adolescents and adults DP Without description 42 days
Laos38 Children, adolescents and adults DP Without description 63 days
Myanmar39 Children, adolescents and adults DP Low to High 42 days
Thailand40 Adolescents and adults DP Without description 28 days
Vietn41 Children, adolescents and adults DP Low 42 days
India, Laos and Tailncia19 Children, adolescents and adults DP Low (Thailand), Without description 63 days
(India and Laos)
India42 Adults DP Without description 63 days

ACTs: artemisinin-based combination therapies; AA: artesunate-amodiaquine; AL: artemether-lumefentrine; ASMQ: artesunate-meoquine;
ASP: artesunate+sulfadoxine-pyrimethamine; DP: dihydroartemisinin-piperaquine.

a fact that limits the quality of information. The comparison difculty in distinguishing whether the events resulted from
between ASMQ and ASP, also based on only one study, pre- malaria or from medication. Regarding the less severe adverse
sented similar results. For all the comparison, the results events, most of the studies did not present statistically
obtained from the segments consisting of 28 and 42 days pre- signicant differences among the groups, although some dem-
sented similar results. onstrate higher frequency of headache, dizziness, sleep distur-
Figures 2 and 3 also detail the results for the outcome treat- bances, nausea and vomiting in the group that used ASMQ.
ment failure, combined by means of meta-analysis, according Although the prolongation of the QT interval corrected for heart
to the type of analysis (ITT or PP) and follow-up time (28, 42 or rate (QTc) was identied in some patients treated with
63 days) for the comparisons between ASMQ and AL and ASMQ ASMQ,19,23,38 its frequency was lower and it was not associated
and DP. It was not possible to combine the results for the other with severe complications.
ACTs since only one study for each outcome evaluated was
identied.
The results regarding safety can be seen in Supplementary
Discussion
Box 1, which presents a qualitative synthesis of the main infor-
mation described in the studies. Deaths related to the use of The information gathered in the present study can assist the
the medicine in analysis were not registered. The descriptions of decision-making process by providing, from clearly established
severe adverse events were rare, although most have been criteria, recommendations on the treatment of uncomplicated
reported in the group that used ASMQ (delirium, severe anxiety, malaria caused by P. falciparum with ASMQ, with implications for
sleep disorders and seizures). Possibly due to the low frequency patients, clinicians and managers. According to Guyatt and col-
of severe adverse events, the selected studies did not identify a laborators, the recommendations must be based on evaluating
statistical difference between the groups evaluated, besides the the quality of the evidence gathered in the review, in the

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Table 2. Evaluation of the quality of articles in terms of risk of bias: review authors judgements about each included study

Reference Random sequence Allocation Blinding Incomplete Selective reporting Other bias
generation concealment outcome

Faye et al. 200720 Unclear risk Unclear risk High risk Unclear risk Low risk Low risk
Faye et al. 201021 Unclear risk Unclear risk High risk Low risk Low risk Low risk
Hutagalung et al. 200522 Low risk Unclear risk High risk Low risk Low risk Low risk
Lefvre et al. 200123 Unclear risk Unclear risk High risk Low risk Low risk High risk
Mayxay et al. 200424 Unclear risk Low risk High risk Low risk Low risk Low risk
Sagara et al. 200825 Low risk Low risk High risk Low risk Low risk Low risk
Saha et al. 201226 Low risk Low risk High risk Low risk Low risk Low risk

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Smithuis et al. 201027 Unclear risk Low risk High risk Low risk Low risk Low risk
Stohrer et al. 200428 Unclear risk Unclear risk High risk Low risk Low risk Low risk
Tine et al. 201229 Unclear risk Unclear risk High risk Low risk Low risk Low risk
Toure et al. 201130 Low risk Low risk High risk Low risk Low risk Low risk
van den Broek et al. 200531 Low risk Unclear risk High risk Low risk Low risk Low risk
Carrasquilla et al. 201232 Unclear risk Unclear risk High risk Unclear risk Low risk Low risk
Ashley et al. 200433 Low risk Low risk High risk Low risk Low risk Low risk
Ashley et al. 200534 Low risk Low risk High risk Low risk Low risk Low risk
Grande et al. 200735 Unclear risk Low risk High risk Low risk Low risk Low risk
Janssens et al. 200736 Low risk Unclear risk High risk Low risk Low risk Low risk
Mayxay et al. 200637 Unclear risk Low risk High risk Low risk Low risk Low risk
Mayxay et al. 201038 Unclear risk Low risk High risk Low risk Low risk Low risk
Smithuis et al. 200639 Low risk Low risk High risk Low risk Low risk Low risk
Tangpukdee et al. 200540 Unclear risk Unclear risk High risk Low risk Low risk Low risk
Tran et al. 200441 Unclear risk Low risk High risk Low risk Low risk Low risk
Valecha et al. 201019 Low risk Low risk High risk Low risk Low risk Low risk
Gargano et al. 201242 Unclear risk Low risk High risk Low risk Low risk Low risk

balance between the desirable and the undesirable effects, in AL, observed ve severe adverse events in 781 individuals in the
the preferences and in the costs involved.43 ASMQ arm and two severe adverse events in 992 individuals in
The quality of the evidence selected in the review was con- the AL arm, resulting in a RR of 2.96 (95% CI 0.6413.76).
sidered, predominantly, moderate, mainly due to the risk of Severe adverse events, including death, associated with the
measurement bias arising probably from the operational dif- use of xed doses of ASMQ were not identied in a descriptive
culties to blind patients and professionals reported in some of experimental study that followed 23 845 individuals treated
the selected studies. It is likely, considering this quality, that the with these xed doses of ASMQ in the Brazilian Amazon.15 This
efcacy is close to the estimates presented in the meta- research also demonstrated that the treatment signicantly
analysis. reduced the incidence rate of malaria by P. falciparum in the
Regarding the balance between desired and undesired municipalities evaluated. According to WHO, meoquine is gen-
effects, the results that were considered important and critical erally well tolerated, although it is associated with an increase
for the recommendation demonstrated that ASMQ presented a in the incidence of nausea, vomiting, dizziness, dysphoria and
similar efcacy when compared to AL and to DP, since statistic- sleep disorders, which in turn are rarely debilitating.8
ally signicant differences in the combined results were not Meoquine has been associated with an increase in the inci-
observed. ASMQ presented a better efcacy when compared to dence of adverse events related to the central nervous system,
AA and ASP, although in both cases the quality of evidence was although it is generally well tolerated when combined with arte-
considered low. As for security, even though some studies have sunate.8 The studies gathered in this review indicate that events
identied an increased frequency of mild adverse events among such as dizziness, headache and neuropsychiatric disorders
patients who used ASMQ, the severe adverse events were rare (severe nightmares, hallucinations, anxiety and insomnia) were
and deaths associated with the use of the drug were not mostly transitory and occurred in greater number in the ASMQ
identied. group. The low frequency of most of these events, particularly
Corroborating with these results, Sinclair and collaborators the neuropsychiatric ones, does not allow the establishment of
presented similar results regarding the efcacy and safety of a clear association between the use of the medications and the
ASMQ when compared to AL.9 The authors, by combining in a adverse events. Sinclair et al.9 by reviewing the literature and
meta-analysis the severe adverse events from seven rando- comparing ASMQ to DP and AL identied similar results to those
mized clinical trials on the use of the combinations ASMQ and presented in this study.

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Table 3. Artesunate-meoquine (ASMQ) vs artemisinin-based combination therapies (ACTs) for treating uncomplicated Plasmodium falciparum
malaria: results, quality of evidence and importance of outcomes

Number of studies/ Follow-up ASMQ failure rate ACT failure rate RR (95% CI) Overall quality Importance
(analysis) (GRADE) of outcomes
(GRADE)

8 studies/28 days (ITT) 76/1361 AL 79/1260 0.89 (0.651.22) Moderatea,b,c,d Important

8 studies/28 days (PP) 22/1420 AL 25/1320 0.92 (0.511.64) Moderatea,b,c,d Important
6 studies/42 days (ITT) 47/606 AL 82/685 0.77 (0.531.11) Moderatea,b,c,d Important
7 studies/42 days (PP) 12/638 AL 17/692 0.72 (0.361.43) Moderatea,b,c,d Important
1 study/63 days (ITT) 23/322 AL 15/152 0.72 (0.391.35) Moderatee Critical

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2 studies/63 days (PP) 3/355 AL 03/178 0.54 (0.112.62) Lowa,b,c,f Critical
5 studies/28 days (ITT) 36/799 DP 21/718 1.31 (0.762.26) Moderatea,b,c,d Important
5 studies/28 days (PP) 1/764 DP 03/699 0.49 (0.112.21) Lowa,b,c,f Important
4 studies/42 days (ITT) 15/503 DP 18/5830 0.89 (0.451.74) Moderatea,b,c,d Important
4 studies/42 days (PP) 1/489 DP 04/569 0.55 (0.112.68) Lowa,b,c,f Important
6 studies/63 days (ITT) 173/1374 DP 245/1719 0.95 (0.791.14) Moderatea,b,c,d Critical
6 studies/63 days (PP) 30/1226 DP 23/1478 1.59 (0.633.99) Lowa,b,c,f Critical
1 study/ 28 days (ITT) 1/143 AA 11/351 0.22 (0.031.71) Lowa,e,f Important
1 study/28 days (PP) 0/142 AA 0/340 Not estimable Lowa,e Important
1 study/63 days (ITT) 23/322 AA 22/52 0.17 (0.100.28) Lowa,e Critical
1 study/63 days (PP) 2/301 AA 14/44 0.02 (0.000.09) Lowa,e Critical
1 study/28 days (ITT) 1/143 ASP 5/159 0.22 (0.031.88) Lowa,e,f Important
1 study//28 days (PP) 0/142 ASP 0/154 Not estimable Lowa,e Important
1 study/42 days (ITT) 2/51 ASP 05/53 0.42 (0.082.09) Lowa,e,f Important
1 study/42 days (PP) 0/49 ASP 05/53 0.10 (0.011.73) Lowa,e,f Important

ACTs: artemisinin-based combination therapies; AA: artesunate-amodiaquine; AL: artemether-lumefentrine; ASMQ: artesunate-meoquine; ASP:
artesunate+sulfadoxine-pyrimethamine; DP: dihydroartemisinin-piperaquine; GRADE: Grading of Recommendations Assessment, Development
and Evaluation Guidelines; ITT: intention-to-treat analysis; PP: per-protocol analysis; RR: relative risk.
a
Serious risk of bias.
b
No serious inconsistency.
c
No serious indirectness.
d
No serious imprecision.
e
Only one study.
f
Serious imprecision.

Regarding the development of drug resistance related to the areas with a history of use of ASMQ were not observed. In this
ACTs, WHO recommends the monitoring of therapeutic efcacy scope, Smithuis and collaborators demonstrated that ASMQ
for at least 28 days after the beginning of treatment, consider- maintained a high efcacy after several years of use in the rou-
ing the results from parasitological examination adjusted by tine in Myanmar.27 Studies conducted in other areas that used
PCR, to distinguish between recrudescence (real treatment fail- ASMQ routinely at the time of the study corroborated these nd-
ure) and new infections.8 For the most appropriate monitoring ings, especially those located in Thailand,22,23,39,40 Vietnam,41
of therapeutic regimens that use meoquine, a follow-up lasting Cambodia36 and Peru.35 The multicentre study in Asia by
63 days is recommended.44 Another important aspect stems Valecha et al. also did not identify statistically signicant differ-
from the hypothesis that the treatment with ASMQ, due to the ences when ASMQ was compared to DP, although it presented
long half-life of meoquine, would increase the risk of drug specic results favourable to DP.19
resistance.30 Phyo et al. when monitoring patients treated with ASMQ
Considering the aspects presented above, the outcome treat- between 2003 and 2013, indicated that after more than
ment failure adjusted by PCR, estimated by means of meta- 15 years of ASMQ use as rst-line treatment, the treatment fail-
analysis in all the evaluations (ITT and PP for all comparisons), ure rates have been increasing in recent years on the Myanmar-
considering different segments (28, 42 and 63 days), did not Thailand border, however, although the cure rates indicate the
indicate statistically signicant differences between ASMQ and increase in resistance, they were not statistically different in
the other ACTs, except in comparison to AA whose results were most of the years evaluated, varying, for example, between 89.8
favourable to ASMQ. Statistically signicant differences when (95% CI 82.394.2) in 2004 and 81.1 (95% CI 68.489.1) in
considering the individual results of the studies conducted in 2013.11 Ladeia-Andrade et al. when evaluated the use of xed

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H. M. Peixoto et al.
Figure 2. Comparison of artesunate-meoquine (ASMQ) vs artemether-lumefentrine (AL) for treating uncomplicated Plasmodium falciparum malaria, outcome failure adjusted by
PCR on 28, 42 and 63 days, analysis by intention-to-treat and per-protocol. (A) total failure (P. falciparum) day 28: intentiontotreat analysis; (B) total failure (P. falciparum) day 28:
per-protocol analysis; (C) total failure (P. falciparum) day 42: intentiontotreat analysis; (D) total failure (P. falciparum) day 42: per-protocol analysis; (E) total failure (P. falciparum)
day 63: intentiontotreat analysis; (F) total failure (P. falciparum) day 63: per-protocol analysis.

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 Transactions of The Royal Society of Tropical Medicine and Hygiene
Figure 3. Comparison of artesunate-meoquine (ASMQ) vs dihydroartemisinin-piperaquine (DP) for treating uncomplicated Plasmodium falciparum malaria, outcome failure adjusted
by PCR on 28, 42 and 63 days, analysis by intention-to-treat and per-protocol. (A) total failure (P. falciparum) day 28: intentiontotreat analysis; (B) total failure (P. falciparum) day
28: per-protocol analysis; (C) total failure (P. falciparum) day 42: intentiontotreat analysis; (D) total failure (P. falciparum) day 42: per-protocol analysis; (E) total failure (P. falciparum)
day 63: intentiontotreat analysis; (F) total failure (P. falciparum) day 63: per-protocol analysis.
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H. M. Peixoto et al.

doses of ASMQ in Vale do Jurua, Brazilian Amazon, did not iden- Competing interests: None declared.
tify molecular evidence of resistance in the local population
infected by P. falciparum.10 Ethical approval: Not required.
The absence of RCTs conducted in Brazil may have repre-
sented a limitation, however, two RCTs developed in scenarios
similar to the Brazilian one - located in Latin America - were
included and presented an efcacy similar to the results com- References
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