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    Definition of endpoints.

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    Posterior mean with 95% CI for odds ratios of each combination treatment with respect to combination SP + AS3 (dotted line) for ACPR at day 28 PCR corrected.

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    Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, White N, 2004. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 363 :9–17.

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Assessment of the Relative Advantage of Various Artesunate-Based Combination Therapies by a Multi-Treatment Bayesian Random-Effects Meta-Analysis

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  • 1 Fondation ACT-ion Afrique, Bruxelles, Belgium; Biostatistical Centre, University of Leuven, Belgium

Over the years, multiple articles on Artemisinin-based Combination Therapies (ACTs) were published, highlighting the relative advantages or drawbacks of these combinations. Many studies were comparative. Because none of the studies compare all combinations and methodology varies between studies, there is no homogeneity. A multi-treatment Bayesian random-effects meta-analysis was designed to assess the relative effect of each combination therapy to artesunate + sulfadoxine-pyrimethamine (4 mg/kg/day for 3 days). By far the most attractive result for the variable adequate clinical and parasitological response at day 28 PCR corrected is given by the combination artemether-lumefantrine. Annual follow-up on the data published is intended to reveal the changes in the relative drug efficacy values of ACTs.

INTRODUCTION

Although resistance to artemether and artesunate is unlikely to occur in view of its complex chemical attack on malaria parasites, in 2001 the World Health Organization (WHO) issued a general recommendation to combine artesunate or artemether monotherapy with another antimalarial drug that has a different mechanism of action than that of the artemisinins.1 The reason behind this recommendation was simple—the probability of selecting parasites that would be resistant to both drugs at the same time could be avoided or significantly delayed. Additional reasons in favor of such a combination therapy are the significant shortening of treatment duration and hence improvement of patient compliance and the advantage of a plurality of drugs that can be used. Several Artemisinin-based Combination Therapies (ACTs) have been put forward. Recommended partner drugs are lumefantrine, combined with artemether in a fixed-dose combination known as Coartem®, mefloquine, pyronaridine, lap-dap (chlorproguanil + dapsone), long-acting sulfonamide (sulfadoxine/sulfamethoxypyrazine) with pyrimethamine, amodiaquine, and piperaquine. The latter products are combined with artesunate except for piperaquine, which is combined with dihydroartemisinin. In 2001, when ACTs were introduced and promoted, hardly any drug fulfilling the criteria was available, apart from Coartem®. In Southeast Asia the combination artesunate with mefloquine was being studied and the other combinations (with sulfadoxine-pyrimethamine, lumefantrine, and piperaquine, etc.) arose progressively, mainly as a co-blister pack containing the artemisinin derivative with one partner drug. Pharmaceutical and clinical development was being investigated for all the combinations. It would therefore take quite a few years before the various combinations would become available, in particular for the fixed-dose combinations where all active ingredients are present in a single tablet.1,2

Over the years clinical research was done by many centers in various countries in distinct geographical areas with different endemicity of malaria and with varying resistance patterns of the parasites. Most studies focused on malaria in children under 5 years of age, whereas other studies did not make this distinction. In addition most studies were comparative, but the comparative ACT drug and the dose could vary between studies. In summary, not much homogeneity existed between the various studies. A well-based interpretation of the results was therefore not easy. An appropriate statistical approach to this problem was required and the opportunity to use a non-classic type of meta-analysis should be used to provide the necessary tool.

MATERIALS AND METHODS

Clinical trial selection.

PubMed was used to retrieve all papers published until October 2005 that contained the keywords “artesunate and combination,” “artemether and combination,” “artesunate combination therapy,” or “artesunate amodiaquine combination.” Papers were included only when they pertained to a randomized, controlled clinical trial and if they evaluated the clinical efficacy of either of the following combination therapies: artemether-lumefantrine (Art-lumef), amodiaquine (AQ) + sulfadoxine-pyrimethamine (SP), AQ + artesunate (AS), SP + AS, mefloquine (MQ) + AS, chloroquine (CQ) + AS, and CQ + SP or if they compared the clinical efficacy of different combinations for treatment of uncomplicated P. falciparum malaria.

Clinical trials studying the efficacy of uncommonly used combination therapies like AS + fosmidomycin, AS + dapsone/proguanil, AS + clindamycin, and dihydroartemisinin + napthoquine/trimethoprim were omitted from the analysis to avoid computational problems in the meta-analysis.

Study design and definition of study endpoints.

The endpoint of the present meta-analysis is Adequate Clinical and Parasitological Response (ACPR) at day 28 Polymerase Chain Reaction (PCR) corrected3,4 as indicated in Figure 1. ACPR at day 28 was defined as the absence of parasitemia on day 28, irrespective of axillary temperature without previously meeting any of the criteria of early treatment failure (ETF), late treatment failure (LTF), or late parasitological failure (LPT). The criteria of ETF are: (1) development of danger signs or severe malaria on day 1, day 2, or day 3 in the presence of parasitemia; (2) parasitemia at day 2 higher than day 0 count irrespective of axillary temperature; (3) parasitemia on day 3 with axillary temperature ≥ 37.5°C; (4) parasitemia on day 3 ≥ 25% of count on day. The criteria of LTF are: (1) development of danger signs or severe malaria after day 3, in the presence of parasitemia without previously meeting any of the criteria of ETF; (2) presence of parasitemia and axillary temperature ≥ 37.5° C (or history of fever) on any day from day 4 to day 28, without previously meeting any of the criteria of ETF. Finally, the criterion of LPF is the presence of parasitemia and axillary temperature ≤ 37.5° C on any day from day 7 to day 28, without previously meeting any of the criteria of ETF or LTF.

Recurrent parasitemia after day 7, as in LTF or LPF, is caused by recrudescence of the original parasite infection or by a re-infection with a new parasite. Because re-infection cannot be considered a treatment failure, it is important to differentiate recrudescence from re-infection if we want to evaluate the efficacy of an antimalarial drug. This differentiation is done by PCR genotyping of the P. falciparum merozoite surface protein 1 (msp1), merozoite surface protein 2 (msp2), and/or glutamate rich protein (glurp) of the parasite in blood samples taken on day of study enrollment and the day of treatment failure. The analysis is followed by gel separation of the obtained PCR DNA fragments. In case of reinfections two different loans for the parasite DNA fragments of day of enrollment and the parasite DNA fragments of the day of treatment failure are obtained on the agarose gel. In case of recrudescence the two loans are the same. All reinfections are considered to be treatment successes and therefore the ACPR rates are corrected.

Statistical analysis.

A multi-treatment random-effects meta-analysis was performed, which differs from a classic random-effects meta-analysis. In a classic meta-analysis one (class of) treatment(s) is compared with a control treatment and one measure of efficacy is determined, which is in this case the odds ratio (OR). The statistical model for the multi-treatment random-effects meta-analysis with I studies and J treatments is given by:

Yij~Bin(nij,πij),i=1,,I,jt(i),log(πij1πij)=αi+βj,jt(i)

where t(i) is the set of treatments that are examined in the ith study, Yij is the number of cured cases in nij patients treated by the jth treatment in the ith study, πij is the corresponding cure probability, αi is the effect of ith study on the logit scale, and βj is the effect of the jth treatment on the log odds ratio scale [i.e., βj = log(ORj)].

The effect of the study is considered to be random to express that the baseline risk differs from study to study because the studies differ in inclusion and exclusion criteria, were executed in different geographical areas, etc. The distribution for the study effect was assumed to be: α1, . , αI ~ N(0,σ2).

The study-specific treatment effects were also considered as random to express our prior belief that the different studies have different protocols such as different patient populations to examine, thereby showing extra variability for the effect of the jth treatment. That is, we assumed here that βj ~ Njj2), γj is the population mean, and τj2 is the population variance of the jth treatment effect. Because of sample size limitations, it was assumed that τl2 = · · · = τJ2 = τ2. The model specification was completed by assuming the following prior distributions: γ1, . , γJ ~ N(0,106), σ−2~γ (0.5, 0.0001), and τ−2 ~ γ (0.5, 0.001).

Note the following aspects of our extension: (1) there are numerous combination therapies; (2) the clinical trials compared just a few of these combination therapies; and (3) an odds ratio for each combination therapy versus the control combination therapy was needed. The parameters were estimated using a WINBUGS 1.45 program written by the authors and is available upon request. Finally, the previously mentioned settings for the prior distributions were varied to examine the sensitivity of the outcome to the specification of the prior distribution.

This software is based on the Bayesian paradigm; therefore our approach is called the multi-treatment Bayesian random-effects meta-analysis.

Our approach yields the posterior mean for the odds ratio βj and the posterior standard deviation, which is an expression of the uncertainty on βj. Furthermore a 95% confidence interval (95% CI) for each combination therapy with respect to the control combination treatment is calculated.

RESULTS

Using the keywords as previously described, approximately 200 papers were obtained via PubMed. Applying the previous exclusion criteria, 32 papers remained (Tables 1 and 2). Each of the selected papers investigated the clinical efficacy of at least one antimalarial combination therapy and provided data on PCR-corrected ACPR at day 28. Fourteen of these papers were used in the Lancet meta-analysis of Adjuik and others6 and in the updated meta-analysis of Jansen and others (unpublished data) (Table 2). The data for these 14 papers was retrieved from the meta-analysis of Adjuik and others.6

Twenty-six trials were conducted in Africa, four in Asia, and two in South America. The antimalarial combination therapies used for comparison against the combination SP + AS3 (12 studies) were SP + AS1 (2 studies), AQ + SP (3 studies), AQ + AS (10 studies), MQ + AS (5 studies), CQ + AS (4 studies), CQ + SP (2 studies), and Art-lumef (6 studies).

SP + AS3 = standard dose of SP plus 3 days of AS’s dose (4 mk/kg/day for 3 days).

SP + AS1 = standard dose of SP plus only 1 day of AS’s dose (4 mk/kg for 1 day).

The percentage of success for each antimalarial combination therapy at day 28 PCR corrected was calculated and is presented in Table 3. The lowest percentage of success was obtained with the combination CQ + AS (45.8%) and the highest percentage of success was obtained with the combination Art-lumef (97.4%).

In this article, we compare the combination therapies to the control treatment SP + AS3, but our approach easily provides the estimate of the odds ratios of the combination therapies to another control treatment. Posterior information for the OR (posterior mean, posterior standard deviation, and 95% CI) with PCR-corrected ACPR at day 28 as endpoint is given in Table 4.

Results are depicted in Figure 2. The most attractive result seems to be obtained by the combination Art-lumef, which showed the highest percentage (97.4%), closely followed by the combination MQ + AS (96.9%). However, the favorable results obtained with the combination MQ + AS came mainly from studies in Southeast Asia. The results obtained with the combination AQ + AS3 are better than those obtained with SP + AS. Finally, there seems to be no evidence of a different treatment effect between the treatment combinations CQ + SP, CQ + AS, SP + AS,1 and AQ + SP with the control treatment.

DISCUSSION

Over the past 10 years multiple comparative studies on ACTs were published, highlighting the relative advantages or drawbacks of these combinations. However, because none of the studies compare all combinations and methodology varies between studies, it is not easy to see clear results in this vast amount of data produced. Therefore a multi-treatment random-effects meta-analysis was used to provide a tool for comparative assessment of various ACTs. In this study the clinical efficacy at day 28 was compared between commonly used combination therapies. Results show that the combination Art-Lumef has a higher clinical efficacy regarding PCR-corrected ACPR at day 28 than all other combinations, but is closely followed by As + MQ. The combinations As + AQ and As + SP are not necessarily inferior but their percentages of success at day 28 PCR corrected are very close to the threshold of 90%.

The value of a drug combination does not depend alone on day 28 PCR-corrected ACPR. Absence of recrudescence is too narrow to judge ACTs. Additional variables, like side effects, re-infection rates, gametocyte carriage, and even cost price and availability of the drug combination were also identified as important and should also be followed in the future.

Artemisinin-based Combination Therapies have consistently been shown to be highly effective, well tolerated, and safe except for AQ combinations, which have frequent side effects.2 The same may apply to the combinations with Lap-dap. Some uncertainty remains concerning the neurotoxicity of the currently deployed combination Art-lumef. Its safety profile should be reviewed.7

One expected benefit of the widespread introduction of ACT for malaria is a reduction in (sub-microscopic) gametocyte carriage. The duration and the rate of gametocyte carriage contribute considerably to mosquito infection and malaria transmission. However, the effect of ACTs on malaria transmission appears to be moderate and restricted to the duration of gametocyte carriage and the proportion of mosquitoes that are infected by carriers.8 In previous studies it was shown that the combination Art-lumef and all the combinations with AS significantly reduced gametocyte carriage.6,9 At this moment, there is no published article that compares the rate and the duration time of gametocyte carriage of all the currently available ACTs and how they contribute to reducing malaria transmission. It would be useful in the future to review the gametocyte carriage profile of all ACTs and to take this variable along in future calculations.

In 2005, Mutabingwa and others10 studied the effectiveness of Art-lumef in the high transmission and resistance area of North Tanzania. This study revealed a high re-infection rate of about 20% after treatment with Art-lumef. The same result was obtained in 2006 with a study in five sentinel sites in Zambia conducted by the National Malaria Control Center. They found re-infection rates fluctuating between 19.2% and 53.8% for Art-lumef.11

Because of this high re-infection rate of the recommended first-line treatment Art-lumef, in the future it would be useful to review the re-infection profile of some newly introduced ACTs like AS + sulfamethoxypyrazine-pyrimethamine (SMP) in fdc format.

CONCLUSION

Our multi-treatment Bayesian random-effects meta-analysis method permits us to follow the annual changes in the relative values of all the previously mentioned variables. A detailed evaluation of each ACT can be made based on data from the published literature. Currently Art-lumef is winning, but this picture may change when the calculations are updated to the data published in 2006–2007.

Table 1

Eighteen included trials after PubMed search

Paper nrTreatment combination(s)StudyYear
* = Information is not given by the papers.
Note: Complete citations for these papers are listed after the references for this manuscript.
1AQ + AS, Art-lumefGhana2003
9AQ + SP, AQ + ASGhana2002
14AQ + AS, SP + AS3Angola2002–2003
15AQ + AS, SP + AS3Sudan2003
16AQ + SP, AQ + AS, Art-lumefTanzania2002–2004
17MQ + ASSudan2003
40AQ + ASRwanda*
43SP + AS3, SP + AS1Kenya1999–2000
48CQ + ASBurkina Faso1999–2000
49SP + AS3, SP + AS1Uganda1999–2000
60MQ + ASBolivia2001
86AQ + SP, SP + AS3Rwanda2001
91CQ + SP, MQ + AS, Art-lumefBangladesh2003
92CQ + SPUganda2002
94Art-lumefThailand2001–2002
97AQ + AS, Art-lumefTanzania*
99Art-lumefKenya, Nigeria and Tanzania*
100SP + AS3Sudan2004
Table 2

Fourteen included trials after PubMed search reviewed in the Lancet paper

Paper nrTreatment combination(s)StudyYear
L 1MQ + ASThai-21992–1993
L 2MQ + ASThai-31992–1993
L 3SP + AS3Gambia1998–1999
L 4CQ + ASBurkina Faso1999–2000
L 5AQ + ASGabon1999–2000
L 6CQ + ASIvory Coast1999–2000
L 7AQ + ASKenya-A1999–2000
L 8SP + AS3Kenya-K1999–2000
L 9SP + AS3Kenya-W1999–2000
L 10SP + AS3Malawi1999–2000
L 11SP + AS3Peru1999–2000
L 12CQ + ASSao Tome and Principe1999–2000
L 13AQ + ASSenegal1999–2000
L 14SP + AS3Uganda-MSF1999–2000
Table 3

Percentages of success for each antimalarial combination therapy at day 28 PCR corrected

Table 3
Table 4

Posterior information for odds ratios of each combination treatment with respect to the combination of SP + AS, for ACPR at day 28 PCR corrected

Random effects
Drug combinationPosterior meanPosterior St. dev95% CI*
* CI = confidence interval.
Art-lumef14.95.966.68; 29.6
AQ + SP1.040.320.56; 1.78
AQ + AS3.391.121.74; 6.07
SP + AS10.430.080.30; 0.60
MQ + AS6.853.962.06; 1.7.0
CQ + AS0.20.180.03; 0.65
CQ + SP0.260.180.06; 0.73
Figure 1.
Figure 1.

Definition of endpoints.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 77, 6; 10.4269/ajtmh.2007.77.1005

Figure 2.
Figure 2.

Posterior mean with 95% CI for odds ratios of each combination treatment with respect to combination SP + AS3 (dotted line) for ACPR at day 28 PCR corrected.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 77, 6; 10.4269/ajtmh.2007.77.1005

*

Address correspondence to Frans Herwig Jansen, Witte Bremlaan 30, 2360 Oud-Turnhout, Belgium. E-mail: fh.jansen@actionafrique.org, fhj@dafra.be

Authors’ addresses: Frans Herwig Jansen, Witte Bremlaan 30, 2360 Oud-Turnhout, Belgium, E-mail: fh.jansen@actionafrique.org. Em-manuel Lesaffre and Maria-Jose Garcia Zattera, Biostatistical Centre, U.Z. St. Rafaël, Catholic University of Leuven, Kapucijnenvoer 35, B-3000 Leuven, Belgium, E-mails: emmanuel.lesaffre@med.kuleuven.be and mjgarcia@uc.cl. Louis Kone Penali, Logements Lycée Classique, Boulevard de France 6, Abidjan- Cocody, Côte d’Ivoire, 22 BP 80 Abidjan 22, E-mail: lpenali@yahoo.fr. Henri Die-Kakou, BP 1544, Abidjan 06, Côte d’Ivoir, E-mail: diekakouhenri@yahoo.fr. Emmanuel Bissagnene, 15 BP 804, Abidjan 15, Côte d’Ivoir, E-mail: bissagnene@yahoo.fr.

REFERENCES

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    World Health Organization, 2001. Antimalarial Drug Combination Therapy. Report of a WHO Technical Consultation. Geneva: World Health Organization. WHO/CDS/RBM/2001.35.

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    Ashley EA, White NJ, 2005. Artemisinin-based combinations. Curr Opin Infect Dis 18 :531–536.

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    World Health Organization, 2006. Guidelines for the Treatment of Malaria. Geneva: World Health Organization. WHO/HTM/MAL/2006.1108.

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    World Health Organization, 2003. Assessment and Monitoring of Antimalarial Drug Efficacy for the Treatment of Uncomplicated Falciparum Malaria. Geneva: World Health Organization. WHO/HTM/RBM/2003.50.

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    Spiegelhalter D, Thomas A, Best N, Lunn D, 2003. WinBUGS Version 1.4 User Manual. MRC Biostatistics Unit, UK. Available at: http://www.mrc-bsu.cam.ac.uk/bugs/winbugs/contents.shtml.

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    Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, White N, International Artemisinin Study Group, 2004. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 363 :9–17.

    • Search Google Scholar
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  • 7

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  • 8

    Bousema JT, Schneider P, Gouagna LC, Drakeley CJ, Tostmann A, Houben R, Githure JI, Ord R, Sutherland CJ, Omar SA, Sauerwein RW, 2006. Moderate effect of artemisinin-based combination therapy on transmission of Plasmodium falciparum. J Infect Dis 193 :1151–1159.

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References of studies included in this meta-analysis (given with paper number) from Table 1

  • 1

    Koram KA, Abuaku B, Duah N, Quashie N, 2005. Comparative efficacy of antimalarial drugs including ACTs in the treatment of uncomplicated malaria among children under 5 years in Ghana. Acta Trop 95 :194–203.

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    Mockenhaupt FP, Ehrhardt S, Dzisi SY, Teun Bousema J, Wassilew N, Schreiber J, Anemana SD, Cramer JP, Otchwemah RN, Sauerwein RW, Eggelte TA, Bienzle U, 2005. A randomized, placebo-controlled, double-blind trial on sulfa-doxine-pyrimethamine alone or combined with artesunate or amodiaquine in uncomplicated malaria. Trop Med Int Health 10 :512–520.

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  • 14

    Guthmann JP, Ampuero J, Fortes F, van Overmeir C, Gaboulaud V, Tobback S, Dunand J, Saraiva N, Gillet P, Franco J, Denoncin A, van Herp M, Balkan S, Dujardin JC, D’Alessandro U, Legros D, 2005. Antimalarial efficacy of chloroquine, amodiaquine, sulfadoxinepyrimethamine, and the combinations of amodiaquine + artesunate and sulfadoxine-pyrimethamine + artesunate in Huambo and Bie provinces, central Angola. Trans R Soc Trop Med Hyg 99 :485–492.

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  • 15

    Hamour S, Melaku Y, Keus K, Wambugu J, Atkin S, Montgomery J, Ford N, Hook C, Checchi F, 2005. Malaria in the Nuba Mountains of Sudan: baseline genotypic resistance and efficacy of the artesunate plus sulfadoxinepyrimethamine and artesuate plus amodiaquine combinations. Trans R Soc Trop Med Hyg 99 :548–554.

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    Mutabingwa TK, Anthony D, Heller A, Hallett R, Ahmed J, Drakeley C, Greenwood BM, Whitty CJ, 2005. Amodiaquine alone, amodiaquine+sulfadoxine-pyrimethamine, amodiaquine +artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: a four arm randomised effectiveness trial. Lancet 365 :1474–1480.

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  • 17

    Adam I, A-Elbasit IE, Elbashir MI, 2005. Efficacies of mefloquine alone and of artesunate followed by mefloquine, for the treatment of uncomplicated, Plasmodium falciparum malaria in eastern Sudan. Ann Trop Med Parasitol 99 :111–117.

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    Rwagacondo CE, Karema C, Mugisha V, Erhart A, Dujardin JC, Van Overmeir C, Ringwald P, D’Alessandro U, 2004. Is amodiaquine failing in Rwanda? Efficacy of amodiaquine alone and combined with artesunate in children with uncomplicated malaria. Trop Med Int Health 9 :1091–1098.

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    Obonyo CO, Ochieng F, Taylor WR, Ochola SA, Mugitu K, Olliaro P, ter Kuile F, Oloo AJ, 2003. Artesunate plus sulfadoxine-pyrimethamine for uncomplicated malaria in Kenyan children: a randomized, double-blind, placebo-controlled trial. Trans R Soc Trop Med Hyg 97 :585–591.

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    Sirima SB, Tiono AB, Konate A, Diarra A, Castelli F, Pinoges L, Mugittu K, Taylor WR, Olliaros PL, 2003. Efficacy of artesunate plus chloroquine for the treatment of uncomplicated malaria in children in Burkina Faso: a doubleblind, randomized, controlled trial. Trans R Soc Trop Med Hyg 97 :345–349.

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  • 49

    Priotto G, Kabakyenga J, Pinoges L, Ruiz A, Eriksson T, Coussement F, Ngambe T, Taylor WR, Perea W, Guthmann JP, Olliaro P, Legros D, 2003. Artesunate and sulfadoxine-pyrimethamine combinations for the treatment of uncomplicated Plasmodium falciparum malaria in Uganda: a randomized, double-blind, placebo-controlled trial. Trans R Soc Trop Med Hyg 97 :325–330.

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    Avila JC, Villaroel R, Marquino W, Zegarra J, Mollinedo R, Ruebush TK, 2004. Efficacy of mefloquine and mefloquine-artesunate for the treatment of uncomplicated Plasmodium falciparum malaria in the Amazon region of Bolivia. Trop Med Int Health 9 :217–221.

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    Rwagacondo CE, Niyitegeka F, Sarushi J, Karema C, Mugisha V, Dujardin JC, Van Overmeir C, van den Ende J, D’Alessandro U, 2003. Efficacy of amodiaquine alone and combined with sulfadoxinepyrimethamine and of sulfadoxine pyrimethamine combined with artesunate. Am J Trop Med Hyg 68 :743–747.

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    Van den Broek I, Muang UA, Peters A, Liem L, Kamal M, Rahman M, Rahman MR, Bangali AM, Das S, Barends M, Faiz AM, 2005. Efficacy of chloroquine + sulfadoxine-pyrimethamine, mefloquine + artesunate and artemether + lumefantrine combination therapies to treat Plasmodium falciparum malaria in the Chittagong Hill Tracts, Bangladesh. Trans R Soc Trop Med Hyg 99 :727–735.

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  • 92

    Checchi F, Piola P, Kosack C, Ardizzoni E, Klarkowski D, Kwezi E, Priotto G, Balkan S, Bakyaita N, Brockman A, Guthmann JP, 2004. Antimalarial efficacy of sulfadoxine–pyrimethamine, amodiaquine and a combination of chloroquine plus sulfadoxine–pyrimethamine in Bundi Bugyo, western Uganda. Trop Med Int Health 9 :445–450.

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  • 94

    Hutagalung R, Paiphun L, Ashley EA, McGready R, Brockman A, Thwai KL, Singhasivanon P, Jelinek T, White NJ, Nosten FH, 2005. A randomized trial of artemether-lumefantrine versus mefloquine-artesunate for the treatment of uncomplicated multidrug resistant Plasmodium falciparum on the western border of Thailand. Malar J 22 :46.

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  • 97

    Mårtensson A, Strömberg J, Sisowath C, Msellem MI, Gil JP, Montgomery SM, Olliaro P, Ali AS, Björkman A, 2005. Efficacy of Artesunate Plus Amodiaquine versus That of Artemether-Lumefantrine for the Treatment of Uncomplicated Childhood Plasmodium falciparum Malaria in Zanzibar, Tanzania. Clin Infect Dis 41 :1079–1086.

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  • 99

    Falade C, Makanga M, Premji Z, Ortmann CE, Stockmeyer M, de Palacios PI, 2005. Efficacy and safety of artemether-lumefantrine (Coartem) tablets (six-dose regimen) in African infants and children with acute, uncomplicated falciparum malaria. Trans R Soc Trop Med Hyg 99 :459–467.

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  • 100

    Adam I, Aelbasit IE, Idris SM, Malik EM, Elbashir MI, 2005. A comparison of the efficacy of artesunate plus sulfadoxinepyrimethamine with that of sulfadoxine-pyrimethamine alone, in the treatment of uncomplicated, Plasmodium falciparum malaria in eastern Sudan. Ann Trop Med Parasitol 99 :449–455. International Artemisinin Study Group

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  • L1-L14

    Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, White N, 2004. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 363 :9–17.

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Footnotes

SP + AS3 = standard dose of SP plus 3 days of AS’s dose (4 mk/kg/day for 3 days).

SP + AS1 = standard dose of SP plus only 1 day of AS’s dose (4 mk/kg for 1 day).

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