MAJOR ARTICLE

CSE THEME ARTICLE

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Randomized Comparison of Amodiaquine plus Sulfadoxine-Pyrimethamine, Artemether-Lumefantrine, and Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in Burkina Faso
Issaka Zongo,1 Grant Dorsey,2 Noel Rouamba,1 Christian Dokomajilar,2 Yves Se re ,1 Philip J. Rosenthal,2 and Jean Bosco Oue draogo1
1

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Institut de Recherche en Sciences de la Sante , Bobo-Dioulasso, Burkina Faso; and 2Department of Medicine, University of California, San Francisco

Background. Combination antimalarial therapy is advocated to improve treatment efcacy and limit selection of drug-resistant parasites. We compared the efcacies of 3 combination regimens in Bobo-Dioulasso, Burkina Faso: amodiaquine plus sulfadoxinepyrimethamine, which was recently shown to be highly efcacious at this site; artemether-lumefantrine, the new national rstline antimalarial regimen; and dihydroartemisinin-piperaquine (DP), a newer regimen. Methods. We enrolled 559 patients 6 months of age with uncomplicated Plasmodium falciparum malaria and randomized them to the 3 regimens. We analyzed the risk of recurrent parasitemia by day 28 and day 42, both unadjusted and adjusted by PCR methods to distinguish recrudescence and new infection. Results. Complete data were available for 517 (92.5%) of the enrolled subjects. Early treatment failures occurred in 5 patients treated with amodiaquine plus sulfadoxine-pyrimethamine and in 2 patients each treated with the other regimens. The day 28 risk of recurrent parasitemia, unadjusted by genotyping, was signicantly higher for patients receiving artemether-lumefantrine than for patients receiving amodiaquine plus sulfadoxine-pyrimethamine (20.1% vs. 6.2%; risk difference, 13.8%; 95% condence interval, 7.0%20.7%) or dihydroartemisinin-piperaquine (20.1% vs. 2.2%; risk difference, 17.9%; 95% condence interval, 11.6% 24.1%). Similar differences were seen for children !5 years of age (54% of the study population) and when outcomes were extended to 42 days. Signicant differences were not seen between outcomes for patients receiving amodiaquine plus sulfadoxinepyrimethamine and outcomes for those receiving dihydroartemisinin-piperaquine. Recrudescences were uncommon (occurring in !5% of patients) in all treatment groups. No serious adverse events were noted. Conclusions. All regimens were highly efcacious in clearing infection, but considering the risks of recurrent malaria after therapy, the amodiaquine plus sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine regimens were more efcacious than the artemether-lumefantrine regimen (the new national regimen in Burkina Faso) for the treatment of uncomplicated P. falciparum malaria. Trial registration. ISRCTN.org identier: ISRCTN94367569. The control of malaria is jeopardized by the increasing prevalence of drug-resistant disease [1]. A consensus has emerged that uncomplicated Plasmodium falciparum malaria should be treated with artemisinin-based combination therapies (ACTs) to improve efcacy and limit the selection of drug-resistant parasites [2, 3]. All ACTs include a potent artemisinin analogue and a longer-acting partner drug. The most widely adopted ACT in Africa is artemether-lumefantrine, which has recently been selected as rst-line therapy by 20 countries [47] and was chosen for this purpose by Burkina Faso in 2005 [8]. However, as is the case in many countries, routine provision of artemether-lumefantrine for uncomplicated malaria has not been widely implemented in Burkina Faso because of limitations on resources and drug availability. In West Africa, where resistance to older regimens is less common than it is in other areas, the combination of amodiaquine plus sulfadoxine-pyrimethamine (AQSP) has shown excellent antimalarial efcacy [911]. AQSP is inexpensive and provides extended drug levels after treatment, offering a potential advantage over some ACT regimens. Indeed, when compared with artemether-lumefantrine therapy in Burkina Faso,
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Received 1 May 2007; accepted 11 June 2007; electronically published 22 October 2007. Reprints or correspondence: Dr. Philip J. Rosenthal, Box 0811, San Francisco General Hospital, University of California, San Francisco, CA 94143 (philip.rosenthal@ucsf.edu). Clinical Infectious Diseases 2007; 45:145361 2007 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2007/4511-0009$15.00 DOI: 10.1086/522985

treatment with AQSP provided similarly strong activity against infecting parasites but better protection against new infections, such that the rate of recurrent malaria within 28 days after therapy was signicantly lower with the AQSP regimen [7]. Treatment with dihydroartemisinin-piperaquine, a newer ACT, has shown excellent antimalarial efcacy in available trials [1218] and appears to offer advantages over artemether-lumefantrine, including simpler dosing and the longer half-life of piperaquine, compared with that of lumefantrine. We compared the antimalarial efcacy and safety of AQSP, artemetherlumefantrine, and dihydroartemisinin-piperaquine for the treatment of uncomplicated malaria in Bobo-Dioulasso, Burkina Faso. PATIENTS AND METHODS Study site. Subjects were recruited from 3 government health dispensaries in Bobo-Dioulasso, in western Burkina Faso. In this region, malaria is holoendemic, with transmission principally occurring during the rainy season (MayOctober). The study was approved by the institutional review boards of the Institut de Recherche en Sciences de la Sante /Centre Muraz (Bobo-Dioulasso, Burkina Faso) and the University of California, San Francisco. Patients. Consecutive patients with fever or a history of recent fever were referred for a Giemsa-stained thick blood smear, and those with a positive smear result were assessed by study clinicians for the following inclusion criteria: age 6 months; weight 5 kg; fever (axillary temperature 37.5C) or fever symptoms within the previous 24 h; absence of history of serious adverse effects related to study medications, including sulfa allergy; no evidence of a concomitant febrile illness; provision of informed consent by the patient or parents or guardians, as well as the ability to participate in a 42-day follow-up; no history of treatment with any antimalarial drug other than chloroquine in the previous 2 weeks; no danger signs or evidence of severe malaria [19]; P. falciparum monoinfection, with a parasite density of 2000200,000 parasites per mL of blood; and hemoglobin level 5.0 g/dL. Patients who satised the inclusion criteria were randomized; those who were excluded were referred to the dispensary staff for care. Patients were excluded after randomization if slide reevaluation demonstrated a parasite density or species outside of the inclusion criteria or if the subject experienced repeated vomiting of study medication on day 0. Baseline evaluation, randomization, and treatment allocation. Randomized patients were assigned a study number, interviewed and examined, and referred for treatment allocation by a study nurse not involved in enrollment or assessment of treatment outcomes. Patients were randomly assigned on the basis of a computer-generated code provided by an off-site investigator to oral treatment with the 3 study regimens: (1)
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artemether-lumefantrine (Coartem; Novartis) administered in tablets containing 20 mg of artemether plus 120 mg of lumefantrine at a dosage of 1 tablet (for patients weighing 514 kg), 2 tablets (for patients weighing 1524 kg), 3 tablets (for patients weighing 2534 kg), or 4 tablets (for patients weighing 35 kg) twice daily for 3 days; (2) dihydroartemisinin-piperaquine (Duocotexcin; Holleypharm) administered in tablets containing 40 mg of dihydroartemisinin and 320 mg of piperaquine at a dosage of 6.4 mg of dihydroartemisinin and 51.2 mg of piperaquine per kg of body weight once daily for 3 days; or (3) AQSP, consisting of amodiaquine (Flavoquine; Aventis) administered at a dosage of 10 mg per kg of body weight on days 0 and 1 and 5 mg per kg of body weight on day 2 plus sulfadoxine-pyrimethamine (Fansidar; Roche) administered at a dosage of 25 mg of sulfadoxine and 1.25 mg of pyrimethamine per kg of body weight on day 0. Scored tablets were split and crushed with water for young children. All treatments were directly observed at the clinic or at home for evening doses. The study was not blinded. Patients were observed for 30 min, and doses were readministered if vomiting occurred; those with repeated vomiting on day 0 were excluded from the study prior to enrollment and were referred for treatment with quinine. Paracetamol (10 mg per kg of body weight every 8 h) was provided for treatment of febrile symptoms. Children with hemoglobin levels !10 g/dL were treated according to Integrated Management of Childhood Illness guidelines with ferrous sulfate for 14 days and antihelminthic treatment, if appropriate. Follow-up procedures and classication of treatment outcomes. Patients were asked to return to the clinic for followup on days 1, 2, 3, 7, 14, 21, 28, 35, and 42 and at any time that they were ill. Subjects who did not return for a scheduled appointment were visited at home. Each visit included completion of a standardized history form, a physical examination, and, except on day 1, a ngerprick for thin and thick blood smear and lter paper storage. Hemoglobin levels were assessed on day 0 and either day 42 or the day of clinical failure. Thick smears were assessed for parasite density and gametocytes. Thin smears to determine speciation were performed for patients who experienced clinical treatment failure after day 3. Patients were followed up for 42 days, and their outcomes were assessed according to World Health Organization (WHO) guidelines as early treatment failure (dened as the presence of danger signs, complicated malaria, or failure to adequately respond to therapy during days 03), late clinical failure (dened as the presence of danger signs, complicated malaria, or fever and parasitemia during days 442), late parasitological failure (dened as asymptomatic parasitemia without clinical ndings during days 742), or adequate clinical and parasitological response (dened as the absence of parasitemia throughout follow-up) [20]. Secondary outcomes included the resolution of fever, parasite clearance, change in hemoglobin level, presence of ga-

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metocytes during follow-up, and the occurrence of adverse events. Patients who experienced treatment failure received quinine (10 mg per kg of body weight orally 3 times per day for 7 days). Patients with evidence of severe malaria or danger signs (i.e., convulsions, lethargy, inability to drink or breastfeed, repeated vomiting, or the inability to stand or sit because of weakness) were referred for treatment with parenteral quinine. Patients were excluded from the study during follow-up for the use of antimalarial drugs outside of the study, serious adverse events requiring a change in treatment, withdrawal of informed consent, or loss to follow-up (dened as not being located within 24 h during days 13 or within 48 h during days 442). At each follow-up visit, study clinicians assessed patients for adverse events and graded them according to scales from the WHO and the National Institutes of Health. Adverse events were dened as untoward medical occurrences, following International Conference on Harmonization guidelines, and serious adverse events were dened as experiences resulting in death, life-threatening experiences, inpatient hospitalization, persistent or signicant incapacity, or medical or surgical intervention to prevent a serious outcome. Laboratory procedures. Blood smears were stained with a 2% Giemsa solution for 30 min. Positive screening smear ndings were reassessed at a central laboratory. Parasite densities were calculated from thick smears as the number of asexual parasites per 200 leukocytes (or per 500 leukocytes if the parasite density was !10 parasites per 200 leukocytes), assuming a leukocyte count of 8000 leukocytes/mL. Smear ndings were considered to be negative when microscopic examination of 100 high-power elds did not reveal parasites. Counts were performed by 2 microscopists; discrepant readings were resolved by a third reader. Gametocytes were recorded as present or absent. Thin blood smears performed on day 0 and on the day of clinical failure were evaluated for parasite species. Hemoglobin levels were measured from nger-prick blood samples using a portable spectrophotometer (HemoCue). Whenever blood specimens were collected, 4 drops were placed onto lter paper, labeled, air-dried, and stored in sealed plastic bags at ambient temperature. Parasite DNA was subsequently extracted using Chelex (BioRad Laboratories) [21]. For patients experiencing treatment failure after day 6, parasites collected at baseline and at the time of treatment failure were genotyped in a stepwise fashion using msp-2, msp-1, and 4 microsatellites [22]. If, for any of the 6 loci, an allele was not shared between day 0 and the day of recurrence, the infection was classied as a new infection. If at least 1 allele was shared between day 0 and the day of recurrence at all 6 loci, the infection was classied as a recrudescence. Statistical analysis. We hypothesized that the risk of recurrent parasitemia after 42 days would differ between the

group receiving the artemether-lumefantrine regimen and either the group receiving AQSP or the group receiving dihydroartemisinin-piperaquine. On the basis of a prior study [7] that had determined the risk of recurrent parasitemia to be 15% with artemether-lumefantrine therapy and 5% with AQSP therapy, we calculated that 176 patients would be needed in each treatment arm (allowing for a 10% loss to follow-up) to detect a 10% difference in the rate of recurrent parasitemia with a 2-sided type I error of 0.05 and 80% power. Data were entered using Epi Info software, version 6.04 (Centers for Disease Control and Prevention), and were analyzed using Stata software, version 8.0 (StataCorp). Efcacy and safety data were evaluated using a modied intention-to-treat analysis that included all enrolled patients. Risks of recurrent parasitemia after 28 and 42 days (adjusted and unadjusted by genotyping) were estimated using the Kaplan-Meier product-limit formula. Data were censored for patients who did not complete follow-up and, for adjusted outcomes, for new infections or infections due to agents other than P. falciparum. Comparisons of treatment efcacy were made using risk differences with exact 95% CIs. Categorical variables were compared using x2 or Fishers exact test, and continuous variables were compared using the independent samples t test. P values were 2-sided without adjustment for multiple comparisons and were considered to be statistically signicant if P .05. RESULTS Enrollment and follow-up. Of 843 screened patients, 580 fullled initial inclusion criteria and were randomized; of these patients, 21 were excluded before enrollment, and 559 were enrolled and treated with study drugs (gure 1). At enrollment there was no signicant difference between treatment groups with respect to sex, age, temperature, parasite density, previous use of antimalarial drugs, or mean hemoglobin level (table 1). Gametocyte carriage was rare. The proportion of patients who did not complete therapy because of repeated vomiting on day 0 (none were excluded for vomiting after day 0), protocol violation, or withdrawal of consent did not differ between the 3 treatment groups (4 of 186 patients for the AQSP group, 3 of 191 patients for the artemether-lumefantrine group, and 8 of 194 patients for the dihydroartemisinin-piperaquine group; P .22, for all pairwise comparisons). During 42 days of follow-up, 517 (92.5%) of 559 subjects completed the study. There was no difference in the risk of withdrawal between the treatment arms (P 1 .05 for all comparisons). The most common reason for study discontinuation was withdrawal of informed consent. Treatment efcacy. Nine patients experienced early treatment failure, including 5 patients in the AQSP group (2 with danger signs [1 with convulsions and 1 with vomiting] and 3 with severe malaria [1 with altered consciousness and 2 with
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Figure 1. Trial prole comparing antimalarial treatment regimens. AL, artemether-lumefantrine; AQSP, amodiaquine plus sulfadoxine-pyrimethamine; DP, dihydroartemisinin-piperaquine.

jaundice]) and 2 each in the artemether-lumefantrine and dihydroartemisinin-piperaquine groups (all with convulsions). Efcacy outcomes were assigned on the basis of time to early treatment failure or recurrent parasitemia, according to WHO recommendations [20]. Outcomes were assessed after 28 and 42 days and considered with and without genotyping to distinguish recrudescence from new infection. Considering outcomes unadjusted by genotyping, AQSP and dihydroartemisinin-piperaquine regimens were superior to the artemether-lumefantrine regimen at both day 28 and day 42 after the initiation of therapy (table 2). Similar differences were seen with evaluation of outcomes in only those patients !5 years of age. In this group, the 28-day risk of treatment failure was 18.8% for the artemetherlumefantrine regimen, compared with 8.5% for the AQSP regimen and 4.2% for the dihydroartemisinin-piperaquine regimen. Risk difference 95% CIs were 0.7%20% for the artemetherlumefantrine regimen versus the AQSP regimen and 5.8%23.4% for the artemether-lumefantrine regimen versus the dihydroar1456 CID 2007:45 (1 December) CSE THEME ARTICLE

temisinin-piperaquine regimen. The 42-day risk of treatment failure was 30.9% for the artemether-lumefantrine regimen, compared with 17.8% for the AQSP regimen and 12.2% for the dihydroartemisinin-piperaquine regimen. Risk difference 95% CIs were 0.9%25.4% for the artemether-lumefantrine regimen versus the AQSP regimen and 7.1%30.2% for the artemetherlumefantrine regimen versus the dihydroartemisinin-piperaquine regimen. Most treatment failures were seen on or after day 21 in the artemether-lumefantrine group, day 28 in the AQSP group, and day 35 in the dihydroartemisinin-piperaquine group (gure 2). Our genotyping methodology included a step-wise algorithm incorporating 6 markers that was recently validated for the discrimination of outcomes in Bobo-Dioulasso [23]. Genotyping was successful for all of the samples that were tested. Considering only early treatment failures and recrudescences, all tested regimens demonstrated excellent efcacy, with a risk of treatment failure of !5% at day 28 and day 42 for all subjects

Table 1. Baseline characteristics of patients receiving either amodiaquine plus sulfadoxine-pyrimethamine, artemether-lumefantrine, or dihydroartemisinin-piperaquine for the treatment of malaria.
Treatment group Amodiaquine plus sulfadoxinepyrimethamine (n p 184) 87 (47) 4.1 (2.59) 100 (54) 38.5 1.3 22 (12) 22,884 1 (0.5) 10.3 2.3 Artemetherlumefantrine (n p 188) 93 (49) 4.0 (37) 103 (55) 38.5 0.9 20 (11) 27,110 0 10.2 2.0 Dihydroartemisininpiperaquine (n p 187) 95 (51) 4.0 (2.58) 100 (53) 38.6 0.9 22 (12) 25,260 3 (1.6) 10.1 2.4

Characteristic Male sex Age, median years (interquartile range) Age !5 years Temperature, mean C SD Chloroquine use within the prior 2 weeks Parasite density, geometric mean parasites/mL Gametocytes present Hemoglobin level, mean g/dL SD

NOTE. Data are no. (%) of patients, unless otherwise indicated.

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(table 2) and for those subjects !5 years of age (data not shown). There were no statistically signicant differences between groups with respect to the risk of genotype-adjusted treatment failure. Only 1 recrudescence occurred after day 28 (this recrudescence occurred at day 42 in a patient treated with artemether-lumefantrine). Secondary outcomes. Fever clearance was slower among patients who received the artemether-lumefantrine regimen than among patients who received the other 2 regimens; persistence of fever on day 1 was signicantly more common in the artemether-lumefantrine group (table 3). More than 80% of patients in all groups cleared fever by day 2. Parasite clearance was slower in the AQSP group than in the other 2 groups. Persistent parasitemia on day 2 was signicantly more common in the AQSP group, but by day 3, parasites had cleared in at least 99% of subjects in each treatment group. Gametocytes appeared infrequently (in 5% of subjects) after treatment in all 3 groups. Hemoglobin levels increased after therapy in all groups, but on the last day of follow-up, the mean hemoglobin level was signicantly lower in the artemether-lumefantrine group, compared with the other 2 groups. Adverse events. All tested regimens appeared to be well tolerated. No serious adverse events were observed. Abdominal pain was reported more often in the AQSP and artemetherlumefantrine groups, headache was reported more often in the artemether-lumefantrine group, and pruritis was reported more often in the AQSP group (table 3). DISCUSSION We compared the efcacy against uncomplicated malaria of 3 drug regimens of particular interest in Burkina Faso. AQSP is a combination of 2 older drugs that has shown surprisingly good efcacy in different parts of Africa [911, 24, 25] and is advocated under current WHO guidelines for the treatment of

malaria where its efcacy has been established and newer ACTs are unavailable [26]. Artemether-lumefantrine is a leading ACT that has shown excellent antimalarial efcacy in Asia [2729] and Africa [46]. Dihydroartemisinin-piperaquine is a newer ACT that has not yet been widely studied but which, in available trials, has shown excellent efcacy in Asia [1618] and Africa [15]. In Bobo-Dioulasso, all 3 regimens were highly efcacious. For each therapy, early treatment failures or recrudescences after treatment were seen in !5% of patients. However, in Africa, recurrent malaria after therapy is commonly attributable to either recrudescence or new infection, and the most practical means of comparing regimens may be to compare their impacts on recurrent malaria. By this measure, both AQSP and dihydroartemisinin-piperaquine were superior to artemether-lumefantrine, with marked decreases in the risk of recurrent malaria during 6 weeks of follow-up. The use of ACTs to treat uncomplicated malaria is now strongly advocated [3]. The ACT selected as rst-line therapy by the largest number of African countries, artemether-lumefantrine, benets from coformulation, approval in multiple countries in the developing world and Europe, and demonstrated excellent efcacy and safety [30, 31]. However, disadvantages of artemether-lumefantrine therapy include the need for twice-per-day dosing, irregular bioavailability, and recommendation for ingestion with a fatty meal to improve drug levels. Dihydroartemisinin-piperaquine is a newer coformulated ACT that requires only single daily dosing and lacks dietary concerns. In limited studies, dihydroartemisinin-piperaquine showed outstanding antimalarial efcacy in Asia [1618] and Africa [15]. Two recent studies directly compared the antimalarial efcacies of artemether-lumefantrine and dihydroartemisinin-piperaquine. In Papua, Indonesia [16], and in central Uganda [32], both regimens showed excellent efcacy based on genotype-corrected recrudescence after therapy. However, in
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Table 2. Treatment efcacy outcomes.

Risk of treatment failure, % (95% CI) Risk category 28-Day risk Unadjusted by genotyping Adjusted by genotyping 42-Day risk Unadjusted by genotyping 11.6 (7.617.4) 30.9 (24.738.3) 7.5 (4.412.5) Adjusted by genotyping 3.9 (1.98.0) 4.1 (2.08.5) 2.2 (0.85.8) 19.4 (11.027.7) 0.2 (3.9 to 4.3)
!.001 23.5 (15.631.3) !.001 4.1 (2.1 to 10.3)

Risk difference, % (95% CI) AL group vs. AQSP group P AL group vs. DP group P AQSP group vs. DP group P

AQSP group

AL group

DP group

6.2 (3.511.0) 20.1 (14.926.7) 2.2 (0.85.8) 3.9 (1.98.0) 3.4 (1.57.3) 2.2 (0.85.8)

13.8 (7.020.7) 0.1 (4.4 to 3.3)

!.001 17.9 (11.624.1)

!.001 4.0 (08.2)

.06 .36 .19 .36

.79

1.1 (2.3 to 4.6)

.51

1.7 (1.9 to 5.2

.91

1.9 (1.8 to 5.6)

.32

1.7 (1.9 to 5.2)

NOTE. AL, artemether-lumefantrine; AQSP , amodiaquine plus sulfadoxine-pyrimethamine; DP , dihydroartemisinin-piperaquine.

both studies, treatment with dihydroartemisinin-piperaquine was followed by signicantly fewer new infections during 42 days of follow-up. Thus, as conrmed in our study, dihydroartemisinin-piperaquine appears to offer benets over artemether-lumefantrine, including simplied dosing and greater posttreatment prophylactic efcacy. Despite the selection of ACTs as rst-line antimalarial therapy by most African countries, including Burkina Faso, implementation of changes in malaria therapy have been slow, in part because of the considerable expense and limited availability of new ACTs. The WHO recommends 1 non-ACT regimen, treatment with AQSP, under limited circumstances [26]. AQSP showed surprisingly good antimalarial efcacy in older studies in East Africa [33, 34], but its efcacy was poor in Tanzania [35] and appears to be decreasing in Uganda [36], likely as a result of high levels of resistance to both amodiaquine and sulfadoxine-pyrimethamine in East Africa. In contrast, AQSP remains an excellent antimalarial regimen in parts of West Af-

rica, where resistance to both component drugs is uncommon [10, 11]. In a recent comparison in Burkina Faso, AQSP and artemether-lumefantrine both showed outstanding efcacy based on measures of recrudescence, but AQSP demonstrated superior posttreatment prophylaxis against new infections over a month of follow-up [7]. In this study, the superior efcacy of AQSP over artemether-lumefantrine in Bobo-Dioulasso was conrmed. Further, the efcacy of AQSP was not signicantly different from that of dihydroartemisinin-piperaquine, although trends favored dihydroartemisinin-piperaquine in all comparisons. Debate persists regarding the importance of a posttreatment prophylactic effect of an antimalarial drug. Some have argued that recrudescences entail greater clinical risk than new infections after therapy and, thus, that prevention of new infections is relatively unimportant [37], but clinical data do not support this assertion. In trials in Uganda, clinical presentations and the likelihood of progression to complicated malaria were the

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Figure 2. Cumulative risk of treatment failure, unadjusted by genotyping. AL, artemether-lumefantrine group; AQSP, amodiaquine plus sulfadoxinepyrimethamine group; DP, dihydroartemisinin-piperaquine group.
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Table 3. Secondary outcomes.

Treatment group Amodiaquine plus sulfadoxinepyrimethamine
a b,c

Outcome Fever clearance Fever on day 1 Fever on day 2 Fever on day 3 Parasite clearance

Artemetherlumefantrine 91/188 (48) 26/188 (14) 15/187 (8) 5/186 (3) 0/185 (0) 3/188 (2) 11.3 1.6 52/188 (28) 21/104 (20) 22/104 (21) 11/188 (6) 27/188 (14) 6/188 (3) 13/188 (7) 3/188 (2)

Dihydroartemisininpiperaquine 70/187 (37) 23/186 (12) 17/184 (9) 6/184 (3) 0/182 (0) 7/184 (4) 11.6 1.6 49/187 (26)

60/184 (33) 35/182 (19) 18/180 (10) 49/179 (27) 2/175 (1)
e

Parasitemia on day 2b,d Parasitemia on day 3 Appearance of gametocytes Hemoglobin level on last day of follow-up, mean g/dL SDb,c,f Adverse event Cough Abdominal pain Headache Pruritis
b,d c c,d

10/183 (5) 11.8 1.4 50/184 (27) 24/102 (24) 14/101 (14) 34/184 (18) 26/184 (14) 10/184 (5) 9/184 (5) 6/184 (3)

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10/112 (9) 11/111 (10) 5/187 (3) 20/187 (11) 8/187 (4) 14/187 (7) 5/187 (3)

Vomiting Anorexia Diarrhea Weakness

a

NOTE. Data are proportion (%) of patients, unless otherwise indicated. Subjective fever within the previous 24 h or temperature 37.5C or prior early treatment failure. Amodiaquine plus sulfadoxine-pyrimethamine group vs. artemether-lumefantrine group (P ! .05). Artemether-lumefantrine group vs. dihydroartemisinin-piperaquine group (P ! .05). d Amodiaquine plus sulfadoxine-pyrimethamine group vs. dihydroartemisinin-piperaquine group (P ! .05). e Only includes patients without gametocytes on day 0. f Day 42 or day of recurrent symptomatic malaria on which rescue therapy was administerd (patients with early treatment failure excluded).
b c

same with recrudescent or new malaria episodes [38]. It has also been suggested that, in areas where reinfection is common, posttreatment prophylaxis would have only a minor impact on malarial incidence [39], but, in fact, with high transmission intensity, the impact of a protective intervention should be large. Indeed, this benet may be greatest in regions with seasonal transmission, such as Bobo-Dioulasso, where the posttreatment prophylactic effect of a therapy may cover a good portion of the transmission season. Both amodiaquine and sulfadoxine-pyrimethamine have caused rare but severe toxicities when used for long-term chemoprophylaxis, and artemisinins are embryotoxic and have caused irreversible neurological changes when administered in high doses to laboratory animals. However, a good deal of experience argues against major concerns regarding toxicities of our study regimens when used for short-term antimalarial therapy, although the tolerability of the AQSP regimen has been lower than that of other regimens in some studies [40]. In our study, reports of some adverse events differed between regimens, but all regimens appeared to be well tolerated. Our results suggest that choices for optimal antimalarial ther-

apy in Africa should be reevaluated. First, in regions where the efcacies of amodiaquine and sulfadoxine-pyrimethamine remain good, as in Burkina Faso, consideration should be given for the use of AQSP for the treatment of uncomplicated malaria, especially when, as a result of the unavailability of ACTs, the alternative is an unacceptable monotherapy. Second, among ACTs, dihydroartemisinin-piperaquine appears to offer particularly promising features, including easy dosing and outstanding antimalarial efcacy, suggesting that this new regimen should be strongly considered for rst-line therapy for malaria in Africa.
Acknowledgments
We thank the clinical study teams at the Colsama, Sarfalao, and Ouezzinville dispensaries in Bobo-Dioulasso; the clinical ofcers; the patients and their parents or guardians; and Christian Dokomajilar and Bryan Greenhouse, for their assistance with genotyping samples. Financial support. Doris Duke Charitable Foundation (2004047 to P.J.R.), Holley Cotec Pharmaceuticals, International Atomic Energy Agency (RAF/6025), and National Budget of the Institut de Recherche en Sciences de la Sante , Burkina Faso. P.J.R. is a Doris Duke Charitable Foundation Distinguished Clinical Scientist. Potential conicts of interest. All authors: no conicts.

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