Doi:10.1016/j.trstmh.2006.03.004

Transactions of the Royal Society of Tropical Medicine and Hygiene (2006) 100, 1013—1018
a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e l s e v i e r h e a l t h . c o m / j o u r n a l s / t r s t Efficacy of chloroquine and
sulfadoxine/pyrimethamine for the
treatment of uncomplicated
falciparum malaria in Koumantou, Mali
Xavier de Radigu`
es , Kandian I. Diallo , Mouctar Diallo ,
Paul Akisa Ngwakum , Hamma Maiga , Abdoulaye Djimd´
Massambou Sacko , Ogobara Doumbo , Jean-Paul Guthmann
a Epicentre, 42 bis, Boulevard Richard Lenoir, 75011 Paris, Franceb M´edecins sans Fronti`eres, 70, rue de Gasperich, L-1617, Luxembourgc Malaria Research and Training Centre, DEAP/FMPOS/University of Bamako, BP 1805, Bamako, Malid Programme National de Lutte contre le Paludisme, Division de la Pr´evention et de la Lutte Contre la Maladie,Direction Nationale de la Sant´ Received 18 August 2005; received in revised form 29 March 2006; accepted 29 March 2006Available online 12 June 2006 KEYWORDS
We report the results of an in vivo antimalarial efficacy study with chloroquine (CQ) and sulfadoxine/pyrimethamine (SP) conducted between 2003 and 2004 in Koumantou, south- ern Mali. A total of 244 children were included in the study; 210 children were followed-up for 28 days according to WHO recommendations, with PCR genotyping to distinguish late recrude- scence from re-infection. Global failure proportions at Day 14, without taking into account re-infections, were 44.2% (95% CI 34.9—53.5%) in the CQ group and 2.0% (95% CI 0.0—4.8%) in the SP group. PCR-adjusted failure proportions at Day 28 were even higher in the CQ group (90.5% (95/105), 95% CI 84.8—96.2%) and relatively low in the SP group (7.0% (7/100), 95% CI 1.9—12.1%). These results show that CQ is no longer efficacious in Koumantou. The use of SP in monotherapy is likely to compromise its efficacy. We recommend the use of artemisinin-basedcombination therapy as first-line treatment for uncomplicated Plasmodium falciparum malariain Koumantou.
2006 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rightsreserved.
∗ Corresponding author. Present address: Epicentre, 8 rue Saint Sabin, 75011 Paris, France. Tel.: +33 140 21 29 14; fax: +33 140 21 28 03.
0035-9203/$ — see front matter 2006 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
1. Introduction
Medicine, Pharmacy and Odonto-Stomatology, University ofBamako, Mali.
In Africa, resistance of Plasmodium falciparum to com- Children aged 6—59 months living within <20 km from the mon antimalarials represents a major obstacle for malaria centre, weighing >5 kg and with suspicion of malaria (axillary control. Resistance to antimalarials is responsible for an temperature ≥37.5 ◦C) were screened. Children with a P. fal- increase in morbidity and mortality in many sub-Saharan ciparum monoinfection and asexual parasitaemia between 2000/␮l and 200 000/␮l, no signs of severity or severe southern Africa shows that recent improvements in child- malaria (including severe anaemia defined by haemoglobin hood mortality due to diarrhoeal and vaccine-preventable <5 g/dl), no history of allergic reactions to the respective diseases have been counterbalanced by rising malaria deaths study drugs, no presence of a concomitant febrile condi- tion with the potential to confound the study outcome, health problem with an annual incidence of 40.9 per 1000, and no severe malnutrition were included if their guardians accounting for 33% of all consultations for health care consented in writing. Recent intake of antimalarials was not an exclusion criteria. As no information on the effi- the major at-risk population and account for 63% of total cacy of these drugs in the study area was available for cases. In this age group, 59% of all deaths are due to any of the drugs, sample size estimates were based on a 50% failure proportion for each drug. Applying a level Resistance levels to chloroquine (CQ), the first-line rec- of significance of 95% and a precision of 10%, 96 chil- ommended drug, of 17—30% have been reported dren per treatment arm were required. Allowing for a 10% A recent study reported 60% resistance to CQ in loss to follow-up, the final sample size was thus raised to 106 children per treatment arm, i.e. 212 children in studies were used, which have been shown to have low sen- Children received one of the study drugs under direct observation and were followed-up for 28 days. Because showed high efficacy of sulfadoxine/pyrimethamine (SP), the transmission season was well advanced and to ensure the second-line drug in Mali, and a recent molecular-based that recruitment could be finished in at least one of the study did not find the DHFR-DHPS quin- arms, the two drugs under study were tested consecu- tuple mutant genotype associated with in vivo SP failure tively, starting with CQ. Outcomes were both clinical and parasitological, with PCR genotyping performed to distin- transmission areas of Mali are needed in order to update guish re-infections from recrudescences due to therapeutic treatment policy-makers. Therefore, a study was carried out and the Malaria Research and Training Centre (MRTC), Uni- 2.3. Treatment and follow-up
versity of Bamako, to evaluate the efficacy of these twoantimalarial drugs.
Upon inclusion, children received either: CQ 25 mg/kg basegiven at 10 mg/kg on Day 0 and Day 1 and at 5 mg/kg 2. Methods
1.25 mg/kg of pyrimethamine and 25 mg/kg of sulfadoxine 2.1. Study site
on Day 0 (Fansidar®; Roche, Basel, Switzerland). Dosageswere expressed as fraction of tablets and adapted to sim- The study was carried out between October 2003 and plify prescription. Drugs were crushed and mixed with water March 2004 in the town of Koumantou, in the Sikasso and sugar, given in a spoon or a syringe to smaller children.
region located in the southern part of Mali. The Kouman- All doses were directly observed and repeated if vomiting tou area is a rural area with 27 000 inhabitants spread occurred within 30 min. Post-treatment visits were on Days over 23 villages. Malaria is present throughout the year, 3, 7, 14, 21 and 28, or any other day in the case of recurrent with a marked increase during the rainy season (i.e.
illness. At each visit, children were assessed clinically, axil- May—November). The site was selected because of the exis- lary temperature was recorded, and thick and thin blood tence of a functional health centre with well trained per- films were inspected. Haemoglobin was measured on Days 0, 14 and 28. Patients who presented haemoglobin <7 g/dl in the neighbouring town of Bougouni. A survey con- Rescue therapy in cases of uncomplicated malaria mented common use of CQ, often given at an inappropriate was oral artemisinin-based combination therapy (ACT) of artemether 20 mg and lumefantrine 120 mg (AT + LU;Coartem®; Novartis, Zurich, Switzerland), whilst i.v. orintrarectal quinine (10 mg/kg/8 h) followed by oral AT + LU 2.2. Study design and procedures
was used in cases of complicated malaria.
On Day 0, a blood sample on filter paper was also taken The study adhered to the latest WHO guidelines for assess- for genotypic analysis and a second sample was collected in ment of therapeutic efficacy of antimalarial treatment in cases of symptomatic parasitaemia on or after Day 9, and at high transmission settings (The study proto- the end of follow-up in the presence of parasitaemia without col was approved by the ethics committee of the Faculty of Efficacy of CQ and SP for uncomplicated falciparum malaria 2.4. Endpoint classification
2.6. Data entry and analysis
Efficacy endpoints (failure or cure) were assigned according Data were recorded in an individual record form and entered to the latest WHO classification Patients were into a locked Excel® spreadsheet and all entries were ver- classified as early treatment failure (ETF) if they met any ified. The data set was analysed using Stata® 8.02 (Stata of the following criteria: (i) progression to severe malaria Corp., College Station, TX, USA). Baseline characteristics of in the presence of parasitaemia on Days 1, 2 or 3; (ii) par- patients in each group were compared using a ␹2 test for cat- asitaemia on Day 2 higher than on Day 0; (iii) any density egorical variables and the Mann—Whitney U-test for contin- of parasitaemia on Day 3 in the presence of fever; or (iv) uous variables non-normally distributed. Failure proportions parasitaemia on Day 3 ≥25% of the Day 0 count, irrespective at Day 14 and Day 28 were calculated as the total number of of fever. After Day 3, patients with recurrent parasitaemia failures (ETF + LCF + LPF) over the total number of analysable were classified as late clinical failure (LCF) if febrile, or late outcomes, and expressed as a percentage with associated parasitological failure (LPF) if they remained afebrile until 95% CI. PCR analysis results were used to adjust failure pro- Day 28. All other children were classified as adequate clini- portions at Days 9—28. Only treatment failures proven to be recrudescence or mixed recrudescence and re-infection Children were withdrawn from the study in the case of: were classified as true failures. Patients for which the PCR (i) vomiting any study dose twice; (ii) withdrawal of consent; result was inconclusive (no DNA isolated) or reported as a (iii) onset of a serious febrile illness other than malaria; (iv) pure re-infection, patients lost to follow-up and secondary intake of any drug with antimalarial properties; (v) skipping exclusions were all excluded from the analysis.
any treatment dose; (vi) mixed parasitaemia; or (vii) anyprotocol violation. Patients who missed follow-up visits and 3. Results
did not come on successive days despite tracing were con-sidered lost to follow-up.
A total of 382 children were screened, of which 244 metthe inclusion criteria: 142 were assigned to the CQ arm 2.5. Laboratory procedures
and 102 to the SP arm One patient (0.4%) waslost to follow-up and 33 (13.5%) were withdrawn (31 inthe CQ arm and 2 in the SP arm). Reasons for withdrawal Capillary blood was obtained by fingerprick sampling. Micro- included intake of antimalarials (4), mixed parasitaemia (4), scopic examination was performed according to WHO guide- onset of serious illness (2), allergy to study drug (1), twice lines (Thick and thin films were prepared on the vomiting the study drug (11) and protocol violation (11).
same slide and stained with 10% Giemsa (pH 7.2) for 15 min.
Amongst the protocol violations, eight were due to para- Asexual parasitaemia was quantified against 200—500 leuko- sitaemia >200 000/␮l and three to parasitaemia <2000/␮l cytes, assuming a white blood cell count of 8000/␮l. All that appeared at the second reading of the Day 0 slides.
the Day 0, Day 2 and Day 3 slides, and at least 10% of The number of patients analysable at Day 14 was 113 and the follow-up slides, were re-read randomly every day and 100 in the CQ and SP arms, respectively. The number of any discordance was resolved by a third reader. Exter- patients analysable at Day 28 was 110 and 100 in the CQ nal quality control on a random sample of slides (n = 152) and SP groups, respectively. Baseline characteristics were was carried out at the MRTC in Bamako, and by an inde- similar across treatment groups, with the exception of tem- pendent laboratory technician in France, yielding an end- perature, haemoglobinaemia and parasite density: children point affecting discordance in <4% of cases. Haemoglobin had a higher temperature (P = 0.04), were more anaemic was measured using a HemoCue® type haemoglobinome- (P = 0.01), but had a lower parasitaemia (P < 0.01) in the CQ Global failure proportions at Day 14, without taking into In high-transmission settings, re-infections occur fre- account re-infections, were 44.2% (95% CI 34.9—53.5%) in quently and confound LCF and LPF endpoints. To identify the CQ group and 2.0% (95% CI 0.0—4.8%) in the SP group.
true failures (recrudescence), blood samples were collected PCR-adjusted failure proportions at Day 28 were even higher on Whatman No. 3 filter paper and analysed at the MRTC in the CQ group (90.5% (95/105), 95% CI 84.8—96.2%), by PCR of P. falciparum DNA extracted from the Day 0 and but were still low in the SP group (7.0% (7/100), 95% CI failure day samples. Procedures in this laboratory relied 1.9—12.1%); ETFs were frequent in the CQ group (29.5% (31/105), 95% CI 20.7—38.4%); in the SP group, there were Cartwright comparing the Day 0 and failure day two ETFs Only 16.0% (17/106) of CQ-treated alleles of the merozoite surface proteins msp-1 and msp-2 as patients but 83.0% (83/100) of those receiving SP were para- well as glurp gene loci. Possible outcomes were: (i) recrude- site free on Day 3. In the CQ group, the majority of treatment scence if the alleles of the pre- and post-treatment samples failures were pure or mixed recrudescence (90.5% (57/63)), were the same for msp-1, msp-2 and glurp; (ii) re-infection whereas none of the children in the SP arm experienced a if the alleles of the pre- and post-treatment samples were distinct; (iii) mixed recrudescence and re-infection if similaralleles were found in the pre- and post-treatment samplesfor all the markers as mentioned above, but with additional 4. Discussion
distinct alleles identified; or (iv) no DNA isolated, if eitheror both the pre- and post-treatment samples could not be This study provides estimates of the in vivo antimalarial effi- cacy of first- and second-line drugs in Mali, where current Details of study inclusion and follow-up of patients in the in vivo antimalarial efficacy study, Koumantou, Mali, 2003—2004.
CQ: chloroquine; SP: sulfadoxine/pyrimethamine.
Baseline (Day 0) characteristics of patients included in the in vivo antimalarial efficacy study, Koumantou, Mali, Antimalarial treatment before inclusion, n (%) Axillary temperature (◦C) (median (IQR)) Moderate anaemia (<8 g/dl), n (%) Asexual parasitaemia (␮l) (geometric mean CQ: chloroquine; SP: sulfadoxine/pyrimethamine; IQR: interquartile range (25—75%).
a Two missing values.
b Three missing values.
data regarding CQ and SP were urgently needed. Method- results between the two arms. A second limitation is the rel- ologically, the 28-day follow-up combined with adjustment atively high number of withdrawals in the CQ arm owing to of the results by PCR analysis provided more realistic esti- some misunderstandings by the staff at the beginning of the mates of efficacy than the traditional 14-day studies.
study. Nevertheless, measures taken (such as further train- The major limitation of our study was the method of ing of nurses and laboratory staff) have probably limited treatment allocation, which was not randomised. This could potential biases. The validity of our data is further supported explain the unequal level of fever, haemoglobin and parasite by the almost non-existent loss to follow-up and the low pro- density at inclusion and does not allow a strict comparison of Failure proportions at Day 28 (clinical and parasitological failures, after PCR adjustment) for the in vivo antimalarial efficacy study, Koumantou, Mali, 2003—2004 CQ: chloroquine; SP: sulfadoxine/pyrimethamine; ETF: early treatment failure; LCF: late clinical failure; LPF: late parasitological failure.
Efficacy of CQ and SP for uncomplicated falciparum malaria We have shown that the in vivo resistance to CQ, the first- Koumantou team for their enthusiasm and excellent work: line antimalarial treatment in Mali, was unquestionably very Dr Hamadoun Yattara, Christiane Dembele, Ali Poudougou, high in Koumatou area, confirming previous reports from Brahima Sidebe, Mamadou Kone, Moussa Diakate, Adama Doumbia, Brehima Koulibaly, Lassina Kone, Aminata Konate erard Fabrice. Many thanks to Dr Bakary Fofana of the MRTC for his help with PCR analysis, and to Dr Amagana Dolo is thus well above the 25% value considered by the WHO of the same institution for performing the external quality as the threshold for changing the drug policy control. Thanks to Kodzo Tupko for performing the second The dramatic impact of CQ resistance on childhood mor- quality control in France. Thanks to Evelyn Depoortere (Epi- bidity and mortality has been well described in western centre), Rony Zachariah and Martin De Smet (MSF, Belgian Africa In Kenya, 69% of deaths due to malaria section) for their external support. This study was funded were attributed to ineffective CQ treatment ( In vivo resistance to SP, which was the second-line anti- References
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Conflicts of interest statement
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