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8-penali (paludo1) final pp54-60.indd

Revue Bio-Africa - N° 7 - 2009, pp. 56-63 COMPARISON OF CLINICAL AND PARASITOLOGIC RESPONSES TO SULFALENE/
PYRIMETHAMINE PLUS AMODIAQUINE VERSUS AMODIAQUINE PLUS ARTESUNATE
IN THE TREATMENT OF UNCOMPLICATED MALARIA IN ENDEMIC AERAS IN AFRICA
PENALI LK1, OFFIANAN AT1, SAMÉ-EKOBO A2, NDIAYE JL3, GAYE O, KUETÉ TH2, BEUGRE GRAH E1, FAYE O3, FAYE B3, BARRO KIKI P4, KONÉ M4 Malgré tous les efforts déployés dans le cadre Le randomisée, multicentrique, l’étude comparative a de divers programmes internationaux, le paludisme été menée simultanément au Cameroun et en Côte-représente encore un énorme problème de santé d’Ivoire au cours des six premiers mois de 2005. publique. Le traitement des patients a été compliquée Méthodes de l’OMS pour l’évaluation de l’effi cacité par l’émergence et la propagation de Plasmodium des antipaludiques a été utilisé et un total de 461 falciparum résistant aux médicaments antipaludiques patients ont été inclus. Les deux traitements ont été réguliers. Ainsi, la recherche s’est concentrée sur une effi cacité comparable avec un taux de réponse l’identification des plus efficaces, mais sûre des clinique et parasitologique de 97% pour sulfalène / modalités de traitement, notamment des combinaisons pyriméthamine + amodiaquine par rapport à 98,1% de médicaments. Dans ce contexte, nous avons étudié pour l’artésunate plus amodiaquine après correction l’effi cacité et l’innocuité d’une combinaison inédite, à PCR. La tolérance était également comparable dans savoir sulfalène / pyriméthamine + amodiaquine, en le comparant à l’amodiaquine plus artésunate (une combinaison récemment adopté comme traitement MOTS-CLÉS: PALUDISME, LE TRAITEMENT, SULFALÈNE/
de première intention dans de nombreux pays). PYRIMÉTHAMINE + AMODIAQUINE, ARTESUNATE PLUS AMODIAQUINE, ABSTRACT
Despite all the effort expended in the context of diverse was conducted simultaneously in Cameroon and Ivory international programmes, malaria still represents a Coast in the fi rst six months of 2005. WHO methods for massive public health problem. The treatment of patients the evaluation of the effi cacy of antimalarial drugs was has been complicated by the emergence and spread used and a total of 461 patients were included. The of Plasmodium falciparum resistant to the regular two regimens were comparably effective with a clinical antimalarial drugs. Thus research has focussed on and parasitologic response rate of 97% for sulfalene/ the identifi cation of more effective but safe treatment pyrimethamine plus amodiaquine compared with 98.1% modalities, notably drug combinations. In this context, for artesunate plus amodiaquine after PCR correction. we have investigated the effi cacy and safety of a novel Tolerance was also comparable in both groups. combination, namely sulfalene/pyrimethamine plus amodiaquine, by comparing it to amodiaquine plus KEYS WORDS: MALARIA, TREATMENT, SULFALENE/PYRIMETHAMINE
artesunate (a combination recently adopted as fi rst-line PLUS AMODIAQUINE, ARTESUNATE PLUS AMODIAQUINE, EFFICACY, The randomised, multicentre, comparative study 1- Malariology Department - Institut Pasteur, Abidjan (Côte d’Ivoire)
2-Laboratory of Parasitology - CHU and FMSB. Yaoundé. (Cameroon)
3- Laboratory of Parasitology - CHU Cheikh Anta Diop. Dakar. (Sénégal)
4- Laboratory of Parasitology - Faculty of Pharmacy Abidjan. (Côte d’Ivoire)
Corresponding author: Louis Penali, 01 BP 490 Abidjan 01 (Côte d’Ivoire)
Tél. (225) 07 34 07 076 ; fax : (225) 22 48 66 63 E-mail : lou.penali@gmail.com
Revue Bio-Africa - N° 7 - 2009, pp. 56-63 INTRODUCTION
At the beginning of the third milennium, treatment of malaria12,13, they are expensive malaria continues to be a global scourge with and sometimes diffi cult to get hold of. The more than 40% of the planet’s population- scarcity of fi nancial resources in most of 2.5 billion people-exposed to the disease. sub-Saharan Africa has led us to believe Every year, malaria is responsible for 1-1.5 that it may be possible to use compounds million deaths in the world, most of these other than the artemisinin derivatives, with being children under fi ve. Somewhere in the good results. Metakelfi n™ (MF), a sulfalene/world, a child dies of malaria every thirty pyrimethamine has not been used for over minutes. Africa accounts for 90% of all three decades and, as a result, it is likely that infections1,2,3,4,5. today’s plasmodia have not been subjected The appearance and spread of chloroquine- to selection pressure from this combination resistant Plasmodium falciparum have made and have remained maximally sensitive it important to understand the sensitivity (except for cases of spontaneous resistance, of different strains to the various 4-amino rare for folic and folinic acid antagonists). quinolines. Resistance to amodiaquine We set out to organise a trial to compare the exists but to a lesser degree than resistance combination of sulfalene/pyrimethamine to chloroquine. Treatment failure rates are plus amodiaquine (Dualkin™ from Pfi zer) and low, in Africa ranging from 0 to 5%6,7. Most artesunate plus amodiaquine (Arsucam™ of the countries of sub-Saharan Africa from Sanofi -Aventis).
have had to confront resistance to 4-amino This prospective, multicentre, randomised quinolines with, as a result, the need to use comparative study was conducted in two sulfadoxine/pyrimethamine for first-line parallel populations who were unaware of which treatment. The resultant selection pressure treatment they were being given. The design drove spread of the resistance of the parasite was that of a non-inferiority trial comparing to this product especially in sub-Saharan two therapeutic combinations, namely Africa8,9,10,11. In the light of this situation, Sulfalene/Pyrimethamine+Amiodaquine therapeutic combinations today constitute a choice option. Although combinations based (AS+AQ) in children and adults living in a on artemisinin are effective and safe in the zone where malaria is endemic.
PATIENTS AND METHODS
. Patients who have given their informed The study was conducted in health care consent to participate (or children whose institutions in two different countries, Ivory parents have given consent) after having Coast and Cameroon. The Study Protocols received explanations of the details of the were approved by Ethics Committees in both . Outpatients; . Patients with uncomplicated malaria (without gastrointestinal symptoms or any The study population comprised people of the signs of severe disease) who could be diagnosed on the basis of clinical criteria ria attending the participating health care (a fever of 37°5 C or above, with or without institutions. All those, of all ages, in whom shivering, aching, generalised pain and malaria was confi rmed by the thick-drop test headache) and in whose blood P. falciparum² and who fulfi lled the inclusion criteria (2003 WHO Protocol) were invited to take part.
. Patients who can take oral drugs;. Patients who are not suffering from severe malnutrition (definition: children . Male and female patients of at least two with a weight-to-height ratio lower than the PENALI LK, OFFIANAN AT1, SAMÉ-EKOBO A., NDIAYE JL, GAYE O., et al. Revue Bio-Africa - N° 7 - 2009, pp. 56-63 median, normalised NCHS/WHO reference study and for every patient with parasites in fi gure by either a factor of over three standard the blood between d7 and d28, in order to deviations or more than 70%; or who have distinguish relapse from re-infection.
symmetrical œdema in both feet); blood chemistry (transaminases, AST/ALT, fi ve year-olds, or of severe or complicated Bilirubin, blood creatinine) were carried out Plasmodium falciparum malaria as stipulated . An initial parasite density of between 2000 and 200000 per microlitre of blood; - The main effi cacy end points were those . In women of child-bearing age (12 and stipulated in the WHO Classifi cation of Res- over), a negative pregnancy test result ; ponse to Treatment, using the 28-day in vivo . No history of hypersensitivity to any of test (WHO/CDS/CSR/EPH/2002.17 WHO/ - Secondary effi cacy end points were time- to the disappearance of parasites from the blood, time-to temperature normalisation, After inclusion, the patients were weighed and the blood gametocyte counts.
Groups. All daily doses of the Study Medication Adverse Events and Serious Adverse Events.
were administered at the health care institution under the supervision of the Investigator or one of the Co-Investigators. If the patient vomited within thirty minutes of taking the drugs, the computer, and analysed using Epi-Info same dose was re-administered. software. All analyses were carried out on both the Intention-to-Treat and Per Protocol - The comparability of the two treatment Patients were given a full physical exami- groups was evaluated on all included patients, nation and their blood was tested for Plasmo- using Student’s Test for continuous variables, dium at inclusion and then again on d1, d2, and the Chi2 test for discrete variables.
d3, d4, d7, d14, d21 and d28. A PCR assay - Secondary end points (safety, compliance) was carried out before the beginning of the were evaluated using the Chi2 test and PENALI LK, OFFIANAN AT1, SAMÉ-EKOBO A., NDIAYE JL, GAYE O., et al. Revue Bio-Africa - N° 7 - 2009, pp. 56-63 2 – RESULTS
Drop-outs
Protocol
violations
Figure 1. Age distribution in the two Treatment Groups
232 patients randomised to
Mean weight: 35 kg
Mean weight: 32.4 kg
Median weight: 25 kg
Median weight: 21 kg
Mean height: 125.2cm
Mean height: 127.4 cm
Median: 119 cm
Median: 125 cm
Figure 2. Weight and height distribution in the two Treatment Groups
A total of 461 patients were recruited between 15 February and 23 April 2005. After randomisation, there were 232 patients in the Sulfalene/Pyrimethamine+Amiodaquine arm and 229 in the Artesunate+Amiodaquine arm. In the fi rst group, the median age was 7 and the mean 12.8; in the second group the corresponding fi gures were 9 and 14.6. Median and mean weights were respectively 21 and 32.4 kg in the fi rst arm, and 25 and 35 kg in the second arm.
PENALI LK, OFFIANAN AT1, SAMÉ-EKOBO A., NDIAYE JL, GAYE O., et al. Revue Bio-Africa - N° 7 - 2009, pp. 56-63 No patient dropped out and no protocol violation was recorded.
Table I. Therapeutic effi cacy: MK+AQ versus AS+AQ
Clinical and parasitologic response rates were over 95% in both arms.
Parasitologic cure
Figure 1. Parasitologic cure rates : MK+AQ versus AS+AQ
Figure 2. Clinical effi cacy
PENALI LK, OFFIANAN AT1, SAMÉ-EKOBO A., NDIAYE JL, GAYE O., et al. Revue Bio-Africa - N° 7 - 2009, pp. 56-63 Table II. Safety : MK+AQ versus AS+AQ
SIDE EFFECTS
MK+AQ AS+AQ
The most common problems were:pruritus, asthænia and vomiting. No serious problem was reported (Table II).
Table III. Laboratory test results: MF+AQ versus AS+AQ
No notable abnormalities in key laboratory parameters (blood creatinine, transaminases and hæmoglobin) were reported in either Group (Table III). DISCUSSION
Sulfalene and sulfadoxine are folic acid antagonists which inhibit a Plasmodium- close to that of sulfadoxine and it therefore specifi c enzyme, dihydropteroate-synthase seems reasonable to combine sulfalene/(DHPS). These drugs bind protein strongly pyrimethamine with amodiaquine since and have relatively long half-lives (65 and it has been shown that a combination of 180 hours respectively)14. Sulfalene/pyrimethamine has not been used is more effective than either product on its for over three decades and, as a result, it is likely own, and that its safety profi le is identical that today’s plasmodia have not been subjected to selection pressure from this combination pyrimethamine. In 2002 (before PCR) in and have remained maximally sensitive. Uganda, Talisuna et al. (10) recorded a Since amodiaquine remains effective (15), we parasitologic effi cacy rate of 85.7%, and in organised a study to compare the combinations Rwanda in 2001, Rwagacondo et al.16 obtained sulfalene/pyrimethamine+amodiaquine and an effi cacy rate of 97.7% with sulfadoxine/artesunate+amodiaquine. PENALI LK, OFFIANAN AT1, SAMÉ-EKOBO A., NDIAYE JL, GAYE O., et al. Revue Bio-Africa - N° 7 - 2009, pp. 56-63 In our study, clinical and parasitologic similar picture was seen for the laboratory responses were comparable with the two test results probing organ function: no combinations (MK+AQ and AS+AQ) on d14: signifi cant change in liver or kidney function 97. 3% versus 99%. By d28, outcomes were was observed. These fi ndings are consistent still comparable : 97% for MK+AQ versus with the published results17,18 and pinpoint 98.1% for AS+AQ after PCR. The most the potential of a combination of sulafalene/common adverse events were pruritus, pyrimethamine and amodiaquine in the asthænia and vomiting with incidences treatment of simple Plasmodium falciparum being comparable on both regimens. A malaria.
CONCLUSION
The effi cacy of the combination Sulfalene/ T h e c o m b i n a t i o n s u l f a l e n e / to that of Artesunate+Amodiaquine. Similarly, fever control and parasite clearance are promising option for the fi rst-line treatment comparable. A reduction in gametocyte load of uncomplicated malaria in Africa although was observed in both groups.
a pharmacovigilance system should be set Both regimens were well tolerated, and up, as for all combinations currently being neither induced significant changes in prescribed.
REFERENCES
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8 - White, N. Antimalarial Drug Resistance. J Clin 3 - Snow R, Trape JF and Marsh K. the past, present and future of childhood malaria mortality in Africa. 2001 Trends parasitol. 9- Djaman JA, Kauffy PC, Yavo W, BASCO LK 17: 593-597.
& KONE M Evaluation in vivo de l’effi cacité thérapeutique de l’association sulfadoxine/ Estimating mortality, morbidity and disability due to malaria among Africa’s non- pregnant (Abidjan, Côte d’Ivoire).Bull. Soc. Pathol. Exot., population. Bull. W.H.O. 1999. 77: 624-640 5 - Nabbarro D and Tayler E. The “Roll Back 10 - Talisuma A, Nalunkuma-kazibwe A, Bakyaita Malaria” campaign. Science 1998. 280: 2067- Net al. Effi cacy of sulphadoxine-pyrimethamine 2068. World Health Organization. Roll Back chloroquine for the treatment of uncomplicated 6- Penali l. k. . ; Coulibaly a. l. ; Kaptue b. ; Konan falciparum malaria in Ugandan children. Tropical d. ; Ehouman a.Réponses parasitologique et Medicine Int Health. 2004. 9: 222-229.
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amodiaquine alone and combined with artesunate in children with uncomplicated malaria. Trop Med 13 - WHO technical consultation on the antimalarial drug combination therapy. Geneva, World Health Organization, 2001.
17- Agnamey P, Brasseur R, Sarrassat S, Cisse M, Gaye O, Sokhna C, Trape JF & Olliaro 14- White N.J., «Clinical pharmacokinetics of the P.Impact de l’utilisation de l’association antimalarial drugs.», Clin. Pharmacokinet., Artesunate+Amiodaquine pour le traitement du paludisme non compliqué en Casamance. 15 - Bray P, Hawley S, Mungthin M et al. Physicochemical properties correlated with 18 - Abacassamo F., Enosse S., Aponte J., et al. drug resistance and the reversal of drug Effi cacy of chloroquine, amodiaquine, sulfado- resistance in Plasmodium falciparum. Mol xine-pyrimethamine and combination therapy with artesunate in Mozambican children with non-complicated malaria. Trop Med Int Health. 2004. 9: 200-208.
PENALI LK, OFFIANAN AT1, SAMÉ-EKOBO A., NDIAYE JL, GAYE O., et al.

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