Effectiveness of artesunate–amodiaquine vs. artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in Nanoro, Burkina Faso: a non-inferiority randomised trial

Authors

  • Halidou Tinto,

    1. Unité de Recherche sur le Paludisme et les Maladies Tropicales Négligées, Centre Muraz, Bobo-Dioulasso, Burkina Faso
    2. Institut de Recherche en Sciences de la Santé, Direction Régionale, Bobo-Dioulasso, Burkina Faso
    3. Clinical Research Unit of Nanoro, Nanoro, Burkina Faso
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  • Salou Diallo,

    1. Clinical Research Unit of Nanoro, Nanoro, Burkina Faso
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  • Issaka Zongo,

    1. Institut de Recherche en Sciences de la Santé, Direction Régionale, Bobo-Dioulasso, Burkina Faso
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  • Issa Guiraud,

    1. Institut de Recherche en Sciences de la Santé, Direction Régionale, Bobo-Dioulasso, Burkina Faso
    2. Clinical Research Unit of Nanoro, Nanoro, Burkina Faso
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  • Innocent Valea,

    1. Unité de Recherche sur le Paludisme et les Maladies Tropicales Négligées, Centre Muraz, Bobo-Dioulasso, Burkina Faso
    2. Clinical Research Unit of Nanoro, Nanoro, Burkina Faso
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  • Adama Kazienga,

    1. Clinical Research Unit of Nanoro, Nanoro, Burkina Faso
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  • Hervé Kpoda,

    1. Unité de Recherche sur le Paludisme et les Maladies Tropicales Négligées, Centre Muraz, Bobo-Dioulasso, Burkina Faso
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  • Hermann Sorgho,

    Corresponding author
    1. Institut de Recherche en Sciences de la Santé, Direction Régionale, Bobo-Dioulasso, Burkina Faso
    2. Clinical Research Unit of Nanoro, Nanoro, Burkina Faso
    • Corresponding Author Hermann Sorgho, Institut de Recherche en Sciences de la Santé, Direction Régionale, Bobo-Dioulasso, Burkina Faso. E-mail: hsorgho@hotmail.com

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  • Jean-Bosco Ouédraogo,

    1. Unité de Recherche sur le Paludisme et les Maladies Tropicales Négligées, Centre Muraz, Bobo-Dioulasso, Burkina Faso
    2. Institut de Recherche en Sciences de la Santé, Direction Régionale, Bobo-Dioulasso, Burkina Faso
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  • Tinga Robert Guiguemdé,

    1. Unité de Recherche sur le Paludisme et les Maladies Tropicales Négligées, Centre Muraz, Bobo-Dioulasso, Burkina Faso
    2. Clinical Research Unit of Nanoro, Nanoro, Burkina Faso
    3. Institut Supérieur des Sciences de la Santé, Bobo Dioulasso, Burkina Faso
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  • Umberto D'Alessandro

    1. Malariology Unit, Institute of Tropical Medicine Prince Leopold, Antwerp, Belgium
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Abstract

Objectives

Artemisinin-based combination therapies (ACTs) are essential for the effective control of falciparum malaria in endemic countries. However, in most countries, such choice has been carried out without knowing their effectiveness when deployed in real-life conditions, that is, when treatment is not directly observed. We report here the results of a study assessing the effectiveness of the two ACTs currently recommended in Burkina Faso for the treatment of uncomplicated malaria, that is, artemether–lumefantrine (AL) and artesunate–amodiaquine (ASAQ).

Methods

Between September 2008 and January 2010, 340 children were randomised to one of the two study arms and followed up for 42 days. Treatment was administered according to routine practices, that is, the first dose was given by study nurses who explained to the parent/guardian how to administer the other doses at home during the following 2 days.

Results

The results showed a significantly higher unadjusted adequate clinical and parasitological response in the ASAQ (58.4%) than in the AL arm (46.1%) at day 28 but these trends were similar after correction with PCR data (ASAQ (89.7%) and AL (89.8%)). New infections started to appear after day 14, first in the AL and then in the ASAQ arm but at day 42 day of follow-up we observed no difference in the occurrence of recrudescent infection.

Conclusion

Despite a lower cure rate than those reported in efficacy studies in which the treatment administration was directly observed, both AL and ASAQ can still be used for the treatment of uncomplicated malaria in Burkina Faso.

Abstract

Objectifs

Les traitements de combinaison à base d'artémisinine (ACT) sont essentiels pour la lutte efficace contre le paludisme à falciparum dans les pays endémiques. Cependant, dans la plupart des pays, un tel choix a été fait sans connaître leur efficacité lorsqu'ils sont déployés dans des conditions réelles, c'est-à-dire, lorsque le traitement n'est pas directement observé. Nous rapportons ici les résultats d'une étude visant à évaluer l'efficacité des deux ACT actuellement recommandés au Burkina-Faso pour le traitement du paludisme non compliqué, c'est-à-dire l'artéméther-luméfantrine (AL) et l'artésunate-amodiaquine (ASAQ).

Méthodes

Entre septembre 2008 et janvier 2010, 340 enfants ont été randomisés dans l'un des deux bras de l’étude et suivis pendant 42 jours. Le traitement a été administré selon les pratiques de routine, c'est à dire la première dose a été administrée par des infirmières de l’étude qui ont expliqué au parent/tuteur comment administrer les autres doses à la maison pendant les deux jours suivants.

Résultats

Les résultats ont montré une réponse clinique et parasitologique adéquate (RCPA) non ajustée significativement plus élevée dans le bras ASAQ (58.4 de%) que dans le bras AL (46.1%) au jour 28, mais ces tendances étaient similaires après correction avec les données de PCR (ASAQ (89.7%) et AL (89.8%)). Les nouvelles infections ont commencé à apparaître après le jour 14, d'abord dans le bras AL, puis dans le bras ASAQ mais au jour 42 de suivi, nous n'avons observé aucune différence dans l'incidence de recrudescence de l'infection.

Conclusion

Malgré un taux de guérison inférieur par rapport à ceux rapportés dans les études d'efficacité dans lesquelles l'administration du traitement a été directement observé, autant AL que ASAQ peut toujours être utilisé pour le traitement du paludisme non compliqué au Burkina-Faso.

Abstract

Objetivos

Las terapias de combinación de artemisinina (TCA) son esenciales para el control efectivo de la malaria por falciparum en países endémicos. Sin embargo, en la mayoría de los países esta opción se ha tomado sin conocer su efectividad en condiciones de la vida real, es decir cuando el tratamiento no se observa de forma directa. Reportamos los resultados de un estudio que evalúa la efectividad de las dos TCAs actualmente recomendadas en Burkina Faso para el tratamiento de la malaria no complicada, es decir artemeter-lumefantrina (AL) y artesunato-amodiaquina (ASAQ).

Métodos

Entre Septiembre 2008 y Enero 2010, se aleatorizaron 340 niños a uno de los dos brazos del estudio y se siguieron durante 42 días. Se administró el tratamiento según las prácticas rutinarias, es decir la primera dosis la entregó una enfermera del estudio que explicó al pariente/guardián como administrar las otras dosis en casa durante los siguientes dos días.

Resultado

Los resultados mostraban una respuesta clínica y parasitológica adecuada no ajustada significativamente mayor en el brazo de ASAQ (58.4%) que en el brazo AL (46.1%) a día 28, pero estas tendencias eran similares después de la corrección con datos de PCR (ASAQ (89.7%) y AL (89.8%)). Nuevas infecciones aparecieron después del día 14, primero en el brazo AL y después en el brazo ASAQ pero en el día 42 de seguimiento no se observaron diferencias en el recrudecimiento de la infección.

Conclusión

A pesar de haber encontrado una tasa de curación menor que aquellas reportados en estudios de eficacia en los que la administración del tratamiento se observaba de forma directa, se puede continuar utilizando tanto la AL como la ASAQ para el tratamiento de la malaria no complicada en Burkina Faso.

Introduction

Artemisinin-based combination therapies (ACT) are essential for the effective control of falciparum malaria in endemic countries (WHO 2007a,b, 2010; Maude et al. 2009). ACTs, mostly artemether–lumefantrine (AL) and artesunate–amodiaquine (ASAQ), are deployed worldwide in over 80 countries, including Burkina Faso (Zwang et al. 2009). However, in most countries the choice of these two specific ACTs was made without knowing their effectiveness when deployed in real-life conditions, that is, when treatment is not directly observed. Indeed, changes in the antimalarial treatment policy have been mainly based on information provided by phase III and IV trials in which treatment administration to selected study subjects and following the manufacturer's prescriptions was directly observed. However, effectiveness may differ from efficacy because of several factors such as incorrect dosing, inappropriate treatment schedule, and concomitant medications with possible drug interactions, all of them likely to occur in rural Africa. Nevertheless, despite the importance of determining it, there is a paucity of information on the effectiveness of ACTs in African countries (Piola et al. 2005; Ngasala et al. 2011a,b). We report here the results of a study assessing the effectiveness of the two ACTs currently recommended in Burkina Faso for the treatment of uncomplicated malaria, that is, AL and ASAQ. These data will contribute to inform the National Malaria Control Program for the ongoing revision of the national antimalarial treatment policy.

Methods

Study area

The study was conducted at the Clinical Research Unit of Nanoro (CRUN-IRSS), Burkina Faso, situated 90 km from Ouagadougou, the capital city. Nanoro Health district is a Roll Back Malaria (RBM) sentinel site for the Burkina Faso National Malaria Control Program (NMCP) and several studies have been launched with the RBM support. The study area is characterised by hyperendemic malaria with seasonal transmission. The entomological inoculation rate is estimated at 50–60 infective bites/man/year (A. Diabaté, personal communication). The commonest vectors are Anopheles gambiae, A. funestus and A. arabiensis. Plasmodium falciparum is the main malaria species. Malaria is the main reason for consultations at health facilities, all year round, with a peak between September and October (Ministere de la Santé/PNLP 2006).

Patients and inclusion criteria

Between September 2008 and January 2010, all children of 6–59 months old attending the Nanoro Medical Center with fever (axillary temperature ≥37.5 °C) or history of fever in the last 24 h were screened for malarial infection. Children weighing 5 kg or more with a P. falciparum mono-infection at a density between 2000 and 200 000/μl and haemoglobin >5 g/dl were included in the study if their parent/guardian provided the informed consent. Exclusion criteria were the following: (i) danger signs (unable to drink or breast-feed; vomiting more than twice in 24 h; recent history of convulsions; unconscious or unable to sit or stand), (ii) severe malaria (WHO 2000), (iii) a documented history of adequate malaria treatment in the preceding two weeks, (iv) any evidence of chronic disease or of a concurrent non-malarial febrile illness and (v) history of serious side effects with the study drugs.

Treatment and follow-up

At the first visit (day 0), patients who met the inclusion/exclusion criteria were randomly assigned to receive either AL (Coartem®; Novartis) or ASAQ (Arsucam®; Sanofi Aventis). Treatment was allocated on the basis of a computer-generated randomisation list provided by the site quality assurance manager. Treatment was administered according to routine practices, that is, the first dose was given by study nurses who explained to the parent/guardian how to administer the other doses at home during the following 2 days. ASAQ was given once daily, at the standard dose of 2.8–5.5 mg/kg and 7.5–15 mg/kg of artesunate and amodiaquine, respectively. AL was administered twice daily according to the body weight as follows: 5–14 kg, one tablet per dose; 15–24 kg, two tablets per dose; 25–34 kg, three tablets per dose. For AL, the parent/guardian was advised to administer it with fat-containing food, for example a glass of milk. Parents/guardians were asked to come back with their child for scheduled visits on days 7, 14, 21, 28, 35 and 42, or if the child was sick between visits (unscheduled visit). If they did not attend scheduled visits, they were visited at home by a fieldworker. Each visit included the completion of a standardised history and physical examination. Besides day 0, before treatment, a blood sample for thick/thin blood smear and for later molecular analysis (filter paper) was collected by finger prick at each scheduled or unscheduled visit. At the end of the 42-day follow-up, treatment outcomes were assessed according to WHO guidelines for regions with intense malaria transmission, that is, adequate clinical and parasitological response (ACPR), early treatment failure (ETF), late clinical failure (LCF) and late parasitological failure (LPF) (WHO 2003). Total treatment failure was the sum of ETF, LCF and LPF. Patients classified as treatment failures were given quinine (10 mg/kg orally twice daily for 7 days). Patients who developed severe malaria or danger signs were treated with parenteral quinine.

Laboratory methods

Thick and thin blood films were stained with Field's stain (Tinto et al. 2002). Parasite density was determined by counting the number of asexual parasites by 200 white blood cells, assuming a white blood cell count of 8000/μl.

For PCR analysis, blood samples were collected on filter paper (Whatman 3MM, Maidstone, UK). Blood samples collected at day 0 and the days of recurrent infection were genotyped to distinguish between recrudescence and new infection. DNA was extracted using the Chelex-100 method (Plowe et al. 1995). Nested PCR was used for the analysis of two P. falciparum polymorphic genetic markers: merozoite surface protein 1 and merozoite surface protein 2 (Msp1 & Msp2) (Ranford-Cartwright et al. 1997). Infections with at least one identical allele for both the Msp1 and Msp2 genes between day 0 and that of recurrent infection were classified as recrudescences; if for at least one genetic marker, there was no common allele between day 0 and that of recurrent infection, this was classified as a new infection.

Ethics

The study protocol was approved by the Institutional Ethics Committee of Centre Muraz, Bobo-Dioulasso, Burkina Faso and conducted in accordance with International Conference on Harmonization and Good Clinical Practices. The trial was registered in the ClinicalTrials.gov registry (ClinicalTrials.gov identifier: NCT01017770). The study purpose and procedures were clearly explained to the potential participants by the study team in the local language.

Statistical analysis

The two drugs were adopted by Burkina Faso National Malaria Control Program on a non-inferiority basis, with ASAQ as the first-line treatment and AL as the alternative therapy. Therefore, the trial was designed as a non-inferiority study to test the hypothesis that the effectiveness of ASAQ was similar to that of AL. It was assumed that effectiveness would be at least 90% for both treatments and that the difference between treatments would not be >10%. Therefore, 170 children per arm would be able to show non-inferiority at the 5% significance level and 90% power and assuming a loss to follow-up of about 10%. Data were double entered and verified with Epi Data, version 3 and analysed with stata, version 8.0. PCR-adjusted and unadjusted ACPRs at day 28 were the primary outcomes; secondary outcomes included PCR-adjusted and unadjusted ACPRs at day 42. Risks of new infection and recrudescence during the 42 days follow-up period (adjusted by genotyping) were estimated with the Kaplan–Meier product-limit formula. Other categorical variables were compared with chi-square or Fisher's exact tests. A value of < 0.05 was considered statistically significant.

Results

During the study period, 576 children were screened for malaria infection, 491 of them (85.2%) had a microscopically confirmed malaria infection, and of these, 340 were included in the study and randomised to one of the two study arms. The large majority of study subjects, 167 in the AL group and 166 in the ASAQ group, completed the follow-up at day 28 and day 42 (Figure 1).

Figure 1.

Trial profile.

The two study groups were comparable at inclusion, with the only exception of the mean temperature which tended to be higher in the AL group (Table 1). Unadjusted ACPR at day 28 was significantly higher in the ASAQ (58.4%) than in the AL arm (46.1%) [risk difference = −12.3; 95% CI: −22.97; −1.68 (= 0.02)] (Table 2). Nevertheless, PCR-adjusted ACPR was similar between ASAQ (89.7%) and AL (89.8%) [risk difference = 0.07, 95% CI: −6.43; −6.57 (= 0.98)]. Unadjusted ACPR at day 42 was low and similar in both study arms; the PCR-adjusted ACPR was around 90%, with no difference between the two study arms (Table 2).

Table 1. Baseline characteristics by study arm
 AL (= 170)ASAQ (= 170)
  1. AL, artemether–lumefantrine; ASAQ, artesunate–amodiaquine.

Mean age in months (SD)26.1 ± 13.725.8 ± 12.2
Male (%)95 (56.2)87 (51.8)
Mean weight in Kg (range)9.8 [5–16.8]9.8 [5–15.6]
Mean temperature (SD)38.2 ± 1.237.9 ± 1.1
Mean haemoglobin (SD)7.4 ± 1.57.4 ± 1.6
Mean (geometric) parasite density (95% CI)17985.7 [15101.7–21420.4]16486.9 [13741.7–19780.5]
Table 2. Efficacy of ASAQ and AL at day 28 and day 42 (%)
OutcomeAL ASAQ Difference [95% CI]P-value
  1. ACPR, adequate clinical and parasitological response; AL, artemether–lumefantrine; ASAQ, artesunate–amodiaquine; ETF, early treatment failure; LCF, late clinical failure; LPF, late parasitological failure; TTF, total treatment failure.

  2. a

    At day 28, there were seven cases (three in the AL arm and four in the ASAQ arm) in which the PCR result was indeterminate; at day 42, there were three additional cases (one in the AL arm and two in the ASAQ arm). These 10 cases were considered as recrudescence.

Day 28(= 167)(= 166)  
PCR unadjusted
ACPR77 (46.1)97 (58.4)−12.33 [−22.97; −1.68]0.02
ETF0 (0.0)0 (0.0)
LCF26 (15.6)23 (13.9)
LPF64 (38.3)46 (27.7)
TTF90 (53.9)69 (41.6)
PCR adjusteda
ACPR150 (89.8)149 (89.7)0.07 [−6.43; −6.57]0.98
ETF0 (0.0)0 (0.0)
LCF5 (3.0)10 (6.0)
LPF12 (7.2)7 (4.2)
TTF17 (10.2)17 (10.2)
Day 42(= 165)(= 165)  
PCR unadjusted
ACPR55 (33.3)61 (37.0)−3.63 [−13.92; 6.66]0.48
ETF0 (0.0)0 (0.0)
LCF29 (17.6)27 (16.4)
LPF81 (49.1)77 (46.7)
TTF110 (66.7)104 (63.0)
PCR adjusteda
ACPR145 (87.9)138 (83.6)4.24 [−3.28; 11.76]0.27
ETF0 (0.0)0 (0.0)
LCF5 (3.0)10 (6.1)
LPF15 (9.1)17 (10.3)
TTF20 (12.1)27 (16.4)

New infections started to appear after day 14, first in the AL and then in the ASAQ arm (Figure 2a). Although the incidence tended to be higher in the AL arm, the difference did not reach statistical significance (= 0.06). There was no difference in the occurrence of recrudescent infection during the follow-up (= 0.43) (Figure 2b).

Figure 2.

Kaplan–Meier estimates of rates of new infections and recrudescence through day 42. Risk of (a) new infections and (b) recrudescences.

Discussion

Although the practice of administering the first dose of an antimalarial treatment and given the remaining tablets to be taken at home by patients is common practice in busy outpatient services of health facilities in malaria endemic countries, there is little information on the effectiveness of ACTs in treating uncomplicated malaria (Piola et al. 2005; Ngasala et al. 2011a,b). The effectiveness of the two ACTs adopted in the Burkina Faso policy of antimalarial treatment, AL and ASAQ, was evaluated in Nanoro, a sentinel site of the National Malaria Control Program. Both treatments were equally efficacious, endorsing the decision of using them for the treatment of uncomplicated malaria, although the proportion of patients with a PCR-adjusted ACPR was slightly lower than that of an efficacy study, carried out in the same area and at approximately the same time. Indeed, in the latter, the PCR-adjusted cure rate was 91.1% for AL and 96.8% for ASAQ (Four Artemisinin-Based Combinations (4ABC) Study Group 2011). An earlier study carried out in the same area in 2006, before the nationwide deployment of ACTs, reported for AL a cure rate of 95.2% (Bassat et al. 2009). ASAQ and AL efficacy was over 90% in other Burkinabe sites (Zongo et al. 2007a; Zongo et al. 2007b; Sirima et al. 2009; Siribié et al. 2012). Therefore, cure rates tended to be higher when the administration of all doses was directly observed, but the difference is not as dramatic as one would expect. This may indicate a good adherence to the treatment although this information was not collected.

Drug bioavailability can vary between individuals, and this depends on several factors, including a good adherence to treatment and diet habit (Kobbe et al. 2008; White et al. 1999; Schmidt & Dalhoff 2002). Indeed, AL needs to be administered with fatty food to maximise lumefantrine absorption and attain adequate therapeutic levels in the plasma (White et al. 1999). However, dietary habits may vary widely according to regional, economic, environmental and cultural factors (Premji et al. 2008); in rural Africa, fat consumption is probably lower than among urban dwellers, and overall, the total fat consumption in sub-Saharan Africa is approximately a third than that of Western countries (FAO 2008). Such differences may explain the variation in effectiveness observed in several studies. In West Africa, a study in Benin found high effectiveness for both AL (94%) and ASAQ (93.2%) (Faucher et al. 2009), while in Ghana, AL effectiveness was lower (88.3%) Kobbe et al. (2008). In Tanzania, lumefantrine plasma concentrations were significantly lower in patients experiencing a recrudescence than in those with a new infection or without any recurrent infection (Ngasala et al. 2011a,b). Nevertheless, other factors besides lumefantrine concentration, such as the timing of the drug administration (Kabanywanyi et al. 2010), may play a role. For example, unsupervised intake of AL was highly efficacious despite the lumefantrine plasma levels concentrations being significantly lower than in patients whose treatment had been supervised (Mutabingwa et al. 2005; Piola et al. 2005; Checchi et al. 2006; Ngasala et al. 2011a,b).

New infections identified during the follow-up are not considered as treatment failures and are excluded from the estimation of treatment efficacy. Nevertheless, distinguishing a new infection from a recrudescence cannot be carried out at the time a patient comes back with a recurrent infection. This needs to be treated with an alternative antimalarial treatment.

Therefore, from operational point of view, and particularly when working in real-life conditions, the post-treatment prophylactic effect of drugs should be considered. Indeed, national authorities may tend to choose treatments that have a lower risk of recurrent infections. In this respect, the crude cure rate at day 28 was significantly lower in the AL than in the ASAQ arm, although they tended to converge at day 42 and ASAQ performed slightly better. Similar findings have been reported in the only study conducted in Burkina Faso and comparing directly these two treatments (Four Artemisinin-Based Combinations (4ABC) Study Group 2011). Nevertheless, it should be noted that recurrent infections started to occur at day 14 while in previous studies carried out in the same area these occurred later, at day 21 (Bassat et al. 2009; Four Artemisinin-Based Combinations (4ABC) Study Group 2011). This can probably be explained by the variable compliance to the treatment, as this was not directly observed, and probably by the variation in absorption as AL needs to be given with a fatty meal to have optimal absorption of lumefantrine. Nevertheless, the collection of additional information such as study participants' adherence to treatment and diet habit might have helped to understand the high rate of recurrent infections. However, this would have required more resources to ensure reliable data. Although this is a limitation for our study, we think that a major bias in the estimation of the two ACTs effectiveness is unlikely.

Conclusion

Since the treatment policy change in 2005, this is the first study comparing the effectiveness of the two recommended regimens, AL & ASAQ. Both treatments showed similar effectiveness, both at day 28 and at day 42. Despite the lower cure rates than those found in efficacy studies in which the treatment administration was directly observed, both AL and ASAQ can still be used for the treatment of uncomplicated malaria in Burkina Faso.

Acknowledgements

We thank the parents of the children included in this study for their participation and the health staff of the Nanoro Medical centre for their collaboration. We thank the Malaria Consortium for its financial support for the fieldwork. The study was also partly funded through a Post-doc training grant by The Institute of Tropical Medicine, Antwerp through the Belgian cooperation Framework Agreement 3 for the laboratory work.

Ancillary