High efficacy of two artemisinin-based combinations (artemether–lumefantrine and artesunate plus amodiaquine) for acute uncomplicated malaria in Ibadan, Nigeria

Authors


Corresponding Author Catherine Olufunke Falade, Department of Clinical Pharmacology, University College Hospital, Ibadan, Nigeria. Tel.: +234 8033264593; E-mail: fallady@skannet.com, lillyfunke@yahoo.com

Summary

Objective  To test the hypothesis that artesunate plus amodiaquine (ASAQ) is as effective as artemether–lumefantrine (AL) in the treatment of acute uncomplicated malaria in Nigerian children.

Methods  In an open label, randomized controlled clinical trial, children aged 6 months to 10 years were randomized to receive artesunate (4 mg/kg daily) plus amodiaquine (10 mg/kg daily) or AL (5–14 kg, one tablet; 15–24 kg, two tablets and 25–34 kg, three tablets twice daily). Both drug regimens were given for 3 days and follow-up was for 28 days.

Results  A total of 132 children (66 in each group) were randomized to receive either ASAQ or AL. Day 28 cure rates in the per protocol (PP) population were 93% for ASAQ and 95% for AL (OR = 0.71, 95% CI = 0.12–3.99, ρ = 0.66). Using Kaplan–Meier product-limit estimates of failure, the median survival time for ASAQ was 21 days and for AL 28 days (P = 0.294). PCR corrected day 28 cure rate for PP populations were 98.4% for ASAQ and 100% for AL. Both drugs were well-tolerated.

Conclusion  ASAQ is as effective as AL and both combinations were efficacious and safe.

Abstract

Objectif  Tester l’hypothèse selon laquelle artésunate + amodiaquine (ASAQ) est aussi efficace que artéméther + luméfantrine (AL) dans le traitement de la malaria aiguë non compliquée chez les enfants nigérians.

Méthodes  Dans un essai clinique randomisé contrôlé ouvert, des enfants âgés de 6 mois à 10 ans ont été randomisés pour recevoir de l’artésunate (4 mg/kg/jour) plus amodiaquine (10 mg/kg/jour) ou de l’artéméther-luméfantrine (un comprimé pour les 5–14 kg, deux comprimés pour les 15–24 kg, et trois comprimés pour les 25–34 kg; deux fois par jour). Les deux types de médication ont été administrés durant 3 jours et un suivi a été effectué pendant 28 jours.

Résultats  132 enfants (66 dans chaque groupe) ont été randomisés pour recevoir soit ASAQ ou AL. Le taux de guérison au jour 28 dans la population per protocole était de 93% pour ASAQ et 95% pour l’AL (OR = 0,71; IC95%: 0,12–3,99; ρ = 0,66). En utilisant les limites d’estimation de l’échec selon le produit de Kaplan Meier, la durée médiane de survie était de 21 jours pour ASAQ et 28 jours pour AL (P = 0,294). Les taux de guérison au jour 28 corrigés par les résultats de la PCR pour les populations per protocole étaient de 98,4% pour ASAQ et de 100% pour l’AL. Les deux médicaments étaient bien tolérés.

Conclusion  ASAQ est aussi efficace que l’AL et les deux combinaisons sont efficaces et sans danger.

Abstract

Objetivo  Evaluar la hipótesis de que el artesunato más amodiaquina (ASAQ) es tan efectivo como el artemeter-lumefantrina (AL) en el tratamiento de malaria aguda no complicada en niños Nigerianos.

Métodos  En un ensayo clínico, abierto, aleatorizado y controlado, niños entre 6 meses y 10 años fueron aleatorizados para recibir artesunato (4 mg/kg diarios) más amodiaquina (10 mg/kg diarios) o artemeter-lumefantrina (5–14 kg; un comprimido, 15–24 kg; dos comprimidos y 25–34 kg; tres comprimidos dos veces al día). Ambos tratamientos fueron dados durante 3 días y el seguimiento fue de 28 días.

Resultados  132 niños (66 en cada grupo) fueron aleatorizados para recibir ASAQ o AL. La tasa de curación a día 28 en la población según protocolo fue del 93% para ASAQ y del 95% para AL (OR = 0.71, 95% CI = 0.12–3.99, ρ = 0.66). Utilizando el estimador de Kaplan Meier de fallo, el tiempo medio de supervivencia fue de 21 días para ASAQ y de 28 días para AL, (P = 0.294). La tasa de curación corregida por PCR para las poblaciones según protocolo fue de 98.4% para ASAQ y del 100% para AL. Ambos medicamentos fueron bien tolerados.

Conclusión  La ASAQ es tan efectiva como la AL y ambas combinaciones fueron eficaces y seguras.

Introduction

Resistance of Plasmodium falciparum to antimalarial drugs is growing rapidly in many African countries, where at least 70% of the global malaria occurs (WHO 2001; Snow et al. 2005). This progressive decline in the sensitivity of P. falciparum is most marked with chloroquine and sulfadoxine–pyrimethamine, which until recently were first-line antimalarial drugs in Nigeria. Failure rates as high as 50% to 95% have been reported for chloroquine in some parts of the country (Sowunmi & Salako 1992; Falade et al. 1997; Federal Ministry of Health 2004). The World Health Organization (2001) has recommended artemisinin-based combination therapy (ACT) for the treatment of malaria in countries experiencing resistance to antimalarial drug monotherapy (World Health Organization 2001). Artemisinin derivatives are noted for rapid reduction of parasite biomass (White 1997). An additional advantage of the artemisinin derivatives is the absence of documented resistance of P. falciparum to the drug despite over 200 years of use (Klayman 1985; Plowe 2003). Artemisinin, the antimalarial extract of Artemisia annua (sweet wormwood), has been in use for centuries as a traditional Chinese medicine to cure fever (Klayman 1985). It is ironical that the best new medicine for malaria is one of the oldest.

The rationale for combination therapy is to improve the cure rate of infections responding inadequately to monotherapy and possibly to prevent or delay the emergence of resistance to other drugs (WHO 2001). Coartemether (Coartem®, Novatis Pharma), a fixed dose combination of artemether and lumefantrine, combines the rapid but short-lived schizonticidal effect of artemether with the slower but more prolonged antimalarial effect of lumefantrine, a highly lipophilic aryl amino alcohol (Lefèvre et al. 2001). When administered alone as a short treatment course over 2–3 days, lumefantrine gives a high cure rate but parasite and fever clearance time is slower than with artemether. Co-artemether combines the treatment advantage of both drugs (Skelton-Stroud et al. 1998). Although artemether–lumefantrine (AL) was first registered as a four-dose regimen, six doses are now the preferred regimen for the treatment of uncomplicated malaria (Falade et al. 2005; Makanga et al. 2006). Amodiaquine, a cheap 4-aminoquinoline in combination with artesunate, is also effective against chloroquine-resistant P. falciparum infection (Adjuik et al. 2002; Sowunmi et al. 2005).

The current national antimalarial policy in Nigeria has adopted ACT as the treatment of choice for acute uncomplicated malaria with preference for AL and artesunate plus amodiaquine (ASAQ) in that order (FMOH 2004). AL (Coartem) was the first ACT to meet pre-qualification criteria set by WHO and initially the only ACT that could be purchased with international fund subsidy from the Global Fund to Fight AIDS, Tuberculosis and Malaria; the UNICEF Fund; or the President’s Malaria Initiative fund (WHO 2006a). The demand for Coartem is thus understandably high and availability may be compromised even to those who can afford the drug. Recently, however, co-blister packs of artesunate and amodiaquine have been certified good manufacturing practice compliant and are now in the WHO WeBuy catalogue for procurement (WHO 2006b).

In this study, we evaluated the comparative efficacy and safety of ASAQ and AL. ASAQ prices are more competitive, and its dosing schedule is more user-friendly; thus it is the recommended alternative to AL in Nigeria for the treatment of acute uncomplicated malaria.

Method and patients

Study site, design and patients

The study was conducted at the General Outpatient Department (GOPD) of the University College Hospital, Ibadan, Nigeria from August 2004 to August 2005. Ibadan is located in the rain forest belt in southwestern Nigeria. Malaria transmission is intense and occurs all year round in the study area. The study was an open label, randomized controlled clinical trial. Girls and boys aged 6 months to 10 years were enrolled in the study if the following inclusion criteria were fulfilled: signs and symptoms compatible with acute uncomplicated malaria, axillary temperature ≥37.5 °C, microscopically confirmed asexual forms of P. falciparum with parasite density of between 2000 and 200 000 parasite/μl, willingness to comply with protocol and parental/guardian written informed consent. Children with severe malnutrition, presence of mixed infection, signs of severe and complicated malaria or other febrile illnesses and history of hypersensitivity to any of the study drugs were excluded from the study.

Sample size determination

The sample size was calculated using the recent WHO guidelines on assessment of antimalarial drugs (WHO 2003). The calculated sample size was 100 patients, 50 patients in each treatment group. An additional 20% of the calculated figure were added to make a minimum sample size of 120, to make up for patients lost to follow-up or withdrawn from the study. The calculation was made assuming a clinical cure rate of 94% for AL and 85% for ASAQ; these values were from recent studies (Adjuik et al. 2002; Falade et al. 2005). This gives a treatment effect size of 9%. The level of precision was taken as 10% at 95% CI.

Ethical issues

The study was conducted in the spirit of Good Clinical Practice and the Helsinki declaration. Ethical clearance was obtained from the University of Ibadan/University College Hospital Joint Institutional Review Committee. A written or witnessed verbal informed consent was obtained from the parent or guardian of each child before any study-related procedure was carried out.

Treatment allocation and case management

At enrolment, children who satisfied the enrolment criteria were examined thoroughly and weighed. Thick and thin blood films were prepared from a finger prick under aseptic conditions and blood spots collected on filter paper for molecular analysis at enrolment. In addition, 5 ml of venous blood was taken by venepuncture for a full blood count (haematocrit, total white blood cell count and differential and platelet count) and blood chemistry.

Enrolled children were allocated to one of two treatment groups according to a pre-generated randomization table. Children randomized to group 1 received ASAQ. Artesunate (Asumax® 50 mg, Sanofi-Synthelabo) was administered at a dose of 4 mg/kg body weight once daily for 3 days (rounded to the nearest quarter tablet) and amodiaquine (Camoquine® 200 mg, Pfizer Pharmaceuticals Limited, Nigeria) at a dose of 10 mg amodiaquine base/kg body weight once daily for 3 days (rounded to the next quarter tablet). Patients randomized to group 2 received AL (Coartem) twice daily for 3 days. Each tablet of AL contained 20 mg artemether and 120 mg lumefantrine. AL was given according to the weight of enrolled children. Children weighing 5 to <15 kg received one tablet, those weighing 15 to <25 kg received two tablets while those weighing 25 to <35 kg received three tablets twice daily for 3 days. Study drugs were administered supervised by a nurse or a doctor and were given with food, fruit drink or dissolved in water. The second daily doses of AL were administered by a nurse or research assistant at the patients’ home supervised. After administration of drugs, patients were observed for 30 min and the dose was re-administered if the patient vomited within the period. In addition, febrile children with axillary temperature ≥38 °C were exposed, tepid-sponged and given oral paracetamol. Children were withdrawn for the following reasons: withdrawal of consent, protocol violation or loss to follow-up.

Patient follow-up

The GOPD, University College Hospital where the study was conducted, is open daily. Parents/guardians were encouraged to bring children to the clinic whenever there was a need for medical attention even when this was outside their appointment days. Children who were not brought to the clinic on scheduled days were visited at home for the follow-up procedure. Study participants were followed up daily on days 0–7 and on days 14, 21 and 28. At each visit children were physically examined and their vital signs recorded. In addition, thick blood films were prepared from finger prick blood samples. These were stained with 10% fresh Giemsa stain and examined for the presence of asexual forms of P. falciparum under a light microscope at ×1000 magnification. Blood spots were also collected on filter paper for molecular analysis at day 28 or at re-appearance of parasitaemia, which ever came first. Venous blood of about 5 ml was taken by venepuncture for full blood count and blood chemistry on days 7 and 28.

Each child (if old enough) and the parent were questioned about symptoms observed following commencement of therapy. Children who failed treatment were re-treated with another course of AL, since a previous study evaluating AL in the same area revealed all treatment failures to be due to re-infection (Falade et al. 2005).

Study outcome classification

Study outcome was classified as early treatment failure (ETF), late clinical failure (LCF), late parasitological failure (LPF) or adequate clinical and parasitological response (ACPR) (World Health Organization 2003). ETF was defined as development of danger signs of malaria or severe malaria on post-treatment days 1, 2 or 3, in the presence of parasitaemia, parasitaemia on day 2 higher than day 0 count irrespective of axillary temperature, parasitaemia on day 3 which is ≥25% of count on day 0 and parasitaemia on day 3 with axillary temperature ≥37.5 °C. LCF was defined as development of danger signs or severe malaria after day 3 in the presence of parasitaemia without previously meeting any of the criteria of ETF and presence of parasitaemia and axillary temperature of ≥37.5 °C on any day from day 4 to day 28, without previously meeting any of the criteria of ETF. LPF on the other hand was defined as presence of parasitaemia on any day from day 7 to day 28 and axillary temperature of <37.5 °C, without previously meeting any of the criteria of ETF or LCF. ACPR was defined as absence of parasitaemia on day 28 irrespective of axillary temperature without previously meeting any of the ETF, LCF or LPF.

Discrimination between recrudescence and re-infections in treatment failures

Previous molecular analyses of P. falciparum malaria in Ibadan (Happi et al. 2003, 2004) revealed that merozoite surface protein-2 (msp-2) was the most informative genetic marker to evaluate parasite diversity and the complexity of P. falciparum infections. Isolates from each P. falciparum infection in the study were characterized on the basis of the fragment size of alleles of msp-2 after amplification by PCR. Infections were defined as polyclonal if parasites in matched primary and post-treatment samples from the same patient showed more than one allele of FC27 or IC1/3D7 families of msp-2. If an isolate had one allele at each of the families, the clone number was taken to be one. A recrudescent infection was defined as the occurrence of the same or a subset of the alleles at each of the families (FC27 or IC1/3D7) of msp-2 in the primary and post-treatment samples. A lack of allelic identity in the two families of msp-2 in matched primary and post-treatment samples indicated a newly acquired infection.

Assessment of safety

An adverse event (AE) was defined as signs, symptoms or abnormal laboratory finding not present at enrolment, but occurring during follow-up, or being present at day 0 and becoming worse during follow-up despite clearance of parasitaemia. All AEs were monitored and recorded. Assessment was by laboratory evaluation, physical examination and by asking about the progress of presenting symptoms and new symptoms noticed during follow-up.

Data analysis

Data collected were recorded in Case Record Forms and entered into Epi-info version 6.04 database for analysis. SPSS version 10 was also used for analysis. Efficacy analysis of the data was done for the intention to treat (ITT) and per protocol (PP) populations. All children enrolled into the study were considered ITT. Patient who completed the study without violating the study protocol were considered as PP population. The effect size and the odds ratio (OR) with 95% CI were used to measure the treatment effect for the main outcomes. In addition, the cumulative survival between the two groups was compared using Kaplan–Meier product-limit estimates of failure. The means and standard deviations (±SD) of normally distributed data were compared using Student’s t-test and analysis of variance (anova). Proportions were compared by chi-square. Results of haematology and liver enzymes over time were analysed using the paired t-test.

Numerical values are given as means ± SD, ρ-values <0.05 was taken as statistically significant.

Results

Patient disposition and demographic data

A total of 132 patients were enrolled in the study (ITT population; Figure 1). There were 61 (46.2%) males and 71 females (53.8%). Sixty-six children were randomized to receive ASAQ or AL. Nine of the enrolled 132 (6.8%) patients were withdrawn from the study. Seven of these (5.3%) were lost to follow-up: four patients from ASAQ group and three from AL group. The parent of one child treated with ASAQ withdrew consent on day 5 because he had to leave the study area; one of the patients treated with AL was withdrawn because the mother had administered chloroquine for a perceived febrile illness on day 6. The child was afebrile and had no patent parasitaemia when seen at the clinic on day 7.

Figure 1.

 Study profile of patients treated with artesunate plus amodiaquine (ASAQ) or artemether–lumefantrine (AL) for the treatment of acute uncomplicated malaria in children in Ibadan, Nigeria.

The characteristics of study participants (Tables 1 and 2) in the two groups were comparable at entry. The three most common presenting complaints were fever (100%), vomiting (51%) and abdominal pain (35%). The study drugs were well-tolerated. Five of 66 (7.6%) children treated with ASAQ and 4/66 (6.1%) treated with AL vomited the drug within 30 min and had to be re-dosed. None vomited after re-dosing and none was withdrawn as a result of recurrent vomiting.

Table 1.   Baseline characteristics of children suffering from acute uncomplicated malaria treated with artesunate plus amodiaquine (ASAQ) and artemether–lumefantrine (AL) in Nigeria
 ASAQALρ-value
Total no.6666
  1. †Student’s t-test.

  2. ‡Chi-square test.

Sex
 Male, n (%)29 (43.9)37 (56.1)0.16†
 Female, n (%)37 (56.1)29 (43.9)
Age (months)
 Mean ± SD53.6 ± 33.4159.2 ± 32.150.31†
 Range6–1186–118
 6–59 months, n (%)38 (57.6)31 (46.9)0.22‡
 ≥60 months, n (%)28 (42.4)35 (53.1)
Weight (kg)
 Mean ± SD15.2 ± 6.8217.46 ± 10.240.09†
 Range6–245–29
Temperature (°C)
 Mean ± SD38.2 ± 0.7738.4 ± 1.060.21†
 Range37.5–40.337.6–40.7
Parasite density (per μl)
 Mean ± SD27 822.12 ± 38 567.1732 022.42 ± 29 141.990.48†
 Range2000–199 8432000–120 242
 Geometric mean10 72619 277
Haematochrit (%)
 Mean ± SD30.4 ± 4.7930.0 ± 5.050.78†
 Range19–4019–40
Percentage with PCV <30%, n (%)32 (48.5)24 (36)0.16‡
Table 2.   Presenting symptoms in children enrolled for the study of artesunate plus amodiaquine (ASAQ) and artemether–lumefantrine (AL) for the treatment of acute uncomplicated malaria in children
SignsASAQ, n (%)AL, n (%)Total
  1. Values are given as n (%).

Fever66 (100)66 (100)132 (100)
Vomiting32(48)35 (53) 67 (51)
Abdominal pain19 (29)28 (41) 47(35)
Anorexia12 (18)16 (24) 28(21)
Irritation10 (15)12 (18) 22 (16)
Headache 7 (11) 4 (6) 11 (8)
Diarrhoea 3 (5) 2 (3)  5 (4)

Results of efficacy evaluation

Sixty-one of 66 (92.4%) patients treated with ASAQ completed the study while 62/66 (94%) of those that receive AL completed the study. These patients who completed the study constitute the PP population. There was no record of ETF during the study. Response to therapy was good and prompt in all study participants. The 24-h parasite reduction was 93% and 95% for ASAQ and AL, respectively, while mean parasite clearance time was 1.22 ± 0.45 days for ASAQ and 1.86 ± 0.61 days for AL (ρ = 0.37). Mean fever clearance times for ASAQ and AL were 1.16 ± 0.45vs. 1.77 ± 0.61 days, respectively (ρ = 0.27). Day 14 cure rates in the PP population were 98.4%vs. 100% (OR = 0.00, 95% CI = 0–17.25, ρ = 0.50) for ASAQ and AL while day 28 cure rates were 91.8% and 95.2% (OR = 0.71, 95% CI = 0.12–3.99, ρ = 0.66) for ASAQ and AL, respectively. Patients treated with AL had a median survival time of 28 days, while those who received ASAQ had a median survival time of 21 days. The log rank test showed that the difference in survival functions for the two drugs was not statistically significant (P = 0.294). Molecular biology analysis showed that all eight patients in whom patent parasite recurred had re-infection, giving PCR corrected cure rates as 100% in the PP population for both ASAQ and AL, respectively (Table 3).

Table 3.   Treatment outcomes in children suffering from uncomplicated malaria treated with artesunate plus amodiaquine (ASAQ) or artemether–lumefantrine (AL)
CharacteristicASAQ, n (%)AL, n (%)ρ-value
  1. †Chi-square test.

  2. ‡Student’s t-test.

Per protocol population
 LCFNilNil 
 LPF5/61 (8.2)3/62 (4.8)0.72†
ACPR
 Day 1460/61 (98.4)62/62 (100)0.50†
 Day 2856/61 (91.8)59/62 (95.2)0.66†
 PCR corrected day 28 cure rate61/61 (100)62/62 (100) 
 Median cumulative survival  time (days)21280.294
ACPR
 Day 1460/66 (90.9)62/66 (93.9)0.51†
 Day 2856/66 (84.8)59/66 (89.4)0.44†
ACPR age <60 months
 Day 1435/37 (94.6)30/31 (96.8)0.65†
 Day 2833/37 (89.2)29/31 (93.6)0.69†
Intent to treat population
 PCR corrected day 28 cure rate60/66 (90.9)62/66 (93.9)0.51†
 FCT (days)1.16 ± 0.451.77 ± 0.610.27‡
 PCT (days)1.22 ± 0.451.86 ± 0.610.37‡
 24 h parasite reduction (%)93950.72†
Haematocrit
 Day 729.7 ± 5.1830.4 ± 4.190.66†
 Day 2833.0 ± 3.7933.4 ± 3.450.94†

Results of safety evaluation

Assessment of AE was made difficult by the predominance of background signs and symptoms of malaria. Common AEs recorded (ITT population) were anaemia, cough and abdominal pains. Nine patients (four in AL group and five in ASAQ group) vomited the first dose of drugs. Other AEs occurred in <1% of patient population. Table 4 shows details of the distribution of AEs recorded during the study. The blood chemistry results showed no statistically significant disturbance in blood chemistry. The study drugs also did not adversely affect liver enzymes. Haematological recovery was good in the two treatment arms (Table 3). The results of paired t-test of day 0 and day 7 samples for liver enzymes showed that there was no significant change in the mean values of the liver enzymes that were assessed in the two treatment groups. However, paired t-test analysis of day 0 and day 7 samples for haematology tests showed a significant transient decline in the neutrophil counts of days 0 and 7 (P = 0.007) in the AL arm which had recovered by day 28 (Table 5). A significant increase in the mean haematocrit values among patients treated with ASAQ comparing days 0 and 28 (P = <0.0001) was also noted. There was no other significant change in the mean values of the other haematology parameters that were assessed in the two treatment groups using the paired t-test (results not shown).

Table 4.   Adverse events (AE) recorded among Nigerian children treated with artesunate plus amodiaquine (ASAQ) or artemether–lumefantrine (AL) for the treatment of acute uncomplicated malaria
Adverse eventASAQ, n (%)AL, n (%)Total
  1. Values are given as n (%).

Vomiting11 (16.6%)9 (13.6%)20/132 (15.26%)
Anaemia11/66 (16.7)8/66 (12.1)19/132 (14.4)
Cough 5/66 (7.8)8/66 (12.1)13/132 (9.8)
Abdominal pain 4/66 (6.1)6/66 (9.1)10/132 (7.6)
Rash 3/66 (4.5)1/66 (1.5)4/132 (3)
Palpitations 0/66 (0)2/66 (3)2/132 (1.5)
Table 5.   Results of paired t-test of haematology parameters evaluated among Nigerian children suffering from acute uncomplicated malaria treated with artemether–lumefantrine or artesunate plus amodiaquine (ASAQ)
Haematology testsDay 0, mean ± sdDay 7, mean ± SDt-valueP-value
  1. *Statistically significant.

Artemether–lumefantrine
 Haematocrit (%)29.77 ± 5.2129.80 ± 4.54−0.0270.979
 Total WBC (per mm3)17 900.0 ± 18 108.5611 176.16 ± 19 172.480.6960.509
 Neutrophil (%)51.5 ± 12.2033.25 ± 11.973.7340.007*
 Platelet (per mm3)18 2500.0 ± 74 484.89216 750.0 ± 121 848.73−6440.540
Artesunate + amodiaquine
 Haematocrit (%)30.29 ± 4.7829.37 ± 5.111.7890.82
 Total WBC (per mm3)4266.67 ± 850.4927 033 ± 321−1.2310.343
 Neutrophil (%)40.33 ± 12.531.33 ± 10.211.1130.381
 Platelet (per mm3)135 333.3 ± 126 175.8125 333 ± 41 016.30.1300.908
Haematology testsDay 0Day 28t-valueP-value
Artemether–lumefantrine
 Haematocrit (%)31.13 ± 4.8432.38 ± 4.44−1.2020.241
 Total WBC (per mm3)6033 ± 568.625966.67 ± 2250.190.0420.970
 Neutrophil (%)49.00 ± 10.8241.67 ± 12.662.5240.128
 Platelet (per mm3)146 000.0 ± 39 585.35173 000.0 ± 113 249.72−0.5990.610
Artesunate + amodiaquine
 Haematocrit (%)30.47 ± 4.6733.23 ± 3.91−3.929<0.0001*
 Total WBC (per mm3)5580 ± 506.955200 ± 921.950.6830.532
 Neutrophil (%)53.00 ± 16.9942.2 ± 15.831.6460.175
 Platelet (per mm3)122 000.0 ± 38 046.03195 600.0 ± 67 500.37−1.6630.172

Discussion

In this study, we assessed the efficacy and safety of ASAQ and AL in the treatment of acute uncomplicated malaria in Nigerian children aged 6 months to 10 years. The results show that ASAQ administered once daily for 3 days is as effective as the six-dose regimen of AL given twice daily for 3 days. The six-dose regimen of AL is currently considered the gold standard for ACT in the treatment of acute uncomplicated malaria (WHO 2001; Makanga et al. 2006). The study was designed specifically to test the null hypothesis at a predetermined effect size of 9% using the OR at 95% CI. The effect size of treatment with ASAQ compared with AL at day 28 in the PP population was 2% (OR = 0.71, 95% CI = 0.12–3.99, ρ = 0.66). Both ACT were not only efficacious but well-tolerated. No study participant was withdrawn as a result of recurrent vomiting. In addition, there was no incidence of any serious AE in the two treatment groups. These findings agree with previous reports from Nigeria (FMOH 2004; Falade et al. 2005; Sowunmi et al. 2005) and other African countries (Falade et al. 2005; Guthmann et al. 2006; Mulenga et al. 2006).

Response to treatment with both ASAQ and AL was prompt in this study, as demonstrated by the rapid parasite and fever clearance times and 24-h parasite reduction rate among patients treated with both ASAQ and AL (Table 3). Mean parasite and fever clearance times of 1.16 ± 0.45 vs. 1.77 ± 0.61 and 1.22 ± 0.45 vs. 1.86 ± 0.61 days for ASAQ vs. AL are pointers to prompt response. These results are consistent with the rapid onset of action of the artemisinin derivatives that both combinations contain (White 1997; Olliaro & Taylor 2004).

It is, however, noteworthy that AL performed better than ASAQ in some of the parameters used for assessment of efficacy. Day 14 and 28 cure rates were higher among children treated with AL than those who received ASAQ (100%vs. 98.4% and 95.2%vs. 91.8% for AL and ASAQ). Twenty-four hour parasite reduction was also marginally higher among the patients treated with AL than those treated with ASAQ (95%vs. 93%). But these differences were not statistically significant (Table 3). Our results are similar to the overall cure rates obtained during the Nigerian national antimalarial survey, which were 96% and 94.7% at day 28 for ASAQ and AL, respectively (FMOH 2004).

Despite pre-enrolment randomization, children randomized to receive ASAQ were younger and weighed less than those randomized to receive AL. However, the differences were not statistically significant and did not seem to have affected the treatment outcome judging from either the cure rates or other parameters for assessment of treatment outcome. Analysis of treatment outcome among the subsegment of children <5 years of age revealed no statistically significant difference in cure rates at days 14 and 28. Haematological recovery was also comparable amongst the two treatment arms of this study (Table 3).

The most common AEs were vomiting, anaemia, cough and abdominal pains. These symptoms are common clinical findings among patients with malaria. It is thus difficult to confidently classify them as drug-related AEs (Table 4). Both drugs were well-tolerated according to clinical and laboratory parameters. No child was withdrawn as a result of AE. The high incidence of anaemia (Table 1) in the children who participated in this study can be explained by the fact that parasitized and some non-parasitized erythrocytes are haemolysed during this parasitic infection. Although amodiaquine has been reported to cause leucopenia after long-term use as a chemoprophylactic agent (Taylor & White 2004), no case of leucopenia was recorded during this study. No patient in this study recorded a total white cell count equal to or below 2500/mm3 which is the lower limit of normal in the study hospital. A significant but transient reduction in neutrophils on day 7 compared with day 0. This however had recovered by day 28. The reason for this incidental finding is not clear.

The Federal Government of Nigeria (FMOH 2004) has adopted ACT as the national antimalarial treatment policy. AL and the combination of ASAQ are the preferred options in that order. The absorption and consequent bioavailability of AL, which is currently the gold standard for ACT treatment of malaria, is greatly improved when administered with food, especially a fatty meal. This is an important component of the Information Education and Communication and public health education that must be provided to health care workers, caregivers and patients. Other major challenges to the adoption of ACT use in Nigeria and other resource poor settings include high-cost, poor availability, inadequate knowledge of ACT use and poor attitudinal disposition of health care workers to ACT use. In a recent study in Zambia, where AL was made available free, only 22% of patients eligible for ACT actually received AL, the only available ACT despite the fact that clinic staff knew they were being observed (Zurovac et al. 2005). If this new treatment option is to be widely accepted in the country, government and stake holders in the health sector would have to ensure that the drugs are highly subsidized, made readily available and provided with adequate public health educational guidelines to the community and health care workers on their appropriate use of artemisinin-containing combinations. The need to jealously guard and prolong the therapeutic useful life of ACTs cannot be over emphasized. The high cure rates recorded for ASAQ and AL in this study and other studies from Africa are impressive. It is of note that all cases of LPF, which occurred during this study, were re-infections. This raises concerns about emergence of drug resistance strains especially in areas of intense transmission as occurs in most parts of Nigeria. A new infection which occurs when drug blood levels are low, especially that of the companion drug with longer half-life, would predispose to emergence of drug-resistant strains after the fast elimination of the artemisinin derivative. A multi-pronged approach to malaria control, which should include insecticide-treated bed net, intermittent preventive therapy and strengthening health care infrastructure is thus ideal.

Conclusion

In conclusion, ASAQ is not inferior to AL in the treatment of acute uncomplicated malaria in children from Ibadan, southwestern Nigeria as both ASAQ and AL were found to be highly efficacious. The two artemisinin-containing combinations showed a good safety profile and were well-tolerated. The Global Fund has provided funding for Coartem in Nigeria and the distribution to health care facilities have commenced in some states of Nigeria. However, correct deployment of ACTs remains a major challenge. The time to ‘ACT’ is now.

Acknowledgements

We thank the children and their families for participating in this study. Our appreciation also goes to the nurses and staff of the General Outpatients Department, University College Hospital, Ibadan for their assistance and to Mrs Iyabo Abdusalam and Mrs Bola Akinyele for technical support. AL (Coartem) was provided by Novartis Pharma, Nigeria; Sanofi-Sycitilabo Nigeria provided artesunate (Asumax) while Pfizer Pharmaceuticals Limited Nigeria provided amodiaquine (Camoquine).

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