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Keywords:

  • malaria;
  • Plasmodium falciparum;
  • dihydroartemisinin;
  • piperaquine;
  • artesunate;
  • amodiaquine
  • malaria;
  • Plasmodium falciparum;
  • dihydroartémisinine;
  • pipéraquine;
  • artésunate;
  • amodiaquine
  • Malaria;
  • Plasmodium falciparum;
  • dihidroartemisinina;
  • piperaquina;
  • artesunato;
  • amodiaquina

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Clinical investigations
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

Objective  Artesunate–amodiaquine (AAQ) is efficacious for the treatment of uncomplicated Plasmodium falciparum malaria in Africa, but little is known about its efficacy in Southeast Asia. We compared the efficacy of dihydroartemisinin–piperaquine (DHP) and AAQ against falciparum malaria in central Vietnam.

Methods  Open, randomized clinical trial of 116 patients (36 children aged 6–14 years, 80 adults aged 15–60 years) were randomly allocated a 3-day course of either DHP (∼2.3 mg/kg dihydroartemisinin plus ∼18.5 mg/kg of piperaquine per day) or AAQ (∼4.4 mg/kg of artesunate plus ∼10.6 mg/kg of amodiaquine per day). The follow-up period was 42 days.

Results  The two drug combinations were well tolerated by all age groups with no obvious drug associated adverse events. Of the patients who completed 42 days of follow-up, 49 were on DHP (15 children, 34 adults) and 49 were on AAQ (14 children, 35 adults). The 42 day cure rates adjusted for reinfection identified by PCR genotyping for the two groups were similar [100% (49/49) and 98% (48/49) for DHP and AAQ, respectively]. With fewer reinfections, DHP appears to possess greater post-treatment prophylactic activity than AAQ.

Conclusion  AAQ, an inexpensive artemisinin-based combination, could be an additional option to DHP for the treatment of multidrug-resistant falciparum malaria in Vietnam.

Objectif:  L’artésunate - amodiaquine (AAQ) est efficace pour le traitement de la malaria non compliquéàPlasmodium falciparum en Afrique, mais on en sait peu sur son efficacité en Asie du sud-est. Nous avons comparé l’efficacité de la dihydroartémisinine (DHP) et celle de l’AAQ contre la malaria falciparum dans le centre du Vietnam.

Méthodes:  Essai clinique randomisé ouvert sur 116 patients (36 enfants de 6 à 14 ans et 80 adultes âgés de 15 à 60 ans) aléatoirement soumis à 3 jours de traitement avec soit DHP (∼ 2,3 mg/kg dihydroartémisinine plus ∼ 18,5 mg/kg de pipéraquine par jour), soit AAQ (∼ 4,4 mg/kg d’artésunate plus ∼ 10,6 mg/kg d’amodiaquine par jour). La période de suivi était de 42 jours.

Résultats:  Les deux combinaisons de médicaments étaient bien tolérées par tous les groupes d’âge sans événements indésirables évidents associés aux médicaments. Parmi les patients qui ont complété 42 jours de suivi, 49 étaient sous DHP (15 enfants, 34 adultes) et 49 sous AAQ (14 enfants, 35 adultes). Les taux de guérison à 42 jours, ajustés par les réinfections identifiés par génotypage PCR, étaient similaires pour les deux groupes [100% (49/49) et 98% (48/49) pour le DHP et AAQ, respectivement]. La DHP, avec moins de réinfections, semble posséder une activité prophylactique post-traitement plus élevée que l’AAQ.

Conclusion:  L’AAQ, combinaison à base d’artémisinine peu coûteuse, pourrait être une option supplémentaire à la DHP pour le traitement de la malaria falciparum multirésistante au Vietnam.

Objetivo:  El artesunato - amodiaquina (AAQ) es un tratamiento eficaz de la malaria no complicada por Plasmodium falciparum en África, pero se conoce poco acerca de su eficacia en el sudeste asiático. Hemos comparado la eficacia de la dihidroartemisinina-piperaquina (DHP) y la AAQ frente a la malaria por falciparum en Vietnam central.

Métodos:  Ensayo clínico abierto y aleatorizado con 116 pacientes (36 niños con edades entre los 6-14 años, 80 adultos con edades entre los 15-60 años) que fueron asignados a un tratamiento de 3-días con DHP (∼2.3 mg/kg dihidroartemisinina más ∼18.5 mg/kg of piperaquina por día) o AAQ (∼4.4 mg/kg de artesunato más ∼10.6 mg/kg de amodiaquina por día). El periodo de seguimiento fue de 42 días.

Resultados:  Las dos combinaciones de medicamentos fueron bien toleradas por todos los grupos de edad, sin ningún efecto adverso obvio asociado. De los pacientes que terminaron el seguimiento de 42 días, 49 habían sido tratados con DHP (15 niños, 34 adultos) y 49 con AAQ (14 niños, 35 adultos). La tasa de curación a día 42, ajustada para reinfección identificada mediante el genotipaje por PCR, fue similar en los dos grupos [100% (49/49) y 98% (48/49) para DHP y AAQ, respectivamente]. Con un menor número de reinfecciones, la DHP parece poseer una mayor actividad profiláctica post-tratamiento que la AAQ.

Conclusión:  La AAQ, un tratamiento barato de combinación basado en la artemisinina, podría ser una opción adicional al DHP para el tratamiento de la malaria multirresistente por falciparum en Vietnam.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Clinical investigations
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

Artemisinin-based combination treatments (ACT) are now advocated as the best therapy for the treatment of Plasmodium falciparum malaria (White 2006; Nosten & White 2007). WHO (2001) currently recommends long-acting affordable antimalarial drugs, such as piperaquine and amodiaquine to be administered with potent artemisinin derivatives for the treatment of uncomplicated falciparum malaria (Yeung et al. 2004). The combination of a highly potent artemisinin compound, which rapidly reduces parasite numbers and an intrinsically less active partner drug that persists sufficiently long enough in the blood to prevent recurrences of malaria is logical and has proven to be effective. ACTs require a 3-day regimen to expose the parasite to the artemisinin derivative for two asexual life-cycles to minimize the opportunity for resistance selection and provide maximum clinical response.

In Vietnam, P. falciparum malaria remains an important public health problem. In an effort to delay the spread of multidrug-resistant falciparum malaria, the Vietnamese National Malaria Programme introduced CV8 in 1998. CV8 is a fixed combination of dihydroartemisinin–piperaquine–primaquine–trimethoprim. Although CV8 is highly efficacious in the treatment of malaria (Giao et al. 2004) there are concerns about the risk/benefit ratio of primaquine and the additional effectiveness of trimethoprim. The primaquine component is of concern because of red blood cell haemolysis in glucose-6-phosphate dehydrogenase deficient individuals and trimethoprim has weak antimalarial activity. Tran and colleagues (2004) reported that trimethoprim did not improve the efficacy of dihydroartemisinin–piperaquine and subsequently recommended that trimethoprim is not necessary. Recently, the Vietnamese Ministry of Health introduced a fixed-dose combination of dihydroartemisinin–piperaquine, marketed as Arterakine, for evaluation in Vietnam.

In the 1970s and 1980s, amodiaquine was used in Vietnam, but with the increasing spread of chloroquine-resistant falciparum malaria and the development and widespread application of artemisinin derivatives, its use diminished markedly. The level of amodiaquine resistance in Vietnam is unknown. In contrast to Vietnam, many African countries still use amodiaquine where it is effective against low to moderate levels of chloroquine-resistant P. falciparum malaria (Watkins et al. 1984; Olliaro et al. 1996; Abacassamo et al. 2004). Recently, amodiaquine as a partner drug in ACT has been evaluated in Africa with cure rates of >90% (Guthmann et al. 2005; Mutabingwa et al. 2005; Grandesso et al. 2006; Karema et al. 2006). Karema et al. (2006) showed that dihydroartemisinin–piperaquine and artesunate–amodiaquine were equally effective (>92%) in treating Rwandan children with uncomplicated P. falciparum malaria. Although serious amodiaquine-induced toxic effects have occurred when amodiaquine is used prophylactically, the drug is well tolerated as a 3-day course for the treatment of falciparum malaria (Luzzi & Peto 1993; Olliaro et al. 1996).

The primary purpose of this study was to compare the efficacy of 3-day courses of dihydroartemisinin–piperaquine and artesunate–amodiaquine in the treatment of uncomplicated P. falciparum malaria in central Vietnam. A secondary outcome was to compare the post-treatment prophylactic activity of the two ACTs.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Clinical investigations
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

Study design, patients, study site and ethics

This was a randomised, open trial carried out at Phuoc Chien Commune, Ninh Hai District, Ninh Thuan Province, Vietnam, which is located about 300 km north of Ho Chi Minh City. The resident population of about 4000 people are mainly of the Rag Lay ethnic group. Malaria transmission is low and seasonal in the commune with the people contracting the disease while cultivating crops on the surrounding forested hillsides (Erhart et al. 2005; Sanh et al. 2008). Patients attending the Phuoc Chien health station with suspected clinical malaria were screened and enrolled in the study if they met the following inclusion criteria: age 5–60 years, monoinfection with P. falciparum; parasite density 200–200 000/μl; fever (tympanic body temperature ≥38 °C) or history of fever in the preceding 24 h; and willingness to be followed-up for 42 days after treatment. Patients with severe malaria, history of another serious medical disease, a history of drug or alcohol abuse, antimalarial treatment within the preceding 7 days, mixed plasmodial infection, and pregnant or lactating females were excluded from the study. Written informed consent was obtained from all adult participants and from parents or legal guardians of minors. The study protocol was approved by the Vietnam Ministry of Health, Vietnam People’s Army Department of Military Medicine and the Australian Defence Human Research Ethics Committee (Approval No. 453/06).

Treatment

Patients were sequentially allocated to the two treatment groups: dihydroartemisinin-piperaquine (DHP, Arterakine, each tablet contained 40 mg dihydroartemisinin and 320 mg piperaquine phosphate, Central Pharmaceutical Factory No. 1, Hanoi, Vietnam) and artesunate–amodiaquine (AAQ, 50 mg artesunate per tablet, Naphaco, Namha Pharmaceutical Joint Stock Company, Nam Dinh City, Vietnam and 100 mg amodiaquine per tablet, Sunoquine, Sunward Pharmaceutical Pty Ltd., Singapore), with the first patient receiving DHP, the second patient AAQ, the third patient DHP, and so on. A weight-based regimen of DHP (per dose 2.4 mg of dihydroartemisinin and 19.2 mg/kg of piperaquine) and AAQ (per dose 4.5 mg of artesunate and 10 mg/kg of amodiaquine) rounded up or down to the nearest half tablet was administered daily for 3 days. For example, for the DHP group a child weighing 20 kg would receive one tablet of Arterakine daily for 3 days and an adult weighing 50 kg would receive 2.5 tablets of Arterakine daily for 3 days. For the AAQ group a child weighing 20 kg would receive 1.5 tablets of artesunate and two tablets of amodiaquine daily for 3 days and an adult weighing 50 kg would receive 4.5 tablets of artesunate and five tablets of amodiaquine daily for 3 days. Each dose was supervised and doses were administered with condensed milk. Patients were observed for 30 min and the dose was repeated in full if vomiting occurred within this time. Patients with parasite reappearance were treated with a 7-day regimen of artesunate (2 mg/kg/day) for P. falciparum and chloroquine for P. vivax as per national policy. Rescue medication with artesunate alone was to be implemented if either parasitaemia had not declined by at least 75% within 48 h of commencing treatment with DHP or AAQ, parasites were still present on day 7 after commencing treatment or after clearing parasitaemia a recurrence of malaria infection occurred.

The expected treatment cure rate was 98% for DHP (Tran et al. 2004) but without a reliable estimate of the antimalarial efficacy of AAQ in Vietnam, we expected a treatment cure rate of only 80% for AAQ. We calculated that a sample size of at least 106 patients would be required to detect a 18% difference in PCR adjusted parasitological failure rate between DHP and AAQ, with 80% power at a 5% significance level and a projected 10% loss to follow-up.

Clinical investigations

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Clinical investigations
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

Thick and thin blood films were collected before commencement of treatment and every 12 h after starting treatment until blood films were negative for three consecutive examinations. Blood films were also collected at days 7, 14, 21, 28, 35 and 42 during the follow-up period. The blood films were stained with Giemsa. Approximately 200 oil immersion fields (magnification ×1000) of each thick blood film were examined by at least two microscopists and parasite densities were quantified against 200 white blood cells (WBC) in each smear, assuming a total WBC count of 8000/μl. Parasite clearance times were determined by noting the time in hours from the commencement of treatment until the asexual parasite count fell below detectable levels in thick blood films. Body temperatures were measured before treatment and every 12 h after starting treatment until the patient’s tympanic body temperature remained <38 °C for more than 48 h. Fever clearance times were determined by noting the time in hours from the commencement of treatment at which the tympanic body temperature remained <38 °C for 48 h.

In addition to microscopy, two blood spots on Whatman filter paper were collected at the same time as blood smears and PCR was used to confirm the Plasmodium species and to distinguish recrudescences from reinfections. DNA was extracted from blood collected on either blood films or on filter spots using the QIAamp DNA mini kit (Qiagen, Cat. #51304) for single round multiplex PCR detection and identification of the four species, P. falciparum, P. vivax, P. ovale and P. malariae, as described by Padley et al. (2003). Multiplex PCR analysis was carried out on patients' blood collected before treatment and at recurrence of malaria infection. PCR genotyping for allelic variation at three loci (merozoite surface proteins 1 and 2 and glutamate rich protein) was used to distinguish recrudescence from reinfection. If at least two alleles were different it was classified as a reinfection.

Adverse events were defined as symptoms that occurred or become severe after commencement of treatment. At each drug administration, the physician recorded any adverse events. Patients had to respond to the non-leading question ‘How do you feel since you took the last tablets?’

Statistical analysis

Descriptive statistics were used to summarise baseline values and demographic data. Normally distributed data were compared using analysis of variance (ANOVA), with 95% confidence intervals (CI) of mean difference or geometric means. Non-normally distributed data were compared using the Mann–Whitney U-test. The primary efficacy end point was the PCR-adjusted cure rates on day 42 of treatment follow-up. End points were assessed using Kaplan–Meier survival analysis with a log-rank test for statistical significance. Secondary efficacy end points were parasite clearance times, fever clearance times, and the occurrence of adverse events. Differences in proportions were compared using the chi-square test with Yates’ correction or by Fisher Exact Test. Data were accepted as significant using the 5% significance level.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Clinical investigations
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

The study was conducted between September 2006 and December 2007. Sixty patients were enrolled on DHP and 56 patients on AAQ (Figure 1). The higher number in the DHP group was due to an adjustment in the recruiting to accommodate for the higher loss to follow-up in the group. The adjustment to recruit more patients in the DHP group was made after 110 of 116 subjects (95%) had already been enrolled in the study. Of the subjects recruited, 32% (19/60) on DHP and 30% (17/56) on AAQ were children (<15 years of age). Six patients in the DHP group and two patients in the AAQ group were lost to follow-up because of work/study reasons or because they did not return to the commune. At admission the demographic and clinical characteristics of the two treatment groups were similar (Table 1). The geometrical mean parasitaemia was comparable between the two groups (11 258 parasites/μl for DHP vs. 14 074 parasites/μl for AAQ). Although not statistically significant, the geometrical mean parasitaemia in children on AAQ was threefold higher than that of the children on DHP. 72% (43/60) of patients on DHP and 73% (41/56) on AAQ were febrile at the time of enrolling in the study.

image

Figure 1.  Trial profile. DHP: dihydroartemisinin–piperaquine; AAQ: artesunate–amodiaquine.

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Table 1.   Baseline characteristics of the patients according to treatment
 DHPAAQ
No. of subjects
 All patients6056
 Children1917
 Adults4139
No. of males (%)
 All patients37 (62%)37 (66%)
 Children14 (74%)11 (65%)
 Adults23 (56%)26 (67%)
Mean age (year) (SD)
 All patients20.6 (12.4)23.5 (13.9)
 Children10.3 (2.5)10.0 (3.1)
 Adults25.3 (12.3)29.4 (12.6)
Mean weight (kg) (SD)
 All patients37.8 (12.3)38.0 (13.2)
 Children23.9 (4.2)23.2 (7.0)
 Adults44.2 (9.0)45.8 (6.5)
Mean temperature (°C) (SD)
 All patients38.5 (1.0)38.5 (1.0)
 Children38.9 (0.9)38.6 (0.9)
 Adults38.3 (1.0)38.5 (1.0)
No. (%) of patients with temp ≥38 °C
 All patients43 (72%)41 (73%)
 Children17 (89%)13 (76%)
 Adults26 (63%)28 (72%)
Geometric mean asexual Plasmodium falciparum/μl (95% CI)
 All patients11 258 (293–128 191)14 074 (240–321 230)
 Children9002 (480–121 693)26 671 (3920–321 230)
 Adults12 503 (293–128 191)10 651 (240–109 374)

The median (interquartile range, IQR) actual antimalarial doses in mg/kg body weight received by the patients per day was significantly higher in children than in adults administered dihydroartemisinin [2.4 mg/kg (IQR, 2.3–2.7 mg/kg) vs. 2.2 mg/kg (IQR, 2.0–2.3 mg/kg), P < 0.001] and piperaquine [19.2 mg/kg (IQR, 18.5–21.8 mg/kg) vs. 17.5 mg/kg (IQR, 16.4–18.5 mg/kg), P < 0.001] but were similar between children and adults administered artesunate [4.6 mg/kg (IQR, 4.4–4.8 mg/kg) vs. 4.4 mg/kg (IQR, 4.4–4.8 mg/kg), P = 0.29] and amodiaquine [10.6 mg/kg (IQR, 10.0–10.8 mg/kg) vs. 10.4 mg/kg (IQR, 10.0–10.9 mg/kg), P = 0.89].

Treatment outcomes as per protocol analysis following DHP and AAQ in the patients with falciparum malaria who either completed the 42-day follow-up period or had a recurrence of malaria during the follow-up period (Table 2) show that median parasite clearance times were similar for the two treatment groups [all patients: DHP: 24.0 h (IQR, 24–36 h) vs. AAQ: 24.0 h (IQR, 24–36 h) P = 0.80], with values higher in children than in adults (36 h vs. 24 h). There was no significant differences in median fever clearance times between patients on DHP [all patients: 24.0 h (IQR, 12.5–24 h)] and AAQ [24.0 h (IQR, 12–24 h)] and values were comparable between children and adults for both treatments.

Table 2.   Treatment outcomes as per protocol after 3-day courses of dihydroartemisinin–piperaquine [DHP, children (n = 15), adults (n = 34)] and artesunate–amodiaquine [AAQ, children (n = 14), adults (n = 35)] in Vietnamese subjects with Plasmodium falciparum malaria
 DHPAAQ
  1. *Mixed infection (Plasmodium falciparum and Plasmodium vivax) was identified in one of three DHP recipients.

  2. Plasmodium malariae was identified in one of five AAQ recipients.

Parasite clearance time, median h (range)
 All patients24 (12–48)24 (12–48)
 Children36 (12–36)36 (12–48)
 Adults24 (12–48)24 (12–36)
Fever clearance time, median h (range)
 All patients24 (12–48)24 (8.5–37)
 Children24 (12–48)25 (9–36)
 Adults24 (8.5–37)24 (9–36)
Recrudescence within 42 days, n/N (%)0/49 (0)1/49 (2.0)
Reinfection within 28 days, n/N (%)0/49 (0)3/49 (6.1)
Reinfection within 42 days, n/N (%)3/49 (6.1)*5/49 (10.2)†

Only one patient on AAQ had a recrudescence by day 42 of follow-up, which was diagnosed on day 14 after commencement of treatment. The PCR-adjusted cure rates were 100% for the DHP group and 98% (95% CI, 87–100%) for the AAQ group (P = 0.3). When including recrudescences and reinfections, the cure rates were 94% (95% CI, 82–98%) for DHP and 88% (95% CI, 75–94%) for AAQ (P = 0.28). There were no significant differences between the treatments in the number of patients with reinfections over the follow-up period (DHP, n = 3 vs. AAQ, n = 5, P = 0.72). Of these patients, two of the three on DHP were diagnosed on day 35 and the third case on day 42. Of the five patients with reinfections after AAQ treatment, one was diagnosed on day 21, two on day 28 and two on day 42. The one patient with P. malariae who was treated with DHP made a full recovery without a recurrence of infection by day 42. Of the six patients with mixed infections of P. falciparum and P. vivax (three treated with DHP and three treated with AAQ), one patient on DHP had a relapse on day 42.

DHP and AAQ were well tolerated with no serious adverse events. The most common adverse events reported before treatment in the DHP and AAQ groups were respectively: fever [52/60 (86.7%) vs. 53/56 (94.6%], headache [42/60 (70.0%) vs. 46/56 (82.1%)] tiredness [32/60 (53.3%) vs. 31/56 (55.4%)], nausea [4/60 (6.7%) vs. 9/56 (16.1%)] and vomiting [4/60 (6.7%) vs. 5/56 (8.9%)]. Two patients (children) in the AAQ group vomited their medication on the first day within 30 min of drug administration and were successfully retreated with the same dose. No patients were known to have vomited after the 30 min observation period. Eleven patients on DHP and 12 patients on AAQ reported adverse events 24 h after treatment started. In the DHP group the adverse events were fever [11/60 (18.3%)], headache [8/60 (13.3%)], and tiredness [6/60 (10.0%)]. Corresponding values for the AAQ group were fever [12/56 (21.4%)], headache [9/56 (16.1%)], and tiredness [7/56 (12.5%)]. All adverse events in both groups were self-limiting and resolved within 48 h after treatment started. It was not possible to determine adverse events attributed to the treatment regimens due to the difficulty of differentiating adverse events from symptoms of malaria.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Clinical investigations
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

Multidrug-resistant P. falciparum malaria is prevalent in central Vietnam, including Ninh Thuan and neighbouring provinces (Morillon et al. 1996). The two ACTs, DHP and AAQ, were highly efficacious in treating P. falciparum infections in both children and adults, with cure rates of 100% and 98%, respectively. For DHP, the result was not unexpected as the ACT has been shown to be highly efficacious in several countries throughout Southeast Asia and Oceania where multidrug resistant-falciparum malaria is prevalent (Denis et al. 2002; Karunajeewa et al. 2004; Ashley et al. 2005; Myint et al. 2007; Ratcliff et al. 2007a). Our findings were comparable to a previous study in Vietnam, in which DHP at a total dose of 6.8 mg/kg dihydroartemisinin and 54 mg/kg piperaquine produced a 56-day cure rate of 98.7% in children and adult patients with uncomplicated falciparum malaria from Binh Phuoc Province in south Vietnam (Tran et al. 2004).

Patients on DHP or AAQ had rapid clinical and parasitological responses with fever clearance and parasite clearance times of about 24 h. The therapeutic response in the present study was faster than that reported elsewhere with DHP (Tran et al. 2004; Ashley et al. 2005; Grande et al. 2007; Janssens et al. 2007; Krudsood et al. 2007; Price et al. 2007; Ratcliff et al. 2007a), artemether–lumefantrine (Krudsood et al. 2007; Ratcliff et al. 2007a) and artesunate–mefloquine (Tran et al. 2004; Ashley et al. 2005; Grande et al. 2007; Janssens et al. 2007) where up to 48 h or longer were required before the majority of patients were afebrile and aparasitemic.

In contrast to the present study, DHP was more efficacious than AAQ in the treatment of uncomplicated P. falciparum in Indonesian recipients from Timika, with significantly higher rates of recrudescence of malaria after AAQ treatment (Hasugian et al. 2007). This difference in efficacy is probably due to the differences in the level of amodiaquine resistance. At Phuoc Chien Commune, the efficacy of amodiaquine alone is unknown. In Indonesia, the efficacy of amodiaquine varies but can be as low as 26% in regions where high levels of chloroquine resistance predominate (Maguire et al. 2006; Ratcliff et al. 2007b).

Although there was no significant difference in the reinfection rates between recipients on DHP and AAQ, reinfections tended to occur later in the DHP group than in the AAQ group. This was probably due to piperaquine having a longer plasma elimination half-life (23–28 days) (Hung et al. 2004; Tarning et al. 2008) than desethylamodiaquine (∼16 days), the active main metabolite of the prodrug amodiaquine (Hombhanje et al. 2005). The post-treatment prophylactic value of DHP was also reported in the Indonesian recipients from Timika, with significantly reduced reinfections with either P. falciparum or P. vivax malaria, compared with AAQ recipients (Hasugian et al. 2007).

Both treatment regimens were well tolerated and adverse events were self-limiting. Other studies (Ashley et al. 2005; Grande et al. 2007; Hasugian et al. 2007; Janssens et al. 2007; Krudsood et al. 2007; Myint et al. 2007; Ratcliff et al. 2007a) have reported DHP to be well tolerated, with gastrointestinal disturbances such as vomiting, nausea and diarrhoea being the most common adverse events. In nine studies involving the efficacy and tolerability of DHP (Myint et al. 2007), the frequency of vomiting ranged between 1.6% and 6.9%, but at Phuoc Chien no patient needed to repeat the dose of DHP. Studies in African children have shown AAQ to be generally well tolerated (Adjuik et al. 2002; Abacassamo et al. 2004; Sowunmi et al. 2005). At Timika, patients treated with AAQ were two- to threefold more likely to develop gastrointestinal disturbances such as nausea (25%vs. 8.6%) and vomiting (7.8%vs. 4.2%) while receiving treatment than DHP recipients (Hasugian et al. 2007). Similarly, a higher frequency of nausea (3.6%vs. 0.8%) and vomiting (6.7%vs. 2.0%) but not diarrhoea (0.4%vs. 3.2%) was reported in Rwandan children treated with AAQ rather than DHP (Karema et al. 2006). However, at Phuoc Chien only two children (3.6%) required a repeat dose of AAQ. The lower frequency of vomiting in the AAQ group and the absence of nausea and diarrhoea in the recipients at Phuoc Chien after both treatments compared with other studies may have been due to the coadministration of the ACTs with condensed milk, which may have minimized the reporting of gastrointestinal disturbances. Another possibility is that because active screening for adverse events was not done it may have led to under-reporting, which would be expected to be similar in both groups.

Since the mid-1990s, a 3-day regimen of artesunate and mefloquine has been the most widely used ACT in Southeast Asia, particularly along the Thai border of Burma and Cambodia, for the treatment of multidrug-resistant P. falciparum malaria (Nosten et al. 1994; Silachamroon et al. 2005). However, artesunate–mefloquine has limitations because of adverse events associated with mefloquine (Palmer et al. 1993), reduced efficacy (Ashley et al. 2006a; Denis et al. 2006; Vijaykadga et al. 2006) and high cost ($US3 for an adult treatment in Vietnam). Until recently, artesunate–mefloquine was only available as separate tablets (Ashley et al. 2006a). As a promising treatment option in Vietnam, DHP is coformulated, better tolerated (Smithuis et al. 2006; Grande et al. 2007) and less expensive (around $US1.50 for an adult treatment in Vietnam) than artesunate–mefloquine. Similarly, AAQ is a well tolerated, affordable ACT at a cost comparable to DHP and is now available as a fixed-dose combination (Coarsucam™) that has been co-developed by Sanofi-Aventis and the non-profit Drugs for Neglected Diseases Initiative (http://www.dndi.org). As with other coformulated antimalarial drugs the reduction in pill burden will ensure better patient compliance and eliminate the possibility of patients taking only one component of the combination (Ashley et al. 2006b).

In conclusion, this pilot study has shown DHP and AAQ to be well tolerated and efficacious in the treatment of uncomplicated falciparum malaria at Phuoc Chien Commune in central Vietnam. Reinfections tended to occur later in DHP recipients compared with AAQ recipients, which suggests that DHP possesses superior post-treatment prophylactic activity than AAQ. Further studies in larger populations using the coformulation of artesunate–amodiaquine are required in other regions of Vietnam to determine the potential of AAQ as an alternative ACT to DHP for first line treatment of P. falciparum malaria in Vietnam.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Clinical investigations
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References

This study was carried out under the auspices of the Vietnam Australia Defence Malaria Project, a defence co-operation between the Vietnam People’s Army and the Australian Defence Force. We thank the Vietnam People’s Army Department of Military Medicine for supporting the study and the financial sponsor, the Australian Defence Force International Policy Division. We also thank the malaria field study team of Dr. Vu Hong Cam, Nguyen Dang Kim, Cao Manh Hung, Cao Van Tam, Nguyen Tien Hai, Cao Van Anh, Nguyen Tan Thoa and Chau Khanh Hung. The authors are most grateful to Dr. Le Ngoc Anh for administrative-logistic support, Michael Waller for statistical analysis, Scott Smith for QA microscopic analysis, Vu Huy Chien for PCR analysis and Dr. Bob Cooper for commenting on the manuscript. The opinions expressed are those of the authors and do not necessarily reflect those of the Defence Health Service or any extant Australian Defence Force policy.

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  8. Acknowledgements
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