Evaluation of the paediatric dose of chloroquine in the treatment of Plasmodium vivax malaria.

BACKGROUND: Chloroquine (CQ) continues to be the first-line medication used worldwide in the treatment of Plasmodium vivax malaria. The dose recommended by the World Health Organization is 25 mg/kg independently of the age of the subject. Nonetheless, the pharmacokinetics and pharmacodynamics of drugs in children are different from those in adults and may influence the drug concentrations in blood and become risk factors for therapeutic failure and/o resistance to CQ. METHODS: This study is a secondary analysis of the data from a clinical trial in which children over 5 years of age were administered 25 mg/kg of CQ, and CQ concentrations in blood were measured at day 7 of follow-up. Models of regression and comparison were used to evaluate and compare the CQ dose taken per kg/body weight, the CQ dose calculated based on body surface area, CQ levels in blood on day 7 and the age of the population. RESULTS: The younger the study population the greater the difference between the dose per kg/body weight (real dose) and that calculated according to the BSA (theoretical dose). The difference between the two doses was -181.206 mg in the 5-9 years of age group (CI 95 % -195.39; -167.02 mg) and -71.39 mg (CI 95 % -118.61; -23.99 mg) in the 10-14-year-old group. The CQ concentrations in blood on day 7 differed in patients over and under 15 years (p = 0.008). A negative correlation was found between the real and theoretical dose (difference in dose) and the age in years (R2 = 0.529, p = 0.001). A negative correlation was also found between the difference in dose (mg) and CQ concentrations on day 7 (ng/ml) (r = -0.337, p = 0.001). Children under 15 years were found to have a higher rate of therapeutic failure than those over 15 (28 vs 4.2 %, respectively) (Kaplan-Meier p = 0.005). CONCLUSIONS: A CQ dose of 25 mg/kg for the treatment of P. vivax malaria may be too low in children as demonstrated by the reduction in CQ concentrations in blood at day 7 of follow-up. This under-dosage is probably associated with the higher rate of therapeutic failure found in children under 15 years (28 vs 4.3 %). These results suggest the need to review the paediatric doses of CQ currently used.

Resistance of infection by Plasmodium vivax to chloroquine in Bolivia.

BACKGROUND: Chloroquine (CQ) over three days plus primaquine (PQ) for seven days is the treatment of choice of infections by Plasmodium vivax in Bolivia, where 95% of the cases of malaria are attributed to this species. The aim of this study was to evaluate the therapeutic efficacy of CQ in this setting. METHODS: Patients in the Amazon region of northern Bolivia, were included in the study from May to November 2011 and the therapeutic efficacy of CQ was evaluated over a 28-day follow-up period. Patients with P. vivax mono-infection received 25 mg/Kg body weight of CQ over three days. The concentrations of CQ + desethylchloroquine (DCQ) in blood were determined at days 7 and 28 of follow up; at follow-up and on the day of treatment failure was administered PQ. RESULTS: One hundred patients fulfilled the inclusion criteria, two were lost to follow up and another two were later excluded for protocol violation. Of the 96 patients who completed the follow up 10 showed TF; one presented continued parasitaemia until day 7 of follow up, three on day 21 and six on day 28 of follow up. The geometric mean of CQ + DCQ on day 7 was 321.7 ng/ml (range 197-535 ng/ml). In six patients with TF the CQ + DCQ concentrations in blood on the day of TF were >100 ng/ml. The rate of resistance was 6.5%. CONCLUSION: The present study demonstrates the presence of resistance to CQ in the treatment of malaria by P. vivax in the Amazon region of Bolivia. New clinical trials are needed to establish alternative treatments against these parasites in this region of South America.

Respuesta terapéutica de Plasmodium vivax a la cloroquina, en Riberalta, Guayaramerín y Yacuiba, Bolivia / Therapeutic response of Plasmodium vivax to chloroquine in Bolivia

Introducción. La determinación de la eficacia de la cloroquina contra Plasmodium vivax permite mejorar la capacidad de vigilancia de la resistencia a los antipalúdicos. Objetivo. Evaluar la eficacia terapéutica de la cloroquina como tratamiento de malaria no complicadapor P. vivax en Riberalta, Guayaramerín y Yacuiba, Bolivia. Materiales y métodos. Se llevó a cabo un estudio de la eficacia in vivo en pacientes mayores de cinco años; se suministró cloroquina (25 mg/kg en tres días) y se hizo seguimiento por 28 días, midiendo los niveles de cloroquina en sangre y desetilcloroquina, el día dos y el día de registro de reaparición de parasitemia. Para la evaluación de la incidencia acumulada de falla del tratamiento, se usó el análisis de supervivencia de Kaplan-Meier. Resultados. Se estudiaron 223 pacientes (Riberalta, 84; Guayaramerín, 80; Yacuiba, 59). Las medias de densidad parasitaria (formas asexuadas) del día 0 en Riberalta fueron de 6.147, en Guayaramerín, 4.251, y en Yacuiba, 5.214 parásitos/μl de sangre. En el mismo orden, los promedios de concentraciones sanguíneas de cloroquina-desetilcloroquina del día 2 fueron de 783, 817 y 815 ng/ml. Mientras en Yacuiba no se presentaron fracasos terapéuticos, en Riberalta ocurrieron con frecuencia de 6,2 % y en Guayaramerín de 10 %. Los valores de cloroquina y desetilcloroquina en sangre de pacientes con fracaso terapéutico fueron menores de 70 ng/ml en el día de reaparición de parasitemia. Conclusión. No se evidenció resistencia de P. vivax a la cloroquina en las tres regiones de evaluación en Bolivia. Se requieren mayores estudios de la concentración de la cloroquina en sangre.

Introduction. Knowledge of the therapeutic efficacy of chloroquine for Plasmodium vivax infections improves the capacity for surveillance of anti-malarial drug resistance. Objective. The therapeutic efficacy of chloroquine as treatment was evaluated for uncomplicated Plasmodium vivax malaria in Bolivia. Materials and methods. An in vivo efficacy study of chloroquine was undertaken in three regions of Bolivia--Riberalta, Guayaramerín and Yacuiba. Two hundred and twenty-three patients (84, 80, and 59 in the three regions, respectively) aged over 5 years old were administered with chloroquine (25 mg/kg/three days) and followed for 28 days. Blood levels of chloroquine and desethylchloroquine were measured on day 2 and on the day of reappearance of parasitemia. The cumulative incidence of treatment failure was calculated using the Kaplan and Meier survival analysis. Results. The mean parasitemias (asexual) on day 0 were 6,147 parasites/μl of blood in the Riberalta population, 4,251 in Guayaramerín and 5,214 in Yacuiba. The average blood concentrations of chloroquine-desethylchloroquine during day 2 were 783, 817, and 815 ng/ml, respectively. No treatment failures were observed in Yacuiba, whereas in Riberalta and Guayaramerín, the frequencies of treatment failures were 6.2% and 10%. Blood levels of chloroquine and desethylchloroquine in patients with treatment failure showed values below 70 ng/ml on the day of reappearance of parasitemia. Conclusion. Resistance of Plasmodium vivax to chloroquine was not demonstrated in three regions of Bolivia.

[Therapeutic response of Plasmodium vivax to chloroquine in Bolivia]. / Respuesta terapéutica de Plasmodium vivax a la cloroquina, en Riberalta, Guayaramerín y Yacuiba, Bolivia.

INTRODUCTION: Knowledge of the therapeutic efficacy of chloroquine for Plasmodium vivax infections improves the capacity for surveillance of anti-malarial drug resistance. OBJECTIVE: The therapeutic efficacy of chloroquine as treatment was evaluated for uncomplicated Plasmodium vivax malaria in Bolivia. MATERIALS AND METHODS: An in vivo efficacy study of chloroquine was undertaken in three regions of Bolivia--Riberalta, Guayaramerín and Yacuiba. Two hundred and twenty-three patients (84, 80, and 59 in the three regions, respectively) aged over 5 years old were administered with chloroquine (25 mg/kg/three days) and followed for 28 days. Blood levels of chloroquine and desethylchloroquine were measured on day 2 and on the day of reappearance of parasitemia. The cumulative incidence of treatment failure was calculated using the Kaplan and Meier survival analysis. RESULTS: The mean parasitemias (asexual) on day 0 were 6,147 parasites/µl of blood in the Riberalta population, 4,251 in Guayaramerín and 5,214 in Yacuiba. The average blood concentrations of chloroquine-desethylchloroquine during day 2 were 783, 817, and 815 ng/ml, respectively. No treatment failures were observed in Yacuiba, whereas in Riberalta and Guayaramerín, the frequencies of treatment failures were 6.2% and 10%. Blood levels of chloroquine and desethylchloroquine in patients with treatment failure showed values below 70 ng/ml on the day of reappearance of parasitemia. CONCLUSION: Resistance of Plasmodium vivax to chloroquine was not demonstrated in three regions of Bolivia.