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ABSTRACT |
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Malaria control efforts need to be designed for the specific environment in which they will be used, taking into account the local epidemiology. Also, the drug-resistant strains of malaria are constantly changing in time and space. This makes regular surveillance of utmost importance: following a particular malaria treatment policy for a particular area and determining any changes in the levels of drug resistance so as to introduce alternative drugs when necessary.
The present study was undertaken on Bioko Island in Equatorial Guinea to assess the efficacy of three treatment regimens: chloroquine and the pyrimethamine/sulfadoxine combination (the first- and second-line drugs, respectively, for uncomplicated falciparum malaria in the country), and quinine (the election for treatment in cases of chloroquine and pyrimethamine/sulfadoxine resistance and for severe malaria). The results obtained were compared with those of passive surveys conducted on the island from 1992–1996 to verify the evolution of malaria drug resistance.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The study was conducted from May–December of 1999 on children at Malabo Regional Hospital. Patients were selected in accordance with the criteria of the WHO protocol:8 briefly, infection with P. falciparum alone, parasitemia >2,000 asexual parasites/µL, age 6–59 months, and no history of previous treatment. The study was approved by the Ethical Committees of the National Malaria Control Program of Equatorial Guinea and the Instituto de Salud Carlos III in Madrid, Spain; informed consent was obtained from the parents of all subjects.
Patients enrolled in the study were initially examined for P. falciparum infection. Name, age, weight, hemoglobin and glycemia data, temperature, and clinical findings were recorded. Scheduled visits were made on days 1, 2, 3, 7, and 14. All visits including the taking of axillary temperature and a brief physical examination. Parents were encouraged to return at any time for additional examination if the child was ill.
Capillary blood was collected for thick and thin blood films on days 0, 1, 2, 3, 7, and 14 or any other day the child was ill. They were stained with Giemsa, and the parasite density was determined by counting asexual malaria parasites against 200 leukocytes, assuming a total white cell count of 8,000 per µL of blood.
Several in vivo tests had been conducted at Malabo Regional Hospital from 1992–1996 on children who met the inclusion criteria:9 in brief, younger than age 10, a blood film positive for asexual forms of P. falciparum alone, and parasite count >1,000/µL of blood. Patients were monitored voluntarily in the hospital for 7 days after treatment and then, on an outpatient basis, on days 10 and 14. Each case also was followed up clinically and parasitologically as mentioned before.
Drug prescriptions. During the trial in 1999, children were assigned on day 0 to receive either chloroquine phosphate 100 or 150 mg (Pharmamed Ltd., Malta) 25 mg/kg over 3 days; pyrimethamine 25 mg/sulfadoxine 500 mg (Pharmamed Ltd.) 1.25/25 mg/kg in one dose; or quinine sulphate 200 or 300 mg (Pharmamed Ltd.) 25 mg/kg daily in three oral doses over a seven-day period. Chloroquine and pyrimethamine/ sulfadoxine were given under direct supervision. Patients with complicated malaria cases were hospitalized and treated with quinine dihydrochloride 300 mg/mL (Pharmamed Ltd.) by intravenous injection. All patients who did not respond to treatment were cured with second- or third-line treatment: pyrimethamine/sulfadoxine, quinine, or Artesunate® (Guilin Pharmaceutical Works, Guangxi, China) plus mefloquine (Eloquine®, Medochemie Ltd., Cyprus).
From 1992–1996, the following treatment regimens were used: chloroquine phosphate (Pharmamed Ltd.) 100 or 150 mg, 35 mg/kg over three days; quinine sulphate (Pharmamed Ltd.) 200 or 300 mg; and pyrimethamine 25 mg/sulfadoxine 500 mg (Pharmamed Ltd.) 1.25/25 mg/kg in one dose. (The quinine sulphate dosage in 1992 of 30 mg/kg daily for four days was extended to five days in 1993 and has been seven days since 1994.)
Clinical and parasitologic responses to therapy were classified according to the WHO criteria:
37.5°C after 48 h with parasitemia greater than that on day 0 or after 72 h with parasitemia, and 3) parasitemia after 72 h 25% of that on day 0. 37.5°C with parasitemia during days 4–14 without meeting the criteria for ETF. Before 1996, the response to treatment was classified according to the previous WHO guidelines in four categories: S, RI, RII, and RIII.9 This classification did not consider the clinical aspects. To compare the results from the studies of both periods, data from 1992–1996 have been reclassified as follows: RI, RII = LTF; RIII = ETF; S = ACR.
Data analysis.
Data were analyzed using Epi-Info v.6 software. Differences in proportions were tested with the 
2 test, and a value of P < 0.05 was considered significant.
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RESULTS |
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The mean age of the children in each treatment group varied from year to year, with significant differences in some cases (in the pyrimethamine/sulfadoxine group, for example, 94.8 months in 1994 and 24.1 in 1996). One could expect lower treatment failure rates in groups with a higher mean age because of a more efficacious response due to greater immunity to P. falciparum. But in analysis of the different study years, age did not seem to have great influence on the failure rate. In the pyrimethamine/sulfadoxine group in 1996, for example, the mean age was the lowest (24.1 months) but there were no failures. In 1999, the quinine group had a significantly lower mean age (23.8 months) than in previous years but the failure rate was similar.
The therapeutic response to chloroquine during the 14d follow-up is shown in table 1
. The failure rate with chloroquine varied from 55% in 1996 to 40% in 1999, but the differences are not statistically significant (P = 0.5). Nevertheless, ETF rates increased progressively over the years, from 6% in 1992 to 30% in 1999, a significant difference (P = 0.009).
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. The failure rate varies from 0% in 1996 to 16% in 1995, but the difference is not statistically significant (P = 0.1). ETF and LTF do not vary significantly over the years, with a mean value for both of 5% in 1999.
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summarizes the results of the in vivo tests for sensitivity to quinine. The short treatment regimen (4–5 days) in 1992 and 1993 resulted in significantly (P = 0.0003) higher failure rates (19% and 22%, respectively) than the 7d regimen (3–5.5%). All failures were LTFs except for one case in 1993.
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DISCUSSION |
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Data reveal an unacceptably high degree of therapeutic failure after chloroquine treatment of uncomplicated childhood malaria. Although there was not a significant change in the global failure rate until 1999, the high level of resistance we found since 1992 (40–55%) represents a serious problem. A clinical failure rate of 25% within 14 days after therapy has been proposed as the upper limit above which treatment should be changed.10 The failure rate in Malabo has been above 25% since 1992.
Another important point regarding chloroquine resistance is the large increase in the ETF rate and its clinical consequences. A very interesting study11 concluded that when chloroquine treatment is associated with a 20% ETF rate, the hemoglobin levels are markedly reduced after 72h and recovery is unsatisfactory, even in children with ACR. These are two reasons anemia increases in children despite chloroquine treatment. The ETF rate for chloroquine in Malabo has risen from 6% in 1992 to 30% in 1999, with the treatment not only proving ineffective but also making matters worse in a relatively uncomplicated case of malaria. A change in the recommended first-line drug should be seriously considered.
As there are few therapeutic options for treating malaria, the second-line pyrimethamine/ sulfadoxine can be an alternative. This drug is still very effective; its failure rate was 10% in 1999 and has not increased significantly since 1992. But a generalized use of the drug could quickly increase the levels of resistance, as has happened in Malawi, Tanzania, and Kenya.12–14 Although resistance may be inevitable, it probably can be slowed down. WHO recommends an antimalarial combination therapy based on the synergistic or additive potential of two or more drugs to improve therapeutic efficacy and also delay the development of resistance to the combination’s individual components.15 Some combinations with pyrimethamine/sulfadoxine and, recently, chlorproguanil—inhibitor of dihydrofolate reductase—and sulfone dapsone (LAPDAP, GlaxoSmithKline, Tanzania, Kenya, Malawi, Botswana and South Africa) are recommended as alternatives for first-line treatment in sub-Saharan countries.16 A decision to change the first-line antimalarial has to consider different aspects of both the country (epidemiologic and economic) and the drugs (efficiency, affordability, acceptability).
Quinine remains an effective drug against P. falciparum malaria in Equatorial Guinea. The global failure rates have been stable since 1994 (but were probably higher in 1992 and 1993 because of a shorter drug regimen), and data are not alarming. Furthermore, it is very probable that treatment failures resulted in part from patients’ lack of adherence to the regimen because of adverse reactions and the prolonged dosage (three times a day for seven days), as nearly all the failures were LTFs. Therefore, the failure rate could be even lower. Quinine, because of its unfavorable dosage and annoying side effects, cannot be considered an alternative for first-line treatment of uncomplicated malaria. It will remain the drug of choice for first-line treatment of severe malaria or for cases of multidrug resistance.
Based on the WHO classification of the clinical failure rates,17 and in accordance with the results obtained in our surveys on Bioko Island, we can conclude that: a) failure rates for chloroquine are in the change period (>25%), and urgent action is needed; b) pyrimethamine/sulfadoxine failure rates are in the alert period (6–15%), and surveillance must be continued; and c) quinine failure rates are in the grace period (<6%), and the drug can be recommended without hesitancy about its efficacy.
Acknowledgments: We thank the families of the study children, the staff of Malabo Regional Hospital for help and support, and the National Malaria Control Program of Equatorial Guinea for permission to carry out this study.
Financial support: This work was supported by the Spanish Agency of International Cooperation and Instituto de Salud ‘Carlos III’ (SBPY-1320/01).
Authors’ addresses: Jesús Roche, Centro Nacional de Medicina Tropical, Instituto de Salud ‘Carlos III,’ Sinesio Delgado 10, 28029 Madrid, Spain. Ana Guerra-Neira and José Raso, Proyecto Control del Paludismo, Hospital Regional de Malabo, PO Box 958, Equatorial Guinea. Agustín Benito, Centro Nacional de Microbiología. Ctra. Pozuelo Km 2, 28220 Majadahonda, Madrid, Spain.
Reprint requests: Jesús Roche, Centro Nacional de Medicina Tropical, Instituto de Salud ‘Carlos III,’ Sinesio Delgado 10, 28029 Madrid, Spain.
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  J. K. Baird Effectiveness of Antimalarial Drugs N. Engl. J. Med., April 14, 2005; 352(15): 1565 - 1577. [Full Text] [PDF]
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