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Different methodological approaches to the assessment of in vivo efficacy of three artemisinin-based combination antimalarial treatments for the treatment of uncomplicated falciparum malaria in African children.

Ashley EA, Pinoges L, Turyakira E, Dorsey G, Checchi F, Bukirwa H, van den Broek I, Zongo I, Urruta PP, van Herp M, Balkan S, Taylor WR, Olliaro P, Guthmann JP - Malar. J. (2008)

Bottom Line: The median [range] difference in point estimates between method 1a (reference) and the others were: (i) method 1b = 1.3% [0 to 24.8], (ii) method 2a = 1.1% [0 to 21.5], and (iii) method 2b = 0% [-38 to 19.3].The standard per-protocol method (1a) tended to overestimate the risk of failure when compared to alternative methods using the same endpoint definitions (methods 1b and 2a).The standard method was also associated with a 34% reduction in the number of patients evaluated compared to the number of patients enrolled.Use of survival analysis is the most appropriate way to estimate failure rates with parasitological recurrence classified as treatment failure on the day it occurs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Epicentre, Paris, France. elizabeth.ashley@epicentre.msf.org

ABSTRACT

Background: Use of different methods for assessing the efficacy of artemisinin-based combination antimalarial treatments (ACTs) will result in different estimates being reported, with implications for changes in treatment policy.

Methods: Data from different in vivo studies of ACT treatment of uncomplicated falciparum malaria were combined in a single database. Efficacy at day 28 corrected by PCR genotyping was estimated using four methods. In the first two methods, failure rates were calculated as proportions with either (1a) reinfections excluded from the analysis (standard WHO per-protocol analysis) or (1b) reinfections considered as treatment successes. In the second two methods, failure rates were estimated using the Kaplan-Meier product limit formula using either (2a) WHO (2001) definitions of failure, or (2b) failure defined using parasitological criteria only.

Results: Data analysed represented 2926 patients from 17 studies in nine African countries. Three ACTs were studied: artesunate-amodiaquine (AS+AQ, N = 1702), artesunate-sulphadoxine-pyrimethamine (AS+SP, N = 706) and artemether-lumefantrine (AL, N = 518).Using method (1a), the day 28 failure rates ranged from 0% to 39.3% for AS+AQ treatment, from 1.0% to 33.3% for AS+SP treatment and from 0% to 3.3% for AL treatment. The median [range] difference in point estimates between method 1a (reference) and the others were: (i) method 1b = 1.3% [0 to 24.8], (ii) method 2a = 1.1% [0 to 21.5], and (iii) method 2b = 0% [-38 to 19.3].The standard per-protocol method (1a) tended to overestimate the risk of failure when compared to alternative methods using the same endpoint definitions (methods 1b and 2a). It either overestimated or underestimated the risk when endpoints based on parasitological rather than clinical criteria were applied. The standard method was also associated with a 34% reduction in the number of patients evaluated compared to the number of patients enrolled. Only 2% of the sample size was lost when failures were classified on the first day of parasite recurrence and survival analytical methods were used.

Conclusion: The primary purpose of an in vivo study should be to provide a precise estimate of the risk of antimalarial treatment failure due to drug resistance. Use of survival analysis is the most appropriate way to estimate failure rates with parasitological recurrence classified as treatment failure on the day it occurs.

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Summary of different analyses. Notes: Shaded boxes represent patients excluded from the analyses. Analysable populations – Figures in parentheses represent the % patients excluded from the enrolled patient population using each method of analysis.
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Figure 2: Summary of different analyses. Notes: Shaded boxes represent patients excluded from the analyses. Analysable populations – Figures in parentheses represent the % patients excluded from the enrolled patient population using each method of analysis.

Mentions: Four different analyses were done. Figure 2 presents the population selected and the methods used for each analysis. The populations differ depending on both the definition of failure and the analytical method used. Efficacy results are presented as point estimates for each drug in each study without making comparisons between treatment arms in the same study. Patients wrongly randomized, who did not meet study inclusion criteria were excluded from all analyses. Withdrawals for other reasons were dealt with in different ways depending on the analytical method used as explained below. Failure rates were calculated as proportions (methods 1a and 1b) or estimated using survival analytical methods (methods 2a and 2b) as follows-


Different methodological approaches to the assessment of in vivo efficacy of three artemisinin-based combination antimalarial treatments for the treatment of uncomplicated falciparum malaria in African children.

Ashley EA, Pinoges L, Turyakira E, Dorsey G, Checchi F, Bukirwa H, van den Broek I, Zongo I, Urruta PP, van Herp M, Balkan S, Taylor WR, Olliaro P, Guthmann JP - Malar. J. (2008)

Summary of different analyses. Notes: Shaded boxes represent patients excluded from the analyses. Analysable populations – Figures in parentheses represent the % patients excluded from the enrolled patient population using each method of analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2527011&req=5

Figure 2: Summary of different analyses. Notes: Shaded boxes represent patients excluded from the analyses. Analysable populations – Figures in parentheses represent the % patients excluded from the enrolled patient population using each method of analysis.
Mentions: Four different analyses were done. Figure 2 presents the population selected and the methods used for each analysis. The populations differ depending on both the definition of failure and the analytical method used. Efficacy results are presented as point estimates for each drug in each study without making comparisons between treatment arms in the same study. Patients wrongly randomized, who did not meet study inclusion criteria were excluded from all analyses. Withdrawals for other reasons were dealt with in different ways depending on the analytical method used as explained below. Failure rates were calculated as proportions (methods 1a and 1b) or estimated using survival analytical methods (methods 2a and 2b) as follows-

Bottom Line: The median [range] difference in point estimates between method 1a (reference) and the others were: (i) method 1b = 1.3% [0 to 24.8], (ii) method 2a = 1.1% [0 to 21.5], and (iii) method 2b = 0% [-38 to 19.3].The standard per-protocol method (1a) tended to overestimate the risk of failure when compared to alternative methods using the same endpoint definitions (methods 1b and 2a).The standard method was also associated with a 34% reduction in the number of patients evaluated compared to the number of patients enrolled.Use of survival analysis is the most appropriate way to estimate failure rates with parasitological recurrence classified as treatment failure on the day it occurs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Epicentre, Paris, France. elizabeth.ashley@epicentre.msf.org

ABSTRACT

Background: Use of different methods for assessing the efficacy of artemisinin-based combination antimalarial treatments (ACTs) will result in different estimates being reported, with implications for changes in treatment policy.

Methods: Data from different in vivo studies of ACT treatment of uncomplicated falciparum malaria were combined in a single database. Efficacy at day 28 corrected by PCR genotyping was estimated using four methods. In the first two methods, failure rates were calculated as proportions with either (1a) reinfections excluded from the analysis (standard WHO per-protocol analysis) or (1b) reinfections considered as treatment successes. In the second two methods, failure rates were estimated using the Kaplan-Meier product limit formula using either (2a) WHO (2001) definitions of failure, or (2b) failure defined using parasitological criteria only.

Results: Data analysed represented 2926 patients from 17 studies in nine African countries. Three ACTs were studied: artesunate-amodiaquine (AS+AQ, N = 1702), artesunate-sulphadoxine-pyrimethamine (AS+SP, N = 706) and artemether-lumefantrine (AL, N = 518).Using method (1a), the day 28 failure rates ranged from 0% to 39.3% for AS+AQ treatment, from 1.0% to 33.3% for AS+SP treatment and from 0% to 3.3% for AL treatment. The median [range] difference in point estimates between method 1a (reference) and the others were: (i) method 1b = 1.3% [0 to 24.8], (ii) method 2a = 1.1% [0 to 21.5], and (iii) method 2b = 0% [-38 to 19.3].The standard per-protocol method (1a) tended to overestimate the risk of failure when compared to alternative methods using the same endpoint definitions (methods 1b and 2a). It either overestimated or underestimated the risk when endpoints based on parasitological rather than clinical criteria were applied. The standard method was also associated with a 34% reduction in the number of patients evaluated compared to the number of patients enrolled. Only 2% of the sample size was lost when failures were classified on the first day of parasite recurrence and survival analytical methods were used.

Conclusion: The primary purpose of an in vivo study should be to provide a precise estimate of the risk of antimalarial treatment failure due to drug resistance. Use of survival analysis is the most appropriate way to estimate failure rates with parasitological recurrence classified as treatment failure on the day it occurs.

Show MeSH
Related in: MedlinePlus