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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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Classification of efficacy endpoints (WHO, 2001).
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Figure 1: Classification of efficacy endpoints (WHO, 2001).

Mentions: Studies of antimalarial drug efficacy remain the primary source of evidence for treatment policy decisions. How these studies should be conducted and interpreted is still a subject for debate. Contentious methodological issues include length of follow-up after treatment, whether to use clinical or parasitological outcomes and which analytical methods are the most appropriate [1-4]. Study designs and data analysis vary; this makes combining and comparing data difficult. The World Health Organization (WHO) has made considerable efforts to standardize methods for the assessment of antimalarial drug efficacy over the last 40 years but these have changed several times, in line with the prevailing opinion at the time. The first in vivo test was developed in 1965 and was designed for the assessment of chloroquine efficacy against falciparum malaria using strictly defined parasitological end points. The protocol was revised in 1967 and 1972, with patients followed up for 28 days and kept in a mosquito-free environment to prevent re-infection. Subsequent modifications to the protocol in 1996 permitted a shorter length of follow-up of 14 days in areas of high transmission, where the main endpoint changed from parasitological clearance without subsequent recrudescence to adequate clinical response, i.e. a patient in whom parasites reappeared without symptoms was still regarded as 'cured'. In 2001, the length of follow-up was increased to 28 days in areas of intense transmission, if PCR genotyping was available, and the concept of late treatment failure incorporating clinical or parasitological failures was introduced. Asymptomatic patients with parasitological failure were followed from the day of reappearance to the last day of follow-up when they were treated if parasites were still present [5-7]. In a more recent document, 'Susceptibility of Plasmodium falciparum to antimalarial drugs', an update of the therapeutic efficacy test and modification of the protocol have been proposed with late parasitological failure defined as "presence of parasitaemia between day 7 and day 28 with temperature ‹37.5°C, without the patient previously meeting any of the criteria of early treatment failure or late clinical failure" [8]. Definitions of endpoints are summarized in Figure 1.


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)

Classification of efficacy endpoints (WHO, 2001).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Classification of efficacy endpoints (WHO, 2001).
Mentions: Studies of antimalarial drug efficacy remain the primary source of evidence for treatment policy decisions. How these studies should be conducted and interpreted is still a subject for debate. Contentious methodological issues include length of follow-up after treatment, whether to use clinical or parasitological outcomes and which analytical methods are the most appropriate [1-4]. Study designs and data analysis vary; this makes combining and comparing data difficult. The World Health Organization (WHO) has made considerable efforts to standardize methods for the assessment of antimalarial drug efficacy over the last 40 years but these have changed several times, in line with the prevailing opinion at the time. The first in vivo test was developed in 1965 and was designed for the assessment of chloroquine efficacy against falciparum malaria using strictly defined parasitological end points. The protocol was revised in 1967 and 1972, with patients followed up for 28 days and kept in a mosquito-free environment to prevent re-infection. Subsequent modifications to the protocol in 1996 permitted a shorter length of follow-up of 14 days in areas of high transmission, where the main endpoint changed from parasitological clearance without subsequent recrudescence to adequate clinical response, i.e. a patient in whom parasites reappeared without symptoms was still regarded as 'cured'. In 2001, the length of follow-up was increased to 28 days in areas of intense transmission, if PCR genotyping was available, and the concept of late treatment failure incorporating clinical or parasitological failures was introduced. Asymptomatic patients with parasitological failure were followed from the day of reappearance to the last day of follow-up when they were treated if parasites were still present [5-7]. In a more recent document, 'Susceptibility of Plasmodium falciparum to antimalarial drugs', an update of the therapeutic efficacy test and modification of the protocol have been proposed with late parasitological failure defined as "presence of parasitaemia between day 7 and day 28 with temperature ‹37.5°C, without the patient previously meeting any of the criteria of early treatment failure or late clinical failure" [8]. Definitions of endpoints are summarized in Figure 1.

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