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Early parasitological response following artemisinin-containing regimens: a critical review of the literature.

Das D, Price RN, Bethell D, Guerin PJ, Stepniewska K - Malar. J. (2013)

Bottom Line: Comparing studies from 2000 to 2005 and 2006 to 2011, the median proportion of patients reported to remain parasitaemic at 72 hours decreased in Africa (1.2% vs 0%, p=0.007), but increased in Asia (0.4% vs 3.9%, p=0.076).These results highlight the normal distribution of early parasitological responses following ACT, and the influence that heterogeneity in study design, host and parasite factors have in confounding a surveillance system based on Day 3 parasite positivity.Greater understanding of factors influencing parasite clearance is crucial, but will require analysis of pooled data from individual patient records.

View Article: PubMed Central - HTML - PubMed

Affiliation: WorldWide Antimalarial Resistance Network, Oxford, UK.

ABSTRACT

Background: Parasitaemia on Day 3 has been proposed as a useful alert of potential artemisinin resistance, however, the normal variation of parasite clearance observed in artemisinin-based combination therapy clinical trials is poorly documented.

Methods: The trends in early parasitological response following treatment with an artemisinin anti-malarial regimen were reviewed. A PubMed literature search identified all studies using an artemisinin regimen for uncomplicated falciparum malaria published between January 2000 and December 2011. Data from clinical studies were extracted for analysis using a standardized questionnaire.

Results: In total 65,078 patients were enrolled into 213 clinical trials with 413 treatment arms containing either an artemisinin derivative alone (n=26) or in combination with a partner drug (n=387). The proportion of patients remaining parasitaemic at 24, 48 and 72 hours was documented in 115 (28%), 167 (40%) and 153 (37%) treatment arms, respectively. Excluding resistance studies in Cambodia, the median proportion of patients still parasitaemic was 53.8% [range 3-95, IQR=30.5-69.2] on Day 1, 6% [range 0-65.9, IQR=2-11.5] on Day 2 and 0 [range 0-12.6, IQR=0-2] on Day 3. Comparing studies from 2000 to 2005 and 2006 to 2011, the median proportion of patients reported to remain parasitaemic at 72 hours decreased in Africa (1.2% vs 0%, p=0.007), but increased in Asia (0.4% vs 3.9%, p=0.076). In 95% of studies the proportion of patients with peripheral parasitaemia was less than 6% at 72 hours.

Conclusions: These results highlight the normal distribution of early parasitological responses following ACT, and the influence that heterogeneity in study design, host and parasite factors have in confounding a surveillance system based on Day 3 parasite positivity. Greater understanding of factors influencing parasite clearance is crucial, but will require analysis of pooled data from individual patient records.

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Temporal trends in publication of anti-malarial clinical trials with an artemisinin-based combination therapy.
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Figure 2: Temporal trends in publication of anti-malarial clinical trials with an artemisinin-based combination therapy.

Mentions: Between January 2000 and December 2011, 213 clinical trials were identified in which a total of 65,078 patients with uncomplicated falciparum malaria were enrolled into 413 treatment arms containing an artemisinin derivative (Figure 1). The median sample size per treatment arm was 110 (range 10–1,475), with most of the data derived from comparative drug trials (189, 89%), of which 177 (83%) were randomized trials. The remaining 24 (11%) studies were single-arm studies. The number of trials published annually increased during the study period from five publications in 2000 to a peak of 28 in 2009, although numbers declined thereafter (Figure 2). Overall 37,192 (57%) patients had P. falciparum mono-infection and 7,908 (12%) had mixed infections on admission. The remaining 19,978 patients were enrolled in studies in which parasite species was not stated; these were mostly conducted in Africa. Follow up was continued for 28 days in 134 (63%) studies, with 50 (24%) extending to 42 days, and 10 (5%) up to 63 days. The proportion of trials with at least 42 days of follow up rose from 20% (15/74) in the period between 2000 and 2005 to 36% (49/138) between 2006 and 2011; p=0.027. The most frequent treatment regimens reported were: artemether-lumefantrine (AL, in 96 treatment arms), artesunate-mefloquine (AS+MQ, N=75), artesunate-amodiaquine (AS+AQ, N=74), artesunate-sulphadoxine-pyrimethamine (AS+SP, N=43), and dihydroartemisinin-piperaquine (DHA+PIP, N=40). In 26 treatment arms, patients received monotherapy only, including either artesunate (N=17), dihydroartemisinin (N=1), artemisinin (N=3), beta-artemether (N=2) and arterolane (N=3). Treatment was supervised completely in 362 (90%) and partially in 30 (7.5%) of the 402 studies in which it this was documented.


Early parasitological response following artemisinin-containing regimens: a critical review of the literature.

Das D, Price RN, Bethell D, Guerin PJ, Stepniewska K - Malar. J. (2013)

Temporal trends in publication of anti-malarial clinical trials with an artemisinin-based combination therapy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3649884&req=5

Figure 2: Temporal trends in publication of anti-malarial clinical trials with an artemisinin-based combination therapy.
Mentions: Between January 2000 and December 2011, 213 clinical trials were identified in which a total of 65,078 patients with uncomplicated falciparum malaria were enrolled into 413 treatment arms containing an artemisinin derivative (Figure 1). The median sample size per treatment arm was 110 (range 10–1,475), with most of the data derived from comparative drug trials (189, 89%), of which 177 (83%) were randomized trials. The remaining 24 (11%) studies were single-arm studies. The number of trials published annually increased during the study period from five publications in 2000 to a peak of 28 in 2009, although numbers declined thereafter (Figure 2). Overall 37,192 (57%) patients had P. falciparum mono-infection and 7,908 (12%) had mixed infections on admission. The remaining 19,978 patients were enrolled in studies in which parasite species was not stated; these were mostly conducted in Africa. Follow up was continued for 28 days in 134 (63%) studies, with 50 (24%) extending to 42 days, and 10 (5%) up to 63 days. The proportion of trials with at least 42 days of follow up rose from 20% (15/74) in the period between 2000 and 2005 to 36% (49/138) between 2006 and 2011; p=0.027. The most frequent treatment regimens reported were: artemether-lumefantrine (AL, in 96 treatment arms), artesunate-mefloquine (AS+MQ, N=75), artesunate-amodiaquine (AS+AQ, N=74), artesunate-sulphadoxine-pyrimethamine (AS+SP, N=43), and dihydroartemisinin-piperaquine (DHA+PIP, N=40). In 26 treatment arms, patients received monotherapy only, including either artesunate (N=17), dihydroartemisinin (N=1), artemisinin (N=3), beta-artemether (N=2) and arterolane (N=3). Treatment was supervised completely in 362 (90%) and partially in 30 (7.5%) of the 402 studies in which it this was documented.

Bottom Line: Comparing studies from 2000 to 2005 and 2006 to 2011, the median proportion of patients reported to remain parasitaemic at 72 hours decreased in Africa (1.2% vs 0%, p=0.007), but increased in Asia (0.4% vs 3.9%, p=0.076).These results highlight the normal distribution of early parasitological responses following ACT, and the influence that heterogeneity in study design, host and parasite factors have in confounding a surveillance system based on Day 3 parasite positivity.Greater understanding of factors influencing parasite clearance is crucial, but will require analysis of pooled data from individual patient records.

View Article: PubMed Central - HTML - PubMed

Affiliation: WorldWide Antimalarial Resistance Network, Oxford, UK.

ABSTRACT

Background: Parasitaemia on Day 3 has been proposed as a useful alert of potential artemisinin resistance, however, the normal variation of parasite clearance observed in artemisinin-based combination therapy clinical trials is poorly documented.

Methods: The trends in early parasitological response following treatment with an artemisinin anti-malarial regimen were reviewed. A PubMed literature search identified all studies using an artemisinin regimen for uncomplicated falciparum malaria published between January 2000 and December 2011. Data from clinical studies were extracted for analysis using a standardized questionnaire.

Results: In total 65,078 patients were enrolled into 213 clinical trials with 413 treatment arms containing either an artemisinin derivative alone (n=26) or in combination with a partner drug (n=387). The proportion of patients remaining parasitaemic at 24, 48 and 72 hours was documented in 115 (28%), 167 (40%) and 153 (37%) treatment arms, respectively. Excluding resistance studies in Cambodia, the median proportion of patients still parasitaemic was 53.8% [range 3-95, IQR=30.5-69.2] on Day 1, 6% [range 0-65.9, IQR=2-11.5] on Day 2 and 0 [range 0-12.6, IQR=0-2] on Day 3. Comparing studies from 2000 to 2005 and 2006 to 2011, the median proportion of patients reported to remain parasitaemic at 72 hours decreased in Africa (1.2% vs 0%, p=0.007), but increased in Asia (0.4% vs 3.9%, p=0.076). In 95% of studies the proportion of patients with peripheral parasitaemia was less than 6% at 72 hours.

Conclusions: These results highlight the normal distribution of early parasitological responses following ACT, and the influence that heterogeneity in study design, host and parasite factors have in confounding a surveillance system based on Day 3 parasite positivity. Greater understanding of factors influencing parasite clearance is crucial, but will require analysis of pooled data from individual patient records.

Show MeSH
Related in: MedlinePlus