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Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient data.

- BMC Med (2015)

Bottom Line: Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin.Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08-1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 °C) (AOR = 1.50 (95 % CI: 1.06-2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21-3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38-5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14-4.51), P = 0.020, compared to dihydroartemisinin-piperaquine).A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs).

Methods: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data.

Results: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5-64.9) on day 1 to 6.7 % (95 % CI: 4.8-8.7) on day 2 and 0.9 % (95 % CI: 0.5-1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08-1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 °C) (AOR = 1.50 (95 % CI: 1.06-2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21-3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38-5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14-4.51), P = 0.020, compared to dihydroartemisinin-piperaquine).

Conclusions: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

No MeSH data available.


Related in: MedlinePlus

Parasite positivity rates (PPRs) on days 2 and 3 following treatment administration. Boxplot showing PPRs for each of the ACTs separately. Only studies with sample size >25 patients were considered for the plot. There were two study sites with day 3 PPR >10 %, both of these sites used the non-fixed presentations of AS-AQ. ACT, artemisinin-based combination therapy; AL, artemether-lumefantrine; AS-AQ, artesunate-amodiaquine; DP, dihydroartemisinin-piperaquine; PPR, parasite positivity rate
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Fig2: Parasite positivity rates (PPRs) on days 2 and 3 following treatment administration. Boxplot showing PPRs for each of the ACTs separately. Only studies with sample size >25 patients were considered for the plot. There were two study sites with day 3 PPR >10 %, both of these sites used the non-fixed presentations of AS-AQ. ACT, artemisinin-based combination therapy; AL, artemether-lumefantrine; AS-AQ, artesunate-amodiaquine; DP, dihydroartemisinin-piperaquine; PPR, parasite positivity rate

Mentions: The presence and density of parasites on day 1 could only be assessed in 55 % (16,196/29,493) of patients (52 studies). The overall parasite clearance rate for all studies was rapid. The PPR decreased from 59.7 % (95 % CI: 54.5–64.9) on day 1 (10,099/16,916) to 6.7 % (95 % CI: 4.8–8.7) on day 2 (1,853/27,496) and 0.9 % (95 % CI: 0.5–1.2) on day 3 (253/28,580). The PPRs on days 1, 2 and 3 were similar for AL, DP and ASAQ-FDC, but higher for the non-fixed formulations of AS-AQ on days 2 and 3 (Table 2). Compared to patients older than 12 years, children from 1 to 5 years had the highest PPR on day 1 (64 %, 6,430/10,053, P <0.001) and day 2 (7.5 %, 1,176/15,677, P <0.001), but there was no age-related difference on day 3. Patients with an initial parasite density >100,000 parasites/μl had a PPR of 82.7 % (1,494/1,807) on day 1, 14.3 % (385/2,696) on day 2 and 1.3 % (37/2,752) on day 3. The corresponding proportions for patients with parasitaemia less than 100,000 parasites/μl were 57.0 % (8,605/15,109), 5.9 % (1,468/24,800) and 0.8 % (216/25,828), respectively for days 1, 2 and 3 (all P <0.05). There were no regional differences or temporal trend in the PPRs on any days during the time period studied, that is, 1999–2012. A detailed summary of the PPRs for each of the treatment regimens stratified by country and calendar year is presented in Additional file 4. In total, there were 22 sites that had a PPR on day 3 exceeding 3 % (Table 3). The risk of day 3 parasitaemia exceeding 3 % was greatest in patients treated with ASAQ-loose NFDC (19.0 %, 8/42) and ASAQ-coblistered NFDC (11.1 %, 1/9) compared to 9.4 % (3/32) for AS-AQ FDC, 5.6 % (2/36) for DP and 7.6 % (8/105) for AL (Table 3). At two sites, the day 3 PPR was higher than 10 %: Miandrivazo, Madagascar, 2006 (n = 68, PPR = 10.3 %, ASAQ-loose NFDC) and Yaoundé, Cameroon, 2005 (n = 101, PPR = 30.1 %, ASAQ-coblistered NFDC) (Fig. 2).Table 2


Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient data.

- BMC Med (2015)

Parasite positivity rates (PPRs) on days 2 and 3 following treatment administration. Boxplot showing PPRs for each of the ACTs separately. Only studies with sample size >25 patients were considered for the plot. There were two study sites with day 3 PPR >10 %, both of these sites used the non-fixed presentations of AS-AQ. ACT, artemisinin-based combination therapy; AL, artemether-lumefantrine; AS-AQ, artesunate-amodiaquine; DP, dihydroartemisinin-piperaquine; PPR, parasite positivity rate
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4561425&req=5

Fig2: Parasite positivity rates (PPRs) on days 2 and 3 following treatment administration. Boxplot showing PPRs for each of the ACTs separately. Only studies with sample size >25 patients were considered for the plot. There were two study sites with day 3 PPR >10 %, both of these sites used the non-fixed presentations of AS-AQ. ACT, artemisinin-based combination therapy; AL, artemether-lumefantrine; AS-AQ, artesunate-amodiaquine; DP, dihydroartemisinin-piperaquine; PPR, parasite positivity rate
Mentions: The presence and density of parasites on day 1 could only be assessed in 55 % (16,196/29,493) of patients (52 studies). The overall parasite clearance rate for all studies was rapid. The PPR decreased from 59.7 % (95 % CI: 54.5–64.9) on day 1 (10,099/16,916) to 6.7 % (95 % CI: 4.8–8.7) on day 2 (1,853/27,496) and 0.9 % (95 % CI: 0.5–1.2) on day 3 (253/28,580). The PPRs on days 1, 2 and 3 were similar for AL, DP and ASAQ-FDC, but higher for the non-fixed formulations of AS-AQ on days 2 and 3 (Table 2). Compared to patients older than 12 years, children from 1 to 5 years had the highest PPR on day 1 (64 %, 6,430/10,053, P <0.001) and day 2 (7.5 %, 1,176/15,677, P <0.001), but there was no age-related difference on day 3. Patients with an initial parasite density >100,000 parasites/μl had a PPR of 82.7 % (1,494/1,807) on day 1, 14.3 % (385/2,696) on day 2 and 1.3 % (37/2,752) on day 3. The corresponding proportions for patients with parasitaemia less than 100,000 parasites/μl were 57.0 % (8,605/15,109), 5.9 % (1,468/24,800) and 0.8 % (216/25,828), respectively for days 1, 2 and 3 (all P <0.05). There were no regional differences or temporal trend in the PPRs on any days during the time period studied, that is, 1999–2012. A detailed summary of the PPRs for each of the treatment regimens stratified by country and calendar year is presented in Additional file 4. In total, there were 22 sites that had a PPR on day 3 exceeding 3 % (Table 3). The risk of day 3 parasitaemia exceeding 3 % was greatest in patients treated with ASAQ-loose NFDC (19.0 %, 8/42) and ASAQ-coblistered NFDC (11.1 %, 1/9) compared to 9.4 % (3/32) for AS-AQ FDC, 5.6 % (2/36) for DP and 7.6 % (8/105) for AL (Table 3). At two sites, the day 3 PPR was higher than 10 %: Miandrivazo, Madagascar, 2006 (n = 68, PPR = 10.3 %, ASAQ-loose NFDC) and Yaoundé, Cameroon, 2005 (n = 101, PPR = 30.1 %, ASAQ-coblistered NFDC) (Fig. 2).Table 2

Bottom Line: Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin.Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08-1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 °C) (AOR = 1.50 (95 % CI: 1.06-2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21-3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38-5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14-4.51), P = 0.020, compared to dihydroartemisinin-piperaquine).A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs).

Methods: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data.

Results: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5-64.9) on day 1 to 6.7 % (95 % CI: 4.8-8.7) on day 2 and 0.9 % (95 % CI: 0.5-1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08-1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 °C) (AOR = 1.50 (95 % CI: 1.06-2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21-3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38-5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14-4.51), P = 0.020, compared to dihydroartemisinin-piperaquine).

Conclusions: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

No MeSH data available.


Related in: MedlinePlus