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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

Maximum day 3 parasite positivity rate (PPR) possible for each of the treatment regimens for a given study sample size. Worst-case estimates were used for the analysis, that is, an upper limit of 95 % CI was assumed to be the true underlying parasite positivity rate on day 3, which was 0.82 %, 0.94 % and 1.42 % for AL, ASAQ-FDC and DP, respectively. The horizontal solid line represents 10 % day 3 WHO threshold and the dotted horizontal line represents 5 % day 3 PPR. The saw-tooth spikes are the result of rounding to the nearest whole number. ACT, artemisinin-based combination therapy; AL, artemether-lumefantrine; ASAQ-FDC, fixed dose combination; DP, dihydroartemisinin-piperaquine; PPR, parasite positivity rate
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Fig4: Maximum day 3 parasite positivity rate (PPR) possible for each of the treatment regimens for a given study sample size. Worst-case estimates were used for the analysis, that is, an upper limit of 95 % CI was assumed to be the true underlying parasite positivity rate on day 3, which was 0.82 %, 0.94 % and 1.42 % for AL, ASAQ-FDC and DP, respectively. The horizontal solid line represents 10 % day 3 WHO threshold and the dotted horizontal line represents 5 % day 3 PPR. The saw-tooth spikes are the result of rounding to the nearest whole number. ACT, artemisinin-based combination therapy; AL, artemether-lumefantrine; ASAQ-FDC, fixed dose combination; DP, dihydroartemisinin-piperaquine; PPR, parasite positivity rate

Mentions: The overall day 3 PPR was 0.58 % (95 % CI: 0.34–0.82) for AL, 0.54 % (95 % CI: 0.14–0.94) for ASAQ-FDC and 0.77 % (95 % CI: 0.11–1.42) for DP. In studies with a sample size greater than 50 patients, the observed PPR was unlikely to exceed 5 % positivity on day 3 (Fig. 4). However, in studies with fewer than 50 patients, the variance around the estimate was extremely wide, so a reliable estimate could not be derived (Table 6, Fig. 4).Fig. 4


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)

Maximum day 3 parasite positivity rate (PPR) possible for each of the treatment regimens for a given study sample size. Worst-case estimates were used for the analysis, that is, an upper limit of 95 % CI was assumed to be the true underlying parasite positivity rate on day 3, which was 0.82 %, 0.94 % and 1.42 % for AL, ASAQ-FDC and DP, respectively. The horizontal solid line represents 10 % day 3 WHO threshold and the dotted horizontal line represents 5 % day 3 PPR. The saw-tooth spikes are the result of rounding to the nearest whole number. ACT, artemisinin-based combination therapy; AL, artemether-lumefantrine; ASAQ-FDC, fixed dose combination; DP, dihydroartemisinin-piperaquine; PPR, parasite positivity rate
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Maximum day 3 parasite positivity rate (PPR) possible for each of the treatment regimens for a given study sample size. Worst-case estimates were used for the analysis, that is, an upper limit of 95 % CI was assumed to be the true underlying parasite positivity rate on day 3, which was 0.82 %, 0.94 % and 1.42 % for AL, ASAQ-FDC and DP, respectively. The horizontal solid line represents 10 % day 3 WHO threshold and the dotted horizontal line represents 5 % day 3 PPR. The saw-tooth spikes are the result of rounding to the nearest whole number. ACT, artemisinin-based combination therapy; AL, artemether-lumefantrine; ASAQ-FDC, fixed dose combination; DP, dihydroartemisinin-piperaquine; PPR, parasite positivity rate
Mentions: The overall day 3 PPR was 0.58 % (95 % CI: 0.34–0.82) for AL, 0.54 % (95 % CI: 0.14–0.94) for ASAQ-FDC and 0.77 % (95 % CI: 0.11–1.42) for DP. In studies with a sample size greater than 50 patients, the observed PPR was unlikely to exceed 5 % positivity on day 3 (Fig. 4). However, in studies with fewer than 50 patients, the variance around the estimate was extremely wide, so a reliable estimate could not be derived (Table 6, Fig. 4).Fig. 4

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