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

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.

Fig. 1

Patient flowchart. AL, artemether-lumefantrine; AS-AQ, artesunate-amodiaquine; DP, dihydroartemisinin-piperaquine; IPD, individual participant data

Fig. 2

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

Fig. 3

Probability of remaining parasitaemic (%) on days 2 and 3 for a given baseline parasitaemia in areas with different levels of transmission for children from 1 to 5 years of age. The probability of remaining positive on a given day was generated using coefficients from the final multivariable logistic regression with random effects for study sites. Zero study site effect was assumed for generating the predicted risk. The difference in risk of positivity for low/moderate setting has been given as δ and associated 95 % confidence interval presented

Fig. 4

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