Randomized Trial of Artesunate-Amodiaquine, Atovaquone-Proguanil, and Artesunate-Atovaquone-Proguanil for the Treatment of Uncomplicated Falciparum Malaria in Children

Tahar, Rachida; Almelli, Talleh; Debue, Camille; Ngane, Vincent Foumane; Allico, Joseph Djaman; Youdom, Solange Whegang; Basco, Léonardo K.

doi:10.1093/infdis/jiu341

Cited by 26 publications

(20 citation statements)

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“…In Miandrivazo (Madagascar), the reported PPR was 10.3 % in 2006 [ 51 ] but less than 1 % in a subsequent trial in the same region (Tsiroanomandidy) [ 52 ]. In Yaoundé, a PPR of 30 % was reported in 2005 [ 53 ]; however, in a study conducted at the same site 7 years later [ 54 ], the PPR was 2.9 % (95 % CI: 3.7–27.2, 2/68) suggesting that the high PPR observed in our dataset could have been an artefact. High day 3 PPR does not necessarily relate to a change in parasite susceptibility to artemisinin; other factors, such as declining immunity [ 55 ], poor drug quality [ 56 ] and variable quality of microscopy [ 57 ] can play major roles.…”

Section: Discussioncontrasting

confidence: 62%

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

2015

BMC Med

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BackgroundArtemisinin-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).MethodsA 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.ResultsIn 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).ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0445-x) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 62%

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

2015

BMC Med

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“…ASAQCPH resulted in a better haematological recovery and higher cure rates, as compared to ASAQ and AL in Nigeria [ 65 ]. The combination ASATPG was highly effective in Cameroonian young children [ 66 ]. ASNAPH is available in Africa and is recommended for use as a single-dose regimen by the manufacturer [ 31 , 67 ].…”

Section: Discussionmentioning

confidence: 99%

Comparison of anti-malarial drug efficacy in the treatment of uncomplicated malaria in African children and adults using network meta-analysis

Youdom

Tahar

Basco

2017

Malar J

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Background: Artemisinin-based combination therapy (ACT) and novel drug combinations are available and used in African countries to treat uncomplicated malaria. Network meta-analysis methods are rarely and poorly applied for the comparison of their efficacies. This method was applied on a set of randomized controlled trials to illustrate its usefulness. Methods:A literature review available in Pubmed was conducted in July 2016. Eligible studies, conducted in subSaharan Africa, published between 2002 and 2016, focused on randomized controlled trials of at least two artemisinin-based combinations to treat uncomplicated malaria in children and adults. Agglomerate data were: the number of PCR-corrected adequate clinical and parasitological response (ACPR) on day 28, used as the primary endpoint in all interventions, the number of participants and the list of treatments. A Bayesian random effect meta-analysis using a binary outcome was the method to compare the efficacy. Ranking measure was used to obtain a hierarchy of the competing interventions. Results:In total, 76 articles were included; 13 treatment regimens were involved and tested in 36,001 patients. Using artemether-lumefantrine (AL) as the common comparator for the entire network, 12 relative treatment effects were estimated and indirect comparisons were obtained. Dihydroartemisinin-piperaquine (DHAP) was shown to be more effective than AL (odds ratio [OR] = 1.92; 95% CI 1.30-2.82; 19,163 patients), ASAQ (OR = 1.70; 95% CI 1.10-2.64; 14,433 patients), and amodiaquine-sulfadoxine-pyrimethamine (AQSP): OR = 2.20; 95% CI 1.21-3.96; 8863 patients. Artesunate-amodiaquine (ASAQ) was comparable to AL (OR = 1.11; 95% CI 0.84-1.45; 21,235 patients). No significant difference was found between artesunate and mefloquine (ASMQ) and AL (OR = 1.20; 95% CI = 0.52-2.8; 13,824 participants). According to treatment ranking, among the WHO-recommended ACT medicines, DHAP was shown to be the most efficacious. Conclusions: Based on the available evidence, this study demonstrated the superiority of DHAP among currently recommended artemisinin-based combinations. The application of the methods described here may be helpful to gain better understanding of treatment efficacy and improve future decisions. However, more data are needed to allow robust conclusions about the results in comparison with novel drugs. Further surveillance of the efficacy of anti-malarial drugs and clinical trials are needed to closely follow the evolution of the epidemiology of drug-resistant malaria in Africa.

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“…The indicator for treatment success was adequate clinical and parasitological response (ACPR). ACPR was de ned as absence of parasitaemia by the end of treatment (days 14, 28, 42, 63) irrespective of axillary temperature without previously meeting any of the criteria for early treatment failure or late clinical failure or late parasitological failure (17)(18)(19)(20). The treatment success was de ned based on PCR genotyping according to current World Health Organisation (WHO) recommendation.…”

Section: Assessment Of Treatment Outcomesmentioning

confidence: 99%

“…A total of 39 studies from 16 records with the same or different ACTs ful lled the inclusion criteria and were included in this systematic review and meta-analysis with a total sample size of 3,747 participants that ranged from a minimum of 48 patients [22] to a maximum of 255 patients [30]. Treatment outcomes in all studies were evaluated by adopting clinical and parasitological criteria based on WHO guidelines [17][18][19][20].…”

Section: Qualitative Synthesismentioning

confidence: 99%

Clinical Efficacy and Safety of Artemisinin-based Combination Therapies in the Treatment of Uncomplicated Plasmodium Falciparum Malaria in Cameroon: A Systematic Review and Meta-Analysis from Individual Patient Data (2004-2020)

Nji¹,

Niba²,

Netongo³

et al. 2020

Preprint

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Background: Cameroon remains a high malaria endemic country. The rapid emergence and spread of Plasmodium falciparum resistant parasites compelled the World Health Organisation (WHO) to recommend the change from monotherapies to artemisinin-based combination therapies (ACTs). This study aimed to assess the clinical efficacy and safety of artemisinin-based combination therapies in the treatment of uncomplicated Plasmodium falciparum malaria in Cameroon from 2004 to 2020.Methods: The preferred reporting items for systematic review and meta-analysis (PRISMA) statement were adopted for the selection of studies. The heterogeneity of the included studies was determined using Cochrane Q and the I2. The random effects model was used as standard to combine studies showing heterogeneity of Cochrane Q with P < 0.10 and I2 > 50.Results: Out of the 4,920 articles and unpublished datasets screened, 16 records with a sample size of 3,737 participants on 8 generic ACTs fulfilled the inclusion criteria. The per protocol (PP) analysis pooled efficacy of the ACTs was 97.9 % (95 % CI, 97.2-98.7, P<0.01). Sub-group analyses were performed for ASAQ, AL and DHAP. The aggregated efficacies of ASAQ, AL and DHAP were 97.5 % (95 % CI, 96.3-98.8, P<0.01), 99.4 % (95 % CI, 98.6-100.0, P=0.39), 98.0 % (95 % CI, 96.3-99.7, P=0.28) respectively. The pooled efficacies were above the WHO minimum benchmark of 90.0%. The ACTs are well tolerated and common adverse events reported were asthenia, diarrhoea, abdominal pain, anorexia, nausea and vomiting, headache and dizziness.Conclusion: This study reported a high pooled efficacy for all ACTs. AL and DHAP were found to have higher cumulative efficacies than ASAQ. The ACTs are still efficacious and well tolerated for the treatment of malaria in Cameroon. However, there is need for continuous monitoring of efficacy of ACTs despite the high cure rates as resistance seems inevitable.

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Randomized Trial of Artesunate-Amodiaquine, Atovaquone-Proguanil, and Artesunate-Atovaquone-Proguanil for the Treatment of Uncomplicated Falciparum Malaria in Children

Abstract: UMIN000003813.

Cited by 26 publications

References 43 publications

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

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

Comparison of anti-malarial drug efficacy in the treatment of uncomplicated malaria in African children and adults using network meta-analysis

Clinical Efficacy and Safety of Artemisinin-based Combination Therapies in the Treatment of Uncomplicated Plasmodium Falciparum Malaria in Cameroon: A Systematic Review and Meta-Analysis from Individual Patient Data (2004-2020)

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