106 research outputs found
Time to scale up molecular surveillance for anti-malarial drug resistance in sub-Saharan Africa
Artemisinin resistance has emerged and spread in the Greater Mekong Sub-region (GMS), followed by artemisinin-based combination therapy failure, due to both artemisinin and partner drug resistance. More worrying, artemisinin resistance has been recently reported and confirmed in Rwanda. Therefore, there is an urgent need to strengthen surveillance systems beyond the GMS to track the emergence or spread of artemisinin and partner drug resistance in other endemic settings. Currently, anti-malarial drug efficacy is monitored primarily through therapeutic efficacy studies (TES). Even though essential for anti-malarial drug policy change, these studies are difficult to conduct, expensive, and may not detect the early emergence of resistance. Additionally, results from TES may take years to be available to the stakeholders, jeopardizing their usefulness. Molecular markers are additional and useful tools to monitor anti-malarial drug resistance, as samples collected on dried blood spots are sufficient to monitor known and validated molecular markers of resistance, and could help detecting and monitoring the early emergence of resistance. However, molecular markers are not monitored systematically by national malaria control programmes, and are often assessed in research studies, but not in routine surveillance. The implementation of molecular markers as a routine tool for anti-malarial drug resistance surveillance could greatly improve surveillance of anti-malarial drug efficacy, making it possible to detect resistance before it translates to treatment failures. When possible, ex vivo assays should be included as their data could be useful complementary, especially when no molecular markers are validated
Strengthening surveillance systems for malaria elimination by integrating molecular and genomic data
Unprecedented efforts in malaria control over the last 15 years have led to a substantial decrease in both morbidity and mortality in most endemic settings. However, these progresses have stalled over recent years, and resurgence may cause dramatic impact on both morbidity and mortality. Nevertheless, elimination efforts are currently going on with the objective of reducing malaria morbidity and mortality by 90% and malaria elimination in at least 35 countries by 2030. Strengthening surveillance systems is of paramount importance to reach those targets, and the integration of molecular and genomic techniques into routine surveillance could substantially improve the quality and robustness of data. Techniques such as polymerase chain reaction (PCR) and quantitative PCR (qPCR) are increasingly available in malaria endemic countries, whereas others such as sequencing are already available in a few laboratories. However, sequencing, especially next-generation sequencing (NGS), requires sophisticated infrastructure with adequate computing power and highly trained personnel for data analysis that require substantial investment. Different techniques will be required for different applications, and cost-effective planning must ensure the appropriate use of available resources. The development of national and sub-regional reference laboratories could help in minimizing the resources required in terms of equipment and trained staff. Concerted efforts from different stakeholders at national, sub-regional, and global level are needed to develop the required framework to establish and maintain these reference laboratories
The use of insecticide-treated nets for reducing malaria morbidity among children aged 6-59 months, in an area of high malaria transmission in central Cote d'Ivoire
Background
Long-lasting insecticidal nets (LLINs) are an important tool for controlling malaria. Much attention has been devoted to determine both the effect of LLINs on the reduction of Plasmodium infection rate and clinically-confirmed malaria cases in sub-Saharan Africa. We carried out epidemiological analyses to investigate whether LLINs impact on Plasmodium prevalence rate and the proportion of clinically-confirmed malaria cases, in five villages in the district of Toumodi, central Cote d'Ivoire.
Methods
From April 2007 to November 2008, a community-based malaria control programme was implemented in the study villages, which involved large-scale distribution of LLINs, and training and sensitization activities within the community. We determined the effect of this programme on Plasmodium prevalence rate, clinically-confirmed malaria cases and parasitaemia rates in children aged 6-59 months through a series of cross-sectional surveys starting in April 2007 and repeated once every 6 months.
Results
We observed a significant decrease in the mean P. falciparum prevalence rate from April 2007 to April 2008 (p = 0.029). An opposite trend was observed from November 2007 to November 2008 when P. falciparum prevalence rate increased significantly (p = 0.003). Highly significant decreases in the proportions of clinical malaria cases were observed between April 2007 and April 2008 (p < 0.001), and between November 2007 and November 2008 (p = 0.001).
Conclusions
Large-scale distribution of LLINs, accompanied by training and sensitization activities, significantly reduced Plasmodium prevalence rates among young children in the first year of the project, whereas overall clinical malaria rates dropped over the entire 18-month project period. A decrease in community motivation to sleep under bed nets, perhaps along with changing patterns of malaria transmission, might explain the observed increase in the Plasmodium prevalence rate between November 2007 and November 2008
Efficacy of ICON® Maxx in the laboratory and against insecticide-resistant Anopheles gambiae in central Côte d'Ivoire
ABSTRACT: BACKGROUND: Long-lasting treatment kits, designed to transform untreated nets into long-lasting insecticidal nets (LLINs), may facilitate high coverage with LLINs where non-treated nets are in place. In this study, the efficacy of ICON(R) Maxx (Syngenta) was evaluated under laboratory conditions and in an experimental hut trial in central Cote d'Ivoire, where Anopheles gambiae s.s. are resistant to pyrethroid insecticides. METHODS: In the laboratory, polyester and polyethylene net samples were treated with ICON(R) Maxx, washed up to 20 times and their efficacy determined in World Health Organization (WHO) cone assays against a susceptible laboratory An. gambiae s.s. colony. Over a 12-month period, the polyester nets were evaluated in a hut trial to determine mosquito deterrence, induced exophily, blood-feeding inhibition and mortality. RESULTS: In the laboratory, ICON(R) Maxx-treated polyethylene nets showed higher efficacy against pyrethroid-susceptible mosquitoes than polyester nets. After 20 washings, insecticidal efficacy in bioassays was 59.4% knockdown (KD) and 22.3% mortality for polyethylene, and 55.3% KD and 17.9% mortality for polyester nets. In experimental huts, treated nets showed strong deterrence, induced exophily and an over three-fold reduction in blood-fed mosquitoes. More than half (61.8%) of the mosquitoes entering the huts with treated nets were found dead the next morning despite high levels of KD resistance. After washing the treated nets, KD and mortality rates were close to or exceeded predefined WHO thresholds in cone bioassays. CONCLUSION: In contrast to previous laboratory investigation, ICON(R) Maxx-treated nets showed only moderate KD and mortality rates. However, under semi-field conditions, in an area where mosquitoes are resistant to pyrethroids, ICON(R) Maxx showed high deterrence, induced exophily and provided a significant reduction in blood-feeding rates; features that are likely to have a positive impact in reducing malaria transmission. The WHO cone test may not always be a good proxy for predicting product performance under field condition
Quantifying the Evolution and Impact of Antimalarial Drug Resistance: Drug Use, Spread of Resistance, and Drug Failure over a 12-Year Period in Papua New Guinea
Background. Antimalarial use is a key factor driving drug resistance and reduced treatment effectiveness in Plasmodium falciparum malaria, but there are few formal, quantitative analyses of this process. Methods. We analyzed drug usage, drug failure rates, and the frequencies of mutations and haplotypes known to be associated with drug resistance over a 12-year period (1991-2002) in a site in Papua New Guinea. This period included 2 successive treatment policies: amodiaquine (AQ) or chloroquine (CQ) from 1991 through 2000 and their subsequent replacement by sulfadoxine-pyrimethamine (SP) plus AQ or SP plus CQ. Results. Drug use approximated 1 treatment per person-year and was associated with increasing frequencies of pfcrt and pfmdr1 mutations and of treatment failure. The frequency of pfdhfr mutations also increased, especially after the change in treatment policy. Treatment failure rates multiplied by 3.5 between 1996 and 2000 but then decreased dramatically after treatment policy change. Conclusions. With high levels of resistance to CQ, AQ, and SP, the deployment of the combination of both drugs appears to increase clinical effectiveness but does not decelerate growth of resistance. Our estimates of mutation and haplotype frequencies provide estimates of selection coefficients acting in this environment, which are key parameters for understanding the dynamics of resistanc
Molecular assays for antimalarial drug resistance surveillance: A target product profile.
Antimalarial drug resistance is a major constraint for malaria control and elimination efforts. Artemisinin-based combination therapy is now the mainstay for malaria treatment. However, delayed parasite clearance following treatment with artemisinin derivatives has now spread in the Greater Mekong Sub region and may emerge or spread to other malaria endemic regions. This spread is of great concern for malaria control programmes, as no alternatives to artemisinin-based combination therapies are expected to be available in the near future. There is a need to strengthen surveillance systems for early detection and response to the antimalarial drug resistance threat. Current surveillance is mainly done through therapeutic efficacy studies; however these studies are complex and both time- and resource-intensive. For multiple common antimalarials, parasite drug resistance has been correlated with specific genetic mutations, and the molecular markers associated with antimalarial drug resistance offer a simple and powerful tool to monitor the emergence and spread of resistant parasites. Different techniques to analyse molecular markers associated with antimalarial drug resistance are available, each with advantages and disadvantages. However, procedures are not adequately harmonized to facilitate comparisons between sites. Here we describe the target product profiles for tests to analyse molecular markers associated with antimalarial drug resistance, discuss how use of current techniques can be standardised, and identify the requirements for an ideal product that would allow malaria endemic countries to provide useful spatial and temporal information on the spread of resistance
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.
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 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
Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine.
Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine
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