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Journal articleWatson O, Slater HC, Verity R, et al., 2017,
Modelling the drivers of the spread of Plasmodium falciparum hrp2 gene deletions in sub-Saharan Africa
, eLife, Vol: 6, ISSN: 2050-084XRapid diagnostic tests (RDTs) have transformed malaria diagnosis. The most prevalent P. falciparum RDTs detect histidine-rich protein 2 (PfHRP2). However, pfhrp2 gene deletions yielding false-negative RDTs, first reported in South America in 2010, have been confirmed in Africa and Asia. We developed a mathematical model to explore the potential for RDT-led diagnosis to drive selection of pfhrp2-deleted parasites. Low malaria prevalence and high frequencies of people seeking treatment resulted in the greatest selection pressure. Calibrating our model against confirmed pfhrp2-deletions in the Democratic Republic of Congo, we estimate a starting frequency of 6% pfhrp2-deletion prior to RDT introduction. Furthermore, the patterns observed necessitate a degree of selection driven by the introduction of PfHRP2-based RDT-guided treatment. Combining this with parasite prevalence and treatment coverage estimates, we map the model-predicted spread of pfhrp2-deletion, and identify the geographic regions in which surveillance for pfhrp2-deletion should be prioritised.
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Journal articleBretscher MT, Griffin JT, Ghani AC, et al., 2017,
Modelling the benefits of long-acting or transmission-blocking drugs for reducing Plasmodium falciparum transmission by case management or by mass treatment
, MALARIA JOURNAL, Vol: 16, ISSN: 1475-2875BackgroundAnti-malarial drugs are an important tool for malaria control and elimination. Alongside their direct benefit in the treatment of disease, drug use has a community-level effect, clearing the reservoir of infection and reducing onward transmission of the parasite. Different compounds potentially have different impacts on transmission—with some providing periods of prolonged chemoprophylaxis whilst others have greater transmission-blocking potential. The aim was to quantify the relative benefit of such properties for transmission reduction to inform target product profiles in the drug development process and choice of first-line anti-malarial treatment in different endemic settings.MethodsA mathematical model of Plasmodium falciparum epidemiology was used to estimate the transmission reduction that can be achieved by using drugs of varying chemoprophylactic (protection for 3, 30 or 60 days) or transmission-blocking activity (blocking 79, 92 or 100% of total onward transmission). Simulations were conducted at low, medium or high transmission intensity (slide-prevalence in 2–10 year olds being 1, 10 or 40%, respectively), with drugs administered either via case management or mass drug administration (MDA).ResultsTransmission reductions depend strongly on deployment strategy, treatment coverage and endemicity level. Transmission-blocking was most effective at low endemicity, whereas chemoprophylaxis was most useful at high endemicity levels. Increasing the duration of protection as much as possible was beneficial. Increasing transmission-blocking activity from the level of ACT to a 100% transmission-blocking drug (close to the effect estimated for ACT combined with primaquine) produced moderate impact but was not as effective as increasing the duration of protection in medium-to-high transmission settings (slide prevalence 10–40%). Combining both good transmission-blocking activity (e.g. as achieved by ACT or ACT + primaquine) and a long durat
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Journal articleOkell L, Griffin JT, Roper C, 2017,
Mapping sulphadoxine-pyrimethamine-resistant Plasmodium falciparum malaria in infected humans and in parasite populations in Africa
, Scientific Reports, Vol: 7, ISSN: 2045-2322Intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine in vulnerable populations reduces malaria morbidity in Africa, but resistance mutations in the parasite dhps gene (combined with dhfr mutations) threaten its efficacy. We update a systematic review to map the prevalence of K540E and A581G mutations in 294 surveys of infected humans across Africa from 2004-present. Interpreting these data is complicated by multiclonal infections in humans, especially in high transmission areas. We extend statistical methods to estimate the frequency, i.e. the proportion of resistant clones in the parasite population at each location, and so standardise for varying transmission levels. Both K540E and A581G mutations increased in prevalence and frequency in 60% of areas after 2008, highlighting the need for ongoing surveillance. Resistance measures within countries were similar within 300 km, suggesting an appropriate spatial scale for surveillance. Spread of the mutations tended to accelerate once their prevalence exceeded 10% (prior to fixation). Frequencies of resistance in parasite populations are the same or lower than prevalence in humans, so more areas would be classified as likely to benefit from IPT if similar frequency thresholds were applied. We propose that the use of resistance frequencies as well as prevalence measures for policy decisions should be evaluated.
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Journal articlePatouillard E, Ghani ACH, Bhatt S, et al., 2017,
Global investment targets for malaria control and elimination between 2016 and 2030
, BMJ Global Health, Vol: 2, ISSN: 2059-7908Background Access to malaria control interventions falls short of universal health coverage. The Global Technical Strategy for malaria targets at least 90% reduction in case incidence and mortality rates, and elimination in 35 countries by 2030. The potential to reach these targets will be determined in part by investments in malaria. This study estimates the financing required for malaria control and elimination over the 2016–2030 period.Methods A mathematical transmission model was used to explore the impact of increasing intervention coverage on burden and costs. The cost analysis took a public provider perspective covering all 97 malaria endemic countries and territories in 2015. All control interventions currently recommended by the WHO were considered. Cost data were sourced from procurement databases, the peer-reviewed literature, national malaria strategic plans, the WHO-CHOICE project and key informant interviews.Results Annual investments of $6.4 billion (95% uncertainty interval (UI $4.5–$9.0 billion)) by 2020, $7.7 billion (95% UI $5.4–$10.9 billion) by 2025 and $8.7 billion (95% UI $6.0–$12.3 billion) by 2030 will be required to reach the targets set in the Global Technical Strategy. These are equivalent to annual investment per person at risk of malaria of US$3.90 by 2020, US$4.30 by 2025 and US$4.40 by 2030, compared with US$2.30 if interventions were sustained at current coverage levels. The 20 countries with the highest burden in 2015 will require 88% of the total investment.Conclusions Given the challenges in increasing domestic and international funding, the efficient use of currently available resources should be a priority
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Journal articleBrady OJ, Slater HC, Pemberton-Ross P, et al., 2017,
Role of mass drug administration in elimination of Plasmodium falciparum malaria: a consensus modelling study
, The Lancet Global Health, Vol: 5, Pages: E680-E687, ISSN: 2214-109XBackgroundMass drug administration for elimination of Plasmodium falciparum malaria is recommended by WHO in some settings. We used consensus modelling to understand how to optimise the effects of mass drug administration in areas with low malaria transmission.MethodsWe collaborated with researchers doing field trials to establish a standard intervention scenario and standard transmission setting, and we input these parameters into four previously published models. We then varied the number of rounds of mass drug administration, coverage, duration, timing, importation of infection, and pre-administration transmission levels. The outcome of interest was the percentage reduction in annual mean prevalence of P falciparum parasite rate as measured by PCR in the third year after the final round of mass drug administration.FindingsThe models predicted differing magnitude of the effects of mass drug administration, but consensus answers were reached for several factors. Mass drug administration was predicted to reduce transmission over a longer timescale than accounted for by the prophylactic effect alone. Percentage reduction in transmission was predicted to be higher and last longer at lower baseline transmission levels. Reduction in transmission resulting from mass drug administration was predicted to be temporary, and in the absence of scale-up of other interventions, such as vector control, transmission would return to pre-administration levels. The proportion of the population treated in a year was a key determinant of simulated effectiveness, irrespective of whether people are treated through high coverage in a single round or new individuals are reached by implementation of several rounds. Mass drug administration was predicted to be more effective if continued over 2 years rather than 1 year, and if done at the time of year when transmission is lowest.InterpretationMass drug administration has the potential to reduce transmission for a limited time, but is not an
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Journal articleWinskill P, Walker P, Griffin J, et al., 2017,
Modelling the cost-effectiveness of introducing the RTS,S malaria vaccine relative to scaling up other malaria interventions in sub-Saharan Africa
, BMJ Global Health, Vol: 2, ISSN: 2059-7908Objectives: To evaluate the relative cost-effectiveness of introducing the RTS,S malaria vaccine in sub-Saharan Africa compared with further scale-up of existing interventions.Design: A mathematical modelling and cost-effectiveness study.Setting: Sub-Saharan Africa.Participants: People of all ages.Interventions: The analysis considers the introduction and scale-up of the RTS,S malaria vaccine and the scale-up of long lasting insecticide treated bed nets (LLINs), indoor residual spraying (IRS) and seasonal malaria chemoprevention (SMC).Main outcome measure: The number of Plasmodium falciparum cases averted in all age groups over a ten year period.Results: Assuming access to treatment remains constant, increasing coverage of LLINs was consistently the most cost-effective intervention across a range of transmission settings and was found to occur early in the cost-effectiveness scale-up pathway. IRS, RTS,S and SMC entered the cost-effective pathway once LLIN coverage had been maximised. If non-linear production functions are included to capture the cost of reaching very high coverage, the resulting pathways become more complex and result in selection of multiple interventions.Conclusions: RTS,S was consistently implemented later in the cost-effectiveness pathway than the LLINs, IRS and SMC but was still of value as a fourth intervention in many settings to reduce burden to the levels set out in the international goals.
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Journal articleOkell LC, Churcher TS, 2016,
Generating the evidence base for malaria elimination: the situation in Haiti
, Lancet Global Health, Vol: 5, Pages: e16-e17, ISSN: 2214-109X -
Journal articleParr JB, Verity R, Doctor SM, et al., 2016,
Pfhrp2-deleted Plasmodium falciparum parasites in the Democratic Republic of the Congo: a national cross-sectional survey
, Journal of Infectious Diseases, Vol: 216, Pages: 36-44, ISSN: 0022-1899Background.Rapid diagnostic tests (RDTs) account for more than two-thirds of malaria diagnoses in Africa. Deletions of the Plasmodium falciparum hrp2 (pfhrp2) gene cause false-negative RDT results and have never been investigated on a national level. Spread of pfhrp2-deleted P. falciparum mutants, resistant to detection by HRP2-based RDTs, would represent a serious threat to malaria elimination efforts.Methods.Using a nationally representative cross-sectional study of 7,137 children under five years of age from the Democratic Republic of Congo (DRC), we tested 783 subjects with RDT-/PCR+ results using PCR assays to detect and confirm deletions of the pfhrp2 gene. Spatial and population genetic analyses were employed to examine the distribution and evolution of these parasites.Results.We identified 149 pfhrp2-deleted parasites, representing 6.4% of all P. falciparum infections country-wide (95% confidence interval 5.1–8.0%). Bayesian spatial analyses identified statistically significant clustering of pfhrp2 deletions near Kinshasa and Kivu. Population genetic analysis revealed significant genetic differentiation between wild-type and pfhrp2-deleted parasite populations (GST = .046, p ≤ .00001).Conclusions.Pfhrp2-deleted P. falciparum is a common cause of RDT-/PCR+ malaria among asymptomatic children in the DRC and appears to be clustered within select communities. Surveillance for these deletions is needed, and alternatives to HRP2-specific RDTs may be necessary.
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Journal articleSlater HC, Okell LC, Ghani AC, 2016,
Mathematical Modelling to Guide Drug Development for Malaria Elimination
, Trends in Parasitology, Vol: 33, Pages: 175-184, ISSN: 1471-5007Mathematical models of the dynamics of a drug within the host are now frequently used to guide drug development. These generally focus on assessing the efficacy and duration of response to guide patient therapy. Increasingly, antimalarial drugs are used at the population level, to clear infections, provide chemoprevention, and to reduce onward transmission of infection. However, there is less clarity on the extent to which different drug properties are important for these different uses. In addition, the emergence of drug resistance poses new threats to longer-term use and highlights the need for rational drug development. Here, we argue that integrating within-host pharmacokinetic and pharmacodynamic (PK/PD) models with mathematical models for the population-level transmission of malaria is key to guiding optimal drug design to aid malaria elimination.
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Journal articleWalker PG, Griffin JT, Ferguson NM, et al., 2016,
Estimating the most efficient allocation of interventions to achieve reductions in Plasmodium falciparum malaria burden and transmission in Africa: a modelling study
, Lancet Global Health, Vol: 4, Pages: e474-e484, ISSN: 2214-109XBACKGROUND: Reducing the burden of malaria is a global priority, but financial constraints mean that available resources must be allocated rationally to maximise their effect. We aimed to develop a model to estimate the most efficient (ie, minimum cost) ordering of interventions to reduce malaria burden and transmission. We also aimed to estimate the efficiency of different spatial scales of implementation. METHODS: We combined a dynamic model capturing heterogeneity in malaria transmission across Africa with financial unit cost data for key malaria interventions. We combined estimates of patterns of malaria endemicity, seasonality in rainfall, and mosquito composition to map optimum packages of these interventions across Africa. Using non-linear optimisation methods, we examined how these optimum packages vary when control measures are deployed and assessed at national, subnational first administrative (provincial), or fine-scale (5 km(2) pixel) spatial scales. FINDINGS: The most efficient package in a given setting varies depending on whether disease reduction or elimination is the target. Long-lasting insecticide-treated nets are generally the most cost-effective first intervention to achieve either goal, with seasonal malaria chemoprevention or indoor residual spraying added second depending on seasonality and vector species. These interventions are estimated to reduce malaria transmission to less than one case per 1000 people per year in 43·4% (95% CI 40·0-49·0) of the population at risk in Africa. Adding three rounds of mass drug administration per year is estimated to increase this proportion to 90·9% (95% CI 86·9-94·6). Further optimisation can be achieved by targeting policies at the provincial level, achieving an estimated 32·1% (95% CI 29·6-34·5) cost saving relative to adopting country-wide policies. Nevertheless, we predict that only 26 (95% CI 22-29) of 41 countries could reduce transmissio
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Journal articleMarshall JM, Touré M, Ouédraogo AL, et al., 2016,
Key traveller groups of relevance to spatial malaria transmission: a survey of movement patterns in four sub-Saharan African countries
, Malaria Journal, Vol: 15, ISSN: 1475-2875 -
Journal articleWhite MT, Shirreff G, Karl S, et al., 2016,
Variation in relapse frequency and the transmission potential of Plasmodium vivax malaria
, Proceedings of the Royal Society of London. Series B, Biological Sciences, Vol: 283, ISSN: 0080-4649There is substantial variation in the relapse frequency of Plasmodium vivax malaria, with fast-relapsing strains in tropical areas, and slow-relapsing strains in temperate areas with seasonal transmission. We hypothesize that much of the phenotypic diversity in P. vivax relapses arises from selection of relapse frequency to optimize transmission potential in a given environment, in a process similar to the virulence trade-off hypothesis. We develop mathematical models of P. vivax transmission and calculate the basic reproduction number R0 to investigate how transmission potential varies with relapse frequency and seasonality. In tropical zones with year-round transmission, transmission potential is optimized at intermediate relapse frequencies of two to three months: slower-relapsing strains increase the opportunity for onward transmission to mosquitoes, but also increase the risk of being outcompeted by faster-relapsing strains. Seasonality is an important driver of relapse frequency for temperate strains, with the time to first relapse predicted to be six to nine months, coinciding with the duration between seasonal transmission peaks. We predict that there is a threshold degree of seasonality, below which fast-relapsing tropical strains are selected for, and above which slow-relapsing temperate strains dominate, providing an explanation for the observed global distribution of relapse phenotypes.
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Journal articlePothin E, Ferguson NM, Drakeley CJ, et al., 2016,
Estimating malaria transmission intensity from Plasmodium falciparum serological data using antibody density models
, Malaria Journal, Vol: 15, ISSN: 1475-2875Background: Serological data are increasingly being used to monitor malaria transmission intensity and havebeen demonstrated to be particularly useful in areas of low transmission where traditional measures such as EIR andparasite prevalence are limited. The seroconversion rate (SCR) is usually estimated using catalytic models in whichthe measured antibody levels are used to categorize individuals as seropositive or seronegative. One limitationof this approach is the requirement to impose a fixed cut-off to distinguish seropositive and negative individuals.Furthermore, the continuous variation in antibody levels is ignored thereby potentially reducing the precision of theestimate.Methods: An age-specific density model which mimics antibody acquisition and loss was developed to make fulluse of the information provided by serological measures of antibody levels. This was fitted to blood-stage antibodydensity data from 12 villages at varying transmission intensity in Northern Tanzania to estimate the exposure rate asan alternative measure of transmission intensity.Results: The results show a high correlation between the exposure rate estimates obtained and the estimated SCRobtained from a catalytic model (r = 0.95) and with two derived measures of EIR (r = 0.74 and r = 0.81). Estimates ofexposure rate obtained with the density model were also more precise than those derived from catalytic models.Conclusion: This approach, if validated across different epidemiological settings, could be a useful alternative frameworkfor quantifying transmission intensity, which makes more complete use of serological data.
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Journal articleGriffi JT, Bhatt S, Sinka ME, et al., 2016,
Potential for reduction of burden and local elimination of malaria by reducing Plasmodium falciparum malaria transmission: a mathematical modelling study
, Lancet Infectious Diseases, Vol: 16, Pages: 465-472, ISSN: 1473-3099 -
Journal articleSlater HC, Griffin JT, Ghani AC, et al., 2016,
Assessing the potential impact of artemisinin and partner drug resistance in sub-Saharan Africa.
, Malaria Journal, Vol: 15, ISSN: 1475-2875BACKGROUND: Artemisinin and partner drug resistant malaria parasites have emerged in Southeast Asia. If resistance were to emerge in Africa it could have a devastating impact on malaria-related morbidity and mortality. This study estimates the potential impact of artemisinin and partner drug resistance on disease burden in Africa if it were to emerge. METHODS: Using data from Asia and Africa, five possible artemisinin and partner drug resistance scenarios are characterized. An individual-based malaria transmission model is used to estimate the impact of each resistance scenario on clinical incidence and parasite prevalence across Africa. Artemisinin resistance is characterized by slow parasite clearance and partner drug resistance is associated with late clinical failure or late parasitological failure. RESULTS: Scenarios with high levels of recrudescent infections resulted in far greater increases in clinical incidence compared to scenarios with high levels of slow parasite clearance. Across Africa, it is estimated that artemisinin and partner drug resistance at levels similar to those observed in Oddar Meanchey province in Cambodia could result in an additional 78 million cases over a 5 year period, a 7 % increase in cases compared to a scenario with no resistance. A scenario with high levels of slow clearance but no recrudescence resulted in an additional 10 million additional cases over the same period. CONCLUSION: Artemisinin resistance is potentially a more pressing concern than partner drug resistance due to the lack of viable alternatives. However, it is predicted that a failing partner drug will result in greater increases in malaria cases and morbidity than would be observed from artemisinin resistance only.
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