Modeling Within-Host Effects of Drugs on Plasmodium falciparum Transmission and Prospects for Malaria Elimination

Achieving a theoretical foundation for malaria elimination will require a detailed understanding of the quantitative relationships between patient treatment-seeking behavior, treatment coverage, and the effects of curative therapies that also block Plasmodium parasite transmission to mosquito vectors. Here, we report a mechanistic, within-host mathematical model that uses pharmacokinetic (PK) and pharmacodynamic (PD) data to simulate the effects of artemisinin-based combination therapies (ACTs) on Plasmodium falciparum transmission. To contextualize this model, we created a set of global maps of the fold reductions that would be necessary to reduce the malaria RC (i.e. its basic reproductive number under control) to below 1 and thus interrupt transmission. This modeling was applied to low-transmission settings, defined as having a R0<10 based on 2010 data. Our modeling predicts that treating 93–98% of symptomatic infections with an ACT within five days of fever onset would interrupt malaria transmission for ∼91% of the at-risk population of Southeast Asia and ∼74% of the global at-risk population, and lead these populations towards malaria elimination. This level of treatment coverage corresponds to an estimated 81–85% of all infected individuals in these settings. At this coverage level with ACTs, the addition of the gametocytocidal agent primaquine affords no major gains in transmission reduction. Indeed, we estimate that it would require switching ∼180 people from ACTs to ACTs plus primaquine to achieve the same transmission reduction as switching a single individual from untreated to treated with ACTs. Our model thus predicts that the addition of gametocytocidal drugs to treatment regimens provides very small population-wide benefits and that the focus of control efforts in Southeast Asia should be on increasing prompt ACT coverage. Prospects for elimination in much of Sub-Saharan Africa appear far less favorable currently, due to high rates of infection and less frequent and less rapid treatment

Mass campaigns with antimalarial drugs: a modelling comparison of artemether-lumefantrine and DHA-piperaquine with and without primaquine as tools for malaria control and elimination

Antimalarial drugs are a powerful tool for malaria control and elimination. Artemisinin-based combination therapies (ACTs) can reduce transmission when widely distributed in a campaign setting. Modelling mass antimalarial campaigns can elucidate how to most effectively deploy drug-based interventions and quantitatively compare the effects of cure, prophylaxis, and transmission-blocking in suppressing parasite prevalence. A previously established agent-based model that includes innate and adaptive immunity was used to simulate malaria infections and transmission. Pharmacokinetics of artemether, lumefantrine, dihydroartemisinin, piperaquine, and primaquine were modelled with a double-exponential distribution-elimination model including weight-dependent parameters and age-dependent dosing. Drug killing of asexual parasites and gametocytes was calibrated to clinical data. Mass distribution of ACTs and primaquine was simulated with seasonal mosquito dynamics at a range of transmission intensities. A single mass campaign with antimalarial drugs is insufficient to permanently reduce malaria prevalence when transmission is high. Current diagnostics are insufficiently sensitive to accurately identify asymptomatic infections, and mass-screen-and-treat campaigns are much less efficacious than mass drug administrations. Improving campaign coverage leads to decreased prevalence one month after the end of the campaign, while increasing compliance lengthens the duration of protection against reinfection. Use of a long-lasting prophylactic as part of a mass drug administration regimen confers the most benefit under conditions of high transmission and moderately high coverage. Addition of primaquine can reduce prevalence but exerts its largest effect when coupled with a long-lasting prophylactic.Comment: 14 pages, 5 figure

Mathematical Modeling of Malaria: Theories of Malaria Elimination

This dissertation describes the development and application of a new mathematical model for simulating the progression of Plasmodium falciparum infections in individuals with no malarial acquired immunity. The model allows for stochastic simulation of asexual and sexual parasitemias as well as the onset of fever and human to mosquito infectivity on a daily time scale. The model components for the asexual and sexual stages were developed elsewhere but are here extended to allow for simulation of the full range of dynamics observed in a subset of malaria therapy patients. As a first application of the model, I calculate the human component of malarial R0, the basic reproductive number. I then compare this value to those from three other models and describe how this quantity can be used to model malaria transmission. The second application of the model incorporates the effects of drug treatment on progression of infection by utilizing modeled pharmacokinetic and pharmacodynamic properties of a variety of antimalarials. I utilize a stage specific proportional killing model for sexual stages, informed from recent in vitro data. The relationship of effect sizes to treatment coverage and type of treatment in both early and late treatment seeking settings is calculated. In the third chapter, I consider the economic and epidemiological ramifications of antimalarial and rapid diagnostic subsidization for malaria control. For the epidemiological modeling I utilize a semi-mechanistic model of the spread of drug resistance parameterized from historical malaria mortality data; for the economic model I consider the effect of rapid diagnostics on the intensive and extensive margins of antibiotics and antimalarials, as well as the benefits to improved targeting of both. I find that rapid diagnostic testing is justified given our baseline assumptions for areas with low proportions of malarious individuals among all treatment-seekers, but that caution is necessary before deployment worldwide. For antimalarial subsidization, we find that this is a cost-effective method for reducing mortality in developing countries, though efforts to delay the onset and slow the spread of resistance are urgently needed

Shrinking the Malaria Map: A Prospectus on Malaria Elimination

\ud Thirty-nine countries across the world are making progress toward malaria elimination. Some are committed to nationwide elimination, while others are pursuing spatially progressive elimination within their borders. Influential donor and multilateral organizations are supporting their goals of achieving malaria-free status. With elimination back on the global agenda, countries face a myriad of questions. Should they change their programs to eliminate rather than control malaria? What tools are available? What policies need to be put into place? How will they benefit from elimination? Unfortunately, answers to these questions, and resources for agencies and country program managers considering or pursuing elimination, are scarce. The 39 eliminating countries are all positioned along the endemic margins of the disease, yet they naturally experience a variety of country characteristics and epidemiologies that make their malaria situations different from one another. The Malaria Elimination Group (MEG) and this Prospectus recognize\ud that there is no single solution, strategy, or time line that will be appropriate for every country, and each is encouraged to initiate a comprehensive evaluation of its readiness and strategy for elimination. The Prospectus is designed to guide countries in conducting these assessments. The Prospectus provides detailed and informed discussion on the practical means of achieving and sustaining zero transmission. It is designed as a road map, providing direction and options from which to choose an appropriate path. As on all maps, the destination is clearly marked, but the possible routes to reach it are numerous. The Prospectus is divided into two sections: Section 1 Eliminating Malaria comprises four chapters covering the strategic components important to the periods before, during, and after an elimination program. Section 2 Tools for the Job, comprises six chapters that outline basic information about how interventions in an elimination program will be different from those in a control setting. Chapter 1, Making the Decision, evaluates the issues that a country should consider when deciding whether or not to eliminate malaria. The chapter begins with a discussion about the quantitative and qualitative benefits that a country could expect from eliminating malaria and then recommends a thorough feasibility assessment. The feasibility assessment is based on three major components: operational, technical, and financial feasibility. Cross-border and regional collaboration is a key subject in this chapter. Chapter 2, Getting to Zero, describes changes that programs must consider when moving from sustained control to an elimination goal. The key strategic issues that must be addressed are considered, including supply chains, surveillance systems, intersectoral collaboration, political will, and legislative framework. Cross-border collaboration is again a key component in Getting to Zero. Chapter 3, Holding the Line, provides recommendations on how to conduct an assessment of two key factors that will affect preventing the reemergence of malaria once transmission is interrupted: outbreak risk and importation risk. The chapter emphasizes the need for a strong surveillance system in order to prevent and, if necessary, respond to imported cases. Chapter 4, Financing Elimination, reviews the cost-effectiveness of elimination as compared with sustained control and then presents the costs of selected elimination programs as examples. It evaluates four innovative financing mechanisms that must support elimination, emphasizing the need for predictable and stable financing. Case studies from Swaziland and two provinces in China are provided. Chapter 5, Understanding Malaria, considers malaria from the point of view of elimination and provides a concise overview of the current burden of the disease, malaria transmission, and the available interventions that can be used in an elimination program. Chapter 6, Learning from History, extracts important lessons from the Global Malaria Eradication Program and analyzes some elimination efforts that were successful and some that were unsuccessful. The chapter also reviews how the malaria map has been shrinking since 1900. xiv A Prosp ectus on Mala ria Elimi natio n\ud Chapter 7, Measuring Malaria for Elimination, provides a precise language for discussing malaria and gives the elimination discussion a quantitative structure. The chapter also describes the role of epidemiological theory and mathematical modeling in defining and updating an elimination agenda for malaria. Chapter 8, Killing the Parasite, outlines the importance of case detection and management in an elimination setting. Options for diagnosis, the hidden challenge of Plasmodium vivax in an elimination setting, and the impact of immunity are all discussed. Chapter 9, Suppressing the Vector, explores vector control, a necessary element of any malaria program. It considers optimal methods available to interrupt transmission and discusses potential changes, such as insecticide resistance, that may affect elimination efforts. Chapter 10, Identifying the Gaps — What We Need to Know, reviews the gaps in our understanding of what is required for elimination. The chapter outlines a short-term research agenda with a focus on the operational needs that countries are facing today. The Prospectus reviews the operational, technical, and financial feasibility for those working on the front lines and considers whether, when, and how to eliminate malaria. A companion document, A Guide on Malaria Elimination for Policy Makers, is provided for those countries or agencies whose responsibility is primarily to make the policy decisions on whether to pursue or support a malaria elimination strategy. The Guide is available at www.malaria eliminationgroup.org

Quantifying the pharmacology of antimalarial drug combination therapy.

Most current antimalarial drugs are combinations of an artemisinin plus a 'partner' drug from another class, and are known as artemisinin-based combination therapies (ACTs). They are the frontline drugs in treating human malaria infections. They also have a public-health role as an essential component of recent, comprehensive scale-ups of malaria interventions and containment efforts conceived as part of longer term malaria elimination efforts. Recent reports that resistance has arisen to artemisinins has caused considerable concern. We investigate the likely impact of artemisinin resistance by quantifying the contribution artemisinins make to the overall therapeutic capacity of ACTs. We achieve this using a simple, easily understood, algebraic approach and by more sophisticated pharmacokinetic/pharmacodynamic analyses of drug action; the two approaches gave consistent results. Surprisingly, the artemisinin component typically makes a negligible contribution (≪0.0001%) to the therapeutic capacity of the most widely used ACTs and only starts to make a significant contribution to therapeutic outcome once resistance has started to evolve to the partner drugs. The main threat to antimalarial drug effectiveness and control comes from resistance evolving to the partner drugs. We therefore argue that public health policies be re-focussed to maximise the likely long-term effectiveness of the partner drugs

Interrupting Malaria Transmission: Quantifying the Impact of Interventions in Regions of Low to Moderate Transmission

Malaria has been eliminated from over 40 countries with an additional 39 currently planning for, or committed to, elimination. Information on the likely impact of available interventions, and the required time, is urgently needed to help plan resource allocation. Mathematical modelling has been used to investigate the impact of various interventions; the strength of the conclusions is boosted when several models with differing formulation produce similar data. Here we predict by using an individual-based stochastic simulation model of seasonal Plasmodium falciparum transmission that transmission can be interrupted and parasite reintroductions controlled in villages of 1,000 individuals where the entomological inoculation rate is <7 infectious bites per person per year using chemotherapy and bed net strategies. Above this transmission intensity bed nets and symptomatic treatment alone were not sufficient to interrupt transmission and control the importation of malaria for at least 150 days. Our model results suggest that 1) stochastic events impact the likelihood of successfully interrupting transmission with large variability in the times required, 2) the relative reduction in morbidity caused by the interventions were age-group specific, changing over time, and 3) the post-intervention changes in morbidity were larger than the corresponding impact on transmission. These results generally agree with the conclusions from previously published models. However the model also predicted changes in parasite population structure as a result of improved treatment of symptomatic individuals; the survival probability of introduced parasites reduced leading to an increase in the prevalence of sub-patent infections in semi-immune individuals. This novel finding requires further investigation in the field because, if confirmed, such a change would have a negative impact on attempts to eliminate the disease from areas of moderate transmission