Abstract
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.
Highlights
Plasmodium falciparum, the most virulent of the Plasmodium species that cause malaria in humans, is responsible for hundreds of millions of cases per year [1]
We predict that areas containing 91% of the at-risk population of Southeast Asia can achieve elimination if at least 93–98% of symptomatic individuals are promptly treated with effective artemisininbased combination therapies (ACTs), based on assessments of treatment and transmission levels as of 2010
The benefit of attaining this level of coverage far outperforms that of adding additional gametocyte-specific transmission-blocking drugs to current artemisinin-based combination therapy (ACT)
Summary
Plasmodium falciparum, the most virulent of the Plasmodium species that cause malaria in humans, is responsible for hundreds of millions of cases per year [1]. Studies agree that overall levels of morbidity and mortality have declined over the past decade, due at least in part to the worldwide scaling up of insecticide-treated bed nets and the use of artemisinin-based combination therapies (ACTs). Public health and malaria infection experts are increasingly promoting the goal of malaria elimination in areas of low transmission [6,7] while planning ways to achieve significant reductions in higher-transmission areas [8,9]. These include insecticide and drug resistance [10,11], under-developed health care systems, shifting public funding priorities, donor fatigue [6], malaria importation [12] and economic constraints [13]. P. falciparum stages differ markedly in their levels of metabolic activity, within-host locations, and susceptibilities to antimalarials. Mathematical modeling can help guide elimination efforts by providing quantitative predictions to assess the feasibility of different intervention and control strategies [15,16,17,18]
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