The Impact of Antimalarial Use on the Emergence and Transmission of Plasmodium falciparum Resistance: A Scoping Review of Mathematical Models

Abstract

The emergence and transmission of resistance to antimalarial treatments continue to hamper malaria elimination efforts. A scoping review was undertaken regarding the impact of antimalarial treatment in the human population on the emergence and transmission of Plasmodium falciparum resistance, to (i) describe the use of mathematical models used to explore this relationship; (ii) discuss model findings; and (iii) identify factors influencing the emergence and transmission of resistance. Search strategies were developed and deployed in six major databases. Thirty-seven articles met the eligibility criteria and were included in the review: nine articles modeled the emergence of resistance, 19 modeled the transmission of resistance, and nine modeled both the emergence and transmission. The proportion of antimalarial use within the population and the presence of residual drug concentrations were identified to be the main predictors of the emergence and transmission of resistance. Influencing factors pertaining to the human, parasite and mosquito populations are discussed. To ensure the prolonged therapeutic usefulness of antimalarial treatments, the effect of antimalarial drug use on the emergence and transmission of resistance must be understood, and mathematical models are a useful tool for exploring these dynamics.

Global Sensitivity Analysis to Study the Impacts of Bed-Nets, Drug Treatment, and Their Efficacies on a Two-Strain Malaria Model

“…These changes are attributed to wide-scale deployment of malaria control strategies. These include the use of conventional insecticide-treated bed-nets (ITNs), long-lasting insecticide nets (LLINs), intermittent preventive treatment (IPT) especially for pregnant women during the anti-natal period, reducing mosquito population through the destruction of breeding sites or killing of the larva stage at breading sites that cannot be destroyed, indoor residual spraying (IRS), and the use of the sterile insect technique [2][3][4][5][6][7][8]. Despite the remarkable progress, malaria remains a major cause of mortality and morbidity in many parts of the world.…”

“…According to the World Health Organization [17], treatment failure is defined as the inability to clear parasites from a patient's blood. The reasons for treatment failures have been generally attributed to suboptimal dosage, re-infections with a new parasite, or a point mutation in the pfcytb gene (see [6,9,12,18,19] and the references therein). One problem associated with treatment failure is that it may lead to antimalarial drug resistance (see [20]), which is defined as the ability of the parasite to survive the administration of a drug in doses equal to, or higher than, those usually recommended [18].…”

“…Some of these factors include human behavior such as poor compliance, vector and parasite biology, malaria treatment failure, host immunity, pathogen superinfection resulting in within-host competition, presence of clinically-immune individuals, the number of people using the drugs, and poor drug quality [18,19,[21][22][23]. While resistance is detrimental in the human population because it leads to death (see [6]), it is advantageous to the Plasmodium population because it confers a survival advantage in the presence of drugs.…”

Early transmission of sensitive strain slows down emergence of drug resistance in Plasmodium vivax

“…Mathematical models provide an understanding of drug resistance to guide the development of malaria programs [21], through both deterministic and stochastic models simulating the implementation of monotherapies and combination therapies [22]. Models also showed the contribution on the emergence of resistant strains due to factors: fitness cost, selection of resistant parasites after treatment, changes in transmission settings, efficiency in drug dose and the role of asymptomatics [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. These previous works inferred that sub-optimal doses, high treatment coverage, and lower levels of immunity have a direct relation to drug resistance.…”

Early transmission of sensitive strain slows down emergence of drug resistance in Plasmodium vivax

“…Although most previous studies focused on P. falciparum resistance, a few works have compared the evolution of drug 14 resistance between both species [5,8,10]. Most of previous studies evaluated P. falciparum-resistance factors such as 15 cost-resistance, selection after treatment, transmission of resistant parasites, epidemiological factors, asymptomatic 16 infections and treatment regimens [11][12][13][14][15][16][17][18][19][20][21][22]. Even though P. vivax caused the 74% of malaria cases in the Americas and 17 the 37% of cases in the Asian Southwest, the impact of drug resistant in parasite prevalence still remains 18 underestimate [23].…”