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

Mario J. C. Ayala, Daniel A. M. Villela

Abstract

The spread of drug resistance of Plasmodium falciparum and Plasmodium vivax parasites is a challenge towards malaria elimination. P. falciparum has shown an early and severe drug resistance in comparison to P. vivax in various countries. In fact, P. vivax differs in its life cycle and treatment in various factors: development and duration of sexual parasite forms differ, symptoms severity are unequal, relapses present only in P. vivax cases and the Artemisinin-based combination therapy (ACT) is only mandatory in P. falciparum cases. We compared the spread of drug resistance for both species through two compartmental models using ordinary differential equations. The model structure describes how sensitive and resistant parasite strains infect a human population treated with antimalarials. We found that an early transmission,i.e., before treatment and low effectiveness of drug coverage, supports the prevalence of sensitive parasites delaying the emergence of resistant P. vivax. These results imply that earlier attention of both symptomatic cases and reservoirs of P. vivax are essential in controlling transmission but also accelerate the spread of drug resistance.

Introduction

The World Health Organization (WHO) estimated 219 million cases of malaria in 2017, most of them caused by Plasmodium falciparum due to high presence in Africa, with 96.6% of total numbers [1]. However, P. falciparum does not maintain such high dominance in other continents, since Plasmodium vivax is diagnosed in 74.1% and 37.2% of cases in the Americas and Southeast Asia, respectively [1]. Understanding conditions that drive the emergence of drug resistance for these species is vital in the goal of ending epidemics of malaria by 2030 in the Sustainable Development Goals (SDG 3.3) in United Nations [

Materials and methods

We developed mathematical models for both Plasmodium vivax and Plasmodium falciparum using ordinary differential equations (ODE) to represent the transmission of two strains: sensitive and resistant. The fundamentals from these models have origin on the well-known Ross-Macdonald model that separates human and mosquito populations by susceptible and infected individuals [46]. Additionally, we implemented a post-treatment state in humans, and we also distinguished infected states by sensitive and resistant strains.

Discussion

We found that early transmission before treatment, asymptomatic human, and low effectiveness of drug coverage support the prevalence of sensitive parasites delaying the emergence of resistant P. vivax. The reproduction numbers of sensitive P. vivax surpassed the reproduction numbers of resistant ones when the infectious period before treatment was greater, and this usually occurs in P. vivax transmission by the early development of gametocytes [52]. This effect produces an increase in the number of P. vivax infected by a shorter incubation period of parasites as a previous model found [40]. It also implies more difficulties in P. vivax elimination and control than P. falciparum, illustrating the lowest effectiveness of current treatment regimens against P. vivax [45, 76, 77]. Previous models also indicated a lower reduction in P. vivax prevalence in same settings than P. falciparum [39, 41] but actually, P. falciparum prevalence is similar to or greater than P. vivax in the same settings suggesting that host acquisition of P. vivax immunity would play a role modulating P. vivax prevalence [78, 79].

Acknowledgments

Authors MA and DV are grateful to Dr. Michael White for providing valuable comments on our work and also to Dr. Otilia Lupi for comments and terminology revisions. DV is a CNPq/Brazil research fellow.

Citation: Ayala MJC, Villela DAM (2020) Early transmission of sensitive strain slows down emergence of drug resistance in Plasmodium vivax. PLoS Comput Biol 16(6): e1007945. https://doi.org/10.1371/journal.pcbi.1007945

Editor: Jennifer A. Flegg, The University of Melbourne Melbourne School of Psychological Sciences, AUSTRALIA

Received: September 5, 2019; Accepted: May 13, 2020; Published: June 17, 2020

Copyright: © 2020 Ayala, Villela. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: MA and DV are grateful for support from Program Print-Fiocruz-CAPES, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, http://www.capes.gov.br), and Fundação Oswaldo Cruz (Fiocruz, http://www.fiocruz.br), and MA is grateful for the scholarship support from Instituto Oswaldo Cruz (IOC, http://www.ioc.fiocruz.br) in the graduate program. DV has support from Conselho Nacional de Desenvolvimento Científico e Tecnológico (National Council for Scientific and Technological Development - CNPq, http://www.cnpq.br, Ref. 424141/2018-3, 309569/2019-2). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.