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How delayed and non-adherent treatment contribute to onward transmission of malaria: a modelling study
  1. Joseph D Challenger1,
  2. Bronner P Gonçalves2,
  3. John Bradley3,
  4. Katia Bruxvoort4,5,
  5. Alfred B Tiono6,
  6. Chris Drakeley2,
  7. Teun Bousema2,7,
  8. Azra C Ghani1,
  9. Lucy C Okell1
  1. 1 MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom
  2. 2 Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, United Kingdom
  3. 3 MRC Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine, London, UK
  4. 4 Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California, USA
  5. 5 Department of Global Health and Development, London School of Hygiene and Tropical Medicine, London, United Kingdom
  6. 6 Public Health Department, Centre National de Recherche et de Formation sur le Paludisme (CNRFP), Ouagadougou, Burkina Faso
  7. 7 Radboud Institute of Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands
  1. Correspondence to Dr Joseph D Challenger; j.challenger{at}imperial.ac.uk

Abstract

Introduction Artemether-lumefantrine (AL) is the most widely-recommended treatment for uncomplicated Plasmodium falciparum malaria. Its efficacy has been extensively assessed in clinical trials. In routine healthcare settings, however, its effectiveness can be diminished by delayed access to treatment and poor adherence. As well as affecting clinical outcomes, these factors can lead to increased transmission, which is the focus of this study.

Methods We extend a within-host model of P. falciparum to include gametocytes, the parasite forms responsible for onward transmission. The model includes a pharmacokinetic–pharmacodynamic model of AL, calibrated against both immature and mature gametocytes using individual-level patient data, to estimate the impact that delayed access and imperfect adherence to treatment can have on onward transmission of the parasite to mosquitoes.

Results Using survey data from seven African countries to determine the time taken to acquire antimalarials following fever increased our estimates of mean total infectivity of a malaria episode by up to 1.5-fold, compared with patients treated after 24 hours. Realistic adherence behaviour, based on data from a monitored cohort in Tanzania, increased the contribution to transmission by 2.2 to 2.4-fold, compared with a perfectly-adherent cohort. This was driven largely by increased rates of treatment failure leading to chronic infection, rather than prolonged gametocytaemia in patients who have slower, but still successful, clearance of parasites after imperfect adherence to treatment. Our model estimated that the mean infectivity of untreated infections was 29–51 times higher than that of treated infections (assuming perfect drug adherence), underlining the importance of improving treatment coverage.

Conclusion Using mathematical modelling, we quantify how delayed treatment and non-adherent treatment can increase transmission compared with prompt effective treatment. We also highlight that transmission from the large proportion of infections which never receive treatment is substantially higher than those treated.

  • malaria
  • treatment
  • pharmacology
  • mathematical modelling

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/bmjgh-2019-001856

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    Footnotes

    • Handling editor Alberto L Garcia-Basteiro

    • Twitter @JDChallenger, @lucy_okell

    • Contributors JDC and LCO conceived the project. JDC developed the model and wrote the first draft of the manuscript. TB contributed to the study design. All authors edited and commented on the manuscript.

    • Funding This work was funded by Medicines for Malaria Venture.

    • Patient consent for publication Not required.

    • Ethics approval All the data analysis conducted during this research was secondary and used studies that had obtained ethical approval previously from the appropriate organisations.

    • Provenance and peer review Not commissioned; externally peer reviewed.