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A double-edged sword: does highly active antiretroviral therapy contribute to syphilis incidence by impairing immunity to Treponema pallidum?
  1. Michael L Rekart1,
  2. Wilfred Ndifon2,
  3. Robert C Brunham3,
  4. Jonathan Dushoff4,
  5. Sang Woo Park5,
  6. Sanjana Rawat6,
  7. Caroline E Cameron6
  1. 1 School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
  2. 2 African Institute for Mathematical Sciences, Muizenberg, Cape Town, South Africa
  3. 3 Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  4. 4 Department of Biology, McMaster University, Hamilton, Ontario, Canada
  5. 5 Department of Mathematics and Statistics, McMaster University, Hamilton, Ontario, Canada
  6. 6 Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada
  1. Correspondence to Dr Michael L Rekart, School of Population and Public Health, University of British Columbia, 2206 East Mall, Rm. 147, Vancouver, BC, Canada V6T 1Z3; Michael.rekart{at}gmail.com

Abstract

Background and hypothesis Recently, the world has experienced a rapidly escalating outbreak of infectious syphilis primarily affecting men who have sex with men (MSM); many are taking highly active antiretroviral therapy (HAART) for HIV-1 infection. The prevailing hypothesis is that HAART availability and effectiveness have led to the perception among both individuals who are HIV-1 infected and those who are uninfected that HIV-1 transmission has become much less likely, and the effects of HIV-1 infection less deadly. This is expected to result in increased sexual risk-taking, especially unprotected anal intercourse, leading to more non-HIV-1 STDs, including gonorrhoea, chlamydia and syphilis. However, syphilis incidence has increased more rapidly than other STDs. We hypothesise that HAART downregulates the innate and acquired immune responses to Treponema pallidum and that this biological explanation plays an important role in the syphilis epidemic.

Methods We performed a literature search and developed a mathematical model of HIV-1 and T. pallidum confection in a population with two risk groups with assortative mixing to explore the consequence on syphilis prevalence of HAART-induced changes in behaviour versus HAART-induced biological effects.

Conclusions and implications Since rising syphilis incidence appears to have outpaced gonorrhoea and chlamydia, predominantly affecting HIV-1 positive MSM, behavioural factors alone may be insufficient to explain the unique, sharp increase in syphilis incidence. HAART agents have the potential to alter the innate and acquired immune responses in ways that may enhance susceptibility to T. pallidum. This raises the possibility that therapeutic and preventative HAART may inadvertently increase the incidence of syphilis, a situation that would have significant and global public health implications. We propose that additional studies investigating the interplay between HAART and enhanced T. pallidum susceptibility are needed. If our hypothesis is correct, HAART should be combined with enhanced patient management including frequent monitoring for pathogens such as T. pallidum.

  • SYPHILIS
  • HIV
  • ANTERETROVIRAL THERAPY
  • MATHEMATICAL MODEL
  • INFECTION

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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Footnotes

  • Handling editor Jackie A Cassell

  • Contributors MLR: conceptualised the original hypothesis, analysed and interpreted the literature, drafted a significant portion of the manuscript and reviewed the rest for intellectual content, coordinated coauthor input, approved the final version, agrees to be the corresponding author and to be accountable for all aspects of the work. WN: helped refine the hypothesis, analysed and interpreted the literature, drafted a significant portion of the manuscript, contributed significantly to the modelling presentation, reviewed the manuscript for intellectual content, approved the final version and agrees to be accountable for all aspects of the work. RCB: helped refine the hypothesis, analysed and interpreted the literature, revised the manuscript critically for intellectual content, contributed to the modelling section, approved the final version and agrees to be accountable for all aspects of the work. JD: helped refine the hypothesis, analysed and interpreted the literature, revised portions of the manuscript and reviewed the rest for intellectual content, drafted the section on mathematical modelling, approved the final version and agrees to be accountable for all aspects of the work. SWP: developed and fine-tuned the model, reviewed the manuscript for intellectual content, approved the final version and agrees to be accountable for all aspects of the work. SR: conducted the initial literature review and analysed the results, reviewed the manuscript for intellectual content, approved the final version and agrees to be accountable for all aspects of the work. CEC: helped refine the hypothesis, analysed and interpreted the literature, drafted a significant portion of the manuscript and reviewed the rest for intellectual content, contributed to the modelling, approved the final version and agrees to be accountable for all aspects of the work.

  • Funding This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers R01AI015334 and R01AI123196 (CEC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • Competing interests None.

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

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