A double-edged sword: does highly active antiretroviral therapy contribute to syphilis incidence by impairing immunity to Treponema pallidum?

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.

Keywords: ANTERETROVIRAL THERAPY; HIV; INFECTION; MATHEMATICAL MODEL; SYPHILIS.

Figure 1

A susceptible-infective-treated model of HIV-1 and Treponema pallidum epidemiology predicts that both highly active antiretroviral therapy (HAART) and behavioural change substantially boost syphilis prevalence above baseline. The model used two risk groups and assortative mixing between groups. Using baseline parameters from the literature, we varied parameters quantifying HAART effects and partnership formation rates on susceptibility to and transmission of T. pallidum. We introduced HAART at 20 years and plotted syphilis prevalence without (left panel) and with (right panel) a threefold effect of HAART on susceptibility to T. pallidum, under different assumptions about the effect of HAART on partnership formation rates (for details and code, see https://github.com/dushoff/Syphilis_and_ARVs). Compared with the baseline of no effect (left panel, black line), the combined effect of increased susceptibility and behavioural change (right panel, coloured lines) is larger than the sum of the effects of behavioural change alone (left panel, coloured lines) and increased susceptibility alone (right panel, black line).