Highly active antiretroviral therapy taken by HIV-positive men who have sex with men may be contributing to the profound escalation in syphilis infections recently observed worldwide, a recent report suggests.

After noting reports of a substantial and rapid rise in syphilis infections around the globe, which have been largely confined to HIV-positive men taking HAART, researchers constructed mathematical models to test the possibility that HAART may inadvertently alter immune responses in ways that enhance the patient’s vulnerability to Treponema pallidum.

Their models confirmed this hypothesis, indicating that both the treatment and behavioral changes associated with its efficacy could raise the incidence of syphilis, said Michael L. Rekart, MD , professor of medicine and global health at University of British Columbia, Vancouver, and his associates.

If these findings are verified in further studies, it will be “imperative” to address this unforeseen sequela before implementing global pre-exposure prophylaxis (PrEP) programs, they noted.

The investigators devised their mathematical models to account for the possibility that either HAART itself, or the use of HAART as a surrogate marker for high-risk sex, or both factors together could influence the association with syphilis. The first model assumed that one or more components of HAART could impair the immune response to T. pallidum, and the second assumed that men taking HAART would perceive themselves as low risk and increase their number of partners, thus heightening their ability to transmit the organism.

Each model demonstrated that immunologic changes or behavioral changes could produce syphilis outbreaks similar to those reported in the literature.

“Strikingly, the peak prevalence of the syphilis outbreak produced by both behavioral and immunologic changes [acting together] is larger than the sum of the peaks of outbreaks produced independently by either type of change,” Dr. Rekart and his associates said (Sex Transm Infect. 2017 Jan 16. doi: 10.1136/sextrans.2016.052870 ).

In other words, HAART-associated immunologic and behavioral changes “can in principle act synergistically to increase syphilis prevalence by amounts comparable with that observed in ongoing outbreaks,” they said.

It is notable that the rates of two other STDs, gonorrhea and chlamydia, have either failed to increase as much or as rapidly as syphilis, or have actually decreased, in the same patient populations. So, the researchers also examined the biological plausibility that HAART could increase patients’ susceptibility to syphilis but not to gonorrhea and chlamydia.

The immune system’s primary clearance mechanism of T. pallidum, macrophage-mediated opsonophagocytosis, requires “unperturbed mitochondrial function to ensure peak metabolic activity within macrophages, opsonic antibody production, and … macrophage activation.” But HIV infection reduces the quality of opsonic antibodies, and some components of HAART significantly suppress mitochondrial function, the proinflammatory response, and macrophage activation. Theoretically, the combination of these factors could impair treponemal clearance via opsonophagocytosis, Dr. Rekart and his associates said.

In contrast, gonorrhea and chlamydia are caused by pathogens that are not so reliant on opsonophagocytosis to be cleared by the immune system. So, HAART would not lead to similar surges in the rates of gonorrhea and chlamydia infection.

Further studies are needed to corroborate these findings. If they are confirmed, the use of both HAART and PrEP will require changes in patient management to mitigate this increased risk for acquiring syphilis and perhaps other disorders, the researchers noted.

“A retrospective case-control and/or a prospective cohort study comparing the prevalence and epidemiological features of infectious syphilis cases among patients who are HIV-1 positive and treated with HAART, patients who are HIV-1 positive and untreated, and patients who are HIV-1-negative … would be enlightening,” the investigators added.

Thie study was supported by the National Institute of Allergy and Infectious Diseases. Dr. Rekart and his associates reported having no relevant financial disclosures.


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