The effects of antiretrovirals (ARVs) on certain mechanisms of the immune system may make individuals more susceptible to syphilis. These findings from a mathematical modeling study, which may apply to those taking ARVs as pre-exposure prophylaxis, or PrEP, in addition to those using them for HIV treatment, may help explain the recent surge in syphilis rates among men who have sex with men (MSM).

While the number of syphilis diagnoses in the United States is much smaller than those of chlamydia and gonorrhea, the syphilis rate is rising much faster than the rates of the other two major bacterial sexually transmitted infections (STIs). Annual syphilis diagnoses rose 128 percent (from 8,700 to 20,000) between 2005 and 2014; chlamydia diagnoses rose 48 percent (from 976,000 to 1,442,000); and gonorrhea diagnoses rose 3.1 percent (from 340,000 to 350,000).

Between 2013 and 2014, chlamydia, gonorrhea and syphilis rates rose by a respective 2.8 percent, 5.1 percent and 15.1 percent.

The syphilis epidemic is largely concentrated among MSM, who have seen rising rates of the STI since at least 2000. Among the 27 states that between 2007 and 2014, collected sex partner data for at least 70 percent of the males diagnosed with syphilis, the proportion of cases among MSM increased steadily to 82.9 percent at the end of the period.

Centers for Disease Control and Prevention/2015 STD Surveillance Report

Among HIV-positive MSM, beginning treatment for the virus may prompt sexual behavioral changes that make them more likely to contract STIs. However, this does not explain why syphilis rates, in particular, should increase so much faster among MSM with HIV compared with rates of chlamydia and gonorrhea.

Some research suggests that ARVs may modify the immune response such that individuals become more susceptible to syphilis infection. For the immune system to protect the body against syphilis, there must be an increase in CD4 immune cells as well as a cascading chemical process that depends on good function in the mitochondria of immune cells (mitochondria are the energy centers of cells).

Not only does HIV suppress CD4 cells (of course, HIV treatment helps restore them) but also certain ARVs suppress mitochondrial function while curtailing an immune response that gives rise to inflammation and the activation of immune cells called macrophages. All this could put those on HIV medications at greater risk for syphilis. By contrast, the immune system’s line of defense against chlamydia and gonorrhea is not as dependent on these immune responses.

Researchers have found that the ARVs in the nucleos(t)ide reverse transcriptase (NRTI) class, in particular Viread (tenofovir disoproxil fumarate, or TDF), inhibit a certain immune response and ultimately result in the replication of older immune cells with a limited ability to protect against certain pathogens, including syphilis. TDF, Viread’s generic shorthand, is the most commonly prescribed ARV for HIV treatment and is included in Truvada (TDF/emtricitabine), which is used as PrEP, and is also used to treat hepatitis B virus (HBV).

“If taking a three-drug [ARV] regimen to treat [HIV] infection is proven to impair immunity to certain pathogens and increase the risk of infectious and non-infectious diseases, then it is logical to assume, until proven otherwise, that there could be similar albeit probably weaker effect when a two-drug [ARV] regimen is taken for PrEP,” says the study’s lead author, Michael Rekart, MD, a clinical professor at the School of Population and Public Health at the University of British Columbia.

Numerous studies of PrEP have not, however, seen a rise in syphilis rates among those taking Truvada as HIV prevention. A recent study of a large cohort of MSM on PrEP in Northern California found increases in chlamydia and gonorrhea but not syphilis.

A recent meta-analysis of numerous PrEP studies did find that the overall rates of STIs are much higher among HIV-negative MSM given Truvada compared with those not taking PrEP, and that the disparity for syphilis was far greater than for the other two STIs. STI rates among those given PrEP were 25 times greater for gonorrhea, 11 times greater for chlamydia and 45 times greater for syphilis, compared with the rates among MSM not given PrEP. These figures do not necessarily imply that going on PrEP actually prompted a rise in STI rates.

Publishing their findings in Sexually Transmitted Diseases, researchers in the new mathematical modeling study examined available scientific literature to help construct a model that would estimate the effects on hypothetical populations of two phenomena: an HIV-treatment-prompted rise in sexual risk taking among people with HIV, specifically an increase in the number of sexual partners, and increased susceptibility to syphilis among people with HIV resulting from ARVs’ effects on the immune response.

The model suggested that such behavior change and ARV-driven increased susceptibility to syphilis could increase the spread of the STI. The model also found that the combination of the two factors led to a wider spread of syphilis than each factor on its own.

The findings warrant future study, the study authors concluded.

In a linked editorial on the paper, three researchers from Johns Hopkins University School of Medicine caution that inadequate screening for chlamydia and gonorrhea compared with syphilis may be behind the disparity in diagnosis rate increases between those STIs and syphilis. Additionally, they warn that the mathematical methods used in the paper do not take into account many complex nuances involved in sexual relationships that may influence the risk of STIs, including the duration of a relationship, the number of overlapping partners or a dropping rate of condom use in long-term relationships.

“We are living in an era where [ARV treatment] is being used to effectively treat and prevent HIV infection,” the editorial writers also cautioned. “To some extent, this seems to have tempered the urgency to control other [STIs]. As history has shown many times over, that would be a costly mistake.”

Centers for Disease Control and Prevention; 2016 STD Prevention Conference.

To read a press release about the study, click here.

To read the study, click here.

To read the accompanying editorial, click here.

Editor’s note: A previous version of this article stated that non-nucleos(t)ide reverse transcriptase inhibitors were perhaps particularly likely to raise susceptibility to syphilis, and also stated that Viread was in that class. The “non-” prefix was an error in that statement. (Additionally, the correct spelling of the NNRTI class of drugs is "non-nucleoside reverse transcriptase.")