Syphilis, Superbugs and Self-Testing: STIs in the Era of HIV Control

At CROI 2026, alongside discussions of metabolic therapies and inflammation, another plenary session brought the audience back to a more familiar — and perhaps more uncomfortable — reality. In her lecture, “Syphilis and Superbugs: Sexually Transmitted Infections in the Era of HIV Control,” Dr. Jeanne Marrazzo addressed a paradox of modern infectious disease care.

We are achieving unprecedented success in HIV control. Yet sexually transmitted infections (STIs) are resurging — rapidly, globally, and unevenly.

The question posed was not only epidemiological. It was existential for HIV medicine: have we entered an era of denial, doom, or destiny when it comes to STIs?

The Numbers We Cannot Ignore

The epidemiological backdrop is stark.

In 2024, more than 2.2 million STIs were reported in the United States alone. Compared to 2015:

• Gonorrhea cases increased by 37% (from ~395,000 to over 543,000).
• Total syphilis cases rose by 155%.
• Congenital syphilis surged by nearly 700%, from 495 to 3,941 cases.

Chlamydia rates remained high, hovering around 1.5 million annual cases.

Behind these aggregate numbers lies a more nuanced pattern. Nearly one-third of primary and secondary syphilis cases in 2024 were diagnosed among men who have sex with men (MSM). Given that MSM comprise roughly 5% of adult men, the incidence in this population is more than 80 times higher than in heterosexual men.

At the same time, women have become the second most affected group. The consequences are severe: the rise in congenital syphilis mirrors increasing primary and secondary syphilis rates among women aged 15–44. The rate of primary and secondary syphilis in this group reached 14.7 per 100,000 in 2024 — translating into thousands of preventable neonatal infections.

Globally, the picture is equally concerning. In a cohort of over 3,000 women in sub-Saharan Africa receiving oral PrEP, nearly one-third had at least one STI at baseline, and incidence exceeded 49 cases per 100 person-years. Most infections were asymptomatic.

The era of HIV viral suppression has not translated into STI control.

Syphilis: An Old Infection, Persistent Challenges

Despite decades of experience, syphilis remains diagnostically and operationally frustrating.

Serologic testing cannot reliably distinguish between past infection, reinfection, or treatment failure. It is an imperfect surrogate for treatment response. Diagnosing congenital syphilis remains particularly complex. And vaccine development has progressed slowly.

Even treatment — long considered straightforward — has been challenged by periodic shortages of benzathine penicillin formulations. In 2024, alternative imported supplies had to be authorized in the United States due to Bicillin L-A shortages.

One reassuring update came from a randomized trial comparing one dose versus three weekly doses of benzathine penicillin G for early syphilis. In 249 participants — 61% of whom were living with HIV — a single 2.4 million unit intramuscular dose was non-inferior to the traditional three-dose regimen. Serologic response rates at six months were 76% in the single-dose group versus 70% in the three-dose group, with similar outcomes among people with HIV.

This finding simplifies management. But it does not address the larger structural problem: delayed diagnosis, inconsistent screening, and missed treatment — particularly in pregnancy.

And, as Dr. Marrazzo reminded the audience, not every rash is syphilis. Emerging pathogens, including sexually transmitted dermatophyte infections such as Trichophyton mentagrophytes genotype VII reported in New York in 2024, can mimic eczema or psoriasis. Diagnostic vigilance remains essential.

Gonorrhea and the Superbug Threat

If syphilis represents a diagnostic challenge, gonorrhea represents a microbiological one.

Antimicrobial resistance in Neisseria gonorrhoeae continues to expand. In European surveillance data from 24 countries, resistance to ciprofloxacin reached 95% in some regions. Resistance to cefixime and rising minimum inhibitory concentrations to ceftriaxone are particularly concerning in parts of Asia. Data from sub-Saharan Africa remain limited.

Two new oral antibiotics have recently entered the landscape: zoliflodacin and gepotidacin, both targeting bacterial type II topoisomerases via novel mechanisms. In trials, microbiologic cure rates for uncomplicated urogenital gonorrhea reached approximately 91–93%, comparable to standard therapy.

Yet enthusiasm is tempered by evolutionary biology. Modeling studies suggest that holding new antibiotics in reserve or deploying them sequentially may paradoxically shorten their useful lifespan. Moreover, certain gonococcal lineages already harbor mutations that confer cross-resistance between these agents.

The race between innovation and resistance is ongoing — and far from settled.

Doxy-PEP: A Disruptive Intervention

Perhaps the most immediately transformative development discussed at CROI was doxycycline post-exposure prophylaxis (Doxy-PEP).

Taken as 200 mg within 72 hours after condomless sex, Doxy-PEP has demonstrated substantial reductions in syphilis and chlamydia among MSM and transgender women in U.S. studies. In Seattle and San Francisco, implementation was associated with sharp declines in syphilis cases among cisgender men.

Unexpectedly, some regions observed declines among cisgender women as well, despite low reported use — suggesting potential indirect effects through sexual networks.

However, the picture is more complex elsewhere. In a Kenyan trial among cisgender women on PrEP, Doxy-PEP showed no significant reduction in STI incidence — largely due to low adherence. A pilot study using weekly directly observed doxycycline demonstrated lower chlamydia incidence, but implementation feasibility remains uncertain.

Meanwhile, concerns about resistance are growing. In French data from the DOXYVAC study, gonococcal isolates from Doxy-PEP users were more likely to show decreased susceptibility to cefixime and to harbor multiple resistance genes, including mosaic penA alleles. No ceftriaxone resistance was detected — but surveillance is critical.

Doxy-PEP may be a medium-term solution to a long-term problem. It is unlikely to replace the need for durable immunity through vaccination.

Vaccines and Self-Testing: Cautious Optimism

Perhaps the most hopeful segment of the plenary focused on vaccines.

Retrospective analyses suggest that the group B meningococcal vaccine (4CMenB) provides approximately 35–41% protection against gonorrhea acquisition. Dynamic modeling in high-risk populations suggests this level of efficacy could justify routine immunization in selected groups. A large phase 2 randomized trial of 4CMenB for gonorrhea prevention is nearing completion, with over 2,300 participants across multiple countries.

Other vaccine platforms, including generalized membrane antigen (GMMA) candidates, are in development.

Diagnostics are evolving as well. In the past two years, the first FDA-approved over-the-counter tests for chlamydia, gonorrhea, and syphilis have become available, including fully at-home nucleic acid amplification tests. A dual treponemal/non-treponemal rapid test is under regulatory review.

These tools could decentralize testing and reduce reliance on syndromic management — particularly important in low- and middle-income countries, where most STIs in women are asymptomatic.

But innovation must be accompanied by affordability and equitable access.

Between Control and Complacency

The plenary concluded with a sobering reflection.

HIV control has advanced dramatically through antiretroviral therapy and PrEP. Yet STI prevention has not kept pace. Behavioral shifts, power imbalances, limited screening access, and structural inequities continue to shape transmission patterns.

No antibiotic, prophylactic strategy, or vaccine will fully compensate for these realities.

The resurgence of syphilis and the emergence of resistant gonorrhea do not signal failure — but they do demand renewed urgency. Innovation in diagnostics, treatment, vaccine development, and implementation must accelerate. Screening during pregnancy must be strengthened. Resistance surveillance must expand globally.

Denial is no longer possible. Doom is not inevitable. Destiny, perhaps, lies in how decisively we respond.

The era of HIV control does not mark the end of sexual health challenges — it marks the beginning of a more complex chapter.