The long-term risk of neurosyphilis in people with HIV experiencing syphilis serologic nonresponse or failure

Rates of syphilis in the U.S. have increased each year for the past 20 years and are elevated in people living

with HIV (PWH). PWH are at higher risk of syphilis complications including neurosyphilis. For decades, the

mainstay of syphilis treatment monitoring has been the serum nontreponemal antibody (NTr) titer (usually

RPR). Guidelines suggest NTr titers should decline by ≥4-fold at 12 months in adequately treated patients with

primary or secondary and 24 months in PWH or those with latent syphilis. Yet, a significant percentage (~12%)

of patients with syphilis will exhibit “serological non-response” (i.e. although asymptomatic, they have a =4-fold increase in NTr titers in the absence of reinfection). Guidelines recommend those with serologic

failure should undergo lumbar puncture (LP), while serologic non-responders should be retreated with 3 doses

of benzathine penicillin G (BPG) and considered for LP, at least if follow up is uncertain or an initial high NTr

titer (>1:32) in latent syphilis does not decline. The concern in these individuals is for undiagnosed central

nervous system (CNS) infection, which could lead over time to relapse or progression to symptomatic

neurosyphilis (SNS). However, LPs come with risks and logistical challenges, additional antibiotics may not be

benign, and healthcare-related costs can be high. Currently, the best management approach (and whether LPs

and additional antibiotics are necessary) for PWH who exhibit serological non-response and serological failure

is uncertain, mainly because, in the antibiotic era, data on long term SNS outcomes in these patients are

lacking. Longitudinal data on incident SNS in PWH comparing those with appropriate serologic response,

serologic failure and serologic non-response following initial treatment are needed to inform often confusing

treatment guidelines. Prospective trials would be ideal but are impractical given the decades of follow-up and

large number of participants needed to identify this relatively uncommon outcome. We therefore propose to

leverage the Johns Hopkins HIV Clinical Cohort-a dynamic and well characterized group followed from 1990-

2024 to 1. Determine SNS incidence over time in PWH with treated syphilis and compare the incidence in

three groups: a. those who exhibit serologic non-response (i.e.