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 decline in NTr titer). Others (1.2-24%) will exhibit “serologic failure” (i.e. asymptomatic but exhibit a sustained >=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. <4 fold decline in NTr) b. serologic failure (i.e. sustained ≥4 fold increase in NTr after treatment) and c. those with appropriate serological response, and 2. Determine whether additional interventions (e.g. CSF examination and/or type and duration of antibiotic treatment) among persons with serologic non-response or failure, are associated with improved serological and clinical (i.e. development of SNS) outcomes. The results of this study have the potential to change national policy, reducing unnecessary lumbar punctures and potentially antibiotic treatment in PWH with serologic non- response or even serologic failure after initial syphilis treatment.