Clinical and serological outcomes for successive syphilis episodes in people with HIV

Syphilis incidence continues to rise globally among people with HIV (PWH), in whom repeated episodes are common and contribute to ongoing transmission. Whether prior infections modify clinical presentation, serological response, or treatment outcomes remains poorly understood. Partial immunity against Treponema pallidum has been proposed, but its clinical relevance across successive episodes has not been evaluated in a prospective cohort. The objective was to compare clinical presentation, time to serological response, serofast status, and seroreversion across successive syphilis episodes in PWH.

Prospective cohort study of adult PWH diagnosed with a confirmed first syphilis episode and subsequent syphilis episodes between January 2016 and December 2024. The primary endpoint was serological response, defined as a ≥4-fold RPR (rapid plasma reagin) titer decline or seroreversion before or at 12 months after treatment; episodes with reinfection before 12 months were excluded. Successive episodes were defined as confirmed reinfections, a ≥4-fold RPR rise after serological response, and they were compared using survival and regression models.

We evaluated 362 syphilis episodes in 183 PWH over 1,445 person-years of follow up. In repeated episodes (1^st vs 2^nd vs ≥ 3), a secondary syphilis stage was less frequent (21% vs 11% vs 13%: p=0.048). Serological response at 12 months was similar in repeated episodes (75%, 83%, and 78%), associated with a high RPR titer and higher nadir CD4+ count (RR 1.004; p=0.047). A shorter inter-episode interval correlated with a faster serological response in the following episode (rho=0.226; p=0.029). Serofast status was more frequent in successive episodes than in the first (33%, 62%, and 64%; p<0.001), and inversely less for seroreversion (57%, 32%, and 20%; p<0.001), after adjusting by time of follow up. A final diagnosis of neurosyphilis was made in 4%, 1%, and no cases, respectively.

Non-treponemal test titers and serological response rates at 12 months are consistent across successive syphilis episodes in PWH. An attenuation of secondary-stage presentation, a shorter inter-episode interval associated with a faster subsequent serological response, and a progressive rise in serofast status not attributable to treatment failure or neurosyphilis are findings compatible with, though not direct evidence of, partial immune memory.