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Background Syphilis and other STIs are resurging among PLWH. In the ART era, syphilis may transiently perturb immune markers and trigger low-level HIV-RNA detectability, but determinants and real-world impact on durable suppression remain uncertain.Methods We analysed our PLWH cohort in care (N=677) at the Infectious Diseases Division, AOU Federico II, Naples, to describe temporal trends and predictors of first incident syphilis after centre entry (Cox model; censoring at last visit). Separately, we performed a self-controlled episode analysis of incident syphilis occurring on ART with documented pre-event HIV-RNA <200 cp/mL. For each episode we extracted CD4, CD8, CD4/CD8 ratio and lymphocytes at T−1 (median 116 days before diagnosis), T0 (diagnosis) and T+1 (median 126 days after). Paired changes were tested (Wilcoxon). Mixed models (random intercept per patient) explored predictors of Δratio. Virological outcomes were detectable HIV-RNA at T0 (≥50 cp/mL, DETECT50), BLIP (50–199 with pre/post <50) and confirmed viraemia (≥200 at T0 and post). DETECT50 predictors were assessed by GEE (clustered by patient).Results Over 6,706 person-years, 101/677 patients developed incident syphilis after entry (1.49/100 PY). In multivariable Cox analysis, MSM (aHR 6.24, 95%CI 3.13–12.45) and male sex (aHR 3.75,1.25–11.29) predicted incident syphilis, while CDC stage did not. Episode incidence increased from 1.30/100 PY (2010–2015) to 3.02/100 PY (2020–2025) ( figure 1); calendar year was associated with higher incidence (IRR 1.056/year, p=0.009; +5.6%/year). Median pre-episode CD4 was 702 (IQR 497–884) cells/mm3. From T−1 to T0, CD4 and CD8 showed no significant change (median ΔCD4 +7, p=0.237; ΔCD8 0, p=0.864), while CD4/CD8 ratio increased modestly (+0.033; p=0.014) (table 1). Post-episode, CD4 and total lymphocytes increased (ΔT0→T+1 +46; p=0.036 and +75, p=0.044, respectively). At syphilis diagnosis, HIV-RNA was ≥50 cp/ml in 32/149 episodes (21.5%); BLIP occurred in 4/149 (2.7%), confirmed ≥200 cp/ml in 3/149(2%). Baseline CD4/CD8 ratio <0.5 strongly predicted DETECT50 (aOR 10.33, 95%CI 2.47–43.20, p=0.001), independently from RPR titre, early syphilis, reinfection and CDC stage. At T0, detectable HIV-RNA occurred more frequently in episodes on PI-based ART (22.2% vs 7.8%). In GEE models, PI use was associated with DETECT50 in univariable analysis (OR 3.04, 95% CI 1.00–9.20, p=0.049), but not after adjustment for per baseline immune status. Higher RPR (≥1:64) was associated with larger Δratio (β +0.185, p=0.043).Conclusions In real-world, virally suppressed PLWH, incident syphilis is increasingly diagnosed and is associated with modest, largely reversible immunological changes and frequent low-level HIV-RNA detectability (one in five episodes,21.5%) without loss of overall suppression. A low pre-event CD4/CD8 ratio identifies individuals at higher risk of virological perturbation, supporting intensified monitoring around syphilis episodes.Abstract OC33 Table 1Trajectories of CD4, CD8, CD4/CD8 ratio and lymphocytes across T-1, TO and T+1 in incident syphilis episodesAbstract OC33 Figure 1Annual incidence rate of syphilis diagnoses in PLWH