HIV and syphilis are sexually transmitted diseases (STDs) that share transmission routes and risks factors. Many countries face the dual challenge of HIV and syphilis epidemics. Co-infection can mutually accelerate disease progression and increase transmission risk, posing a major challenge to global public health. This retrospective study was based on a cohort of people living with HIV (PLWH). All PLWH diagnosed between 2016 and 2023 were included. The Chi-square test was used to compare demographic and clinical characteristics between groups. Factors associated with syphilis co-infection were assessed using multivariate logistic regression, with adjusted odds ratio (aOR) and 95% confidence interval (95%CI) estimated. Kaplan-Meier analysis was used to estimate the cumulative probability of immune reconstitution (IR) and virological failure (VF) in syphilis co-infection versus HIV mono-infected individuals. Multivariate Cox regression was used to evaluate adjusted hazard ratio (aHR) and 95% CI for factors associated with IR and VF. To reduce potential confounding, we used propensity score matching (PSM) to balance baseline covariates between the syphilis co-infection and HIV mono-infection groups. All statistical analyses were performed by SPSS 23.0 and R 4.3.3. Among 39,924 PLWH in Jiangsu Province (2016–2023), the prevalence of syphilis co-infection was 14.1% (5,645/39,924). Factors independently associated with higher odds of co-infection included age < 60 years, male sex, current HIV stage, single, Han ethnicity, history of STDs, and homosexual HIV transmission. In the IR analysis, 56.6% of PLWH achieved IR. After stratifying by syphilis stage, primary syphilis was associated with a higher probability of IR before matching (log rank P < 0.001), but this difference disappeared after PSM (log rank P = 0.99). Latent syphilis showed no significant association with IR. In the virological failure (VF) analysis, latent syphilis co-infection was associated with an increased risk of VF in Cox regression models both before (log rank P = 0.0011) and after PSM (log rank P = 0.0032). Primary syphilis had no significant effect on VF. Younger age at ART initiation, early HIV stage, higher baseline CD4 + T cell count, and college or higher education were protective against VF and/or promoted IR. HIV/syphilis co-infection prevalence was high among PLWH in Jiangsu. Latent syphilis co-infection independently increases the risk of VF. Younger age at ART initiation, current HIV stage, and higher education protected against VF and/or promoted IR; male, migrant, and homosexual HIV transmission were risk factors for poorer IR. Integrated screening and management of syphilis are essential to optimizing HIV treatment outcomes.
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