Syphilis is a sexually transmitted disease that has become a public health problem, especially in vulnerable populations. A systematic review and time-free meta-analysis of the publications on the molecular detection of syphilis and mutations associated with antibiotic resistance, CORE group, and syphilis genotypes in PubMed databases, Scielo, and Cochrane was performed, and the last search was conducted in June 2022. Proportions were calculated, and standard errors and confidence intervals were reported for all results of interest. We included 41 articles for quantitative extraction and data synthesis. An increase was observed in the proportion of subjects diagnosed with syphilis and the presence of the A2058G mutation during the 2018–2021 period compared to 2006 (70% 95%CI 50–87 vs. 58% 95%CI 12–78), and we observed that the greater the proportion of the population participating in men who have sex with men (MSM) (<50% and >50%) syphilis increased (78% 95%CI 65–90 vs. 33% 95%CI 19–49). In conclusion, we suggest that there are a set of characteristics that are contributing to the resurgence of syphilis and the selective pressure of bacteria. The MSM population could be a vulnerable factor for this scenario and the global presence of A2058G and A2059G mutations that confer resistance to macrolides.

Much is known about the natural history of syphilis; however, less is known about the immune response against it, and even less is known about people living with HIV (PLWH). Due to the lack of an animal model to study host‒pathogen interactions, it remains unclear how the host eliminates the bacteria. Here, we attempt to elucidate the immune response against infection by summarizing all the reported data in a systematic review. We found that only seven papers included PLWH, and they did not accurately describe the immune response against Treponema pallidum since only lymphopenia was reported upon coinfection. On the other hand, at least sixteen papers described the host‒pathogen interaction in individual cell populations. Using this information, we established the kinetics of the immune response against syphilis and hypothesized how CD4+ T cells, such as Th17 and T rex cells, worsen the progression of the disease in PLWH through their hallmark cytokines, IL-10 and IL-17, and how these two cytokines may play important roles as biomarkers.