Sexually transmitted co-infections as biological modifiers of HPV-driven cervical carcinogenesis: a systematic integrative review

Persistent high-risk human papillomavirus (HR-HPV) infection is necessary but not sufficient for cervical cancer, which caused approximately 350,000 deaths in 2022. Co-infections with Chlamydia trachomatis (CT), herpes simplex virus type 2 (HSV-2), and HIV may modify cervical carcinogenesis, but causal inference is constrained by confounding, study heterogeneity, and limited mechanistic validation in human tissue. This systematic integrative review (PRISMA 2020) searched PubMed, Embase, Scopus, Web of Science, and the Cochrane Library (January 2015 to March 2026); risk of bias was assessed using the Newcastle-Ottawa Scale and ROBINS-I, and certainty of evidence using GRADE. HIV co-infection shows the strongest evidence: approximately 6-fold risk elevation, a confirmed CD4 dose-response, and residual risk that persists despite antiretroviral therapy (GRADE: high). CT is associated with 2-4-fold elevations in observational studies, but substantial heterogeneity, residual sexual-behavior confounding, funnel-plot asymmetry suggesting publication bias, and attenuation of the HPV-adjusted independent effect (OR 1.76, 95% CI 1.03-3.01) leave causality uncertain (GRADE: Low-Moderate). HSV-2 associations are inconsistent: pooled cervical cancer risk was elevated (OR 3.01, 95% CI 2.24-4.04), but most estimates were unadjusted for HPV status, prospective studies are non-significant, and mechanistic evidence derives from non-human models (GRADE: low). A context-dependent syndemic effect appears in HIV co-infected populations. In conclusion, HIV meets criteria for a probable causal modifier of HPV-driven carcinogenesis, supporting WHO-endorsed intensified screening for women living with HIV; CT’s role remains uncertain pending rigorous confounder control; and HSV-2 does not meet the threshold for independent co-factor classification. Priorities include prospective cohorts and human cervical-tissue mechanistic validation.