B-cell activation markers and cancer risk in people with HIV: An integrative case-control and Mendelian randomization analysis

Early and continuous antiretroviral therapy (ART) reduces cancer risk in people with HIV (PWH), yet residual risk potentially driven by persistent B-cell activation remains. We used observational and genetic triangulation to evaluate whether baseline B-cell biomarkers are associated with subsequent cancer risk. We conducted: (i) a nested case-control study within the INSIGHT trials (158 cases and 313 matched controls) assessing B-cell biomarkers (sCD23, sCD27, sCD30, CXCL13) in PWH; and (ii) two-sample Mendelian randomization (MR) to evaluate likely causal relationships between these proteins and 23 cancer types using general-population genome-wide association studies. Median time from study entry to cancer diagnosis was 2.9 years. In PWH, CXCL13 was associated with overall cancer risk (highest tertile vs. lowest tertile OR 2.36, 95% CI 1.24-4.5), driven by infection-related cancers (N = 82; OR 4.81, 1.76-13.1) and lymphoma (N = 36; OR 9.92, 1.58-62.2). The CXCL13 association remained robust among virally suppressed participants (P = 0.018). sCD30 was also associated with infection-related cancers (OR 2.77, 1.09-7.03). sCD23 showed a linear association with infection-related cancer (OR per SD 1.42, 1.01-2.00), though tertile-based analyses were non-significant. In the general population, MR meta-analyses showed null associations for these biomarkers across 23 cancer types (P > 0.05). Our study links B-cell markers with cancer risk in PWH, identifying CXCL13 as a marker of infection-related cancer risk despite effective ART, highlighting a "residual inflammatory gap" for modern risk stratification. The lack of causal MR signals suggests these proteins are markers of HIV-associated immune activation rather than universal etiological factors for cancer.