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Background Simplified antiretroviral therapy (ART) effectively manages HIV, yet its long-term hepatic safety is debated. This study evaluates HBV serological evolution and reactivation risks among people living with HIV (PLWH) in Ferrara, focusing on isolated HBcAb management when switching to dual regimens.Materials and Methods A single-center, real-world study was conducted at the Ferrara HIV Center, including PLWH with 2025 follow-up visits with HBV serological markers. We aimed to profile the prevalence and fluctuations of HBV markers and reactivation risk in simplified ART, identifying predisposing factors to develop personalized follow-up strategies for optimized hepatic outcomes. Data from HIV diagnosis (T0) and study period (T1) were compared for HBV serological evolution. HBV DNA was tested in HBsAb-/HBcAb+ cases to detect occult reactivation.Results We included 544 PLWH, mostly European (82.7%), males (71%), aged 35–65 (74.3%), mean age 54,87, median 57, CDC A2 (32.4%); 41.9% were on simplified ART at T1. We found a dynamic evolution of HBV serological markers from T0 to T1: HBsAg fell (5.5% to 2%), while HBsAb (48.2%) and HBcAb (37.1%) rose significantly. Among the 368 PLWH with paired data, 6% achieved HBsAg loss, suggesting a favorable trend in viral clearance: nearly half (45.5%) of these were receiving HBV-active drugs and were mostly European males (81.8%), aged 35–65 (68.2%), with CDC stage B3 (31.8%), CD4 >500 cells/mm 3 (81.8%), and a high HCV coinfection rate (75%), often associated with HBsAg clearance due to viral interference. Conversely, the loss of HBsAb observed in 8.7% of the 355 individuals with complete paired data raises concerns regarding the long-term persistence of humoral immunity; they were mostly males (74.2%), European (87.1%), aged 35–65 years (87.1%), CDC A2-B3 (25.8%-23.6%), CD4 >500 cells/mm3 (87.8%). At T1, 37.1% of the total cohort was HBcAb+, indicating a high prevalence of prior HBV exposure. Among patients on simplified ART, HBsAb negativity reached 45.5%, with 28% presenting an HBsAb-/HBcAb+ profile. HBV reactivation was limited to a single case involving a patient treated with a triple-drug regimen that did not include an HBV-active component.Conclusions Our study shows significant HBV serological fluctuations in PLWH. While some achieved HBsAg loss, linked to HBV-active ART and HCV coinfection, the concurrent loss of HBsAb and documented reactivation highlight persistent vulnerabilities, emphasizing the need for rigorous monitoring when switching to simplified regimens lacking HBV coverage. While these patients can still switch to these treatments, HBV DNA monitoring should be integrated into clinical practice, moving beyond occasional testing toward a systematic approach at predefined intervals. Additionally, identifying predictive factors is vital to focus on high-risk cases. Data reinforce the importance of high vigilance and individualized screening to ensure long-term hepatic safety.Table 1, table 2Abstract P96 Table 1Demographic and clinical characteristics of the study population (N = 544)Abstract P96 Table 2This table presents the prevalence of HBsAg, HBsAb, and HBcAb markers among the study cohort (N = 544). Results are categorized as positive, negative, or borderline for both time points: T0, representing the time of HIV diagnosis, and T1, representing the follow-up control during the study period. The proportion of missing data for each marker at baseline is also indicated