Persistent ALT Elevation and Liver Outcomes After DAA-Induced HCV Cure in People With HIV: Impact of HBV and HDV Co-Infections

HBV replication is commonly suppressed by HCV, and eradication of HCV with direct-acting antivirals (DAAs) may favour HBV reactivation. Data on long-term hepatic outcomes after HCV clearance in people living with HIV (PLWH) with triple viral infections are limited. We analysed all HIV/HCV co-infected participants in the ICONA and HepaICONA cohorts with complete HBV serology who achieved a sustained virological response (SVR) after DAA therapy. Participants were classified as HIV/HCV, HIV/HCV with isolated anti-HBc positivity (IHBc), or HIV/HCV/HBV, with HDV testing when available. The outcomes included ALT normalisation, hepatitis flares, and two composite clinical endpoints: CO1 (HCC, hepatic decompensation, liver transplantation, or death) and CO2 (the same plus FIB-4 progression > 3.25 in non-cirrhotics). Among 1182 PLWH, 478 had HIV/HCV, 651 had HIV/HCV + IHBc, and 53 had HIV/HCV/HBV co-infection; six were HDV RNA-positive. The prevalence of triple co-infection was 16.6% among HCV-viraemic participants. Triple co-infection reduced the likelihood of ALT normalisation (aHR 0.66, 95% CI: 0.45, 0.97); this effect was related to active HDV replication (aHR 0.39, 95% CI: 0.16, 0.94). Over 5213 person-years, 26 hepatitis flares occurred (IR 0.50/100 PYFU), with only one confirmed HBV reactivation (IR 0.25/100 PYFU). Neither triple nor quadruple infection predicted severe liver events. In PLWH, HCV/HBV co-infection is relatively common but does not appear to increase hepatic morbidity after HCV cure under tenofovir-based ART. Persistent ALT elevation after DAA therapy is mainly driven by replicating HDV, supporting routine HDV testing and timely antiviral management in this population.