Hepatic decompensation is the major driver of mortality in patients with HCC treated with atezolizumab plus bevacizumab: The impact of successful antiviral treatment
Authors: Celsa Ciro , Cabibbo Giuseppe , Fulgenzi Claudia Angela Maria , Battaglia Salvatore , Enea Marco , Scheiner Bernhard , D’Alessio Antonio , Manfredi Giulia F. , Stefanini Bernardo , Nishida Naoshi , Galle Peter R. , Schulze Kornelius , Wege Henning , Ciccia Roberta , Hsu Wei-Fan , Vivaldi Caterina , Wietharn Brooke , Lin Ryan Po-Ting , Pirozzi Angelo , Pressiani Tiziana , Dalbeni Andrea , Natola Leonardo A. , Auriemma Alessandra , Rigamonti Cristina , Burlone Michela , Parisi Alessandro , Huang Yi-Hsiang , Lee Pei-Chang , Ang Celina , Marron Thomas U. , Pinter Matthias , Cheon Jaekyung , Phen Samuel , Singal Amit G. , Gampa Anuhya , Pillai Anjana , Roehlen Natascha , Thimme Robert , Vogel Arndt , Soror Noha , Ulahannan Susanna , Sharma Rohini , Sacerdoti David , Pirisi Mario , Rimassa Lorenza , Lin Chun-Yen , Saeed Anwaar , Masi Gianluca , Schönlein Martin , von Felden Johann , Kudo Masatoshi , Cortellini Alessio , Chon Hong Jae , Cammà Calogero , Pinato David James 
Published: July 2024

Background and Aims:
Unlike other malignancies, hepatic functional reserve competes with tumor progression in determining the risk of mortality from hepatocellular carcinoma (HCC). However, the relative contribution of hepatic decompensation over tumor progression in influencing overall survival (OS) has not been assessed in combination immunotherapy recipients.

Approach and Results:
From the AB-real observational study (n = 898), we accrued 571 patients with advanced/unresectable hepatocellular carcinoma, Child-Pugh A class treated with frontline atezolizumab + bevacizumab (AB). Hepatic decompensation and tumor progression during follow-up were studied in relationship to patients’ OS using a time-dependent Cox model. Baseline characteristics were evaluated as predictors of decompensation in competing risks analysis. During a median follow-up of 11.0 months (95% CI: 5.1–19.7), 293 patients (51.3%) developed tumor progression without decompensation, and 94 (16.5%) developed decompensation. In multivariable time-dependent analysis, decompensation (HR: 19.04, 95% CI: 9.75–37.19), hepatocellular carcinoma progression (HR: 9.91, 95% CI: 5.85–16.78), albumin-bilirubin (ALBI) grade 2/3 (HR: 2.16, 95% CI: 1.69–2.77), and number of nodules >3(HR: 1.63, 95% CI: 1.28–2.08) were independently associated with OS. Pretreatment ALBI grade 2/3 (subdistribution hazard ratio [sHR]: 3.35, 95% CI: 1.98–5.67) was independently associated with decompensation, whereas viral etiology was protective (sHR: 0.55, 95% CI: 0.34–0.87). Among patients with viral etiology, effective antiviral treatment was significantly associated with a lower risk of decompensation (sHR: 0.48, 95% CI: 0.25–0.93).

Conclusions:
Hepatic decompensation identifies patients with the worst prognosis following AB and is more common in patients with baseline ALBI >1 and nonviral etiology. Effective antiviral treatment may protect from decompensation, highlighting the prognostic disadvantage of patients with nonviral etiologies and the importance of multidisciplinary management to maximize OS.