Immunotherapy Responses in Viral Hepatitis-Induced HCC: A Systematic Review and Meta-Analysis

Abstract

Background: Hepatocellular carcinoma (HCC) is a prevalent liver cancer with poor prognosis, often linked to hepatitis B (HBV) and C (HCV) infections. This meta-analysis evaluates the efficacy of immunotherapy in HCC, particularly in cases arising from viral hepatitis. Methods: In adherence to PRISMA Statement 2020 guidelines, the immunotherapeutic outcomes comprised objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Data were analyzed from randomized controlled trials up to April 2024 using the fixed-effects models in R (V.4.3.3.) and RevMan (Cochrane). Results: This study included 9 trials with 5316 patients. The ORR was slightly higher in the viral group at 27.93% compared to 24.07% in the non-viral group, though this difference was not significant (p = 0.15). Viral HCC patients exhibited a median PFS of 7.3 months (IQR: 6.2-8.4) compared to 5.8 months (IQR: 5.48-6.13) in non-viral patients, a significant improvement (p = 0.005). Similarly, median OS was longer in the viral group at 16.8 months (IQR: 12.99-20.61) versus 15.2 months (IQR: 13.25-17.15) for non-viral HCC, which was also significant (p < 0.0001). The median OS for viral HCC was 16.8 months (IQR: 14.11-19.49 months), with HBV patients experiencing slightly higher survival at 17.15 months (IQR: 14.3-20 months) compared to 16.8 months (IQR: 12.99-20.61 months) for HCV patients; this difference was not statistically significant (p = 0.89). Conclusions: Immunotherapy shows potential in treating HCC, with significantly better outcomes in viral HCC, particularly HBV-associated cases. The heterogeneity highlights the need for personalized treatment approaches based on the viral background of HCC patients. Further research should aim to optimize these therapies to improve survival rates.

Keywords: cancer treatment; clinical trials; hepatitis B; hepatitis C; hepatocellular carcinoma; immunotherapy; objective response; personalized medicine; survival.

Figure 1

PRISMA flowchart depicting the study selection process.

Figure 2

Forest plot of ORR with ICI use in hepatitis-induced showing a consistent significant effect across the viral group studies and no comparable significant difference from the non-viral group (A) and non-viral groups (B). HBV (C) and HCV-only (D) outcomes showing comparable treatment efficacy are also depicted [37,41,42].

Figure 3

Forest plot of PFS with ICI use in hepatitis-induced and non-viral groups, indicating a statistically significant favorable effect of ICIs on PFS in the overall HCC patient population (effect size computations are depicted) [37,38].

Figure 4

(A) Forest plot of PFS in hepatitis-induced and non-viral groups with ICI use across 6 trials with 13 arms with data on proportional survival outcomes, indicating a non-significant effect but a trend towards better PFS in the viral group [34,35,37,38,40]. (B) Forest plot of OS in HBV vs. HCV groups with ICI use across five trials and six total arms with data on proportional survival outcomes, showing significant difference favoring HBV patients [35,37,38].

Figure 5

Forest plot of OS in hepatitis-induced and non-viral groups with ICI use across three arms with reported data on SD [38,39]. Kelley-2022 arm 2 refers to COSMIC-312’s second arm. Yao-2020, B1 and C2 arms refers to two arms of CheckMate 040.

Figure 6

(A): Forest plot of OS in hepatitis-induced and non-viral groups with ICI use across 6 trials with 13 arms with data on proportional survival outcomes, indicating a non-significant trend towards better survival in the hepatitis-induced group compared to the non-viral group [34,35,36,37,38,40]. (B): Forest plot of OS in HBV vs. HCV groups with ICI use across five trials and six total arms with data on proportional survival outcomes indicating a non-significant difference [34,35,36,37,38].

Figure 7

Comparison of OS and PFS between responders and non-responders across various trials.

Figure 8

Kaplan–Meier survival curves comparing HBV, HBV/HCV, HCV, and non-viral groups.

Figure 9

Forest plot of overall survival hazard ratios across clinical trials.

Figure 10

Summary trends of biases and study-by-study findings [34,35,36,37,38,39,40,41,42].