Correlation of HBV DNA and Hepatitis B Surface Antigen Levels With Tumor Response, Liver Function and Immunological Indicators in Liver Cancer Patients With HBV Infection Undergoing PD-1 Inhibition Combinational Therapy

Abstract

BackgroundThus far, few studies have investigated the safety and efficacy of programmed death-1 (PD-1) immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) antibodies in patients with hepatitis B virus (HBV)-related liver cancer.ObjectiveTo investigate the effect of combination therapy with programmed death-1 (PD-1) immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) on HBV-related liver cancer.MethodsUntil January 31, 2022, liver cancer patients with hepatitis B surface antigen (HBsAg) or HBV DNA positivity, treated with PD-1 ICIs and TKIs combined with nucleoside analogs (NAs), were retrospectively reviewed. The correlation between the change in HBV DNA and HBsAg levels and tumor response was analyzed using the χ2 test. Cox univariate and multivariate survival analyses and Kaplan–Meier curves were used to identify and compare risk factors and overall survival (OS).ResultsA total of 48 patients were enrolled in the study, with an objective response rate (ORR) of 31.3%, a disease control rate (DCR) of 66.7%; the incidence of adverse events was mostly mild. A significant decrease in HBV DNA and HBsAg levels was observed at 12 and 24 weeks compared with the baseline (p < 0.05). Compared to patients with progressive disease (PD), patients with disease control showed a more significant decrease in HBV DNA and HBsAg levels at 12 and 24 weeks (p < 0.001). Eleven patients showed elevations in HBV DNA level and one of them showed HBV reactivation; however, the reactivation was not associated hepatitis. Moreover, eight patients showed elevation in HBsAg. Elevation in HBV DNA level was associated with poor tumor response (P=0.001, OR=18.643 [95% CI: 3.271–106.253]). Cox survival analysis suggested that HBV DNA increase (P=0.011, HR=4.816, 95% CI: 1.439–16.117) and HBsAg increase (P=0.022, HR=4.161, 95% CI: 1.224–16.144) were independent risk factors associated with survival time. Kaplan–Meier curves suggested that patients who exhibited an increase in HBV DNA (6.87 months vs undefined, log-rank test: p= 0.004) and HBsAg (8.07 months vs undefined, log-rank test: p= 0.004) levels had a shorter median survival time (MST). Patients without increased HBsAg showed better baseline liver function and routine blood tests (p<0.05) than patients with increased HBsAg. An increase in C-reactive protein (CRP) and interleukin-6 (IL-6), and a decrease in T lymphocytes, CD4+ T lymphocytes, and B lymphocytes at 1-week post-treatment associated with HBsAg well-controlled.ConclusionHBV-related liver cancer patients treated with combination therapy showed improved efficacy and safety profiles. Combination therapy has some effect on HBV infection, and a correlation between tumor response and antiviral efficacy was found. Elevation of HBV DNA and HBsAg levels may indicate poorer tumor response and survival time. Better baseline liver function and early immune activation may be associated with decline in HBsAg levels.

The safety concerns regarding immune checkpoint inhibitors in liver cancer patients rising mainly from CHB

“…These findings support the results of our current study, which showed a decrease in HBsAg levels, particularly in patients with a baseline HBsAg level >1000 IU/mL. Our data suggest that ICIs may also have a role in antiviral functions ( Hagiwara et al, 2022 ; Pan et al, 2022 ).…”

Efficacy and Safety of Immune Checkpoint Inhibitors in Patients with Cancer and Hepatitis B or C: A Systematic Review and Meta-Analysis

“…A total of 21 studies reported ORR data [ 4 , 6 – 9 , 11 – 14 , 16 , 18 – 28 ], involving 815 uninfected patients and 1,061 hepatitis patients. This meta-analysis showed ( Figure 2 ) that the pooled ORR of uninfected patients, HCV patients, and HBV patients was 18.10% (95% CI: 12.00%–25.00%), 23.95% (95% CI: 16.36%–32.28%), and 26.49% (95% CI: 21.12%–32.19%), respectively.…”

“…Fourteen studies included DCR parameters [ 4 , 6 – 8 , 12 – 14 , 16 , 20 – 23 , 26 , 27 ]. The pooled DCR of uninfected patients and HCV and HBV patients was 58.74% (95% CI: 46.89%–70.13%), 67.83% (95% CI: 52.01%–82.14%), and 65.79% (95% CI: 58.86%–72.43%).…”

“…The incidence of immune-related adverse events (irAEs) in hepatitis patients and uninfected patients was further combined. A total of 13 studies reported irAEs [ 4 , 7 , 8 , 10 – 12 , 14 , 16 , 18 – 20 , 22 , 27 ]. irAEs were classified into all grades and grades 3-4.…”

“…The incidence of HBV reactivation (HBVr) and HCV reactivation (HCVr) induced by immunotherapy is not clear. Among the 878 hepatitis patients we included, 4 HBVr and no HCVr were observed [ 16 , 22 , 26 ], so we thought that the probability of hepatitis reactivation caused by ICIs was relatively low. In addition to HBVr and HCVr, immune-mediated hepatotoxicity constitutes one of the reasons why researchers exclude clinical trials because hepatitis patients are often accompanied by baseline damage of liver function.…”