Anti-PD-1 monoclonal antibody suppresses hepatitis B virus in patients with hepatocellular carcinoma

To the Editor: The efficacy of anti-programmed death 1 (anti-PD-1) antibodies in treating advanced hepatocellular carcinoma (HCC) is well established. Given that the hepatitis B virus (HBV) is a major cause of HCC and that evidence regarding the interaction between anti-PD-1 antibodies and HBV is limited, we explored the changes in HBV following treatment with finotonlimab, an anti-PD-1 antibody, in patients with HCC. We demonstrated that finotonlimab suppressed HBV replication and maintained viral stability, potentially correlating with improved clinical outcomes. This analysis, involving a relatively large sample size, underscores the dual benefit of anti-PD-1 antibodies in treating patients with HCC and concurrent HBV infection. These findings support further research on the effects and mechanisms of PD-1 antibodies in HBV treatment, potentially contributing to the development of new therapeutic strategies for chronic hepatitis and HCC.

HBV infection is a known cause of HCC, and high levels of HBV deoxyribonucleic acid (DNA) are associated with poor outcomes. Anti-PD-1 antibodies enhance the immune response against tumor cells by blocking the PD-1 pathway, which also improves the immune response against viral infections. Patients with HBV-induced liver cancer may benefit more from immune checkpoint inhibitors than those with nonviral causes, such as nonalcoholic steatohepatitis.^[1] We previously reported a phase 3 study (NCT04560894) comparing finotonlimab,^[2] combined with SCT510 (a bevacizumab biosimilar), and sorafenib in patients with HCC. The combination demonstrated significantly longer median overall survival (OS; 22.1 vs. 14.2 months; P = 0.0008) and progression-free survival (7.1 vs. 2.9 months; P <0.0001) compared to sorafenib.^[3] Here, we specifically examined the effects on HBV in patients receiving finotonlimab plus SCT510 or sorafenib and analyzed the mutual effects of antiviral and cancer suppression associated with anti-PD-1. This study was conducted in accordance with good clinical practice and applicable laws and regulations. All methods were performed in accordance with relevant guidelines and regulations. The study was approved by the Independent Ethics Committee (Ethics Committee Of Chinese PLA General Hosptial) before the clinical study was conducted. Written informed consent was obtained from all patients.

In the phase 3 study, eligible participants were required to have no prior systemic treatment, adequate liver function, and documented HBV infection with HBV DNA levels <2000 IU/mL or 10,000 copies/mL. We analyzed the dynamics of HBV DNA levels after treatment with finotonlimab (200 mg Q3W [every three weeks, defined as a cycle], intravenously) plus SCT510 (15 mg/kg Q3W, intravenously) or sorafenib (400 mg orally twice daily). Viral deterioration was defined as a transition from negative to positive HBV DNA levels or an increase above the baseline. Time to viral deterioration (TTD) was determined using the Kaplan–Meier method, and hazard ratios with 95% confidence intervals (CIs) were calculated using a Cox proportional hazards model to compare the risks between the treatment groups. P values were two-sided and P <0.05 was considered statistically significant.

The analysis included 329 patients with pre- and posttreatment HBV DNA results (finotonlimab group, n = 244; sorafenib group, n = 85). The baseline demographic and disease characteristics were generally balanced between the two groups [Supplementary Table 1, http://links.lww.com/CM9/C846]. In the finotonlimab and sorafenib groups, 85.7% (209/244) and 90.6% (77/85) of the patients, respectively, were male. The median follow-up period was 21.0 (95% CI: 19.8–22.0) months in the finotonlimab group and 18.3 (95% CI: 15.8–19.4) months in the sorafenib group. A declining trend in HBV DNA levels was observed in the finotonlimab group compared to the sorafenib group [Figure 1A]. Significantly more patients in the sorafenib group (45.9%, 39/85) experienced viral deterioration than those in the finotonlimab group (36.5%, 89/244). The median TTD in the finotonlimab group was significantly longer than that in the sorafenib group (18.8 months [95% CI: 12.0–not evaluable] vs. 5.6 [95% CI: 2.9–13.7] months, Figure 1B). The hazard ratio was 0.54 (95% CI: 0.37–0.79; P = 0.0012). This significant difference persisted throughout the observational period [Supplementary Table 2, http://links.lww.com/CM9/C846]. Subgroup analyses of TTD based on disease stage, liver function, and HBV expression consistently demonstrated a longer median TTD in the finotonlimab group than in the sorafenib group [Supplementary Figure 1, http://links.lww.com/CM9/C846]. Additionally, in the finotonlimab group, a correlation was observed between OS and HBV DNA levels; patients with longer OS (above the median OS) consistently had lower HBV DNA levels than those with shorter OS (below the median OS) [Figure 1C].

Figure 1.

(A) Changes in HBV DNA from baseline over time in the finotonlimab and sorafenib groups. A declining trend in HBV DNA levels was observed in the finotonlimab group compared to the sorafenib group. (B) Kaplan–Meier curve shows the TTD of HBV DNA in patients with HCC who received finotonlimab or sorafenib. The median TTD in the finotonlimab group was significantly longer than that in the sorafenib group (18.8 months vs. 5.6 months). (C) Changes in HBV DNA levels over time in patients with OS above the median OS (blue line) vs. below the median OS (brown line) in the finotonlimab group. Patients with longer OS (greater than the median OS) consistently had lower HBV DNA levels compared to those with shorter OS (less than the median OS). (D) The diagram of the mutual effects of HBV suppression and anticancer effects. DNA: Deoxyribonucleic acid; GT: Greater than; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HR: Hazard ratio; LE: Less than or equal to; NE: Not evaluable; OS: Overall survival; TTD: Time to deterioration.

This analysis, involving a relatively large sample size, underscores the dual benefit of anti-PD-1 antibodies in treating patients with HCC and concurrent HBV infection. Finotonlimab appears to suppress viral replication and maintain HBV stability, which may correlate with improved clinical outcomes such as prolonged survival and reduced tumor progression. The observed decline in HBV DNA levels could be attributed to immune system recovery and the activation of effector CD8⁺ T cells from previously exhausted states, along with tumor reduction.^[4] Meanwhile, suppression of HBV by anti-PD-1 treatment may reduce the formation of immunosuppressive microenvironments, diminishing the inflammatory and oncogenic stimuli that facilitate tumor growth [Figure 1D].^[5] A limitation of this study is that, although greater suppression of HBV replication was observed in the immune checkpoint inhibitors (ICI) group than in the sorafenib group, suggesting a potential contribution from ICI treatment, this dataset does not allow differentiation between the antiviral effects attributable to ICI therapy and those resulting from anti-HBV treatment. Research in this area remains limited, and further prospective studies are needed to validate these findings and clarify their underlying mechanisms.

Funding

This work was funded by the National Science and Technology Major Projects of China (No. 2019ZX09732-001).

Conflicts of interest

Sinocelltech Ltd. sponsored this work. C.L., D.L., and L.X. are employees of Sinocelltech Ltd. and have stock ownership and/or potential option interest in the company. The authors declare no other conflict of interest.

Supplementary Material

cm9-139-2199-s001.pdf ^{(824.4KB, pdf)}