Highlights
1. Prospective observational data confirms that the risk of HBV reactivation is comparable between HCC patients with low (≤ 500 IU/ml) and high (> 500 IU/ml) baseline HBV DNA loads when receiving concurrent antiviral prophylaxis.
2. The study reported HBV reactivation rates of 4.5% in the low-load group and 6.1% in the high-load group, with no statistically significant difference (p = 0.29).
3. Frequency of HBV-associated hepatitis and interruptions in immune checkpoint inhibitor (ICI) therapy did not differ significantly between the two groups, suggesting that high baseline viral load should not be a barrier to advanced immunotherapy.
Introduction: The Intersection of HBV and Immunotherapy in HCC
Hepatocellular carcinoma (HCC) remains a global health challenge, particularly in regions where chronic Hepatitis B Virus (HBV) infection is endemic. The therapeutic landscape for advanced HCC has been revolutionized by immune checkpoint inhibitors (ICIs), specifically those targeting the programmed cell death-1 (PD-1) or its ligand (PD-L1). However, a persistent concern in clinical practice is the risk of HBV reactivation (HBVr). During immunotherapy, the restoration of T-cell function can theoretically lead to an intense immune response against HBV-infected hepatocytes, or conversely, immune modulation might facilitate viral replication.
Historically, most landmark clinical trials for ICIs in HCC have enforced strict inclusion criteria regarding baseline HBV DNA levels, often excluding patients with a viral load exceeding 100 or 500 IU/ml. This cautious approach has left a significant portion of the real-world patient population—those with high baseline viral loads—without clear evidence-based guidance. This prospective study (NCT04680598) sought to address this gap by evaluating whether high baseline viral load truly increases the risk of HBVr when patients are protected by modern antiviral agents.
Study Design and Methodology
This prospective observational study was conducted to compare the clinical outcomes and HBVr rates among HBsAg-positive HCC patients treated with PD-1/L1 antibodies. The researchers recruited 1,015 participants between December 2020 and February 2024. A critical component of the study protocol was the requirement for all participants to receive concurrent antiviral prophylaxis starting with the initiation of ICI treatment.
Participant Stratification
The study population was divided into two distinct cohorts based on baseline viral load:
1. HBV DNA-low group: Patients with baseline HBV DNA ≤ 500 IU/ml (n = 356).
2. HBV DNA-high group: Patients with baseline HBV DNA > 500 IU/ml (n = 659).
The primary endpoint was the rate of HBV reactivation, defined according to standard clinical criteria (typically a significant increase in HBV DNA from baseline or absolute thresholds for those previously undetectable). Secondary endpoints included the incidence of reactivation-associated hepatitis and the rate of ICI treatment interruptions due to hepatic complications.
Key Findings: Safety and Viral Dynamics
The results of this large-scale prospective analysis provide reassuring data for clinicians managing complex HCC cases. Despite the high DNA group having more aggressive disease characteristics, the safety outcomes related to viral reactivation remained stable.
Baseline Characteristics and Disease Burden
It is noteworthy that the HBV DNA-high group represented a more clinically challenging population. This group had significantly higher proportions of patients with:
– HBeAg positivity (24.1% vs 7.0%, p < 0.001)
– ALBI (Albumin-Bilirubin) grade 2-3 (49.9% vs 33.7%, p < 0.001)
– BCLC (Barcelona Clinic Liver Cancer) stage C (83.3% vs 72.5%, p < 0.001)
These factors typically correlate with a poorer prognosis and higher potential for liver dysfunction, yet they did not translate into a significant increase in viral complications under the cover of antiviral therapy.
HBV Reactivation and Clinical Safety
The primary analysis revealed that HBV reactivation occurred in 4.5% of the DNA-low group compared to 6.1% in the DNA-high group. The relative risk (RR) was calculated at 1.24 (95% CI: 0.81-1.89; p = 0.29). This lack of statistical significance indicates that baseline viral load is not a primary driver of reactivation risk when potent antiviral prophylaxis is utilized.
Furthermore, the clinical consequences of reactivation were manageable. HBV reactivation-associated hepatitis occurred in only 1.7% of the low group and 2.3% of the high group (p = 0.53). Most importantly for oncology outcomes, the rate of ICI treatment interruptions due to any cause—including liver-related issues—was comparable between groups (25.8% vs 30.5%, p = 0.12).
Expert Commentary: Shifting the Paradigm
The findings of the NCT04680598 study have significant implications for the design of future clinical trials and daily oncological practice. For years, the oncology community has operated under the assumption that high viral loads represent a ‘ticking time bomb’ during immunotherapy. This study suggests that the ‘bomb’ can be effectively defused by nucleos(t)ide analogues (NAs) such as entecavir or tenofovir.
Biological Plausibility and Mechanistic Insights
The mechanism of HBVr under ICI therapy is distinct from that of cytotoxic chemotherapy or B-cell depleting agents (like rituximab). While chemotherapy causes direct immunosuppression, ICIs enhance the immune system. The reactivation observed in this study likely reflects a complex interplay between restored T-cell activity and the baseline viral reservoir. The fact that reactivation rates remained low in the high-DNA group suggests that NAs are highly effective at suppressing viral replication even when the immune system is being pharmacologically stimulated.
Clinical Generalizability and Limitations
While the results are promising, clinicians should note that this was an observational study. The management of antiviral therapy (choice of drug and duration) was consistent with standard care but not strictly randomized. Additionally, the study emphasizes the necessity of ‘concurrent’ prophylaxis; these results should not be used to justify withholding antiviral treatment in patients with high viral loads.
Conclusion: Implications for Clinical Practice
This prospective study provides robust evidence that HCC patients with HBV DNA > 500 IU/ml can safely receive PD-1/L1 inhibitor therapy, provided they are on concurrent antiviral prophylaxis. The risk of HBV reactivation and associated hepatitis is low and does not significantly differ from patients with low baseline viral loads. These findings support a more inclusive approach to immunotherapy for HBV-related HCC, potentially expanding life-prolonging treatments to a wider patient population.
Funding and Trial Registration
This study was registered at ClinicalTrials.gov (NCT04680598). Funding was provided by various national and regional health research grants dedicated to the advancement of cancer therapy and infectious disease management.
References
1. Du Z, Lai Z, Huang Y, et al. HBV Reactivation in Patients with Hepatocellular Carcinoma Treated with PD-1/L1 Antibodies and Concurrent Antiviral Prophylaxis Agents: A Prospective Observational Study. Clin Cancer Res. 2025 Dec 8. doi: 10.1158/1078-0432.CCR-25-2859. PMID: 41359400.
2. El-Khoueiry AB, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017.
3. Lau G, et al. Risk of HBV reactivation in patients with cancer receiving immune checkpoint inhibitors: A systematic review. Hepatology. 2021.