Not So Quiet on the Viral Front: Low-Level HBV Viraemia Undermines Immunotherapy in HCC

Abstract

Hepatocellular carcinoma (HCC) constitutes one of the leading causes of cancer-related death worldwide [1]. Over the last decade, the treatment strategy for advanced HCC has shifted from single agent multikinase inhibitors (MKIs) to combinations between immune checkpoint inhibitors (ICI), antiangiogenic agents and MKIs, with a significant improvement in patient outcomes [2-5]. The efficacy of these agents is attributed to their mechanism of action in modulating the tumour immune microenvironment, suppressing tumour angiogenesis and blocking various tumour proliferation signalling pathways.

Despite its declining prevalence rate, with the integration of universal vaccination programmes, chronic hepatitis B virus (HBV) infection remains a major risk factor for the development of HCC globally, and especially in Africa, East and Southeast Asia [6]. Studies support that most of the HBV-associated HCC present a more aggressive phenotype with poorer survival and response rate outcomes when compared to non-viral HCC, owing to the oncogenic effects of HBV-DNA integration into the host genome [7, 8].

In the recently published article in the Liver International, Li et al. present the results of a multicentre retrospective study of HBV infected patients with unresectable HCC who received ICI-based treatments, in which they aim to evaluate the effect of low-level viraemia (LLV) on treatment efficacy and survival outcomes [9]. They included 329 patients, of which 170 had LLV after 48 weeks of nucleoside analogues (NAs) antiviral treatment, and 159 had maintained viral response (MVR). In both groups, patients received ICI combinations, including a heterogeneous variety of molecular targeted therapies with or without additional locoregional treatments, as first or subsequent line therapy. The investigators demonstrated that the LLV group was associated with significantly worse ICI-based treatment outcomes compared to the MVR group, with objective response rate (ORR) 21.2% versus 36.5% (p = 0.002) and disease control rate (DCR) 78.8% versus 92.5% (p < 0.001), respectively. Survival outcomes were also worse in the LLV group compared to the MVR group, with median progression-free survival (mPFS) being 7.6 versus 12.6 months (p < 0.001) and median overall survival (mOS) 22.8 versus 40.0 months (p < 0.001), respectively. Differential expression analysis of proteomic data from a subset of patients' serum samples identified proteins involved in immune response regulation that were differentially expressed between the MVR and LLV group.

It is now well established that administration of ICIs in patients with chronic HBV infection receiving NAs is safe with a rate of HBV reactivation as low as 1% (95% CI 0%–2%) and a significantly reduced risk of HBV-related hepatitis (OR = 0.05, 95% CI [0.01–0.28]) [10, 11]. Chronic HBV infection creates a unique immunosuppressive tumour microenvironment (TME) due to deregulation of immune cells, like effector T-cell exhaustion and accumulation of regulatory T-cell and myeloid-derived suppressor cells (MDSCs) leading to tumour immune evasion [12-14]. Due to continuous viral stimulation, the chronically immunosuppressed TME in LLV patients may contribute to the impaired efficacy of ICIs, as shown by the authors. The proteomic analysis also supports this hypothesis. Their study found that inflammatory response proteins such as FMS-like tyrosine kinase 3 ligand (Flt3L), a regulator of anti-tumour immune response, were significantly downregulated in the LLV group, whereas signalling lymphocytic activation molecule family 1 (SLAMF1), a modulator of T-cell activation, and fibroblast growth factor 5 (FGF-5), a growth factor involved in activation of tumour proliferation signalling pathways, were upregulated. Most patients in the LLV group presented with advanced liver fibrosis and liver dysfunction, as expressed by an aspartate aminotransferase to platelet ratio index (APRI) > 2, fibrosis-4 score (FIB-4) > 3.25 and albumin-bilirubin (ALBI) grade decline from baseline to follow-up. OS was significantly shorter in these patients, compared to patients with APRI ≤ 2 (14.0 vs. 38.9 months, p < 0.001) and FIB-4 ≤ 3.25 (14.1 vs. 40.0 months, p < 0.001). On multivariate analysis, solely LLV emerged as an independent risk factor for worse OS (HR = 0.522, 95% CI 0.348–0.781; p = 0.002). A potential explanation for these findings is that the worse prognosis in the LLV group may be associated with deterioration of the background chronic liver disease and decompensated liver function due to low-level HBV viraemia.

The complexity of HCC treatment lies in the delicate balance between delivering effective anti-cancer therapy while at the same time preserving underlying liver function. Liver decompensation has been widely characterised as a key driver of mortality in patients with HCC, and the prognosis of patients discontinuing systemic therapy because of liver decompensation is significantly worse than patients discontinuing because of HCC progression [15]. Successful antiviral therapy reduces the risk of liver decompensation, thus improving the overall oncological outcomes [14]. In patients with HBV-related HCC, it is well established that antiviral treatment provides a significant survival benefit, even in those who are not considered eligible for active anti-cancer therapy [15].

The findings reported by Li et al. on Liver International reinforce the importance of HBV suppression in preventing liver decompensation and improving survival in patients with advanced HCC receiving ICI, underscoring the value of appropriate hepatitis serology screening, timely antiviral treatment initiation and ongoing hepatology input.

However, despite the relevance of these findings, their validity is limited by several factors. A key limitation lies in the heterogeneity of treatment regimens used, including combinations of ICIs with multiple MKIs—such as lenvatinib, sorafenib and donafenib—many of which fall outside established international guidelines. Additionally, the use of locoregional therapies, including hepatic arterial infusion chemotherapy (HAIC), alongside systemic treatments further complicates the data interpretation, as these multimodal strategies are not routinely employed in most clinical settings. As such, the study's context-specific treatment landscape may limit the applicability of its conclusions to broader patient populations. Furthermore, the reported mOS in the MVR group (40.0 months) is significantly higher than the survival outcomes reported in ICI trials for advanced HCC [1, 2]. A potential explanation could be that a prerequisite for all patients included in the study was continuous HBV antiviral therapy for over 1 year, thus leading to the exclusion of a significant proportion of patients with poorer prognosis of less than 1 year. Finally, although the results of the proteomics analysis are undoubtedly relevant, the very small sample size (20 patients) restricts their applicability, requires further mechanistic studies to validate the findings.

Despite these caveats, the study by Li et al. offers valuable insights into the role of LLV in HBV-related HCC treated with ICI-based regimens. Their findings underscore the importance of achieving and maintaining effective viral suppression to mitigate the risk of liver decompensation and improve survival outcomes. As the management of HCC continues to evolve with a number of ICI combinations being available for patients with unresectable HCC, this study reinforces the critical role of antiviral therapy and highlights the need for a multidisciplinary, integrated treatment strategy. Ensuring timely HBV screening, close hepatology collaboration, and ongoing antiviral management should remain central pillars in the care of patients with HBV-related HCC.

C.K. declares no competing interests. A.D. received educational support for congress attendance and consultancy fees from Roche and Chugai, and speaker fees from Roche, AstraZeneca, Eisai and Chugai.