Discussion
To date, it has been confirmed that the HBV DNA level is positively correlated with the up-regulated expression of PD-1 on T cells, which is closely linked to the formation of HCC immunosuppressive microenvironment[17, 18]. The PD-1/PD-L1 axis also plays an important role in HBV replication[19]. Recently, the combination regimens of PD-1/PD-L1 inhibitor and an antiangiogenic therapy have been proven to be an optimal treatment for advanced HCC[7, 8, 20, 21]. However, the interaction between HBV load and anti-PD-1/PD-L1 therapy remains controversial, particularly in patients who do not receive a continuous antiviral therapy. Several studies have reported high HBV load as a risk factor for HBV reactivation and hepatic impairment during anti-PD-1/PD-L1 therapy[22, 23], while other reports demonstrated that PD-1/PD-L1 inhibitors can be safe and effective in cancer patients with either chronic HBV or HCV infection[24, 25]. Most of the relevant studies did not explore whether antiviral therapy can improve the efficacy and safety of anti-PD-1 treatment in combination with an antiangiogenic therapy. In the current study, we found that baseline HBV load did not affect the prognosis of HCC patients receiving anti-PD-1 combined with an antiangiogenic therapy, while PD-1 inhibitors did not aggravate HBV reactivation and hepatic impairment in patients given TAF prophylaxis.
Since evidence regarding whether HBV infection affects the prognosis of HCC patients receiving anti-PD-1 based therapy is scarce, patients with a high baseline HBV DNA level were always excluded from clinical trials regardless of the antiviral strategies utilized, limiting their efficiency and generalizability. In the KETNOTE-224 study, tumour response was comparable between patients with and without HBV/HCV infection[25]. Similarly, the CheckMate 040 study reported similar tumour responses among patients with advanced HCC, irrespective of HCC aetiology[24]. However, patients with a higher baseline HBV DNA level (usually >500 IU/mL or >2000 IU/mL) were excluded, and whether baseline HBV DNA level affected the clinical prognosis of HCC patients receiving anti-PD-1 based therapy was not assessed in the above clinical trials. In a retrospective study in China, the baseline HBV load was found to have no significant impact on the prognostic outcomes or rates of hepatic impairment during anti-PD-1 blockade[26]. According to our results, similar ORR and DCR were observed in patients with low and high baseline HBV DNA levels. In addition, there was no significant difference in PFS between patients with a higher or lower baseline HBV loads. Importantly, our data highlight that HBV load may not affect the prognosis of HCC patients receiving anti-PD-1 therapy combined with an antiangiogenic therapy.
Whether PD-1 inhibitors aggravate HBV reactivation and hepatic impairment is another concern of anti-PD-1-based therapies. In a phase Ib study comparing nivolumab with and without an HBV therapeutic vaccine, in virally suppressed patients with HBeAg (-) chronic HBV, PD-1 inhibitor was demonstrated to be well tolerated and led to HBsAg decline in most patients[27]. In a study comparing HBV reactivation between patients with low and high HBV DNA loads, who were undergoing anti-PD-1 blockade treatment, similar incidences of HBV reactivation and HBV-associated hepatitis were observed[28]. In the current study, only 2 of the 70 patients (2.9%) experienced HBV reactivation, which was a lower rate compared to patients with other cancer types in another study[29]. The reason for this discrepancy may be that all patients in our study simultaneously received TAF prophylaxis. Continuous and effective antiviral treatment was shown to improve the prognosis of HCC patients receiving anti-PD-1 blockade with high viral loads in our previous study (recently accepted article, doi: 10.21037/atm-21-3020). Nevertheless, the specific role of TAF in the protection against HBV reactivation or hepatic impairment has not been elucidated, since TAF has been proven to have a greater plasma stability and higher renal safety than TDF. In addition, we did not observe any cases of HBV-related hepatic impairment during the follow-up period. Taken together, we suggest that HBV-HCC patients accept first-line antiviral prophylaxis such as TAF before and during the period of anti-PD-1-based therapy.
The current study is not free from certain limitations. First, this single-arm study was designed retrospectively, which may have caused bias in the selection of patients. The implications of this study need to be verified by future clinical studies with larger sample sizes. Second, the overall survival (OS) data were not included in the analysis, as the follow-up period was not long enough, and only two patients died until the observation deadline. Finally, patients with HCV infection were excluded from the final analysis, and the influence of HCV loads on these patients remains unclear.
In conclusion, our study provides evidence that baseline HBV loads do not affect the prognosis of HCC patients receiving anti-PD-1 in combination with antiangiogenic therapy, while PD-1 inhibitors do not aggravate HBV reactivation and hepatic impairment in patients given TAF prophylaxis. However, as this was a non-randomized retrospective study, our data should not be taken as non-biased or used to guide clinical decisions without a further proof derived from prospective clinical trials.

CONFLICT OF INTEREST/STUDY SUPPORT:

Specific author contributions: Jinzhang Chen and Guosheng Yuan conceived and designed the study. Xiaoyun Hu, Rong Li, Qi Li and Mengya Zang participated in the acquisition of the data. Guosheng Yuan participated in analysis, or interpretation of the data. Jinzhang Chen and Guosheng Yuan participated in the drafting of the article or critical revision for important intellectual content. Xiaoyun Hu, Rong Li, Guosheng Yuan and Jinzhang Chen contribute to the revision of article. All authors were involved in the approval of the version to be published and agreement to be accountable for all aspects of the work.
Guarantors of the article: Guosheng Yuan and Jinzhang Chen are the guarantors.
Financial support: This study was partly supported by grants from the National Natural Science Foundation of China (82102879), the Natural Science Foundation of Guangdong Provence (2021A1515012518), the Postdoctoral Research Foundation of China (No. 2021M691468). The funding agencies had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study involving human participants were in accordance with the 1975 Declaration of Helsinki. The Ethical Committee of Nanfang Hospital, Southern Medical University granted approval for this study, and written informed consent was obtained from each patient before the procedure.
Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.