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.