Dear Editor,

Lau et al. shared their views and guidance in “APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy” [1]. It provides clear guidelines for whether HBV patients need preventive use of nucleos(t)ide analogues (NUCs) during immunotherapy, anti-tumor therapy, and antiviral therapy with other viral hepatitis or AIDS. In addition, their “two-stage” theory of hepatitis due to HBV reactivation appropriately explains the immunological mechanism of HBVr in the situation above. However, there are still a few points in the present manuscript that require further clarification.

The title of this manuscript is “APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy”. To be precise, some of the therapeutic drugs listed therein: immune checkpoint inhibitors (ICIs), tyrosine-kinase inhibitors (TKIs), direct-acting antiviral agents (DAAs), non-HBV active HAART therapy, however, do not belong to immunosuppressive therapy (IST). Therefore, is it necessary to provide a more recapitulative title?

HBV reactivation may occur in tumor patients with chronic HBV infection under ICIs treatment. However, is this caused by ICIs treatment? It is worth discussing. PD-1 receptors are expressed on T cells and primary B cells playing a role in differentiation and apoptosis of these cells. The binding of PD-1 and PD-L1 can inhibit the activation of T cells and cause T cells apoptosis to inhibit immune response. Over expression of PD-L1 can be detected in many human tumor tissues. The expression level of PD-L1 on tumor cells upgraded inducing apoptosis of anti-tumor T cells to prevent tumor cells from host immune system [2]. Anti-PD-1/Anti-PD-L1 drugs exert their anti-tumor effect by blocking the binding of PD-1 and PD-L1 to increase activation, reactivation and proliferation of T cells [3]. Therefore, it is inappropriate to classify ICIs as ISTs.

The expression of PD-L1 in the liver of patients with chronic viral hepatitis B increased, and the expression of PD-1 in liver-specific T cells increased [4]. Blocking the PD-1/PD-L1 pathway can restore the function of depleted HBV-specific T lymphocytes and promote viral clearance. A conference report from ASSLD in 2017 based on the results of two studies proposed that PD-1 molecule can be an important therapeutic target of hepatitis B. A phase Ib single-center study found that the PD-1 inhibitor nivolumab can effectively reduce HBsAg levels in patients with chronic hepatitis B [5]. One of the side effects of immune check inhibitors is immune inflammation, including immune hepatitis, which support our viewpoint. To overcome this side effect, dose selection for anti-PD-1/anti-PD-L1 in the treatment of chronic hepatitis B is still in clinical trials. In addition, seven clinical studies studying on the treatment of PD-1/PD-L1 in hepatitis B/HCC associated with hepatitis B are currently available at Clinical Trials (ClinicalTrials.gov identifier: NCT04465890, NCT02017587, NCT04638439, NCT04133259, NCT04680598, NCT04233840, NCT04294498).

The Asian cohort of the CheckMate 040, a study of nivolumab in adults with advanced HCC reported that in Asian cohort, patients with HBV, HCV or those uninfected had objective response rates of 13%, 14% and 21%, respectively, and the changes in viral kinetics were not associated with nivolumab-related significant hepatic adverse events [6]. Cachexia in patients with advanced tumor can provide conditions for virus reactivation. In addition, tumor immune microenvironment unbalance can change the proportion of immune cells, which will also change the efficacy of PD-1/PD-L1 inhibitors. Are immune checkpoint inhibitors a therapy or a high-risk factor for HBVr in HBsAg (+) patients? More experiments and discussion are still needed.