Are immune-checkpoint inhibitors immunosuppressive to hepatitis B virus?

Excerpt

Cai et al. raised the concern whether immune-checkpoint inhibitors (ICIs) should be embraced into the category of immunosuppressive therapy (IST) as described in the recent APASL guideline on management of hepatitis B reactivation [1]. This is an important question and has been broadly discussed during the construction of the guideline [2]. Since the approval of the first ICI anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) for advanced-stage melanoma in 2011, there has been a rapid expansion of ICIs-which now also include antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1) for the treatment of a wide variety of cancer. In parallel, hepatitis B virus (HBV) reactivation has also been increasingly recognized in those oncology patients with concomitant HBV infection, treated with ICI, as detailed in the guideline [2]. In brief, the current literature suggested that the use of ICIs in certain patients could suppress the host immune control on HBV replication. This is evidenced by the demonstration of enhanced HBV replication in HBsAg positive patients treated with ICIs by a number of studies [3]. Specifically, in the Asian cohort of the CheckMate 040 international, multicentre, open-label, phase I/II study of nivolumab in adults with advanced HCC, 11% (5/47) of patients with HBV had > 1 log increase in HBV DNA [4]. Consistent with these findings, a recent study using disproportionality signal analysis based on reporting odds ratio (ROR) and 95% confidence intervals (CI), pembrolizumab was found to have a significantly strong signal association with HBV reactivation, with ROR of 2.32 (95% CI 1.11–4.28) (p = 0.013) [5]. The exact mechanism is still unclear, but apparently is in contradiction to our previous findings that blocking the PD-1-mediated pathway could enhance HBV-specific CD8 T-cell proliferation and inflammatory cytokine production, leading to resolution of acute HBV infection [6]. On the other hand, in preliminary early phase human study, it had also been shown that virally suppressed HBeAg-negative patients treated with anti-PD-1 correlate with HBsAg decline [7]. This led one to question whether ICIs will instigate or suppress host immune response to HBV? To note, PD-1 expression is not only found in effector CD8 + T cells but also in regulatory T (T_reg) cells [8]. T_reg cells represent an immunosuppressive subset of CD4⁺ T cells characterized by the expression of the master transcription factor forkhead box protein P3 (FOXP3) and play an essential role in maintaining self-tolerance. The blockade of the latter can be immunosuppressive. In keeping with this, the frequency of PD-1⁺CD8⁺ T cells relative to that of PD-1⁺ Treg in the tumor microenvironment has been proposed as a better predictor of clinical efficacy of PD-1 blockade therapies than others such as PD-L1 expression or tumor mutational burden. Recently, hyperprogressive disease (HPD) has also been described in a subset of patients with HCC treated with PD-1 inhibitor and is associated with worse progression-free and overall survival [9].Taking together, ICIs are likely to exert different effects in patients with different immune landscapes. To ease its practical use by various medical disciplines which might be involved in the management HBV reactivation, we have included ICIs into the category of IST in our current guideline. With the advance in the clinical applications of ICIs, further large-scale studies are warranted to elucidate the impact of each ICI in the risk HBV reactivation among patients with chronic as well as resolved HBV infections. …