Study Selection and Characteristics of Included Studies

A total of 321 titles were identified through database searches, of which 18 were included in this review (Fig. 1) [10,11,12,13,14,15,16, 17•, 18, 19••, 20,21,22,23,24,25,26,27]. The current systematic review thus comprises 18 studies, including 10 case reports and 8 observational studies.

Fig. 1

Flow chart depicting the selection of publications

The Pooled HBVr in Patients with HBV Past Infections Receiving Ibrutinib

Among the eight observational studies [12,13,14,15,16, 17•, 18, 19••], five with a low risk of bias were included in the meta-analysis. The other three studies had a relatively high risk of bias, as presented in Table S2 [13,14,15]. The pooled prevalence of HBVr in patients with HBV past infection from the remaining five studies is 6.6% (95% CI, 2.9–14.6) (Fig. 2A). The duration of reactivation spanned from 2 [19••] to 42 months [18]. Table 1 represents the characteristics of the eight studies. The sensitivity analysis demonstrated the robustness of the overall prevalence (Fig. 2B), indicating that it is not influenced by any individual study.

Fig. 2

The pooled HBV reactivation in patients with HBV past infections receiving ibrutinib. A Forest plot, B sensitivity analysis using leave-one-out approaches

Table 1 Characteristics of the observational studies of patients with past HBV infectionThe HBVr in Patients with HBV Past Infections Receiving Acalabrutinib and Zanubrutinib

There was a single report that characterized HBVr in patients with a history of HBV infection who were treated with zanubrutinib and acalabrutinib. This report, authored by Chiu et al. [19••], described one case of reactivation among 14 patients (7.1%) with past HBV infection who received acalabrutinib. Interestingly, no cases of reactivation were observed in the one patient who received zanubrutinib.

HBVr in Patients with HBsAg-Positive Infection

Two reports described HBVr in patients with chronic HBV infection. Chiu et al. [19••] reported that among patients who received acalabrutinib without HBV prophylaxis, one out of one (1/1) with chronic HBV infection experienced HBVr. In contrast, Ni et al. [13] observed no reactivation in four patients with chronic HBV infection (0/4) who received entecavir as a preventive measure before receiving BTKIs.

HBVr in Patients with HBV Past Infection on Prophylaxis Therapy Compared with Those Without HBV Prophylaxis

Two studies addressed HBVr among patients who received prophylaxis with lamivudine before ibrutinib administration and continued during the study follow-up period [12, 17•].

In one study, HBVr in the prophylaxis group was occurred in 1/73 patients (1.4%) compared to 1/35 (2.9%) in those without HBV prophylaxis [17•]. The other study revealed that there were no cases of reactivation in those on HBV prophylaxis (0/5) compared to 1/7 in those without HBV prophylaxis [12].

Clinical Presentation of Those Who Developed HBVr

Table 2 presents the demographics and clinical presentation of patients who experienced HBVr. Eighteen cases of HBVr were reported, with 14 associated with ibrutinib, including two occult hepatitis B infections and 12 past HBV infections. One case was associated with zanubrutinib in HBV past infection patients, and three cases were recorded for acalabrutinib (one chronic HBV, two past HBV). Of the reported cases, 10 were observed in individuals aged over 60, compared to 7 cases in those under 60 years old. Among them, 13 were males and 4 were females. The age and sex of one patient were not reported [11]. The majority of HBVr incidents occurred within the first year after initiating BKIs. The clinical outcomes of HBVr included five cases of HBV-associated hepatitis flare, five cases of HBV-associated liver failure, six cases of asymptomatic rises in HBV DNA, and two deaths attributed to HBVr. Besides the two fatalities, HBV antiviral treatment successfully normalized liver functions and eliminated serum HBV in most cases, with only two cases experiencing suboptimal HBV control after 6 months.

Table 2 Characteristics of the patients who developed HBV reactivationDeath Attributed to HBV Reactivation

In their studies, Adnet et al. and Sun et al. [11, 23] documented two instances of death caused by HBVr in patients with prior HBV infection. One case was associated with using ibrutinib [23], while the other was linked to acalabrutinib [11]. Adnet et al. further reported a false-negative result for HBsAg, attributed to the hook effect, which led to a delay in providing appropriate care and hospitalizing the patient. In both instances, hepatic failure and subsequent death occurred abruptly within a week.

HBV Reactivation Following Discontinuation of BKIs

According to Herishanu et al. and Hammond et al. [18, 21], HBVr has been observed even after discontinuing ibrutinib, with reactivation occurring at 1.5 and 22 months, respectively. Another study by Ni et al. reported HBVr at 7.5 months after stopping zanubrutinib [13].

False Negativity of HBsAg Following Reactivation

False-negative HBsAg detection following reactivation was reported by Tsuruya et al. and Adnet et al. [23, 25]. In the study by Tsuruya et al. [25], false negativity of HBsAg was observed due to the presence of triple HBsAg escape mutations: Q101K, M133L, and G145A, particularly affecting the “a” determinant domain. The G145A mutation specifically reduced HBsAg production to the extent that it was undetectable using the HISCL HBsAg assay (with a detection limit of 30 mIU/mL). However, it was detectable using the LUMIPULSE HBsAg-HQ assay (Fujirebio, Tokyo, Japan) with a lower detection limit of 5 mIU/mL. In another case reported by Adnet et al. [23], falsely negative HBsAg results were initially observed due to the hook effect, which caused a falsely negative HBsAg result. This delay in accurate diagnosis led to a delay in providing appropriate care and hospitalization to the patient. Unfortunately, the patient experienced hepatic encephalopathy as well as multiple organ failure and ultimately succumbed to death attributed to HBVr, which occurred a week after starting entecavir treatment.