Reactivation of hepatitis B virus in HBsAg-negative patients with hepatocellular carcinoma

Abstract

Background & aims: Despite increasing attention to hepatitis B virus (HBV) reactivation in hematologic settings, information on reactivation in hepatitis B surface (HBsAg)-negative patients with hepatocellular carcinoma (HCC) remains unknown. This study aimed to determine the incidence and risk factors of HBV reactivation in HBsAg-negative patients undergoing transarterial chemoembolization (TACE).

Methods: A total of 109 HBsAg-negative patients with HCC were consecutively recruited for this study and treated with either mono- (n = 75), combination-drug TACE (n = 20), or combination-drug TACE plus radiotherapy (n = 14). With serial monitoring of virological markers every 2-3 months, patients were observed for HBV reactivation (defined as the reappearance of HBV DNA or sero-reversion of HBsAg) in comparison with control subjects with HBsAg-negative cirrhosis (n = 16) or HBsAg loss (n = 46).

Results: During the study period, HBV reactivation occurred in 12 (11.0%) and 1 (1.6%) patients in the TACE and control groups, respectively. The median level of HBV DNA at reactivation was 5,174 copies/ml (range: 216-116,058). Of the 12 patients with HBV reactivation, four (33.3%) developed clinical hepatitis, including one patient who suffered from decompensation. All antiviral-treated patients achieved undetectable HBV DNA or HBsAg loss after commencement of antiviral drugs. TACE was significantly correlated with a high incidence of HBV reactivation, with increasing risk of reactivation with intensive treatment. On multivariate analysis, treatment intensity and a prior history of chronic hepatitis B remained independently predictive of reactivation.

Conclusions: TACE can reactivate HBV replication in HBsAg-negative patients, with a dose-risk relationship between treatment intensity and reactivation. Patients with prior chronic HBV infection who are to undergo intensive TACE should be closely monitored, with an alternative approach of antiviral prophylaxis against HBV reactivation.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Patient enrollment and assessment.

Fig 2

A, Kaplan-Meier curves of HBV reactivation for the HCC and control groups. Patients with HCC undergoing TACE had significantly more frequent episodes of HBV reactivation during follow-up than controls without TACE, with estimated 12- and 24-month rates of 7.7% vs. 0% and 15.9% vs. 2.0%, respectively (P = 0.006, log-rank test). B, Comparison of HBV reactivation between the HCC and control groups. The risk of HBV reactivation was highest with combo + RT, followed by combo-TACE and mono-TACE, with estimated 24-month rates of 44.3%, 37.8%, and 6.2%, respectively (P = 0.001, log-rank test). C, Comparison of HBV reactivation according to prior CHB status. Patients with prior CHB had a significantly higher incidence of HBV reactivation than those without, with estimated 24-month rates of 53.7% and 7.5%, respectively (P < 0.001, log-rank test).

Fig 3. A and B, Clinical hepatitis associated with HBV reactivation according to treatment intensity.

(A) ALT levels at HBV reactivation in reactivated patients (P = 0.321). (B) Hepatitis due to HBV reactivation according to treatment intensity among the entire patient group with HCC. The incidence rates of reactivation hepatitis were 1.3% (1/75) for mono-TACE, 5.0% (1/20) for combo-TACE, and 14.3% (2/14) for combo + RT (P for trend = 0.021).