Hepatitis B virus reactivation in HBsAg-negative, anti-HBc-positive patients receiving immunosuppressive therapy: a systematic review

BACKGROUND: The optimal management of HBsAg-negative, anti-HBc-positive patients who receive immunosuppression remains unclarified. We systematically reviewed the available data on potential predictors of the risk of hepatitis B virus (HBV) reactivation in such patients. METHODS: A literature search identified 55 studies with 3640 HBsAg-negative, anti-HBc-positive patients who received immunosuppressive regimens. RESULTS: HBV reactivation was reported in 236 (6.5%) patients. The pooled HBV reactivation rates did not differ between patients with detectable or undetectable HBV DNA in studies with hematological diseases or regimens containing rituximab, but it was higher in patients with detectable than in those with undetectable HBV DNA who were taking rituximab-free regimens (14% vs. 2.6%; risk ratio [RR] 12.67, 95% CI: 95%CI 2.39-67.04, P=0.003) or had non-hematological diseases, although the latter was not confirmed by sensitivity analysis (RR 8.80, 95%CI 0.71-109.00, P=0.09). The pooled HBV reactivation rates were lower in patients with positive than in those with negative anti-HBs in studies with hematological (7.1% vs. 21.8%; RR 0.29, 95%CI 0.19-0.46, P<0.001) or non-hematological (2.5% vs. 10.7%; RR 0.28, 95%CI 0.11-0.76, P=0.012) diseases, and rituximab-containing (6.6% vs. 19.8%; RR 0.32, 95%CI 0.15-0.69, P=0.003) or rituximab-free (3.3% vs. 9.2%; RR 0.36, 95%CI 0.14-0.96, P=0.042) regimens. CONCLUSIONS: The risk of HBV reactivation is high; therefore, anti-HBV prophylaxis should be recommended in HBsAg-negative, anti-HBc-positive patients with hematological diseases and/or rituximab-containing regimens, regardless of HBV DNA and anti-HBs status. In contrast, patients with non-hematological diseases or rituximab-free regimens have a low risk of HBV reactivation and may not require anti-HBV prophylaxis if they have undetectable HBV DNA and positive anti-HBs.