Low Risk of Hepatitis B Reactivation in Patients With Severe COVID-19 Who Receive Immunosuppressive Therapy

Sergio Rodríguez-Tajes; Anna Miralpeix; Josep Costa; Ester López-Suñé; Montserrat Laguno; Anna Pocurull; Sabela Lens; Zoe Mariño; Xavier Forns


J Viral Hepat. 2020;28(1):89-94. 

In This Article


The results of our study show that a short course of immune modulator therapy does not appear to increase the risk of HBV reactivation in patients with severe COVID-19 with markers of past HBV infection. Drugs used to treat the disproportionate immune response after SARS-CoV-2 infection (mainly IL-6 receptor antagonists or high-dose corticosteroids) are considered of moderate risk for HBV reactivation in HBsAg-negative/anti-HBc-positive individuals.[5,6] Nevertheless, we decided to recommend NUC prophylaxis for several reasons. First, a significant proportion of patients admitted to the hospital with severe COVID-19 are old males with significant comorbidities, which are considered risk factors for HBV reactivation. Second, SARS-CoV-2 infection induces significant lymphopenia, which might increase the possibility of HBV reactivation. Finally, due to the extremely high burden of the pandemics on our healthcare system, we could not guarantee a proper follow-up after patient discharge from the hospital, particularly older patients who returned to a nursing home. The latter is highly recommended for patients at risk of HBV reactivation if no prophylaxis is indicated.

Despite the strong recommendation to include HBV prophylaxis in patients undergoing immune suppressive treatment, not all treating physicians indicated entecavir. The latter allowed us to compare outcomes of individuals with and without HBV prophylaxis. The main baseline features of both groups were comparable, and we only detected positive HBV-DNA in two patients who had not received entecavir prophylaxis. The two cases were anti-HBs negative. In both cases, HBV-DNA remained below the limit of quantification and was not accompanied by ALT elevations.

Our data regarding the low risk of HBV reactivation using IL-6 receptor antagonists are supported by some reports in patients with rheumatoid arthritis.[10,11] In a recent study, which included 152 patients with resolved HBV infection treated with disease-modifying anti-rheumatic drugs (25 with tocilizumab), the risk of HBV reactivation was very low (<5%).[10] Nevertheless, patients who were anti-HBs negative showed a significantly higher incidence of HBV reactivation (15%), as already reported in other studies.[7] Reactivation, defined as detectable HBV-DNA at any point during therapy, tended to occur several months after immunosuppressive treatment initiation (in contrast with the short course therapy in our scenario). In cases where HBV-DNA did not rise above the limit of quantification, antiviral treatment was not indicated and the final outcome was excellent. A completely different scenario applies to patients with active infection (HBsAg positive), in whom cases of reactivation and even fulminant hepatic failure have been reported during tocilizumab therapy.[12]

Regarding the high prevalence of abnormal aminotransferases, our results are consistent with other articles were the liver impairment has been reported in up to 75% in patients with severe COVID-19.[13] The mechanism of liver damage during COVID-19 is not fully understood but it seems related, at least in part, with the highly activated inflammatory status[14] (though it can be influenced by multiple additional factors, as drug toxicity). The elevation of aminotransferases is usually mild and transient,[15] as seen in our patients.

Our study has several limitations. First, the small sample size, which does not allow to draw definitive conclusions. Second, the fact that this was not a randomized study: the decision to indicate NUC prophylaxis in HBsAg-negative anti-HBc-positive patients depended on the treating physician, although we did not find significant differences between treated and untreated patients. Third, the duration of NUC prophylaxis is arguable. We based our decision on the fact that most patients received a single dose of immune modulator. Moreover, except for patients with suspected organizing pneumonia, duration of corticosteroid treatment did not overcome 1 month. In addition, due to characteristics of patients with severe COVID-19 (old age, comorbidities, residency at nursing homes), we chose to minimize pill burden and medical interventions.

In summary, our data show that the risk of HBV reactivation in patients with severe COVID-19 and resolved HBV infection undergoing immune modulator treatment is low. Follow-up after patient discharge is recommended, but if this is not possible due to the burden of the pandemic, a short course of antiviral prophylaxis may be a safe alternative in patients without anti-HBs.