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

Abstract and Introduction


A significant proportion of patients infected with SARS-CoV-2 develop severe respiratory symptoms due to an excessive immune response. Treatment of this condition may include immunosuppressive therapies, such as IL-6 receptor antagonists and corticosteroids, which pose a risk for patients with active or past hepatitis B virus (HBV) infection. In this prospective cohort study, we analysed the risk of HBV reactivation in patients with severe COVID-19 and resolved HBV infection undergoing immunosuppressive therapy. From 15th March to 30th April 2020, 600 patients with severe COVID-19 were admitted to our hospital and treated with immune modulators. Data regarding HBV infection were available in 484, of whom 69 (14%) were HBsAg negative/anti-HBc positive. For these patients, HBV reactivation prophylaxis with entecavir was strongly recommended. Complete follow-up was available in 61 patients: 72% were male, median age was 67 years, and anti-HBs was >10 IU/mL in 72%. The immunosuppressive drug most used was tocilizumab (72%). Despite HBV prophylaxis recommendation, 38 (62%) patients received entecavir and 23 (38%) did not. Baseline features of both groups were similar. At follow-up, we found no cases of HBsAg seroreversion and only 2 (3%) patients (no prophylaxis group) had detectable serum HBV-DNA (<15 IU/mL). Both were anti-HBs negative and had normal aminotransferase levels. Our data show that the risk of HBV reactivation in patients with severe COVID-19 and resolved HBV infection undergoing immunosuppressive treatment is low. However, if a systematic follow-up after hospital discharge is unfeasible in patients without anti-HBs, a short course of antiviral prophylaxis may be a safe option.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally, causing a pandemic with more than 34 million infections worldwide and 1 millon fatalities so far. COVID-19 (the disease caused by SARS-CoV-2) is usually mild, but around 20% of infected individuals develop severe respiratory symptoms that require hospitalization and, in some cases, intensive care support.[1,2] Although the pathogenesis of SARS-CoV-2 infection is not yet completely understood, in some patients there is an excessive immune response to the virus, known as a 'cytokine storm'. The latter mediates severe lung inflammation, and for this reason, patients are treated with immunosuppressive therapies aimed at limiting immune-mediated damage.[3] Corticosteroids, IL-6 and IL-1 receptor antagonists, and Janus kinase inhibitors are some of the drugs that have been used in patients with severe COVID-19. The use of these drugs may pose a risk for patients with active or past hepatitis B virus (HBV) infection.

Hepatitis B reactivation associated with immune suppressive and biological therapies is an important cause of morbidity and mortality in patients with current or past exposure to HBV.[4] In HBsAg-positive patients, HBV reactivation is defined as a sudden and rapid increase in HBV-DNA levels in patients with previously detectable DNA or reappearance of HBV-DNA in individuals who did not have viremia before the initiation of immune suppressive therapy.[5] In individuals who are initially negative for HBsAg and anti-HBc positive, HBV reactivation is defined by appearance of HBsAg and/or HBV-DNA. Following HBV reactivation, ALT elevation can occur and, in some cases, this can evolve into a fulminant hepatic failure.

The risk of HBV reactivation is highly dependent on the status of HBV infection, as well as on the type of immune suppressive therapy. The highest risk of reactivation occurs in patients with active or past HBV infection treated with B-cell–depleting agents such as rituximab, and in HBsAg-positive patients who receive high-dose corticosteroids, anthracyclines or potent TNF-alfa inhibitors.[5–7] Except for high-dose corticosteroids, all the immune modulators used to treat cases of severe COVID-19 are considered of low risk, particularly in HBsAg-negative anti-HBc-positive patients.

Since past HBV infection is a relatively common condition (≈10%),[8] our aim was to assess the risk of HBV reactivation and the utility of nucleoside analog (NUC) prophylaxis in HBsAg-negative/anti-HBc-positive patients who were admitted to the hospital for severe COVID-19 and underwent immune suppressive therapy.