HBV: React Before the Virus Does

The Key to Preventing HBV Reactivation

William F. Balistreri, MD


April 01, 2015

In This Article

HBV Reactivation: Definition and Significance

The potential for progression of liver injury in patients in the inactive HBsAg carrier state is usually low; however, the potential exists for immune suppression-related reactivation of hepatitis B, which may occur in 24%-88% of patients. Reactivation can also occur in 3%-25% of patients who have recovered from HBV infection and are anti-HBc positive, with or without anti-HBs, but with no detectable HBsAg in serum.[10,11,12]

Reactivation of hepatitis B is defined as an abrupt increase in the pace of HBV replication, marked by a rise in HBV DNA levels, in a person with previously stable or undetectable levels; this is usually accompanied by liver injury (a "hepatitis flare"), as shown by elevations in serum alanine aminotransferase (ALT) levels.[2,5,13] In HBsAg carriers, reactivation is diagnosed by de novo detection of HBV DNA or a 10-fold increase in HBV DNA level when compared with the baseline value.[2,3,4,5] In patients with resolved or recovered infection, reactivation is characterized by "reverse seroconversion" to an HBsAg-positive status (reappearance of HBsAg in an anti-HBc–positive, HBsAg-negative patient).[2]

Reactivation of HBV can occur spontaneously but is more often reported to occur following the initiation of a wide variety of immune-suppressive therapies for the treatment of cancer or autoimmune disease and in patients who are solid-organ transplant recipients.[2,5,14,15] The clinical concern is that HBV reactivation in the context of immunosuppressive therapy is often associated with severe clinical symptoms.

On the basis of serologic status and the type and intensity of the immune suppression regimen, Di Bisceglie and colleagues[2] emphasize a gradation in clinical severity:

  • Silent HBV reactivation, which is an asymptomatic increase in HBV DNA levels without an increase in ALT levels; or

  • Overt HBV reactivation, which can be mild (defined as a rise in serum ALT levels without jaundice or symptoms), moderate (the appearance of jaundice or clear symptoms of liver injury such as fatigue or dark urine), or severe (the appearance of features of liver failure such as coagulopathy or hepatic encephalopathy).

The clinical picture of acute viral hepatitis may last for several weeks and delay further chemotherapy by several cycles. The reported mortality rate with reactivation of HBV is as high as 25%.[2,16] Thus, reactivation of HBV is a serious concern given its risk for hepatic failure, but this concern is compounded by its role in jeopardizing the successful treatment of a curable malignancy.[17]

HBV Reactivation: Risk Factors/Stratification

The immune system plays a critical role in suppressing HBV viral replication; thus, immunosuppression has long been recognized to increase the risk for HBV reactivation.[17,18] Reactivation of HBV virus as a complication of cancer chemotherapy and kidney transplantation was initially described in the late 1970s.[14,15] Patients who are HBsAg positive are much more likely to experience reactivation of HBV than those with recovered or resolved infection (HBsAg negative but anti-HBc positive).[19]

Risk factors include the nature, complexity, and immunologic potency of the immunosuppressive regimen.[19,20,21] The most common clinical scenarios and drugs associated with reactivation of hepatitis B include cancer chemotherapy,[22] solid-organ or bone marrow/stem cell transplantation,[23,24] and immunosuppressive therapy for such conditions as rheumatoid arthritis, psoriasis, or inflammatory bowel disease (IBD).[25] The implicated agents include conventional chemotherapeutic agents and injectable or infused biologic agents such as anti-CD20 (ofatumumab [Arzerra®] and rituximab [Rituxan®]), anti-tumor necrosis factor (TNF) agents, and corticosteroids.[2,26]

There is a risk gradient associated with each of the different immunosuppressive regimens. Therefore, to guide clinicians, the AGA report categorized immunosuppressants into low-, moderate-, or high-risk groups on the basis of estimates of reactivation using available evidence.[3,4]

The high-risk group of drugs was defined by an anticipated incidence of HBV reactivation in more than 10% of cases. Patients considered to be at the greatest risk for HBV reactivation are those who are HBsAg and anti-HBc positive or who are HbsAg negative and anti-HBc positive and are to be treated with such B-cell–depleting agents as rituximab or ofatumumab.[3,4] Patients who are HBsAg positive and anti-HBc positive to be treated with such anthracycline derivatives as doxorubicin (Doxil®) or epirubicin (Ellence®) and HBsAg-positive and anti-HBc–positive patients to be treated with moderate- or high-dose corticosteroids for 4 weeks or longer are also at high risk. The AGA recommends antiviral prophylaxis over no prophylaxis for patients at high risk undergoing immunosuppressive drug therapy.[3,4]

The moderate-risk group was defined by anticipated incidence of HBV reactivation of 1%-10% of cases. The AGA suggests antiviral prophylaxis over monitoring for patients at moderate risk who are undergoing immunosuppressive drug therapy.[3,4]

The AGA suggests against routinely using antiviral prophylaxis in patients undergoing immunosuppressive drug therapy who are at low risk for HBV reactivation, defined by anticipated incidence of HBV reactivation of less than 1% of cases.[3,4]


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