COMMENTARY

HBV: React Before the Virus Does

The Key to Preventing HBV Reactivation

William F. Balistreri, MD

Disclosures

April 01, 2015

In This Article

When Does HBV Reactivation Occur?

Reactivation Following Chemotherapy

In 1991, Lok and colleagues reported that among patients being treated with a variety of chemotherapy regimens for non-Hodgkin lymphoma, HBV reactivation occurred in 48% of HBsAg-positive individuals, in 4% of anti-HBc–positive patients, but in none of the patients with no evidence of previous HBV infection (eg, anti-HBc negative).[2,27] Reactivation-related liver failure occurred in 7%, 2%, and 0% of patients, respectively.

Loomba and colleagues[28] reviewed studies directed toward prevention of HBV reactivation during chemotherapy in HBsAg-positive patients. Reactivation, which they defined as an increase in serum HBV DNA by at least 10-fold with elevations in serum ALT levels, occurred in 32% of HBsAg-positive patients. Liver failure occurred in 13% and death in 7% of the patients.

Seto and colleagues[29] studied 260 patients who were receiving rituximab-containing chemotherapy; 24% were HBsAg negative and anti-HBc positive. During a median of 70 weeks, the cumulative rate of HBV reactivation was 42%; reactivation occurred at a median of 23 weeks (range, 4-100 weeks) after rituximab treatment. The only significant risk factor that was positively associated with HBV reactivation was an undetectable anti-HBs at baseline.

The FDA Adverse Event Reporting System (AERS) collated more than 100 cases of fatal HBV reactivation in persons receiving rituximab therapy with previous or chronic HBV infection. Reports of rituximab-associated HBV reactivation led to the expanded box warning by the FDA, which strongly recommended that all patients about to undergo B-cell–depletion therapy be screened for HBV and that those candidates who are found to be positive should be considered for antiviral prophylaxis.[10,11,30,31]

Reactivation Following Biologic Agents

TNF inhibitors are highly associated with induction of HBV reactivation in view of their immunologic potency, their ubiquitous use across subspecialties, and the need for long-term administration. However, the HBV reactivation rate is lower in patients treated with anti-TNF-alpha than in chemotherapy recipients.[32]

Perez-Alvarez and colleagues[33] identified reports of 257 patients with active or recovered HBV infection treated with anti-TNF agents. Elevations in serum ALT levels were noted in 42%, symptomatic liver disease in 16%, reappearance of HBV DNA in 39%, and death related to liver failure in 5%. HBV reactivation occurred more frequently in patients receiving infliximab therapy compared with those receiving etanercept (Enbrel®). HBV reactivation was more frequent in patients who were HBsAg positive (38%) compared with those who were HBsAg negative but anti-HBc positive (5%). Approximately 40% of HBsAg carriers and 5% of anti-HBc–positive but HBsAg-negative patients developed HBV reactivation during TNF inhibitor administration in the treatment of IBD.[33]

Reactivation Following Solid-Organ Transplantation

Reported rates of HBV reactivation range from 50%-90% in HBsAg-positive patients who have undergone kidney transplantation. In these patients, reactivation is associated with liver failure, accelerated progression to cirrhosis and hepatocellular carcinoma, and increased liver-related mortality.[34] Following liver transplantation for HBV-associated liver disease, the risk for recurrent hepatitis B is 80% unless a prophylaxis regimen is instituted (oral antiviral agents with or without hepatitis B immunoglobulin).[2] The use of a liver from a donor who recovered from hepatitis B (HBsAg negative, anti-HBc positive) is associated with a 50%-75% risk for HBV infection in the recipient; this can also be prevented by antiviral prophylaxis.

Mechanisms of HBV Reactivation

Most individuals who have serologic recovery from HBV infection (HBsAg negative, anti-HBs positive, and anti-HBc positive) have undetectable HBV DNA in serum; however, HBV persists in the liver.[34] A characteristic of HBV infection is the persistence of its episomal DNA (covalently closed circular DNA), the viral transcriptional template, sequestered in the nucleus of infected hepatocytes.[35]

Viral replication is controlled by the immune system. HBV replication and the development of liver disease occur when there is an imbalance between viral mechanisms promoting persistence and host immune control.[36] The initial event in viral reactivation is thought to be disruption in the ability of the host immune system to control HBV replication.[2,13] However, the specific cellular immunologic mechanisms are not known.[4]

Salpini and colleagues[37] performed HBsAg ultra-deep sequencing in patients who developed HBV reactivation to decipher genetic features underlying this phenomenon. Of patients with reactivation, 52% were treated with rituximab, 35% with various chemotherapeutic agents, and 14% with corticosteroids only for inflammatory diseases. Before HBV reactivation, 52% of these patients had isolated anti-HBc positivity as the sole serologic marker for HBV, and 31% were inactive carriers. The investigators reported that 76% of the patients with HBV reactivation carried HBsAg mutations localized in immune-active regions of the protein. Some of these mutations were localized in T-cell epitopes, whereas others hampered the recognition of anti-HBs by providing additional N-linked glycosylation sites. This work indicates that HBV reactivation is supported by escape mutants and that reactivation correlates with HBsAg mutations endowed with enhanced capability to evade immune response.

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