HBV reactivation can cause severe liver injury with jaundice, hepatic failure, and death.
Occurs in patients receiving immunosuppressive drug therapy.
Prophylactic anti viral therapy is highly effective in preventing HBV reactivation.
Rate of HBV reactivation among patients who are HB-sAg-positive and receiving chemotherapy is 40%.
Among patients who have reactivation on chemotherapy, the risk of liver failure is 13% in the risk of mortality is 16%.
Reactivation of hepatitis B virus (HBV) is a syndrome characterized by the reappearance of HBV particles in patients with previously resolved HBV or an increase in HBV viremia in patients with previously inactive chronic hepatitis B.
Reactivation hepatitis B can occur spontaneously, but it is more commonly triggered by immunosuppressive therapies.
Reactivation can cause significant morbidity and mortality but is preventable if at-risk individuals are identified through screening and started on antiviral prophylaxis if indicated.
In patients with chronic hepatitis B defined as HBV surface antigen positive [HBsAg+] for at least 6 months and measurable HBV DNA in the blood, or a a rise in HBV DNA above baseline.
In patients with resolved HBV (HBsAg−, anti-HBV-core antibody positive [anti-HBc+]), reactivation is defined by either the appearance of HBV DNA in the blood or conversion to the HBsAg+ state: reverse seroconversion.
The key molecular agent driving HBV reactivation is covalently closed circular DNA (cccDNA).
During an acute HBV infection, HBV viral particles enter hepatocytes by receptor-mediated endocytosis.
The partially double-stranded HBV genome is imported to the nucleus.
In the nucleus both viral and host machinery complete a full-length cccDNA molecule, or mini-chromosome.
The mini-chromosome persists as the reservoir for both new viral particles and more cccDNA.
Acute HBV infection in adults generally resolves without development of chronic hepatitis B, the persistent cccDNA poses a risk for reactivation.
Both patients with chronic hepatitis B and patients with resolved HBV are at risk for HBV reactivation in the setting of chronic immunosuppression.
Reactivation rates with immunosuppression are as high as 41.5% (resolved HBV) and 70% (Chronic hepatitis B ).
HBV life cycle. Step 1: viral particles are first internalized through receptor-mediated endocytosis by binding cell surface transporters.
Step 2: nucleocapsids are then uncoated in the cytoplasm, releasing the partially double-stranded viral genomes that are imported into the nucleus.
Step 3: viral genomes are converted to cccDNA molecules.
Step 4: cccDNA serves as a template for viral mRNA, which in step 5 is exported to the cytoplasm.
Step 6: cytoplasmic mRNA is translated to produce the viral surface, core, polymerase, and X proteins.
Viral capsids assemble, incorporating genomic viral RNA, which is reverse transcribed back into a viral DNA genome.
Step 7: the resulting nucleocapsid cores can either enter the endoplasmic reticulum to be exported from the cell or recycle their genomes into the nucleus to replenish the reservoir of cccDNA.
HBV reactivation manifests in several ways, including: (1) silent reactivation, elevated viral load without overt hepatitis; (2) HBV-associated hepatitis, elevated viral load and evidence of clinical, biochemical, or histological hepatitis; and (3) fulminant liver failure, elevated viral load with hepatic synthetic dysfunction, encephalopathy, and coagulopathy.
Prevention of HBV reactivation is critical and requires: (1) recognizing the need to screen patients about to receive immunosuppressive therapies, (2) stratifying risk based on virological data and immunosuppression regimen, and (3) tailoring management based on risk to close monitoring with on-demand antiviral therapy or antiviral prophylaxis.
Moderate or low risk: on-demand therapy-monitor HBsAg and/or HBV DNA every 1-3 months; treat if +DNA or reverse seroconversion.
Patients with a >10% and >1% risk for reactivation are considered high and moderate risk, respectively.
Most guidelines recommend that any patient due to receive chronic immunosuppression or cytotoxic chemotherapy should be screened for HBsAg and anti-HBc regardless of endemicity.
HBV screening patterns at a cancer center showed that only 16.7% of 10,729 patients had HBV serologies checked: prevalence rate of CHB was 1.5% and the prevalence rate of isolated anti-HBc positivity was 7.4%, suggesting that many at-risk patients were missed.
Patients with CHB have a higher risk than patients with resolved HBV.
Hematopoietic stem cell transplant (HSCT) recipients and B cell–depleting therapies, such as rituximab, confer the highest risk.
Anthracyclines and moderate-dose corticosteroids confer higher risk than other immunosuppressive agents.
For patients with CHB, antiviral prophylaxis therapy should be started before and continued well after cessation of immunosuppression, generally 12 to 18 months if high-potency therapies are used and 6 to 12 months for other agents.
Once antiviral prophylaxis is withdrawn, continued biochemical monitoring, citing a large proportion of reactivation cases occurring after antiviral withdrawal.
Resolved HBV patients on potent immunosuppression should be treated similarly to immunosuppressed patients with chronic hepatitis B with prophylaxis starting before immunosuppression, continued 12 to 18 months after cessation, and monitoring for 12 months after antiviral withdrawal.
For resolved HBV patients not on a high-potency regimen, it is recommended these patients be monitored with serial labs: alanine aminotransferase, HBV DNA, HBsAg, at 1- to 3-month intervals and up to 12 months after cessation of therapy with on-demand antiviral therapy if needed.
Guidelines recommend the nucleoside inhibitors tenofovir and entecavir (ETV) as first-line therapy for both prophylaxis and treatment, citing several meta-analyses demonstrating higher efficacy and barriers to resistance compared with lamivudine.
The rate of HBV reactivation was significantly lower in the entecavir group, 4.82%, compared with the lamivudine group (18.08%).
Significantly lower HBV reactivation rates with tenofovir disoproxil fumarate compared with lamivudine.
During an acute HBV infection, HBV viral particles enter hepatocytes by receptor-mediated endocytosis.
The partially double-stranded HBV genome is imported to the nucleus, where both viral and host machinery complete a full-length cccDNA molecule, or mini-chromosome.
This mini-chromosome persists as the reservoir for both new viral particles and more cccDNA.
Acute HBV infection in adults generally resolves without development of CHB, persistent cccDNA still poses a risk for reactivation.
Both patients with CHB and patients with resolved HBV are at risk for HBV reactivation when undergoing chronic immunosuppression.
In areas where HBV is endemic, HBV reactivation rates with immunosuppression are as high as 41.5% with resolved HBV and 70% in CHB).
HBV reactivation manifests clinically by: silent reactivation, elevated viral load without overt hepatitis; HBV-associated hepatitis, elevated viral load and evidence of clinical, biochemical, or histological hepatitis; and by fulminant liver failure, elevated viral load with hepatic synthetic dysfunction, encephalopathy, and coagulopathy.
Prevention of HBV reactivation requires: recognizing the need to screen patients about to receive immunosuppressive therapies, stratifying risk based on virological data and immunosuppressive regimen, and management based on risk, from close monitoring, antiviral therapy or antiviral prophylaxis.
Patients with a >10% and >1% risk for reactivation are considered high and moderate risk, respectively.
Most guidelines recommend that any patient due to receive chronic immunosuppression or cytotoxic chemotherapy should be screened for HBsAg and anti-HBc regardless of endemicity.
Practice patterns fall short of this recommendation.
A review of HBV screening patterns at a cancer center report low screening rates.
Patients with CHB have a higher risk than patients with resolved HBV.
Among immunosuppressive regimens, hematopoietic stem cell transplant (HSCT) recipients and B cell–depleting therapies, such as rituximab confer the highest risk.
Anthracycline and moderate-dose corticosteroids confer higher risk than other immunosuppressive agents.
For patients with CHB, antiviral prophylaxis should be started before and continued well after cessation of immunosuppression, generally 12 to 18 months if high-potency therapies are used and 6 to 12 months for other agents.
Once prophylaxis agents are withdrawn, continued biochemical monitoring occurs, as a large proportion of reactivation cases occurring after antiviral withdrawal.
Resolved HBV patients on high-potency immunosuppression should be treated similarly to immunosuppressed patients with CHB, with prophylaxis starting before immunosuppression, and continued 12 to 18 months after cessation, and monitoring for 12 months after antiviral withdrawal.
Guidelines recommend the nucleoside inhibitors tenofovir and entecavir (ETV) as first-line therapy for both prophylaxis
and treatment: higher efficacy and barriers to resistance compared with lamivudine.