Understanding hepatitis B virus reactivation in non-Hodgkin's lymphoma patients with resolved HBV infection
Imagine finishing cancer treatment, only to face a life-threatening liver infection you didn't know you still carried. This isn't theoretical—it's the reality for many non-Hodgkin's lymphoma patients with a history of hepatitis B. In 2025, doctors reported a tragic case of a patient who had apparently beaten hepatitis B decades earlier. Their blood tests showed protective antibodies, all traces of the virus seemed gone, and they had no symptoms. Then came lymphoma treatment with powerful immunosuppressive drugs, including rituximab. Suddenly, the hepatitis B virus reactivated violently, appearing without the usual antibody response, ultimately proving fatal despite medical intervention 5 .
This scenario represents one of oncology's most insidious complications: hepatitis B virus (HBV) reactivation. For the millions living with both resolved hepatitis B and blood cancers, this threat looms large during treatment.
The very therapies that save them from cancer can inadvertently awaken dormant viruses, with potentially devastating consequences. Understanding this phenomenon isn't just academic—it's crucial for patient safety, affecting treatment decisions and outcomes across medical specialties.
Hepatitis B is notoriously difficult to completely eradicate from the human body. Unlike many viruses that leave after acute infection, HBV has a remarkable ability to embed its genetic material permanently inside liver cells. This occurs through covalently closed circular DNA (cccDNA), which serves as a molecular blueprint for producing new virus particles 8 .
Even when the immune system successfully controls the infection—clearing the detectable virus from the blood and producing protective antibodies—these viral blueprints can remain dormant in the liver for decades, waiting for an opportunity to reawaken 8 .
Under normal circumstances, the immune system—particularly B-cells and T-cells—maintains constant surveillance, suppressing any hepatitis B virus that tries to reactivate from these reservoirs. However, when patients receive immunosuppressive therapies for conditions like non-Hodgkin's lymphoma, this delicate balance is disrupted 8 .
B-cell depleting therapies like rituximab pose particular risk because they directly target the very cells that produce antibodies against viruses like hepatitis B 6 8 .
HBV establishes infection with cccDNA forming reservoirs in liver cells
Immune system controls viral replication; patient develops antibodies (anti-HBs, anti-HBc)
Cancer treatment (chemotherapy, immunotherapy) weakens immune surveillance
Dormant HBV begins replicating, potentially leading to hepatitis flares and liver damage
While we've long known that patients with active hepatitis B or positive core antibodies face reactivation risks, a 2025 study from Guangdong Provincial People's Hospital made a startling discovery: even lymphoma patients who tested negative for both hepatitis B surface antigen (HBsAg) and HBV DNA—the so-called "double-negative" patients—could experience reactivation 1 9 .
This comprehensive research analyzed 616 double-negative lymphoma patients treated between 2019 and 2021. The results challenged conventional medical wisdom:
| Characteristic | Category | Number of Patients | Reactivation Cases | Reactivation Rate |
|---|---|---|---|---|
| HBcAb Status | Positive | 410 | 41 | 10.00% |
| Negative | 206 | 3 | 1.46% | |
| Age Group | ≤60 years | 376 | 15 | 3.99% |
| >60 years | 240 | 29 | 12.08% | |
| Gender | Male | 358 | 24 | 6.70% |
| Female | 258 | 20 | 7.75% |
Studying hepatitis B reactivation requires sophisticated laboratory tools to detect subtle changes in viral behavior and immune response. The Guangdong study employed several advanced techniques that represent the gold standard in viral hepatitis research 9 :
Function: Fully automated electrochemiluminescence detection
Application: Quantifies HBsAg and HBcAb with high precision
Function: Automated nucleic acid extraction and amplification
Application: Detects and quantifies HBV DNA levels as low as 20 IU/mL
Function: Specific binding to viral antigens and DNA
Application: Ensures consistent, reproducible test results across studies
Function: Quantitative PCR for viral load measurement
Application: Tracks minute changes in viral replication activity
In response to mounting evidence, medical organizations have updated their guidelines. The American Gastroenterological Association's 2025 recommendations emphasize:
The Canadian Association for the Study of the Liver similarly recommends triple-panel testing (HBsAg, anti-HBs, and anti-HBc) for all adults, reflecting growing recognition that reactivation risk extends beyond the obvious candidates 4 .
The case of Bruton tyrosine kinase inhibitors is particularly instructive—a 2025 study documented the first HBV-related death in a patient receiving zanubrutinib despite previous entecavir prophylaxis, highlighting the potent immunosuppression of these newer agents 7 .
The silent threat of hepatitis B reactivation in apparently cured patients represents one of modern medicine's most challenging paradoxes: how to manage invisible viral reservoirs awakened by life-saving treatments. The tragic case of the anti-HBs positive, anti-HBc positive lymphoma patient who succumbed to reactivation reminds us that our current screening methods, while improved, remain imperfect 5 .
The groundbreaking discovery that reactivation can occur even in double-negative patients underscores how much we still have to learn about viral latency 1 9 . It suggests that current serological markers may miss some at-risk individuals and that age plays a more significant role than previously recognized.
As cancer treatments evolve toward more targeted immunotherapies, the landscape of HBV reactivation risk will continue to shift. The recent inclusion of CAR-T cell therapy and immune checkpoint inhibitors as recognized risk factors in major guidelines demonstrates this evolving understanding 2 8 .
For patients and doctors alike, the lesson is clear: comprehensive HBV screening using the triple panel (HBsAg, anti-HBs, and anti-HBc) should be standard before starting any immunosuppressive therapy. For those with evidence of past infection, close consultation with both oncologists and liver specialists is essential to balance cancer treatment efficacy with hepatitis B reactivation prevention.
Though challenges remain, the growing recognition of this threat—and the development of clearer management guidelines—offers hope that future patients can receive life-saving cancer treatments without awakening this sleeping dragon.