HBV Reactivation: How Biologics and Chemotherapy Trigger Liver Risks - And How to Prevent It

When someone starts treatment for cancer or an autoimmune disease, they expect relief - not a sudden, dangerous flare-up of a virus they didn’t even know they carried. But for people with hidden hepatitis B virus (HBV), powerful drugs like biologics and chemotherapy can accidentally wake up the virus, leading to liver failure or death. This isn’t rare. It happens more often than most doctors and patients realize - and it’s almost always preventable.

What Exactly Is HBV Reactivation?

HBV reactivation means a dormant hepatitis B virus suddenly starts multiplying again in the body. It doesn’t mean you got a new infection. It means your immune system, which had kept the virus under control for years, got knocked out by drugs meant to treat something else. Once that happens, the virus can flood your liver, trigger inflammation, and destroy liver cells. In severe cases, it leads to acute liver failure - and about 5 to 10% of these cases are fatal.

This isn’t theoretical. In the 1970s, doctors first noticed it in cancer patients getting chemotherapy. Back then, many died without knowing why. Today, we know the trigger: immunosuppression. The stronger the drug, the higher the risk. Drugs like rituximab (used for lymphoma), anthracyclines (common in breast cancer), and even checkpoint inhibitors like pembrolizumab can cause reactivation. Even radiation therapy carries a 14% risk in people with past HBV infection.

Who’s at Risk? It’s Not Just Carriers

Many people think only those who test positive for HBsAg - the surface antigen - are at risk. That’s a dangerous myth. About 1 in 10 people globally have been exposed to HBV. Some cleared it naturally. Their bodies still carry traces: the core antibody (anti-HBc) stays positive for life. These people are called “resolved” or “occult” carriers. They feel fine. They don’t need treatment. But if you give them strong immunosuppressants? Their risk of reactivation jumps to 10-18%, especially with high-dose chemo or stem cell transplants.

Here’s how the risk breaks down by group:

• HBsAg-positive: 20-81% risk, depending on the drug. Rituximab? Up to 73%. Stem cell transplant? Over 80%.
• HBsAg-negative, anti-HBc-positive: 1-18% risk. Highest with B-cell depleting drugs and high-dose chemo.
• Both negative: Less than 0.1% risk. No prophylaxis needed.

That’s why screening isn’t optional - it’s the first line of defense. You can’t protect someone if you don’t know they’re at risk.

The Three Stages of Reactivation

HBV reactivation doesn’t happen overnight. It follows a clear pattern:

1. Stage 1: Silent Replication - Immunosuppression weakens the body’s control over the virus. HBV DNA levels rise, but liver enzymes (ALT, AST) stay normal. No symptoms.
2. Stage 2: Immune Rebound - As the immune system starts recovering (or the drug wears off), T-cells attack infected liver cells. ALT spikes. Jaundice, fatigue, nausea appear. This is when liver damage accelerates.
3. Stage 3: Resolution or Failure - If antivirals are given early, the virus is suppressed and the liver heals. If not? Liver failure, transplant, or death.

The biggest danger? Stage 1. No symptoms. No warning. By the time jaundice shows up, it’s often too late.

Which Drugs Are the Biggest Threat?

Not all immunosuppressants are equal. Here’s what the data says:

Notice something? Even drugs labeled as “low-risk” can be dangerous if you’re unaware of past HBV exposure. That’s why universal screening is non-negotiable.

Screening: The Simple Test That Saves Lives

Before any immunosuppressive therapy - whether it’s for rheumatoid arthritis, lymphoma, or breast cancer - every patient needs two blood tests:

• HBsAg - tells you if the virus is currently active.
• Anti-HBc - tells you if you’ve ever been exposed.

If HBsAg is positive? You’re at high risk. Start antivirals before the first dose of chemo or biologic. If anti-HBc is positive but HBsAg is negative? You’re still at moderate-to-high risk. Prophylaxis is still recommended for most high-intensity therapies.

Don’t wait for symptoms. Don’t assume the patient “never had hepatitis.” Many people never knew they were infected. In Asia and Africa, up to 10% of the population has past HBV. Even in the UK and US, 0.5-1% of adults are anti-HBc positive. That’s tens of thousands of people at risk every year.

Prophylaxis: The Right Drug, the Right Time

Once screening identifies risk, prophylaxis is simple and effective. The two go-to antivirals are:

• Tenofovir (TDF or TAF)
• Entecavir

Both are powerful, have minimal side effects, and rarely lead to resistance. Studies show they cut reactivation risk from over 40% down to under 5%.

Timing matters:

• Start antivirals at least one week before starting immunosuppression.
• Continue for 6-12 months after therapy ends. For B-cell depleting agents like rituximab, go for 12 months - the immune system takes longer to recover.
• For checkpoint inhibitors, continue for at least 6 months after the last dose.

A 2022 study in the New England Journal of Medicine showed 6 months is enough for most patients - a big shift from older guidelines that pushed for a full year. But for rituximab? Stick with 12. Don’t guess. Follow the data.

Why Do So Many Patients Still Get Hit?

Screening works. Prophylaxis works. So why do cases still happen?

Because implementation is broken.

A 2020 survey found only 58% of community oncologists screen patients before starting treatment. In academic hospitals? 89%. That’s a 31-point gap. Why? Busy clinics. Lack of protocols. Assumptions. “They’re young. They’re healthy. They wouldn’t have hepatitis.”

One case report tells the whole story: a 52-year-old man with lymphoma got rituximab without screening. Three weeks later, he was in liver failure. He died. He’d been born in Bangladesh. His family never told him he had hepatitis as a child. No one asked.

At UCSF, they fixed this by adding automated alerts in their electronic health record. If a patient is scheduled for chemo and hasn’t had HBV screening, the system blocks the order until it’s done. Result? Reactivation rates dropped from 12.3% to 1.7% in just five years.

What About the Cost? Is It Worth It?

Some argue screening and prophylaxis are too expensive. But the math doesn’t add up.

Screening costs $20-$50 per patient. A full course of tenofovir for 6 months? About $300. Treating acute liver failure? $100,000+. A transplant? Over $800,000.

Dr. Anna S. Lok at the University of Michigan says the number needed to treat to prevent one reactivation is just 3. That’s better than most cancer screenings.

And the cost of not doing it? Legal liability. In 12% of oncology malpractice claims involving infections, HBV reactivation was the cause. Hospitals are now being sued for failing to screen. The FDA now requires HBV warnings on every biologic’s label. Ignorance is no longer an excuse.

What’s Next? The Future of Prevention

The tools are getting better. Point-of-care rapid tests - like the OraQuick HBV test - are coming. In 2023, they’re expected to get FDA approval. Imagine a doctor’s office doing a finger-prick test before giving the first dose of rituximab. No lab wait. No missed steps.

Companies like Tempus Labs are now embedding HBV status into genomic cancer reports. Your tumor profile will also tell you: “HBV status: positive - prophylaxis required.”

But the biggest barrier isn’t technology. It’s culture. Too many doctors still think, “This isn’t my problem.” Hepatitis B is liver disease. Liver disease is gastroenterology. But reactivation happens because of oncology, rheumatology, transplant medicine. It’s a team sport.

Every specialist who prescribes immunosuppressants needs to know: Screen first. Treat early. Don’t wait for symptoms.

Bottom Line: Don’t Let a Hidden Virus Kill

HBV reactivation is one of the most preventable disasters in modern medicine. We have the tests. We have the drugs. We have the guidelines. What we’re missing is consistency.

If you’re a patient about to start chemo, a biologic, or a transplant - ask: “Have you checked for hepatitis B?” If you’re a doctor - make screening mandatory. Don’t assume. Don’t delay. One blood test, one conversation, could save a life.

Because sometimes, the biggest threat isn’t the cancer. It’s the virus you never knew was there.