HBV Reactivation: How Biologics and Chemotherapy Trigger Liver Risks and How to Prevent Them

When someone starts chemotherapy or a biologic like rituximab for cancer or rheumatoid arthritis, the last thing on their mind is their liver. But for people who’ve had hepatitis B in the past-even if they feel fine-these treatments can wake up a sleeping virus. That’s HBV reactivation, and it’s not rare. It can turn a routine treatment into a life-threatening liver crisis.

What Exactly Is HBV Reactivation?

Hepatitis B virus (HBV) doesn’t always disappear after infection. In about 5-10% of adults, the immune system clears the virus completely. But in others, especially those infected as children, the virus hides in the liver. It’s inactive, silent, and harmless-until something weakens the immune system.

That’s when reactivation happens. The virus wakes up, starts copying itself, and attacks the liver. Blood tests show a sudden spike in HBV DNA. Liver enzymes like ALT and AST rise. The patient gets jaundice, fatigue, nausea-and in severe cases, acute liver failure. Without treatment, 5-10% of these cases are fatal.

It’s not just about being HBV-positive. Even people who’ve cleared the virus (HBsAg-negative but anti-HBc-positive) are at risk. Their immune system used to keep HBV in check. But when immunosuppressive drugs shut down that defense, the virus can come back.

Which Treatments Carry the Highest Risk?

Not all drugs are created equal when it comes to triggering HBV reactivation. Some are high-risk, others low. The difference isn’t subtle-it’s life or death.

High-risk drugs (20-81% reactivation risk):

• Anti-CD20 monoclonal antibodies like rituximab and ofatumumab
• Anthracycline-based chemotherapy (used for lymphoma and breast cancer)
• Hematopoietic stem cell transplants (both autologous and allogeneic)

For example, a 2016 study in Blood found that 73% of HBsAg-positive lymphoma patients on rituximab had HBV reactivation if they didn’t get antiviral protection. That’s more than 7 in 10 people. The same study showed that with prophylaxis, that number dropped to under 5%.

Intermediate-risk drugs (1-10% risk):

• Conventional chemotherapy without high-dose steroids
• TNF-alpha inhibitors (like infliximab for Crohn’s or rheumatoid arthritis)
• Tyrosine kinase inhibitors like ibrutinib
• Transarterial chemoembolization (TACE) for liver cancer

Even these carry real danger. A 2020 study in JCO found that 18% of patients with resolved HBV infection (anti-HBc-positive, HBsAg-negative) had reactivation after high-dose chemo. That’s nearly 1 in 5.

Low-risk drugs (under 1% risk):

• Non-cytotoxic targeted therapies (like some hormone blockers)
• Non-TNF biologics (like IL-6 inhibitors)
• Most radiation therapy

But even here, exceptions exist. Radiation therapy can trigger reactivation in anti-HBc-positive patients with liver cancer, with one 2020 study showing a 14% rate.

Checkpoint Inhibitors: The New Wild Card

Immunotherapy drugs like pembrolizumab and nivolumab (PD-1 inhibitors) are changing cancer treatment. They work by revving up the immune system to attack tumors. But that same mechanism can backfire in people with hidden HBV.

A 2019 study in Hepatology followed 24 HBsAg-positive cancer patients on PD-1 inhibitors who weren’t on antivirals. 5 of them (21%) had HBV reactivation. Some developed severe hepatitis. The scary part? Their HBV DNA was undetectable before treatment. No warning signs. No red flags.

This means doctors can’t assume that low viral load equals low risk. Even patients who were "cleared" can relapse. Guidelines now say: if you’re HBsAg-positive and starting checkpoint inhibitors, you need prophylaxis-no exceptions.

Screening: The Simple Step That Saves Lives

The best way to prevent HBV reactivation? Know who’s at risk before you start treatment.

The standard test is simple: two blood tests.

• HBsAg: Tells you if the virus is currently active.
• Anti-HBc: Tells you if you’ve ever been infected.

If HBsAg is positive, you’re a carrier. You need antiviral prophylaxis before any immunosuppressive therapy.

If HBsAg is negative but anti-HBc is positive, you’ve had past infection. You’re still at risk-especially with high-dose chemo, stem cell transplants, or rituximab. For these patients, guidelines now recommend monitoring HBV DNA every 1-3 months during and after treatment. Some experts recommend prophylaxis too, especially for high-risk regimens.

If both are negative, you’re safe. No screening needed.

Dr. Robert G. Gish from the Hepatitis B Foundation says it plainly: "The cost of screening is negligible compared to the human and financial costs of managing reactivation." One blood test, $20-$50, can prevent a $500,000 liver transplant.

Prophylaxis: The Right Drug, the Right Time

If you’re at risk, you need antiviral medication before you start immunosuppressive therapy.

The two go-to drugs are tenofovir and entecavir. Both are powerful, safe, and taken as one pill a day. They suppress HBV replication so well that reactivation rates drop from 40-70% to under 5%.

Timing matters.

• Start antivirals at least 1 week before chemotherapy or biologics.
• Keep taking them during treatment.
• Continue for at least 6 months after treatment ends-for high-risk drugs, go up to 12 months.

A 2018 study in Clinical Infectious Diseases followed 1,245 HBsAg-positive patients. Those who took entecavir before and during treatment had only a 3.2% reactivation rate. Those who didn’t? 48.7%. That’s a 93% reduction.

For checkpoint inhibitors, the same rules apply. Don’t wait for symptoms. Start early.

Why Are So Many Patients Still at Risk?

The science is clear. The guidelines are solid. So why do people still die from preventable HBV reactivation?

Because implementation is broken.

A 2020 survey in Oncology found that only 58% of community oncologists screen patients before starting chemo. At academic centers? 89%. That’s a huge gap.

One reason? Many doctors don’t think it’s their job. "That’s the hepatologist’s problem," they say. But hepatologists don’t see these patients until it’s too late.

Another reason? Lack of systems. No automated alerts in electronic health records. No checklist built into the prescription flow. No one reminding the nurse to order the test.

UCSF solved this by adding mandatory HBV screening alerts to their EHR. Their reactivation rate dropped from 12.3% to 1.7% in just five years.

A case in Hepatology Communications tells the rest of the story: a 52-year-old man with lymphoma got rituximab. No screening. No prophylaxis. He died of liver failure two months later. His family sued. The hospital settled.

What’s Changing Now?

The field is evolving fast.

In 2022, a major study in the New England Journal of Medicine showed that 6 months of antiviral prophylaxis after treatment is enough for most patients. That’s half the time previously recommended. It reduces side effects, cost, and pill burden.

Point-of-care tests are coming. The OraQuick HBV rapid test, expected to be FDA-approved in late 2023, could give results in 20 minutes during a clinic visit. Imagine screening a patient right before their first chemo appointment.

Big tech is getting involved too. In January 2023, Tempus Labs partnered with Gilead Sciences to include HBV status in their genomic cancer reports. If your tumor is being analyzed for mutations, your HBV status will be flagged too.

And the market is growing. The global HBV screening market will hit $612 million by 2027. Why? Because lawsuits, deaths, and regulatory pressure are forcing hospitals to act.

What Should You Do?

If you’re about to start any of these:

• Chemotherapy
• Rituximab, ofatumumab, or similar biologics
• Stem cell transplant
• Checkpoint inhibitor therapy
• TACE for liver cancer

Ask for HBV screening. Don’t wait. Don’t assume you’re safe because you’ve never had jaundice or felt sick. You might not know you had hepatitis B.

If you’re a doctor or nurse: make screening part of your standard protocol. Add it to your checklist. Set up EHR alerts. Train your team.

If you’re a patient with past HBV infection: tell your oncologist, rheumatologist, or transplant team. Bring your old blood work. Don’t let them guess.

HBV reactivation isn’t inevitable. It’s preventable. With a simple test and a simple pill, thousands of lives can be saved every year.

The tools are here. The evidence is clear. The only thing missing is consistent action.