Hepatitis B virus reactivation in seronegative patients with latent hepatitis B treated with ibrutinib Journal of Virology

A 61-year-old woman presented with chronic lymphocytic leukemia (CLL) in November 2000. From February 2001 to June 2002, she was treated with fludarabine, mitoxantrone, and dexamethasone, followed by chlorambucil.

She was in good health until 2021, when she developed a tonsil mass, which a biopsy revealed was small lymphocytic lymphoma (SLL). She received the anti-CD20 antibody rituximab, but during the first infusion she could tolerate less than 10% of the intended dose and subsequently developed a severe infusion reaction, leading to discontinuation of treatment. Treatment was then changed to ibrutinib (420 mg/day). Before starting rituximab, she was negative for HBsAg and anti-HBc. Serum HBV-DNA was not detected.


Four months after ibrutinib treatment, her alanine aminotransferase (ALT) level suddenly increased to 350 U/L. HBsAg was positive, and the HBV DNA quantification was 1.92 × 108 IU/ml, confirming hepatitis B-related hepatitis. She had not received any blood products in the previous months and had no known HBsAg+ household contacts. Antibodies to hepatitis A, hepatitis C, and hepatitis E viruses were negative. Ultrasonography did not reveal any liver pathology. Since there was no clinical or serological evidence of HBV exposure in recent years, HBV reactivation was diagnosed as seronegative latent hepatitis B infection. Entecavir 0.5 mg/day was started.

Results and follow-up actions

After entecavir treatment, her liver function improved and her HBV DNA level decreased from 1.92 × 108 IU/ml increased to 33,900 IU/ml within 4 months. Intentional overdose of paracetamol (the exact dose ingested is unknown) complicates the clinical course. ALT rose to 1956 U/L, and aspartate aminotransferase rose to 1324 U/L. N-acetylcysteine ​​improved. However, her serum HBV DNA was still high at 33,900 IU/ml. Tenofovir alafenamide 25 mg/day was added for better HBV control. At the last follow-up visit 6 months after the first HBV reactivation, she remained asymptomatic with an ALT of 180 U/L and HBV DNA of 2450 IU/ml (Fig. 1). Her blood values ​​obtained before, during, and after HBV reactivation are shown in Table 1.

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figure 1

Overview of hematological disorders and hepatitis B virus reactivation

Table 1 Blood values ​​obtained before, during and after reactivation

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