Reactivation of hepatitis B virus after transarterial chemo-embolization for hepatocellular carcinoma in one patient with negative hepatitis B surface antigen
Authors: Hung-Hsu Hung, Chien-Wei Su, Jaw-Ching Wu, Shou-Dong Lee
Journal: Journal of Hepatology (2009)

Successful use of entecavir for a severe case of reactivation of hepatitis B virus following polychemotherapy containing rituximabJournal of HepatologyVol. 51Issue 6PreviewHepatitis B virus (HBV) reactivation following treatment with rituximab has been reported in patients with either HBsAg-positive, or HBsAg-negative and anti-HBc positive infection. Patients with severe reactivation often have a fatal outcome despite treatment with lamivudine. The use of entecavir has not been reported in patients with severe HBV reactivation. Full-Text PDF Open Access We read with interest the excellent paper by Sanchez et al., demonstrating successful entecavir treatment of a patient who developed severe reactivation of hepatitis B virus (HBV) due to potent chemotherapy containing rituximab [[1]Sanchez M.J. Buti M. Homs M. Palacios A. Rodriguez-Frias F. Esteban R. Successful use of entecavir for a severe case of reactivation of hepatitis B virus following polychemotherapy containing rituximab.J Hepatol. 2009; 51: 1091-1096Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar]. The reactivation of HBV following treatment with chemotherapy is well recognized and the incidence can be substantially decreased by pre-emptive anti-viral therapy [[2]Hsu C. Hsiung C.A. Su I.J. Hwang W.S. Wang M.C. Lin S.F. et al.A revisit of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-Hodgkin's lymphoma: a randomized trial.Hepatology. 2008; 47: 844-853Crossref PubMed Scopus (264) Google Scholar]. It occurs in two clinical settings: (1) in chronic carriers with positive hepatitis B surface antigen (HBsAg) and (2) in those with prior HBV infection who are HBsAg-negative and have antibodies against hepatitis B core antigen (anti-HBc) [3European Association for the Study of the LiverEASL Clinical Practice Guidelines: management of chronic hepatitis B.J Hepatol. 2009; 50: 227-242Abstract Full Text Full Text PDF PubMed Scopus (1481) Google Scholar, 4Yeo W. Chan T.C. Leung N.W. Lam W.Y. Mo F.K. Chu M.T. et al.Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab.J Clin Oncol. 2009; 27: 605-611Crossref PubMed Scopus (532) Google Scholar]. For HBsAg-positive patients with hepatocellular carcinoma (HCC), transarterial chemo-embolization (TACE) can also lead to the reactivation of HBV replication [[5]Jang J.W. Choi J.Y. Bae S.H. Yoon S.K. Chang U.I. Kim C.W. et al.A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization.Hepatology. 2006; 43: 233-240Crossref PubMed Scopus (167) Google Scholar]. Nevertheless, whether TACE causes severe reactivation of the virus for patients with resolved HBV infection is still unknown. Herein, we report a case with negative HBsAg presenting with reactivation of HBV after the application of TACE for HCC (see Fig. 1). This 78-year-old male patient had a history of HBV infection for more than three decades with irregular follow-up. HBsAg loss was found in 2006. However, he had no detectable antibody to hepatitis B surface antigen (anti-HBs) at that time and had not received follow-up since then. This time, HCC was diagnosed due to an abdominal computed tomography (CT) scan disclosing a solitary mass 8.3 cm in size with early enhancement in the arterial phase and rapid washout in the portal-venous phase at the right lobe of the liver. Serum biochemistry test results were as follows: alanine aminotransferase (ALT) 33 IU/L (normal, 0–40 IU/L), aspartate aminotransferase (AST) 80 IU/L (normal, 5–45 IU/L), total bilirubin 0.45 mg/dl (normal, 0.2–1.6 mg/dl), and alpha-fetal protein (AFP) 122,000 ng/ml (normal, <20 ng/ml). The HBV markers were as follows: HBsAg negative, anti-HBs negative, and anti-HBc positive (see Fig. 1). The patient refused resection surgery and underwent TACE three times from October 2008 to February 2009. However, elevated serum AST (628 IU/L) and ALT (637 IU/L) levels were found in April 2009. Serum HBsAg reverted back to positive and the HBV DNA level was 3.84 × 105 IU/ml measured by polymerase chain reaction (PCR) (Roche Diagnostics, Basel, Switzerland) with a limit of detection of 6 IU/ml. Anti-viral therapy with entecavir was prescribed in a dosage of 0.5 mg orally once a day with the diagnosis of chronic hepatitis B with acute exacerbation. After entecavir therapy for two months, serum HBsAg became negative again with undetectable HBV DNA by PCR. The serum bilirubin level was not elevated in this period. According to the recent clinical practice guidelines of the European Association for the Study of the Liver (EASL), all candidates for chemotherapy should be tested for HBsAg and anti-HBc before treatment [[3]European Association for the Study of the LiverEASL Clinical Practice Guidelines: management of chronic hepatitis B.J Hepatol. 2009; 50: 227-242Abstract Full Text Full Text PDF PubMed Scopus (1481) Google Scholar]. HBsAg-positive patients should receive pre-emptive anti-viral therapy during therapy and an additional 12 months of consolidation therapy after the cessation of chemotherapy. However, for HBsAg-negative, anti-HBc-positive patients, pre-emptive anti-viral therapy for HBV is not routinely suggested. Anti-viral therapy is initiated when the reactivation of HBV occurs. However, severe fetal reactivation of HBV has been reported for such patients receiving potent chemotherapy, even in the case of early application of anti-viral therapy with lamivudine [1Sanchez M.J. Buti M. Homs M. Palacios A. Rodriguez-Frias F. Esteban R. Successful use of entecavir for a severe case of reactivation of hepatitis B virus following polychemotherapy containing rituximab.J Hepatol. 2009; 51: 1091-1096Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 6Wu J.M. Huang Y.H. Lee P.C. Lin H.C. Lee S.D. Fatal reactivation of hepatitis B virus in a patient who was hepatitis B surface antigen negative and core antibody positive before receiving chemotherapy for non-Hodgkin lymphoma.J Clin Gastroenterol. 2009; 43: 496-498Crossref PubMed Scopus (24) Google Scholar]. Hence, pre-emptive anti-viral therapy, the application of more potent anti-viral therapy when reactivation occurs, or closer monitoring may be needed for such patients. Similarly, for HBsAg-positive patients with HCC undergoing TACE, HBV reactivation associated with hepatitis flares have been reported in previous studies [5Jang J.W. Choi J.Y. Bae S.H. Yoon S.K. Chang U.I. Kim C.W. et al.A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization.Hepatology. 2006; 43: 233-240Crossref PubMed Scopus (167) Google Scholar, 7Jang J.W. Choi J.Y. Bae S.H. Kim C.W. Yoon S.K. Cho S.H. et al.Transarterial chemo-lipiodolization can reactivate hepatitis B virus replication in patients with hepatocellular carcinoma.J Hepatol. 2004; 41: 427-435Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. HCC patients often also suffer from impaired liver functional reserve at the time of diagnosis and treatment. This may cause a more serious and profound impact if the reactivation of HBV occurs during therapy. In a previous study, HBV reactivation emerged in 30 of 146 (20.5%) patients with HCC undergoing TACE [[7]Jang J.W. Choi J.Y. Bae S.H. Kim C.W. Yoon S.K. Cho S.H. et al.Transarterial chemo-lipiodolization can reactivate hepatitis B virus replication in patients with hepatocellular carcinoma.J Hepatol. 2004; 41: 427-435Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. More importantly, three of them died of hepatic decompensation. Pre-emptive lamivudine therapy has been demonstrated to reduce the incidence of hepatitis due to HBV reactivation [[5]Jang J.W. Choi J.Y. Bae S.H. Yoon S.K. Chang U.I. Kim C.W. et al.A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization.Hepatology. 2006; 43: 233-240Crossref PubMed Scopus (167) Google Scholar]. However, long-term lamivudine therapy causes the selection of drug-resistant HBV mutants, which may be fatal in patients with impaired liver functional reserve. Consequently, the application of more potent anti-viral therapy with higher genetic barriers of resistance, such as entecavir, may improve clinical outcomes. For patients who are sera HBsAg-negative and anti-HBc-positive, the incidence and management strategy of HBV reactivation during TACE for HCC have not been well studied to date. Our current case highlights that reactivation of HBV does occur in such patients. Additionally, HBsAg loss with undetectable serum HBV DNA was achieved within two months of entecavir therapy. Consequently, in the case of patients with negative serum HBsAg but positive anti-HBc, it is still mandatory to closely monitor serum ALT, HBsAg, as well as HBV DNA levels after the application of TACE, as with those receiving potent chemotherapy. Anti-viral therapy should be prescribed immediately when the reactivation of HBV occurs. Entecavir may serve as a suitable therapy for such patients with advanced hepatic fibrosis and impaired liver functional reserve. In conclusion, our study demonstrates that the reactivation of HBV associated with clinically significant hepatitis can occur in HBsAg-negative, but not in anti-HBc-positive patients with HCC undergoing TACE. Prompt anti-viral therapy with entecavir can suppress viral replication efficiently with the rapid achievement of virological as well as serological response. Nothing to report for all authors.