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Letters to the Editor |
Unità Operativa di Ematologia e Centro Trapianti Cellule Staminali Emopoietiche, Ospedale Oncologico di riferimento Regionale "Armando Businco", Cagliari
Correspondence: Emanuele Angelucci, MD, U.O. Ematologia e Centro Trapianti Cellule Staminali Emopoietiche, Ospedale Oncologico di Riferimento Regionale "Armando Businco", via Edward Jenner, 09121 Cagliari. E-mail:emnang{at}tin.it
Key words: chemotherapy, rituximab, HBV, potential occult carrier, reactivation.
The risk of developing hepatitis B virus (HBV) related liver disease in isolated anti-HBc carriers1 undergoing chemo or chemo-immunotherapy for non-Hodgkin’s lymphoma is not well known. The use of rituximab has been reported to cause even fatal HBV-related liver disease in this category of patients.2–5
In an attempt to solve this problem, we retrospectively analyzed 1,087 patients with non-Hodgkin’s lymphoma seen from January 1989 through June 2006. Since then, in our Unit, all newly diagnosed patients undergo measurement of HBsAg, anti-HBs, anti-HBc, HBeAg, and antiHBe.
Patients were monitored by liver function tests during and after therapy as follows; on day 1 and day 14 of each cycle, every month for the first six months after completion of chemotherapy, then every 3–4 months for 24 months, and thereafter twice a year.
When a patient developed liver disease (defined as 
three-fold increase in alanine aminotransferase [AST] from baseline exceeding the upper limit of normal [>45 IU/L ] or an absolute increase of ALT to more than 100 IU/L)6 we investigated HBsAg. Liver disease attributable to HBV in potential occult carriers was defined as the re-emergence of HBsAg in HBsAg negative/ anti-HBc positive subjects (reverse seroconversion).1
Cheson’s criteria were used to define the response to lymphoma treatment.7
Non-parametric data are expressed with median (range). For parametric groups, the 
2 test was used to compare the two groups. The risk of HBV related liver disease was calculated using the Kaplan-Meier method.8 The retrospective observational protocol study was approved by the Institutional Review Board.
Of 1,087 non-Hodgkin’s lymphoma patients, 55 (5%) were overt HBV carriers, 394 (36%) were isolated anti- HBc positive, while 638 (58%) showed negative HBV markers or only anti-HBs antibodies. We focused on the 394 potential occult carriers: 200 males, 194 females, median age 62 years (range 34–80). The main lymphoma diagnosis was diffuse large B-cell lymphoma (n=185, 47%).
Of the 394 anti-HBc positive patients, 245 (62%) received chemotherapy and 74 (19%) had immuno-chemotherapy with anti-CD20 monoclonal antibody. Twenty-nine (7%) received other treatment (radiotherapy, interferon, antibiotics etc.) and 46 (12%) did not receive therapy (watch and wait) (Table 1).
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Four of the 394 patients (1%) developed HBV-related liver disease: 2 out of 245 (0.8%) patients treated with chemotherapy only and 2 out of 74 (2.7%) treated with immuno-chemotherapy (p<0.05). No HBV-related liver disease occurred in patients who were simply monitored or in those treated with other therapies. The one year Kaplan-Meier8 risk of HBV-related liver disease in patients treated with immuno-chemotherapy was 3%.
Three out of four events occurred as a consequence of the first line of therapy; one event occurred as a consequence of the third line of therapy.
HBV-related liver disease occurred five months after discontinuation of cytotoxic therapy in 3 cases while in the other patient it occurred during immuno-chemotherapy, disrupting the chemotherapy schedule.
Two out of 4 patients were treated with lamivudine for hepatitis. The other 2 patients received only support treatment (pre-lamivudine era). Transaminase and bilirubin peaks were respectively 9 and 5 times the upper limit of normal in patients treated with Lamivudine, and 37 and 7 times the upper limit of normal in patients treated with support therapy.
All of the 4 patients obtained clinical remission of hepatitis with long-lasting persistence of HBsAg.
Two out of 4 patients obtained complete remission of the lymphoma, even though one of them relapsed and required further therapy. The other 2 patients died with progressive disease.
At present, with the increase in immunosuppressive therapy, the problem of HBV reactivation has become more common. A few cases of even lethal reverse seroconversion in isolated anti-core carriers have been reported after the use of rituximab.2–5,9 However, there is clear evidence of the advantage of using rituximab.10 The risk of rituximab induced HBV-related liver disease must be assessed.
In our center, complete assessment of HBV status has been routine clinical practice in all new lymphoma patients since 1989. Therefore, a retrospective analysis in a uniform population is feasible. One third of Lymphoma patients had isolated anti hepatitis B core positivity.
Our incidence of HBV-related liver disease (2.7%) was significantly greater in the anti-CD20 antibody group. Our results are limited by the fact that retrospective analyses can underestimate the events, particularly after one year post-therapy. Furthermore, none of these patients were on long-term maintenance therapy with rituximab. Larger, multicenter prospective observational trials are necessary to address this issue. A potential occult HBV carrier (i.e. isolated antiHbc) must be treated with the best clinical therapy available even including monoclonal antibodies. While a policy of prophylaxis remains controversial, close monitoring is mandatory.
Acknowledgments
authors wish to thank Stanley L. Schrier for critical reading and suggestions
References
This article has been cited by other articles:
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  Y. X. Koo, D. S.W. Tan, B. H. Tan, R. Quek, M. Tao, and S. T. Lim Risk of Hepatitis B Virus Reactivation in Patients Who Are Hepatitis B Surface Antigen Negative/Antibody to Hepatitis B Core Antigen Positive and the Role of Routine Antiviral Prophylaxis J. Clin. Oncol., May 20, 2009; 27(15): 2570 - 2571. [Full Text] [PDF]
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W. Yeo, N. W.Y. Leung, V. T.C. Chan, and P. K.S. Chan Reply to Y.X. Koo et al J. Clin. Oncol., May 20, 2009; 27(15): 2571 - 2572. [Full Text] [PDF]
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 Y. X. Koo, D. S.W. Tan, I. B. Tan, M. Tao, and S. T. Lim Hepatitis B Virus Reactivation in a Patient With Resolved Hepatitis B Virus Infection Receiving Maintenance Rituximab for Malignant B-Cell Lymphoma Ann Intern Med, May 5, 2009; 150(9): 655 - 656. [Full Text] [PDF]
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 R. Liang How I treat and monitor viral hepatitis B infection in patients receiving intensive immunosuppressive therapies or undergoing hematopoietic stem cell transplantation Blood, April 2, 2009; 113(14): 3147 - 3153. [Abstract] [Full Text] [PDF]
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 J. M. Bergua, C. Cabrera, H. Banas, M. Marignani, M. C. Cox, G. Delle Fave, L. Milazzo, S. Antinori, and J. L. Dienstag Hepatitis B virus infection. N. Engl. J. Med., January 15, 2009; 360(3): 304 - 305. [Full Text] [PDF]
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 A. Torresin, M. Feasi, and G. Cassola Hepatitis B reactivation prophylaxis in immune-suppressed patients Haematologica, November 1, 2008; 93(11): e65 - e65. [Full Text] [PDF]
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C. Targhetta, M.G. Cabras, and E. Angelucci Risk of HBV liver disease in isolated antiHbc patients receiving immuno-chemotherapy for non Hodgkin lymphoma Haematologica, November 1, 2008; 93(11): e66 - e66. [Full Text] [PDF]
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