SEARCH

SEARCH BY CITATION

Keywords:

  • hepatitis B reactivation;
  • chemotherapy;
  • lami- vudine;
  • lymphoma

Abstract

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

Summary. Chemotherapy for non-Hodgkin's lymphoma (NHL) patients with chronic hepatitis B virus (HBV) infection may be accompanied by severe hepatitis. Of 86 consecutive NHL patients, 11 (12·8%) exhibited a positive serum HBsAg. Six of these patients (54·5%) developed acute exacerbation of chronic HBV infection following chemotherapy and received lamivudine. Five of the six patients demonstrated a clinical improvement, one patient died from fulminant hepatic failure owing to delayed lamivudine therapy and poor compliance. These data suggest that HBsAg screening is necessary before commencing chemotherapy for NHL patients in a hyperendemic area and that lamivudine is effective in treating hepatitis B reactivation during chemotherapy.

Reactivation of hepatitis B virus (HBV) replication has been well described during chemotherapy for chronic hepatitis B patients with haematological malignancies (Liang et al, 1990; Kumagai et al, 1997). To date, treatment for this severe hepatitis includes supportive care, the use of corticosteroids, plasma exchange, and/or interferon α and β. Although some success with interferon has led some authors to recommend concomitant interferon treatment with chemotherapy (Kumagai et al, 1997), these methods are still controversial. Recently, lamivudine was reported to be effective for the treatment of chemotherapy-induced hepatitis (Clark et al, 1998; Yeo et al, 1999). We prospectively screened serum HBV surface antigen (HBsAg) among NHL patients over a period of 3 years in order to determine the HBV carrier rate and the frequency of acute exacerbation among chronic HBV carriers following chemotherapy for non-Hodgkin's lymphoma (NHL). All chronic HBV carriers exhibiting an acute HBV reactivation were treated with lamivudine.

Patients and methods

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

From December 1997 to December 2000, a total of 86 consecutive and de novo NHL (stages I to IV) (Harris et al, 1994) patients whose serum HBsAg had prospectively been examined were treated using a standard CHOP (cyclophosphamide, adriamycin, vincristine and prednisolone) regimen for NHL in our hospital. Among them, 11 (12·8%) patients revealed a positive serum HBsAg. Six patients were men and five were women. The mean age was 45 years (range: 26–73). Liver function tests were normal for all 11 patients prior to their chemotherapy. Abdominal imaging studies were performed for these patients. One of the 11 patients (patient 3) was diagnosed with liver cirrhosis and a positive hepatitis B e antigen (HBeAg); the other 10 patients were diagnosed with normal to mild parenchymal liver disease and a positive anti-HBe antibody prior to treatment. Liver cirrhosis was diagnosed according to imaging findings (small liver with nodular surface and coarse parenchyma), evidence of portal hypertension sign (oesophageal varices) and thrombocytopenia.

Liver function tests were performed prior to each cycle of chemotherapy being commenced, and also during times of evident symptoms and signs of HBV acute exacerbation. An acute exacerbation was defined as a phenomenon of an abrupt elevation of serum alanine aminotransferase (ALT, normal < 40 IU/l) to more than 300 IU/l for patients whose original ALT levels and total bilirubin levels (Tbil, normal < 24 µmol/l) were within normal limits. If acute exacerbation of the chronic HBV infection occurred various tests were performed including screening tests for hepatitis markers (IgM anti-HBc, HBV DNA, anti-HCV antibody, anti-Delta antibody and IgM anti-HAV antibody), and tests of the antibody for the Epstein–Barr virus, cytomegalovirus and antinuclear antibody, the patients being then treated with lamivudine (100–150 mg/d). Notably, one of the patients underwent lamivudine therapy (100 mg/d) prior to HBV reactivation as prophylaxis for 2 weeks subsequent to the third chemotherapy treatment. HBV DNA and liver function tests were followed regularly. HBV DNA was detected using a hybridization capture kit (Digene Diagnostics, MD, USA).

Results

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

Of 11 patients exhibiting a positive serum HBsAg who were accepted for classic CHOP chemotherapy, six (54·5%) developed acute exacerbation of chronic HBV infection. Five of the six patients received lamivudine 100–150 mg/d subsequently, and only one patient prior to their diagnosis of acute hepatitis B exacerbation. The clinical characteristics and course of the six patients are shown in Table I. The median number of chemotherapy sessions prior to HBV reactivation was three (range: 2–7). The mean duration of the reactivation from the latest chemotherapy cycle was 4 weeks (range: 3–4).

Table I.  Clinical characteristics and courses of the study patients.
Patient Sex/Age (years) Diagnosis* ALT/TBil/PT(NT)/HBV DNA (at onset of HBV reactivation) Chemotherapy cycles before HBV reactivationInterval between diagnosis of reactivation and latest chemotherapy (weeks) Survival from the time of diagnosis of HBV reactivation (d)
  • *DLCL, diffuse large B-cell lymphoma; DMCL, diffuse mixed large and small B-cell lymphoma; FMCL, follicular mixed large and small B-cell lymphoma; staging according to revised European–American classification of malignant lymphoma (Harris et al, 1994).

  • ALT, alanine transaminase (normal range < 40 IU/l); TBil, total bilirubin (normal < 24 µmol/l); PT(NT), Prothrombin time (normal control).

  • Still surviving at time of writing.

1F/28DMCL, stage IV342/10·3/10·3(10·1)/2·424743
2M/58DLCL, stage II705/27·4/12·4(10·3)/30·944568
3M/51DLCL, stage III525/130/ > 50(10·0)/187924721
4F/40T cell-rich B-cell lymphoma, stage Ix670/15·4/12(10·3)/25·674300
5M/26DMCL, stage II843/265/28·6(10·2)/29·63323
6F/72FMCL, stage III327/8·6/9·8(10·0)/0·7434127

In five patients, liver function improved with lamivudine therapy and survived. One patient (patient 5) died. For patient 3, who exhibited a cirrhotic liver, the existing ascites subsided and the prothrombin time normalized after 2 months of lamivudine therapy. For all six patients, the time required for the HBV DNA levels to fall to undetectable levels was approximately 1 month following the commencement of lamivudine therapy. For one patient (patient 3), HBeAg seroconversion was detected 1 month subsequent to lamivudine therapy. With continuing lamivudine use, the residual course of chemotherapy for patients was performed at full doses for three patients (patients 1, 2 and6), while two other patients (patients 3 and 4) refused further chemotherapy. For three of the surviving patients (patients 1, 2 and 3), lamivudine was used for a period of 10–12 months and then the patients were followed-up for, respectively, periods of 15, 7 and 13 months. During the period of lamivudine therapy and follow-up, these patients remained in clinical remission from lymphoma, without any recurrence of lymphoma or HBV reactivation. Two other patients (patients 4 and 6) continued lamivudine therapy and demonstrated a stationary lymphoma status. Patient 5 did not commence lamivudine therapy until 7 d after the onset of HBV reactivation; meanwhile, the Tbil level increased from 49·6 µmol/l up to 265 µmol/l during this time. This particular patient showed poor compliance (discontinued lamivudine for 1 week) during lamivudine therapy; he died as a result of fulminant hepatic failure complicated with pneumonia on d 23 of lamivudine therapy.

Discussion

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

Hepatitis B virus infection is a worldwide problem. In Taiwan, the carrier rate among the general population is around 15–20% (Tong et al, 1971). Cytotoxic chemotherapy for malignancy, particularly among HBV carriers, may induce acute exacerbation of the hepatitis B and also fulminant hepatic failure, especially when chemotherapy is withdrawn (Lau et al, 1989; Lok et al, 1991). In a retrospective study of 105 HBV carriers with lymphomas, 22 (21%) developed hepatic complications and six (27%) of them died from hepatic failure following cessation of cytotoxic treatment (Liang et al, 1990). In another recent study of 45 HBV carriers treated for malignant lymphoma, 17 (37·8%) developed hepatitis and seven (41·2%) of those affected died of hepatic failure subsequent to discontinuing chemotherapy (Kumagai et al, 1997). These significant morbidity and mortality rates clearly indicate that these are very serious complications of chemotherapy. In the present study, we noted a high rate (12·8%) of HBV carriers in Taiwanese NHL patients (compatible with the HBV carrier rate of the general population in Taiwan), and a high frequency (54·5%) of HBV reactivation for these patients during chemotherapy.

Lamivudine, an oral nucleoside analogue, may demonstrate potent inhibitory effects upon HBV in vitro and in vivo (Lai et al, 1998). The drug was found to be potentially effective for patients who experienced HBV reactivation following chemotherapy (Clark et al, 1998; Yeo et al, 1999). In our study, lamivudine (100–150 mg/d) was commenced for five NHL patients following the diagnosis of HBV reactivation. Most HBV reactivations were observed subsequent to the first three cycles (2nd, 4th, 2nd, 7th and 3rd cycle respectively) of chemotherapy, with an increase in ALT levels being recorded approximately 4 weeks after the chemotherapy administration; we thus prescribed lamivudine prophylatically for one patient following the third cycle of chemotherapy. Asymptomatic HBV reactivation was detected for this patient as a result of regular liver function tests being conducted prior to the fourth cycle of chemotherapy. A rather prompt normalization of liver function was noted during this patient's lamivudine therapy, and the chemotherapy regimen was therefore instituted without delay. In other reports (Lau et al, 1989; Al-Taie et al, 1999; Silvestri et al, 2000), most HBV reactivations were observed subsequent to the first two cycles of chemotherapy. These observations and our experience suggest that lamivudine should be commenced as early as possible for prophylaxis or treatment of HBV reactivation.

The long-term follow-up of patients with HBeAg-negative/HBV DNA-positive chronic hepatitis B treated with lamivudine for 12 months has revealed that the initially demonstrated response was only transient, as most of thepatients relapsed following therapy withdrawal (Santantonio et al, 2000). In our study, for five HBeAg-negative patients the suppression of HBV DNA was accompanied by normalization of ALT and an observable clinical improvement, apart from patient 5 in whom a progressively increased Tbil level and prothrombin time was observed. At the time of writing, Patients 1 and 2 have achieved a sustained virological and biochemical response to lamivudine therapy for 15 and 7 months, respectively, subsequent to the discontinuation of lamivudine. Further study with alarger pool of HBeAg-negative patients with or without NHL, and with a longer follow-up period are needed todetermine the sustained response rate to lamivudine therapy.

At the commencement of lamivudine therapy, two of our study participants (Patients 3 and 5) had already exhibited hepatic failure. Patient 3 responded well to lamivudine, demonstrating a sustained response for 15 months after lamivudine discontinuation. Unfortunately, patient 5 died from fulminant hepatic failure complicated with pneumonia and respiratory failure. It remains difficult to define the contributing factors to the different outcomes for these two patients owing to different patient backgrounds, different severities of hepatic failure and an unpredictable rate of disease progression. Patient 5, however, did not commence lamivudine therapy immediately after the diagnosis of HBV reactivation and not, in fact, until the TBil level had increased to 265 µmol/l. Seven days after commencing lamivudine therapy, lamivudine was interrupted for 1 week owing to poor compliance. The delayed treatment to this patient and his relatively poor compliance may have constituted the major causes of this patient's death.

There is no clue to predict which NHL patients with HBV reactivation will demonstrate serious complications, although, as has been shown here, serum HBsAg screening for NHL patients, the early commencement of lamivudine therapy and good patient compliance are important for the treatment of HBV reactivation during chemotherapy among NHL patients.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

This study was supported by research grants CMRP-1001 from Chang Gung Memorial Hospital to C. M. Lee.

References

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References
  • Al-Taie, O.H., Mark, H., Gassel, A.M., Wihelm, M., Weissbrich, B. & Scheurlen, M. (1999) Prevention of hepatitis B flare-up during chemotherapy using Lamivudine: case report and review of the literature. Annals of Haematology, 78, 247249.
  • Clark, F.L., Drummond, M.W., Chambers, S., Chapman, B.A. & Patton, W.N. (1998) Successful treatment with lamivudine for fulminant reactivated hepatitis B infection following intensive therapy for high-grade non-Hodgkin's lymphoma. Annals of Oncology, 9, 385387.DOI: 10.1023/A:1008206519571
  • Harris, D.S., Jaffe, E.S., Banks, P.M., Chan, J.K., Cleary, M.L., Delsol, G., DeWolf-Peeters, C., Falini, B. & Gatter, K.C. (1994) A revised European-American classification of malignant lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood, 84, 13611392.
  • Kumagai, K., Takagi, T., Nakamura, S., Sawada, U., Kura, Y., Kodama, F., Shimano, S., Judoh, I., Nakamura, H., Sawada, K. & Ohnoshi, T. (1997) Hepatitis B virus carriers in the treatment of malignant lymphoma: an epidemiological study in Japan. Annals of Oncology, 8, S107S109.
  • Lai, C.L., Chien, R.N., Leung, N.W., Chang, T.T., Guan, R., Tai, D.I., Ng, K.Y., Wu, P.C., Dent, J.C., Barber, J., Stephenson, S.L. & Gray, D.F. (1998) A one-year trial of lamivudine for chronic hepatitis B. New England Journal of Medicine, 339, 6168.
  • Lau, J.Y., Lai, C.L., Lin, H.J., Lok, A.S., Liang, R.H., Wu, P.C., Chan, T.K. & Todd, D. (1989) Fetal reactivation of chronic hepatitis B virus infection following withdrawal of chemotherapy in lymphoma patients. Quarterly Journal of Medicine, 73, 911917.
  • Liang, R.H., Lok, A.S., Lai, C.L., Chan, T.K., Todd, D. & Chiu, E.K. (1990) Hepatitis B infection in patients with lymphomas. Hematology and Oncology, 8, 261270.
  • Lok, A.S., Liang, R.H., Chiu, E.K., Wong, K.L., Chan, T.K. & Todd, D. (1991) Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Gastroenterology, 100, 182188.
  • Santantonio, T., Mazzola, M., Iacovazzi, T., Miglietta, A., Guastadisegni, A. & Pastore, G. (2000) Long-term follow-up of patientswith anti-HBe/HBV DNA-positive chronic hepatitis B treated for 12 months with lamivudine. Journal of Hepatology, 32, 300306.DOI: 10.1016/S0168-8278(00)80076-8
  • Silvestri, F., Ermacora, A., Sperotto, A., Patriarca, F., Zaja, F., Damiani, D., Fanin, R. & Baccarani, M. (2000) Lamivudine allows completion of chemotherapy in lymphoma patients with hepatitisB reactivation. British Journal of Haematology, 108, 394396.DOI: 10.1046/j.1365-2141.2000.01847.x
  • Tong, M.J., Sun, S.C., Schaeffer, B.T., Chang, N.K., Lo, K.J. & Peters, R.L. (1971) Hepatitis-associated antigen and hepatocellular carcinoma in Taiwan. Annals of Internal Medicine, 75, 687691.
  • Yeo, W., Steinberg, J.L., Tam, J.S., Chan, P.K., Leung, N.W., Lam, K.C., Mok, T.S. & Johnson, P.J. (1999) Lamivudine in the treatment of hepatitis B virus reactivation during cytotoxic chemotherapy. Journal of Medical Virology, 59, 263239.DOI: 10.1002/(SICI)1096-9071(199911)59:3<263::AID-JMV1>3.3.CO;2-O