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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Characterization of patients with HBV reactivation ()
  7. Discussion
  8. Acknowledgements
  9. References

Background : Chronic hepatitis B virus carriers receiving chemotherapy develop a high hepatitis B virus reactivation rate (38–53%) with a high mortality (37–60%). Few studies have characterized the efficacy of lamivudine in the treatment of chemotherapy-induced hepatitis B virus reactivation.

Aim : To determine whether lamivudine prophylaxis reduces chemotherapy-induced hepatitis B virus reactivation and mortality.

Methods : The medical records of all hepatitis B surface antigen-positive patients with malignancy treated with chemotherapy since 1995 at the National University Hospital of Singapore were identified, and divided into those who received lamivudine prophylaxis before chemotherapy (P) and those who did not (NP).The parameters examined included gender, age, malignancy type, steroid usage, number of chemotherapy courses and regimens, follow-up duration and hepatitis B virus status. The outcome measures were hepatitis B virus reactivation (abrupt rise of serum alanine aminotransferase to > 200 IU/L) and reactivation death. Patients with primary hepatoma or liver metastasis were excluded.

Results : Thirty-five patients were identified: 16 in the P group and 19 in the NP group. The baseline characteristics of the two groups were similar. Seven of the 19 patients in the NP group and none of the 16 patients in the P group developed reactivation (36.8% vs. 0%, P=0.009). Six of the seven patients in the NP group who developed reactivation received lamivudine at that time, but five died (mortality, 71.4%), whilst no patient in the P group died from reactivation (P=0.064).

Conclusions : Prophylactic lamivudine appears to prevent hepatitis B virus reactivation and its associated mortality in patients treated with chemotherapy. This should be confirmed with prospective studies.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Characterization of patients with HBV reactivation ()
  7. Discussion
  8. Acknowledgements
  9. References

The World Health Organization estimates that 350 million people have been infected by hepatitis B virus (HBV) world-wide, a substantial proportion of whom live in Asia, with prevalence rates of 5–15% of the population.1 Consequently, it is not uncommon for chronic hepatitis B patients to have concurrent illnesses, such as unrelated malignancies or diseases that require immunosuppression, such as renal transplantation, auto-immune or rheumatic disease. The treatment of these conditions with chemotherapy or immunosuppressive agents may lead to the potential problem of HBV reactivation, a well-recognized event,2–6 that potentially can be fatal. Reactivation of HBV in chronic HBV carriers receiving chemotherapy occurred in 48% in a prospective study of patients receiving chemotherapy for non-Hodgkin's lymphoma,2 and in 52.7% in a questionnaire survey in Japan of haematological malignancies.3 The published mortality rates from such reactivations vary from 3.7%2 to 37.5%,4 perhaps reflecting differences in the studies and the small cohorts reported.

With the advent of effective nucleoside analogue therapy, such as lamivudine, it may be possible to prevent HBV reactivation and potential mortality by prophylaxis. Consequently, our aim was to determine whether the prophylactic administration of lamivudine before chemotherapy could prevent or reduce the rate of reactivation and mortality.

Patients and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Characterization of patients with HBV reactivation ()
  7. Discussion
  8. Acknowledgements
  9. References

All case records of patients who had received chemotherapy between January 1995 and June 2000 at a tertiary teaching hospital in Singapore (National University Hospital) were retrieved by a comprehensive computerized search. Concurrently, we obtained a computerized database of all patients testing positive for hepatitis B surface antigen at the National University Hospital. Patients who matched both searches were identified as index patients for the study, and their case records were accessed for analysis. This computerized search complemented and validated a previous list of patients who had been referred for management of hepatitis B in the setting of malignancy.

Patients who were referred to the gastroenterology service with hepatitis B prior to the commencement of chemotherapy were all started on lamivudine. Patients who began chemotherapy without lamivudine prophylaxis were detected either on presentation with symptomatic reactivation, or subsequently during the computerized search. Patients who were prescribed lamivudine, 100–300 mg, before the initiation of chemotherapy were identified as the prophylactic (P) group, whilst those who were not prescribed prophylactic lamivudine were considered as the control or non-prophylactic (NP) group. The NP group included patients who received lamivudine at the time of reactivation. Patients were excluded from analysis if they had primary hepatocellular carcinoma or secondary metastasis involving the liver. As the study was retrospective, none of the investigators was blinded to the group assignment.

The following baseline parameters were examined to determine whether there were differences between the two groups: age, race, gender, type of malignancy, corticosteroid usage, number of courses of chemotherapy, number of regimens of chemotherapy, hepatitis B e antigen (HBeAg), antibody to HBeAg (anti-HBe) and HBV DNA status before chemotherapy and at the time of reactivation. The main outcome measures were reactivation due to HBV and mortality from HBV reactivation. Reactivation was defined as a serum alanine aminotransferase level of > 200 IU/L (normal, < 70 IU/L7) attributable to HBV in the absence of other viral hepatitis, systemic infections, malignant infiltrations or hepatotoxic drugs. Mortality was attributed to HBV reactivation if HBV reactivation and subsequent liver failure resulted in death. Other causes of mortality were also recorded.

Statistical analyses were performed by Pearson chi-squared and Fisher's exact tests, using SPSS. Statistical significance was defined as a P value of < 0.05.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Characterization of patients with HBV reactivation ()
  7. Discussion
  8. Acknowledgements
  9. References

In total, there were 43 patients available for analysis, but six patients with hepatocellular carcinoma and two patients with secondary liver metastasis were excluded, leaving 35 patients available for further analysis. Of the 35 patients, 16 had received prophylactic lamivudine (P) and 19 had not received prophylactic lamivudine (NP). All patients had normal serum alanine aminotransferase levels prior to chemotherapy. Of these 43 patients, 22 were referred before chemotherapy commenced, seven were referred at the time of reactivation following chemotherapy and 14 were subsequently detected by computerized screening.

There were no HBV reactivations (0/16) in the P group but, in the NP group, the HBV reactivation rate was 36.8% (7/19), a difference that was highly significant (P=0.009) (Table 1). As there were no reactivations in the P group, no reactivation-related mortality was seen. In contrast, there were five of seven (71.4%) HBV reactivation-related deaths in the NP group (P=0.064) which showed a trend towards significance. When mortality from all causes was examined, there was no statistical difference between the two groups. There were three deaths from other causes in the P group: progression of disease in one and overwhelming neutropenic sepsis in the remaining two. There was one death in the NP group due to other causes: progression of disease.

Table 1.  Outcomes
 ProphylacticNon- prophylacticP value
  1. HBV, hepatitis B virus.

HBV reactivation rate
 Number of patients1619 
 Number of HBV reactivations07 (36.8%)0.009
Mortality
 HBV reactivation050.064
 Non-reactivation (including cancer   mortality)310.28
 All causes360.39

There were no statistical differences in any of the parameters examined between the two groups, including gender, age, race, type of malignancy, duration of follow-up, number of courses or regimens of chemotherapy and the use of corticosteroids (Table 2).

Table 2.  Baseline patient characteristics and viral status
Patient characteristicsProphylacticNon-prophylacticP value
  • Anti-HBe, antibody to HBeAg; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus.

  • *

     Pearson's chi-squared test. Others, Fisher's exact test.

Number of patients1619 
Median age (range) (years)47.5 (25–75)54 (28–75)0.36
Sex: female/male4/129/100.29
Type of malignancy
 Haematological/solid tumours8/84/150.09
Corticosteroid used10/16 (62.5%)12/19 (63.2%)1.00
No. of chemotherapy courses (range)5.5 (1–60)6 (1–16)0.78
No. of regimens of chemotherapy
 1st, 2nd, 3rd, 4th9, 4, 2, 012, 6, 1, 10.59*
Length of follow-up (range) (months)11.5 (1–41)12 (0.5–49)0.42*
Viral status pre-chemotherapy
 HBeAg-positive2/16 (12.5%)1/15 (6.7%)1.00
 Anti-HBe-positive12/15 (80%)12/13 (92.3%)0.60
 HBV DNA-positive5/14 (35.7%)0/1 (0%)0.67

Information on the viral serology and HBV DNA was somewhat incomplete in both groups of patients, given that this was a retrospective study. HBV DNA status was available pre-chemotherapy in 87.5% (14/16) of patients in the P group, but only in one of 19 patients in the NP group (Table 2). At the time of reactivation, HBV DNA was tested in all seven patients, and not surprisingly six were HBV DNA-positive. When comparing the reactivation and non-reactivation groups, the HBeAg-positive status (1/7 or 14.3% vs. 3/23 or 13.1%) and anti-HBe-positive status (6/7 or 85.7% vs. 13/15 or 86.7%) were similar. This was also the case in the NP and P groups (Table 2). However, comparison of HBV DNA between the reactivation and non-reactivation groups showed a trend towards significance (P=0.07) as expected (6/7 or 85.7% vs. 6/17 or 35.3%). All patients received full courses of chemotherapy for their diseases, except for those who developed HBV reactivation.

Sixteen patients received prophylactic lamivudine which was started 5 days (median) (range, 1–18 days; mean ± s.d., 6.25 ± 5.34 days) prior to the onset of chemotherapy. In these cases, the short time between the initiation of lamivudine and chemotherapy was driven by the urgency to treat the malignant disease. Of the 16 patients on prophylactic lamivudine, only one stopped lamivudine at 2 months after completing chemotherapy without any adverse events. The other 15 patients remained on lamivudine on completion of chemotherapy for a median duration of 7.75 months (range, 2–32.75 months; mean ± s.d., 11.85 ± 9.38 months). None of the patients on lamivudine developed lamivudine resistance.

Characterization of patients with HBV reactivation (Table 3)

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Characterization of patients with HBV reactivation ()
  7. Discussion
  8. Acknowledgements
  9. References
Table 3.  Data on the seven patients who developed hepatitis B virus (HBV) reactivation
 1234567*
  • DLCL, diffuse large cell lymphoma; HGBCC, high-grade B-cell centroblastic lymphoma; Mets, metastasis; NHL, non-Hodgkin's lymphoma; NSCLC, non-small-cell lung cancer; A, Abbot (picogram DNA/mL); C, Chiron (megaequivalents DNA/mL); Dexa, dexamethasone; Pred, prednisolone; CG, cisplatin, gemcitabine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; CMF, cyclophosphamide, methotrexate, 5-fluorouracil; PCV, lomustine, vincristine, procarbazine; RTx + 5FU, adjuvant radiotherapy + 5-fluorouracil; ALT, serum alanine aminotransferase (normal, 10–70 IU/L); Bil, total bilirubin (normal, 5–30 µmol/L); PT, prothrombin time (normal, 11.5–14.5 s); NA, not available; chemo, chemotherapy.

  • *

     Did not receive lamivudine (Lam). Others received Lam at time of reactivation.

Malignancy typeAstrocytoma,  grade 3   transformationBreast, T2N0M0NHL, DLCLBreast, T2N0M0Rectal Duke C,  T3N1M0NHL, HGBCCNSCLC, Mets to brain
Peak ALT at reactivation28437629465381427361457
Peak Bil 13  7 127428 181 40164
Peak PTNANA  23.9 19.5> 100 14.1 17.7
Viral serologyHBeAg+Anti-HBe+Anti-HBe+Anti-HBe+Anti-HBe+Anti-HBe+Anti-HBe+
HBV DNA titre108, A0, C70, C1213, C9100, CNA, A3.8, A
Steroid usageNoneDexa IV, 4 mgPred p.o., 100 mgDexa IV, 4 mgNonePred p.o., 100 mgDexa IV, 8 mg
Type of chemoPCVCMFCHOPCMFRTx + 5FUCHOPCG
No of chemo courses  before flare 2 2  5 4 1 5 3
Days from last chemo212710528102115
OutcomeAlive. Continued chemo  on Lam. Anti-HBe  seroconverted after  5 months of LamAlive.  Stopped Lam  13 months  after flareDeceased day 10Deceased day 23Deceased day 7Deceased day 22Deceased day 17
Cause of death  Hepatic failure  with sepsisHepatic failure  with sepsisHepatic failure  with encephalopathyHepatic failure  with sepsisHepatic failure  with hepatorenal  syndrome

Symptomatic patients (jaundice, fever, lethargy, peripheral oedema, nausea and anorexia) during reactivation had universally poorer outcomes: all five patients eventually died. The numbers were too small to determine statistical differences.

Six of the seven patients who developed reactivation were prescribed lamivudine at that time, but only two patients survived despite this treatment. Lamivudine was prescribed at a dose of 100–300 mg and treatment was started at a median of 2.5 days (range, 0–8 days) after the identification of HBV reactivation.

Patients had undergone a range of chemotherapy courses at the time of onset of HBV reactivation (range, 1–5), with a median of three chemotherapy courses. HBV reactivation occurred during the post-chemotherapy phase, ranging from 10 to 105 days (median, 21 days; mean, 32.4 days) from the last chemotherapy dose.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Characterization of patients with HBV reactivation ()
  7. Discussion
  8. Acknowledgements
  9. References

In regions in which chronic HBV infection is endemic, such as in Singapore, HBV screening should be performed prior to commencement of chemotherapy. Lamivudine, a nucleoside analogue, is effective in suppressing HBV DNA via the inhibition of HBV DNA polymerase.8 Our study has shown, for the first time, that lamivudine prophylaxis prevents chemotherapy-related HBV reactivation, and can reduce the related reactivation mortality. Although this study was analysed retrospectively, our HBV reactivation rate of 36.8% is comparable with that of other studies, including those conducted prospectively.2, 9 Bias alone cannot explain the effectiveness of lamivudine in preventing reactivations in all patients belonging to the prophylactic group. An alternative strategy for treating chemotherapy-related HBV reactivation has been proposed by Yeo et al., who initiated lamivudine therapy at the time of HBV reactivation.10 In their series of eight patients, despite treatment with lamivudine during the early stage of chemotherapy-induced HBV reactivation, one of the eight patients (12.5%) died from this event. Lamivudine therapy may thus not be able to prevent severe liver dysfunction and mortality despite the control of viral replication. This is particularly true if patients are not recognized as having hepatitis B before chemotherapy begins.

In a study by Markovic et al., the mortality rate in the setting of severe liver dysfunction with supportive therapy alone was as high as 60%.4 Our mortality of 71.4% may reflect even more severe liver dysfunction at the time of presentation in our patients with reactivation. Prospective studies with close monitoring may detect liver dysfunction early and allow intervention with lamivudine before liver damage becomes too severe.9

Similar to other published reports,2, 8 reactivation in our series occurred following chemotherapy (mean, 32.4 days; median, 21 days) and usually on average after the third chemotherapy course.

Lamivudine, 100–300 mg, effectively induces HBV DNA suppression in 94–98% of patients with chronic hepatitis B, and can be achieved within 8 days of commencement.11 In this study, lamivudine was started 5 days (median) (range, 1–18 days) before chemotherapy, suggesting that lamivudine prophylaxis can be commenced close to the time of chemotherapy and still be effective; this is important as patients with malignancy cannot afford to delay chemotherapy. The safety of starting lamivudine prophylaxis close to the initiation of chemotherapy is also supported by the finding that HBV reactivation occurs 10–105 days (mean, 32.4 days; median, 21 days) after the last chemotherapy dose, and not during chemotherapy itself.

It is possible that the level of pre-chemotherapy HBV DNA may predict chemotherapy-induced HBV reactivation; however, the current study is unable to answer this question.

How long should lamivudine therapy continue in the setting of HBV patients receiving chemotherapy? The longest time to reactivation in our patient cohort was 105 days. This suggests that patients should receive a minimum of 4 months of lamivudine after the last course of chemotherapy. Further studies are needed to define the duration of prophylaxis. In principle, once chemotherapy has been completed and immune recovery has occurred, patients should be able to stop lamivudine with close monitoring of their HBV replication status and liver function.

In summary, we have found that prophylactic lamivudine may prevent HBV reactivation in patients receiving chemotherapy for malignancy, and appears to show a trend towards a reduction in mortality from HBV-associated reactivation. The disparity in HBV reactivation between the two groups of patients in our study cannot be explained by bias alone. Lamivudine is clearly effective in the treatment of hepatitis B, as well as in HBV reactivations due to chemotherapy; consequently, it is probable that lamivudine may prevent reactivations from occurring. The risk of death from such an event appears to be related to the timing of detection and intervention. The earlier the intervention with lamivudine, the more likely it is that therapy will be effective. Lamivudine is a life-saving drug for patients with hepatitis B; patients with concurrent malignancy and hepatitis B may be another indication for its use, whether as prophylaxis or for treatment of reactivation. As this is a retrospective study, the findings will need to be confirmed by prospective studies.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Characterization of patients with HBV reactivation ()
  7. Discussion
  8. Acknowledgements
  9. References

Ms Vasanthi Perumal, Ms Shuet Ting Lai and Mr Cham Kong Chung are acknowledged for their kind assistance.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Characterization of patients with HBV reactivation ()
  7. Discussion
  8. Acknowledgements
  9. References
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    Lok ASF, Liang RHS, Chiu EKW, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy: report of a prospective study. Gastroenterology 1991; 100: 1828.
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    Nakamura Y, Motokura T, Fujita A, Yamashita T, Ogata E. Severe hepatitis related to chemotherapy in hepatitis B virus carriers with hematologic malignancies. Cancer 1996; 78: 22105.
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    Markovic S, Drozina G, Vovk M, Fidler-Jenko M. Reactivation of hepatitis B but not hepatitis C in patients with malignant lymphoma and immunosuppressive therapy. A prospective study in 305 patients. Hepato-Gastroenterol 1999; 46: 292530.
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    Kumagai K, Takagi T, Nakamura S, et al. Hepatitis B virus carriers in the treatment of malignant lymphoma: an epidemiological study in Japan. Ann Oncol 1997; 8: S1079.
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    Lau JYN, Lai CL, Lin HJ, et al. Fatal reactivation of chronic hepatitis B virus infection following withdrawal of chemotherapy in lymphoma patients. Q J Med 1989; 73: 9117.
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    Lok ASF, Lai CL. Acute exacerbations in Chinese patients with chronic hepatitis B virus (HBV) infection. Incidence, predisposing factors and etiology. J Hepatol 1990; 10: 2934.
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    Dienstag JL, Perrillo RP, Schiff ER, Bartholomew M, Vicary C, Rubin M. A preliminary trial of lamivudine for chronic hepatitis B infection. N Engl J Med 1995; 333: 165761.
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    Yeo W, Chan PKH, Zhong S, et al. Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors. J Med Virol 2000; 62: 299307.
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    Yeo W, Steinberg JL, Tam JS, et al. Lamivudine in the treatment of hepatitis B virus reactivation during cytotoxic chemotherapy. J Med Virol 1999; 59: 2639.
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    Lai CL, Ching CK, Tung AKM, et al. Lamivudine is effective in suppressing hepatitis B virus DNA in Chinese hepatitis B surface antigen carriers: a placebo-controlled trial. Hepatology 1997; 25: 2414.