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

Hepatitis B reactivation is a major cause of morbidity and mortality in patients undergoing chemotherapy for lymphomas. These patients may experience direct liver-related complications or reduced cancer survival because of interruptions in chemotherapy. Our aim was to compare the costs and outcomes of 2 different chronic hepatitis B management strategies. In hepatitis B carriers undergoing chemotherapy, we pursued a decision analysis model to compare the costs and clinical outcomes of using lamivudine prophylaxis versus initiating lamivudine only when clinically overt hepatitis occurred. Our results indicate that the use of lamivudine prophylaxis is cost-effective. Even though the use of lamivudine prophylaxis was associated with an incremental cost of $1530 per patient ($18,707 versus $17,177), both the number and severity of hepatitis B reactivations were reduced. None of the patients in the prophylaxis group had liver-related deaths versus 20 who died in the no-prophylaxis group. Cancer deaths were also reduced from 47-39 with lamivudine prophylaxis, presumably because of the increased need for cessation or modification of chemotherapy in patients who had severe hepatitis B virus flares. The incremental cost-effectiveness ratio of using lamivudine prophylaxis was $33,514 per life year saved. Conclusion: Our results provide pharmacoeconomic support for the use of lamivudine prophylaxis in patients undergoing chemotherapy for lymphoma treatment. (HEPATOLOGY 2007.)

Hepatitis B virus (HBV) infection is an important medical and public health concern, and it is a leading cause of cirrhosis and hepatocellular carcinoma.1, 2 Patients with hepatitis B are at risk of viral reactivation when undergoing cytotoxic or immunosuppressive chemotherapy for malignancies, particularly lymphomas.3 The incidence of HBV reactivation may be as high as 50% and is associated with an overall liver-related mortality of 5%.4, 5 Even in patients who are able to recover from hepatitis B reactivation, their cancer survival may be impaired because of alterations or cessation of the initially intended chemotherapy course.6, 7

The pathogenesis of HBV reactivation during or after chemotherapy appears to be related to an increase in viral replication during immunosuppression with a resultant increase in hepatocyte destruction and inflammation upon immune reconstitution.3–5 Lamivudine, a nucleoside analogue, has been shown to be effective in inhibiting viral replication and decreasing viral load.8–10 Various strategies have been proposed in patients with hepatitis B undergoing chemotherapy to prevent viral replication. It has been suggested that the earlier use of lamivudine, before overt clinical hepatitis, is most efficacious.11 The use of prophylactic lamivudine can decrease the incidence of HBV reactivation from 30%-80% to 0%-17%.12–17

The aim of this study was to compare the efficacy and costs of 2 management strategies in patients with hepatitis B undergoing chemotherapy: (1) lamivudine prophylaxis and (2) lamivudine use only in patients with evidence of an HBV reactivation. Because lamivudine has been shown to be effective in preventing HBV reactivation, is inexpensive, and is associated with few adverse effects, we believed that the use of lamivudine prophylaxis would be most cost-effective.

Patients and Methods

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

Decision Model.

We compared 2 strategies for the management of chronic hepatitis B patients undergoing chemotherapy for lymphoma treatment. In the first strategy, all patients were given lamivudine prophylaxis before the initiation of chemotherapy, and this continued for 6 months after the cessation of chemotherapy. Adefovir was coadministered if patients developed a hepatitis B reactivation despite lamivudine use. In the second strategy, patients received lamivudine only if there was clinical evidence for HBV reactivation. Adefovir was used in this model if patients developed lamivudine resistance, which was estimated to be 20% for the year of the model.18 A decision analysis model was created for each strategy to simulate the costs and health outcomes for patients assigned to each of these strategies (Fig. 1). The model was constructed with TreeAge (Williamstown, MA) software.

thumbnail image

Figure 1. Decision analysis model.

Download figure to PowerPoint

In each strategy, patients had an opportunity to develop an HBV reactivation. For every patient that did develop a reactivation, they could have been continued on chemotherapy or have had their chemotherapy aborted or modified. From that point, they could then go on to recover from the HBV reactivation or die from fulminant hepatic failure. Patients who recovered from or did not have HBV reactivation either died or survived their lymphoma. The follow-up time was 1 year for each of the groups. The institutional perspective was adopted in all analyses.

Natural History of Hepatitis B Reactivation.

The natural history of HBV reactivation in patients undergoing chemotherapy was obtained from a systematic review of Medline literature. Data from 14 studies published from various parts of the world between 1990 and 2006 that examined HBV reactivation in lymphoma patients undergoing chemotherapy were collected (Table 1).12–17, 19–26 Seven of these studies compared the prophylactic use of lamivudine during chemotherapy to the empiric use of the drug,12–17, 26 6 studies restricted lamivudine to the treatment of reactivation,20–25 and 1 study examined only the prophylactic use of lamivudine.19

Table 1. Summary of Publications of Lamivudine Prophylaxis in Patients Undergoing Chemotherapy
 Prophylaxis (N)No Prophylaxis (N)Lymphoma (N)Chemotherapy Regimen (N)Reactivation
Prophylaxis (N)No Prophylaxis (N)
  1. 2-CdA indicates 2-chlorodeoxyadenosine, cladribine; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; ACVB, doxorubicin, cyclophosphamide, vindesine, bleomycin; ACVBP, intensified CHOP-like regimen; BACOP, bleomycin, doxorubicin, cyclophosphamide, vincristine, prednisone; CEOP, cyclophosphamide, epirubicin, vincristine, prednisone; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CNOP, cyclophosphamide, mitoxantrone, vincristine, prednisone; COPP, cyclophosphamide, vincristine, procarbazine, prednisolone; EDAP, etoposide, dexamethasone, cytosine arabinoside, cisplatin; FL, fludarabine; HL, Hodgkin's lymphoma; m-BACOD, methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone; MACOP-B, methotrexate, doxorubicin, cyclophosphamide, prednisone, bleomycin; N/A, not applicable; NHL, non-Hodgkin's lymphoma; PACEBOM, prednisone, doxorubicin, cyclophosphamide, etoposide, bleomycin, vincristine, methotrexate; and proMACE-cytaBOM, prednisolone, adramycin, cyclophosphamide, etoposide, cytosine arabinoside, methotrexate, leucovorin, bleomycin, vincristine.

Li et al.1240116NHL 147Anthracyclines 146760
   HL 9Steroids 144  
Leaw et al.131153NHL 64CEOP, MACOP-B, PACEBOM, BACOP, ACVB, m-BACOD017
Idilman et al.1443NHL 6CHOP 502
   HL 1ABVD 1, 2-CdA 1  
Lau et al.151515NHL 24CHOP 3, CEOP 708
   HL 6ABVD 4, COPP 3, Others 13  
Shibolet et al.1674NHL 10CHOP 702
   HL 1Others 4  
Lee et al.171120NHL 31CHOP 29, EDAP 1, proMACE-cytaBOM 1117
Rossi et al.19130NHL 12CHOP 6, FL 22N/A
   HL 1ACVBP 2, others 3  
Liao et al.20011NHL 11CHOP 11N/A6
Faggioli et al.21022NHL 22CNOP, CEOP, proMACE-CytaBOMN/A9
Yeo et al.22015UnspecifiedUnspecifiedN/A6
Picardi et al.23012NHL 12Fludarabine-based without steroidsN/A5
Markovic et al.24044NHL 41UnspecifiedN/A8
   HL 4   
Lok et al.25078NHL 78BACOP, m-BACOD, othersN/A28
Persico et al.26318NHL 21Unspecified012

Lymphoma and Chemotherapy.

Cancer survival was highest in patients receiving prophylaxis, regardless of the chemotherapy course.12–16, 19 Those who did not receive prophylaxis but were able to complete chemotherapy uneventfully12–16, 20, 22, 23 had higher survival rates than those who did not receive prophylaxis and had interruptions in their chemotherapy.12–16, 20, 22, 23 The cancer-related death rate for patients who did not have hepatitis B viral reactivation was not available from these studies and was assumed to be equal to the cancer death rate in the prophylaxis group of patients who did not have HBV reactivation and were able to complete their scheduled chemotherapy. If HBV reactivation did occur, the mean time to the episode was after the third cycle of chemotherapy.13–15, 19–25

Treatment and Follow-Up Strategies.

The lamivudine prophylaxis strategy was made to simulate current recommendations for the management of patients with chronic hepatitis B undergoing chemotherapy for lymphoma.3 Patients were started on daily lamivudine 1 week before the initiation of chemotherapy, and this continued for 6 months after the cessation of chemotherapy. If a patient in either treatment strategy developed an HBV reactivation while on lamivudine, he was then started on daily adefovir in combination with lamivudine. The use of adefovir was based on studies that treated patients who developed lamivudine-escape mutants while undergoing chemotherapy.27–29 The rate of lamivudine resistance was estimated to be 20% at 1 year.18, 30, 31 Although there have been reports of HBV reactivation after lamivudine withdrawal, we did not include this phenomenon in our model because our study design used lamivudine for 6 months following chemotherapy cessation.32, 33 The intended chemotherapy course was, on average, 6 cycles, each 3 weeks apart. Patients were followed in an oncology clinic once per chemotherapy cycle (3 weeks) and in a hepatology clinic once every 3 months. If an HBV reactivation developed or if there was clinical suspicion of an HBV reactivation, the frequency of the hepatology clinic visits was increased to once every month. Laboratory tests were checked every 3 weeks, including a complete blood count, chemistry panel (including creatinine), and liver tests (to include bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total protein, and albumin). HBV DNA levels were checked only in those with suspected reactivation.


The institutional cost perspective was used in the decision analysis model. All costs for medical procedures and visits were obtained from Medicare reimbursement schedules or from current literature (Table 1), and all drug costs were derived from average wholesale prices.34 The cost of end-of-life care was derived from mean annual medical expenditures and adjusted for 2006 dollars.35 Adjustments were made by healthcare inflation rates according to the Bureau of Labor Statistics.36 All costs are denoted in US dollars for the year 2006 and rounded to the nearest dollar amount. One-way sensitivity analyses were carried out for corresponding costs of lymphoma and HBV treatments. The baseline costs increased or decreased by 50%.


Effectiveness was defined as increased survival in the number of years per patient. Adjustments for the quality of life were not performed. The incremental cost-effectiveness ratio (ICER) was calculated as the ratio of the change in the cost to the change in the health benefit (measured in life years).37 The ICER was compared to the generally accepted price ceiling of $50,000 per life year saved.37 All variables, including the costs of treatment, reactivation rates, and survival rates were evaluated in 1-way sensitivity analyses to determine their individual effects in the overall cost-effectiveness decision (shown later in Table 5). A 2-way sensitivity analysis was executed to establish the values at which the administration of prechemotherapy prophylaxis was most cost-effective. In this method, 2 parameters were varied simultaneously to model changing clinical environments. Pairs of values were elucidated that provided equal cost benefits for both clinical treatment options (Fig. 2).37, 38

Table 5. One-Way Sensitivity Analysis
VariableCost Effectiveness
BaselineRangeProphylaxis PreferredNo Prophylaxis Preferred
  • HBV indicates hepatitis B virus.

  • *

    Cancer mortality for patients on prophylaxis who reactivated and completed chemotherapy.

  • Cancer mortality for patients on prophylaxis who reactivated and aborted/delayed chemotherapy.

  • Cancer mortality for patients not on prophylaxis who reactivated and completed chemotherapy.

  • §

    Cancer mortality for patients not on prophylaxis who reactivated and aborted/delayed chemotherapy.

End-of-life care35,00017,500–52,50018,500–45,00015,000–18,500
Cancer mortality 1*0.0780–0.4290–0.310.31–0.429
Cancer mortality 20.0780–0.4290–0.230.23–0.429
Cancer mortality 30.0890–0.750.016–0.750–0.016
Cancer mortality 4§0.1090–0.140.077–0.140–0.077
Cancer mortality without reactivation nor prophylaxis0.0780–0.4290.0622–0.4290–0.0622
Chance of reactivation with prophylaxis0.0960–0.1750–0.175No values
Chance of reactivation without prophylaxis0.4380.182–0.850.38–0.850–0.38
Chance of aborting/delaying chemotherapy without prophylaxis0.7110–10.4–10–0.4
HBV mortality without prophylaxis with aborted/delayed chemotherapy0.1090–0.140.073–0.140–0.073
HBV mortality on prophylaxis with aborted/delayed chemotherapy00–10–0.20.2–1
HBV mortality on prophylaxis00–10–0.30.3–1
Cancer mortality with prophylaxis and no reactivation0.0780–0.4290–0.0880.088–0.429
thumbnail image

Figure 2. Two-way sensitivity analysis. Lamivudine prophylaxis is considered cost-effective for value combinations below the ICER limit of $50,000 per life year saved. No prophylaxis was cost-effective above the threshold line.

Download figure to PowerPoint


In our model, we assumed the following:

  • 1
    All issues not related to HBV should occur with equal frequency in all arms of the study, and they therefore were not included in the model.
  • 2
    All patients who did not have HBV reactivation should be able to complete chemotherapy without interruption.
  • 3
    All lymphoma patients were treated with cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone, as this was the most frequently used regimen in the referenced publications (Table 1).
  • 4
    All deaths related to HBV reactivation were assumed to occur within 2 weeks after reactivation onset,20, 39–41 and all deaths related to lymphoma were assumed to occur at 1 year.
  • 5
    There was no significant morbidity or mortality related to the use of either lamivudine or adefovir.
  • 6
    Cancer survival was similar between patients who had a reactivation but were able to complete chemotherapy and those who did not have an HBV reactivation.
  • 7
    Liver transplantation was not an option for patients with severe HBV reactivation because of lymphoma.

We also assumed 100% compliance in all patients for both chemotherapy and HBV-related medications.


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

Baseline Results.

Using the decision analysis model, we were able to simulate the clinical outcomes, effectiveness, and costs associated with prophylaxis for hepatitis B reactivation in patients receiving chemotherapy. To increase the generalizability of our model, we varied all event probabilities and costs (Tables 2 and 3).

Table 2. Cost Assumptions
VariableBaseline (range)References
  • All costs are in US dollars. CBC indicates complete blood count; and CHOP, cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone.

  • *

    Clinical cost for both gastroenterology and oncology.

  • Monthly drug costs.

End-of-life care$35,000 (17,500-52,500)35, 36
CHOP cycle$446 (184-669)34
Clinical visit*$242 (121-363)Medicare
Comprehensive metabolic panel$70 (35-105)Medicare
Hepatitis B DNA$120 (60-180)Medicare
CBC with differential and platelets$110 (55-165)Medicare
Lamivudine$270 (135-405)34
Adefovir$676 (338-1014)34
Table 3. Baseline Assumptions
VariableBaseline (%)*References
  • HBV indicates hepatitis B virus.

  • *

    The ranges are shown in parentheses.

  • The cancer death rate in patients who did not have hepatitis B viral reactivation was not available from these studies and was assumed to be the equal to the cancer death rate in the prophylaxis group who did not have HBV reactivation and were able to complete the scheduled chemotherapy.

Reactivations among HBV carriers  
 Prophylaxis9.6 (0–17.5)12–17, 19, 26
 No prophylaxis43.8 (18.2–85.0)12–17, 20–26
Disruption of chemotherapy due to HBV reactivation  
 Prophylaxis60.0 (50–100)12–14, 17, 19
 No prophylaxis71.1 (0–100)12, 14, 17, 20, 23
HBV-associated liver death in those who continued chemotherapy  
 Prophylaxis012, 14, 17, 19
 No prophylaxis3.8 (0–25)12, 14, 17, 20, 23
HBV-associated liver death in those who had disruption in chemotherapy  
 Prophylaxis012, 14, 17, 19
 No prophylaxis10.9 (0–14.0)12, 14, 17, 20, 23
Cancer death in those who had HBV reactivation and continued chemotherapy  
 Prophylaxis7.8 (0–42.9)12–16, 19
 No prophylaxis8.9 (0–75)12–16, 20, 22, 23
Cancer death in those who had HBV reactivation with disruption in chemotherapy  
 Prophylaxis7.8 (0–42.9)12–16, 19
 No prophylaxis10.9 (0–75)12, 14–16, 19, 20, 22, 23
Cancer death in those who did not have HBV reactivation  
 Prophylaxis7.8 (0–42.9)
 No prophylaxis7.8 (0–42.9)

Using the baseline assumptions derived from published literature, we extrapolated the clinical costs and outcomes to a cohort of 1000 patients, with 500 in each treatment strategy group (Table 4). We found that prophylaxis increased the cost to $18,707 from $17,177 per patient. However, prophylaxis was effective in reducing the number of HBV reactivations (48 versus 219), liver-associated deaths (0 versus 20), and cancer-associated deaths (39 versus 47). Prophylaxis was also associated with prolonging life years from 0.876 in the no-prophylaxis group to 0.922 in the prophylaxis group. The ICER was $33,514 per life year. With a ceiling of $50,000 per patient per year, prophylaxis was the preferred strategy.

Table 4. Summary of Costs and Effectiveness
ProphylaxisNo Prophylaxis
  1. The 1000-patient cohort had 500 patients in each strategy arm. LY indicates life year.

Total costs per patient$18,707$17,177
Reactivations (number per arm)48219
Effectiveness (LY per patient)0.9220.876
Deaths (number per arm)  

Sensitivity Analyses.

Lamivudine prophylaxis was the most cost-effective strategy in a 1-way sensitivity analysis for most varied variables (Tables 4 and 5). The incremental cost-effectiveness of prophylaxis exceeded $50,000 per life year saved when the costs of dying were less than $18,500 and the monthly lamivudine cost was greater than $333. Also, as the incidence of reactivations in the no-prophylaxis group decreased below 0.38, no prophylaxis became cost-effective. As cancer mortality increases for patients receiving prophylaxis or as cancer mortality decreases for patients not receiving prophylaxis, no prophylaxis becomes cost-effective. In a 2-way sensitivity analysis (Fig. 2), the changing cost of lamivudine was compared to a changing rate of HBV reactivation without prophylaxis. Rising costs coupled with proportionally increased reactivations did not modify the most cost-effective decision.


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

Hepatitis B reactivation poses a significant risk to patients undergoing chemotherapy. Recent studies have shown that prophylaxis with lamivudine before the initiation of chemotherapy reduces both the incidence and severity of HBV reactivations.12–17, 19–26 However, no studies have investigated the use of prophylactic lamivudine in an economic analysis. In this study, we compared the costs and clinical outcomes of 2 different strategies for chronic hepatitis B carriers undergoing chemotherapy for lymphoma treatment. Our results indicate that the prophylactic use of lamivudine is a cost-effective strategy in comparison with the initiation of lamivudine only when overt hepatitis becomes evident.

Under baseline assumptions, the lamivudine prophylaxis strategy was cost-effective, with an ICER of $33,514 per life year. No liver-related deaths occurred in the prophylaxis group versus 20 deaths in the no-prophylaxis group. Cancer deaths were also reduced from 47 in the no-prophylaxis group to 39 in the prophylaxis group. To increase the generalizability of our study, 1-way sensitivity analyses were performed on all variables. Lamivudine prophylaxis was the preferred strategy when the cost of death was high, the cost of lamivudine was low, and, for most clinical event ranges, all baseline assumptions were included.

Our study has several limitations. First, our tested parameters were from studies including few patients with nonrandomized groups. The studies also differed in their lymphoma subtypes, inclusion criteria, and management strategies. Nevertheless, we were able to calculate a weighted mean and varied rates like those described in the literature to increase generalizability. Another limitation was that the use of adefovir in lamivudine-resistant patients undergoing chemotherapy has been described only in the context of case reports.27–29 In nonchemotherapy patients, the sequential use or combination use of adefovir has been established and is believed to be effective in lamivudine resistance.42, 43 Other medications against HBV such as entecavir and telbivudine were not included in our model because of the lack of data. The duration of time for which lamivudine was continued after the cessation of chemotherapy was another potential limitation. This varied significantly between the 14 studies, from 4 weeks to 2 years. There is no general consensus for the optimal duration of lamivudine treatment after the cessation of chemotherapy, but on the basis of the discussions in several publications, we proposed continuing lamivudine for 6 months after the cessation of chemotherapy.16, 33 The wide range in the results may have been due in part to the variability of lamivudine usage.

Several clinical problems arise with the use of lamivudine as a monotherapy. For instance, the rate of lamivudine resistance is estimated to be approximately 20% at 1 year.18, 30, 31 Our model accounted for the risk of lamivudine resistance by the addition of adefovir in cases of escape mutants. This strategy has been shown to be effective in a number of studies.27–29 The selection of lamivudine-resistant strains may also lead to cross-resistance to future therapies.44, 45 Our analysis was performed with lamivudine, which, to the best of our knowledge, has been the only drug studied for prophylactic purposes in patients receiving chemotherapy. The lack of clinical experience with alternative therapies such as adefovir, entecavir, and telbivudine in this setting limits their incorporation into the current cost-effectiveness study. Another potential limitation with the use of lamivudine is the phenomenon of HBV reactivation after drug withdrawal.32, 33 However, the phenomenon has been described in only 2 studies in which patients were treated for a short time after chemotherapy cessation (4 weeks to 3 months). In our model, we did not include the phenomenon of HBV reactivation because lamivudine was continued for a prolonged period of time (i.e., 6 months) after chemotherapy cessation.

Lymphomas are a heterogeneous group of diseases. Although certain subtypes may not require any treatment, others are almost universally fatal. Our results are not likely to be generalizable to other disease states because of potentially unique rates and timing of HBV reactivation. Future studies should explore the costs and effectiveness of HBV prophylaxis in different disease states such as hepatocellular carcinoma,46 breast cancer,47 nasopharyngeal carcinoma,48 rheumatologic diseases,49 renal transplants,50 lung transplants,51 and inflammatory bowel diseases.52

In our model, the prophylactic use of lamivudine was associated with 171 fewer HBV reactivations and 28 fewer overall deaths. It follows logically then that chronic HBV carriers should be started on lamivudine prophylaxis before chemotherapy and those whose HBV status is unknown should be screened for the presence of HBV infection. In parts of the world where HBV is endemic, such as Southeast Asia, sub-Saharan Africa, and parts of the Pacific and Amazon basins, the prevalence of HBV is as high as 8%-20%, and screening is certainly warranted. Even in nonendemic parts, such as North America and Western/Northern Europe, the prevalence is estimated to be 0.2%-0.5%.53 Given the relative ease of screening with the hepatitis B surface antigen, we believe that this is a cost-effective and life-saving strategy.

To date, there is no consensus on whether patients with positive DNA levels should be treated before the initiation of chemotherapy or whether there is an HBV DNA level below which the initiation of chemotherapy is considered safe. A recent case series by Yeo et al.11 suggested that viral replication precedes clinical hepatitis by approximately 2 weeks in patients undergoing chemotherapy. However, because the level of HBV DNA that may be associated with hepatitis B reactivation has not been determined, a safer strategy may be to treat all patients with a positive hepatitis B surface antigen test at the initiation of chemotherapy, regardless of the HBV DNA status.

In summary, this study provides strong support for the use of lamivudine for prophylaxis against hepatitis B reactivation in patients undergoing chemotherapy for lymphomas. The results of our model indicate that it is cost-effective to prescribe lamivudine in patients with known hepatitis B 1 week before chemotherapy and for 6 months after the cessation of chemotherapy.


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

We thank Martin L. Lee, Ph.D., of the Department of Biostatistics at the University of California at Los Angeles for his expert opinion regarding the statistical analysis. We also thank Mark Roach for his assistance in obtaining cost data.


  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  • 1
    Ganem D, Prince AM. Hepatitis B virus infection—natural history and clinical consequences. N Engl J Med 2004; 350: 11181129.
  • 2
    Lee WM. Hepatitis B virus infection. Med Prog 1997; 337: 17331745.
  • 3
    Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. HEPATOLOGY 2006; 43: 209220.
  • 4
    Xunrong L, Yan AW, Liang R, Lau GKK. Hepatitis B virus (HBV) reactivation after cytotoxic or immunosuppressive therapy—pathogenesis and management. Rev Med Virol 2001; 11: 287299.
  • 5
    Liang R, Lau GKK, Kwong YL. Chemotherapy and bone marrow transplantation for cancer patients who are also chronic hepatitis B carriers: a review of the problem. J Clin Oncol 1999; 17: 394398.
  • 6
    DeVita VT, Hubbard SM, Longo DL. The chemotherapy of lymphomas: looking back, moving forward—the Richard and Hinda Rosenthal Foundation award lecture. Cancer Res 1987; 47: 58105824.
  • 7
    Koak LW, Halpern J, Olshen RA, Horning SJ. Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: results of a tree-structured survival analysis. J Clin Oncol 1990; 8: 963977.
  • 8
    Lai CL, Chien RN, Leung NWY, Chang TT, Guan R, Tai DI, et al. A one year trial of lamivudine for chronic hepatitis B. N Engl J Med 1998; 339: 6168.
  • 9
    Doong SL, Tsai CH, Schinazi RF, Liotta DC, Cheng YC. Inhibition of the replication of hepatitis B virus in vitro by 2′,3′-dideoxy-3′-thiacytidine and related analogues. Proc Natl Acad Sci U S A 1991; 88: 84958499.
  • 10
    Ahmed A, Keeffe EB. Lamivudine therapy for chemotherapy-induced reactivation of hepatitis B virus infection. Am J Gastroenterol 1999; 94: 249251.
    Direct Link:
  • 11
    Yeo W, Chan PKS, Chan HLY, Mo FKF, Johnson PJ. Hepatitis B virus reactivation during cytotoxic chemotherapy-enhanced viral replication precedes overt hepatitis. J Med Virol 2001; 65: 473477.
  • 12
    Li YH, He YF, Jiang WQ, et al. Lamivudine prophylaxis reduces the incidence and severity of hepatitis in hepatitis B virus carriers who receive chemotherapy for lymphoma. Cancer 2006; 106: 13201325.
  • 13
    Leaw SJ, Yen CJ, Huang WT, Chen TY, Su WC, Tsao CJ. Preemptive use of interferon or lamivudine for hepatitis B reactivation in patients with aggressive lymphoma receiving chemotherapy. Ann Hematol 2004; 83: 270275.
  • 14
    Idilman R, Arat M, Soydan E, Toruner M, Soykan I, Akbulut H, et al. Lamivudine prophylaxis for prevention of chemotherapy-induced hepatitis B virus reactivation in hepatitis B virus carriers with malignancies. J Viral Hepat 2004; 11: 141147.
  • 15
    Lau GKK, Yiu HHY, Fong DYT, Cheng HC, Au WY, Lai LSF, et al. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology 2003; 125: 17421749.
  • 16
    Shibolet O, Ilan Y, Gillis S, Hubert A, Shouval D, Safadi R. Lamivudine therapy for prevention of immunosuppressive-induced hepatitis B virus reactivation in hepatitis B surface antigen carriers. Blood 2002; 100: 391396.
  • 17
    Lee GW, Ryu MH, Lee JL, Oh S, Kim E, Lee JH, et al. The prophylactic use of lamivudine can maintain dose-intensity of adriamycin in hepatitis-B surface antigen (HBs Ag)-positive patients with non-Hodgkin's lymphoma who receive cytotoxic chemotherapy. J Korean Med Sci 2003; 18: 849854.
  • 18
    Lok AS, McMahon BJ. AASLD Practice Guidelines: chronic hepatitis B. HEPATOLOGY 2001; 34: 12251241.
  • 19
    Rossi G, Pelizzari A, Motta M, Puoti M. Primary prophylaxis with lamivudine of hepatitis B virus reactivation in chronic HBsAg carriers with lymphoid malignancies treated with chemotherapy. Br J Haematol 2001; 115: 5862.
  • 20
    Liao CA, Lee CM, Wu HC, Wang MC, Lu SN, Eng HL. Lamivudine for the treatment of hepatitis B virus reactivation following chemotherapy for non-Hodgkin's lymphoma. Br J Haematol 2002; 116: 166169.
  • 21
    Faggioli P, Paschale MD, Tocci A, Luoni M, Fava S, De Paoli A, et al. Acute hepatic toxicity during cyclic chemotherapy in non-Hodgkin's lymphoma. Haematologica 1997; 82: 3842.
  • 22
    Yeo W, Chan PKS, Zhong S, Ho WM, Steinberg JL, Tam JS, 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.
  • 23
    Picardi M, Pane F, Quintarelli C, De Renzo A, Del Giudice A, De Divitiis B, et al. Hepatitis B virus reactivation after fludarabine-based regimens for indolent non-Hodgkin's lymphomas: high prevalence of acquired viral genomic mutations. Haematologica 2003; 88: 12961303.
  • 24
    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. Hepatogastroenterology 1999; 46: 29252930.
  • 25
    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: 182188.
  • 26
    Persico M, De Marino F, Russo GDG, Morante A, Rotoli B, Torella R, et al. Efficacy of lamivudine to prevent hepatitis reactivation in hepatitis B virus-infected patients treated for non-Hodgkin's lymphoma. Blood 2002; 99: 724725.
  • 27
    Fouillard L, Serfaty L, Gozlan J. Adefovir therapy for lamivudine escape and hepatitis B virus reactivation after reduced intensity conditioning allogeneic stem cell transplantation. Bone Marrow Transplant 2006; 37: 625626.
  • 28
    Cortelezzi A, Vigano M, Zilioli VR, Fantini NN, Pasquini MC, Deliliers GL, et al. Adefovir added to lamivudine for hepatitis B recurrent infection in refractory B-cell chronic lymphocytic leukemia on prolonged therapy with campath-1H. J Clin Virol 2006; 35: 467469.
  • 29
    Enomoto M, Nishiguchi S, Seki S, Yamane T, Hino M. Adefovir dipoxil to prevent exacerbation of lamivudine-resistant hepatitis B infection during chemotherapy for non-Hodgkin's lymphoma. Am J Gastroenterol 2004; 99: 16191620.
    Direct Link:
  • 30
    Lok AS, McMahon BJ. AASLD Practice Guidelines: chronic hepatitis B: update of recommendations. HEPATOLOGY 2004; 39: 857861.
  • 31
    Gauthier J, Bourne EJ, Lutz MW, Crowther LM, Dienstag JL, Brown NA, et al. Quantitation of hepatitis B viremia and emergence of YMDD variants in patients with chronic hepatitis B treated with lamivudine. J Infect Dis 1999; 180: 17571762.
  • 32
    Hui CK, Cheung WWW, Au WY, Lie AK, Zhang HY, Yueng YH, et al. Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with haematological malignancies on completion of cytotoxic chemotherapy. Gut 2005; 54: 15971603.
  • 33
    Dai MS, Chao TY, Kao WY, Shyu RY, Liu TM. Delayed hepatitis B virus reactivation after cessation of preemptive lamivudine in lymphoma patients treated with rituximab plus CHOP. Ann Hematol 2004; 83: 769774.
  • 34
    PDR Staff. Red Book. 110th ed. Thomson Healthcare (Montvale, NJ); 2006.
  • 35
    Hoover D, Crystal S, Kumar R. Medical expenditures during the last year of medical expenditures during the last year of life: findings from the 1992-1996 Medicare current beneficiary survey. Health Serv Res 2002; 37: 16251642.
  • 36
    U.S. Department of Labor Bureau of Labor Statistics. Consumer price index calculator. Available at: Accessed May 2007.
  • 37
    Russell LB, Gold MR, Siegel JE, Daniels N, Weinstein MC. The role of cost-effectiveness analysis in health and medicine. JAMA 1996; 276: 11721177.
  • 38
    Petitti D. Meta-Analysis, Decision Analysis, and Cost-Effectiveness Analysis. New York, NY: Oxford University Press; 2000.
  • 39
    Webster A, Brenner MK, Prentice HG, Griffiths PD. Fatal hepatitis B reactivation after autologous bone marrow transplantation. Bone Marrow Transplant 1989; 4: 207208.
  • 40
    Mertens T, Kock J, Hampl W, Schlicht HJ, Tillmann HL, Oldhafer KJ, et al. Reactivated fulminant hepatitis B virus replication after bone marrow transplantation: clinical course and possible treatment with ganciclovir. J Hepatol 1996; 25: 968971.
  • 41
    Yoshiba M, Sekiyama K, Sugata F, Okamoto H, Yamamoto K, Yotsumoto S. Reactivation of precore mutant hepatitis B virus leading to fulminant hepatic failure following cytotoxic treatment. Dig Dis Sci 1992; 37: 12531259.
  • 42
    Peters MG, Hann HW, Martin P, Tillinger W, Reinisch W, Fueger GF, et al. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology 2004; 126: 91101.
  • 43
    Perillo R, Hann HW, Mutimer D, Willems B, Leung N, Lee WM, et al. Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology 2004; 126: 8190.
  • 44
    Gerolami R, Bourliere M, Colson P, Halfon P, Borentain P, Henry M, et al. Unusual selection of rtA181V HBV mutants cross-resistant to adefovir following prolonged lamivudine monotherapy: report of two cases. Antivir Ther 2006; 11: 11031106.
  • 45
    Yang H, Qi X, Sabogal A, Miller M, Xiong S, Delaney WE IV. Cross-resistance testing of next-generation nucleoside and nucleotide analogues against lamivudine-resistant HBV. Antivir Ther 2005; 10: 625633.
  • 46
    Yeo W, Lam KC, Zee B, Chan PS, Mo FK, Ho WM, et al. Hepatitis B reactivation in patients with hepatocellular carcinoma undergoing systemic chemotherapy. Ann Oncol 2004; 15: 16611666.
  • 47
    Dai MS, Wu PF, Shyu RY, Lu JJ, Chao TY. Hepatitis B virus reactivation in breast cancer patients undergoing cytotoxic chemotherapy and the role of preemptive lamivudine administration. Liver Int 2004; 24: 540546.
  • 48
    Yeo W, Hui EP, Chan ATC, Ho WM, Lam KC, Chan PK, et al. Prevention of hepatitis B Reactivation in patients with nasopharyngeal carcinoma with lamivudine. Am J Clin Oncol 2005; 28: 379384.
  • 49
    Tsai FC, Hseih HC, Chen DS, Shen JC, Chen DS. Reactivation of hepatitis B virus in rheumatologic patients receiving immunosuppressive agents. Dig Dis Sci 2006; 51: 16271632.
  • 50
    Murakami R, Amada N, Sato T, Orii T, Kikuchi H, Haga I, et al. Reactivation of hepatitis and lamivudine therapy in 11 HBsAg-positive renal allograft recipients: a single center experience. Clin Transplant 2006; 20: 351358.
  • 51
    Shitrit AB-G, Kramer MR, Bakal I, Morali G, Ari ZB, Shitrit D. Lamivudine prophylaxis for hepatitis B virus infection after lung transplantation. Ann Thorac Surg 2006; 81: 18511852.
  • 52
    Esteve M, Saro C, Gonzalez-Huix F, Suarez F, Fome M, Viver JM. Chronic hepatitis B reactivation following infliximab therapy in Crohn's disease patients: need for primary prophylaxis. Gut 2004; 53: 13631365.
  • 53
    World Health Organization. Hepatitis B. Available at: Accessed May 2007.