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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Conclusions
  7. Conclusion and recommendation
  8. Acknowledgements
  9. References

Background  Reactivation of hepatitis B virus infection in asymptomatic hepatitis B surface antigen carriers undergoing chemotherapy or immunosuppressive therapy is a well-documented and potentially fatal complication. Data supporting the use of lamivudine for primary prophylaxis have emerged, but its use remains controversial and is not standardized.

Aim  To review current randomized-controlled trials, randomized trials and prospective case series to provide a clinically applicable, evidence-based recommendation.

Methods  The published literature was identified using a MEDLINE/PubMed search with secondary review of cited publications, and inclusion of all prospective studies.

Results  In nine prospective trials and one randomized-controlled trial, the rate of hepatitis among subjects receiving lamivudine prophylaxis ranged from 0% to 20% (16 of 173, 9.2%), compared with 33–67% among controls. Of patients receiving prophylaxis, 0–24% (15 of 173, 8.7%) developed hepatitis B virus reactivation, compared with 29–56% of controls. Three reactivation-related mortalities were reported (one receiving prophylaxis, two controls). No patients withdrew secondary to toxicity or development of lamivudine-resistant mutations.

Conclusions  The available data show a four- to sevenfold decrease in the rate of hepatitis and hepatitis B virus reactivation in patients who receive lamivudine prophylaxis. It is thus recommended that all hepatitis B surface antigen carriers receive lamivudine, or a comparable anti-viral agent, as prophylaxis from the initiation of chemotherapy until at least 1 year following its completion.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Conclusions
  7. Conclusion and recommendation
  8. Acknowledgements
  9. References

Hepatitis B virus (HBV) has infected over 2 billion people worldwide, placing it among the most significant global health burdens.1 Sequelae of HBV infection, including acute liver failure, cirrhosis and hepatocellular carcinoma, are responsible for an estimated 1.2 million deaths per year.2 The World Health Organization estimates between 350 and 400 million people globally are chronic hepatitis B surface antigen (HBsAg) carriers. As a consequence of increasing immigration from highly endemic areas, such as China, Southeast Asia and Africa, the prevalence of chronic HBsAg carriers in the United States continues to rise, with the US accounting for 1.5  million of the worldwide chronic HBsAg carriers.3,4 A growing number of published reports of HBV reactivation-related morbidity and mortality, have made this population the focus of considerable investigation, including the role of prophylactic anti-viral therapy.5–8

HBV reactivation

Among HBV-infected patients with a negative hepatitis B e antigen (HBeAg) serological test, up to 22% may develop spontaneous reactivation of HBV infection ranging from asymptomatic elevation of serum HBV DNA levels to acute liver failure.5,9–11 The majority of reported cases of reactivation are among patients with detectable HBsAg.6,12,13 However, patients receiving cytotoxic, immunosuppressive or chemotherapeutic agents, who are HBsAg-negative but positive for antibody to hepatitis B core antigen (anti-HBc) alone or with antibody to hepatitis B surface antigen (anti-HBs) have also, though less frequently, been reported to reactivate HBV infection.14–19

Reactivation of HBV infection has been observed in a variety of clinical settings, including liver transplantation, partial hepatic resection for hepatocellular carcinoma, pregnancy, immunosuppression [both iatrogenic and infectious, including chemotherapy and human immunodeficiency virus (HIV) infection], withdrawal of immunosuppression, bone marrow transplantation and spontaneously.5,8,12,20–25 Pooled analyses of patients with HBV reactivation suggest a highly disparate risk of reactivation based on the presumed medical comorbidity or treatment leading to immunosuppression. Rates of reactivation following partial hepatic resection, pregnancy, or among cases of spontaneous reactivation have been reported to occur in 24% of cases or less.5,23 In contrast, a nearly threefold higher rate, >60%, was observed in a prospective study of HBsAg-positive patients who received cytotoxic therapy.17 The form of cytotoxic therapy, with or without additional immunomodulatory treatment, may further influence the risk of reactivation. Patients with haematological malignancies, including lymphoma, receiving high-dose glucocorticoids as a component of their chemotherapy regimen are believed to be at greatest risk (as high as 67%), relative to reactivation associated with solid tumours treated with chemotherapy regimens without glucocorticoids (40% or less).17,26–32

Though HBV reactivation may be asymptomatic, reactivation may also result in clinically significant hepatitis, delay of chemotherapy and decreased overall survival.20,30,33,34 Among patients with haematological malignancies, the rate of hepatitis may be as high as 50–60%, though HBV reactivation only accounts for half of these cases.18,26–30,35–37 During HBV reactivation-induced hepatitis, there is loss of antibody to hepatitis B e antigen (anti-HBe) and reappearance of HBeAg. Elevated HBV DNA levels confirm the diagnosis of active (replicative) HBV infection.38 The serological presence of HBeAg and increase in viral load, demonstrating HBV reactivation, often coincide with the initiation of immunosuppressive therapy or its withdrawal.39,40 In cases of HBV reactivation during initial chemotherapy, delay of cytotoxic therapy may be necessary for as long as 100 days, contributing to lower disease-free and overall survival for patients with a malignancy associated with HBV reactivation.41,42 The mortality rate directly associated with HBV reactivation, predominantly secondary to acute liver failure, ranges from 4% to 60%.17,26,29,33,36,43–45

Anti-viral treatment and prophylaxis

Hepatitis B virus reactivation that occurs following hepatic resection, pregnancy, or spontaneously has been treated successfully with interferon, nucleoside analogues, ganciclovir and famciclovir.18,46,47 For patients who reactivate during or associated with withdrawal of chemotherapy, immunosuppression, or other cytotoxic treatment, the choice of therapy is more challenging and typically less successful. The tendency for reactivation to occur upon the withdrawal of immunosuppression led to therapies including the reinstitution of immunosuppression. This was believed to inhibit the immune response mediating hepatic damage; however, treatment was typically ineffective.48,49 The myelotoxicity of ganciclovir and haematopoietic toxicity of interferon have prevented their use among patients with pre-existing cytopenias secondary to chemotherapy.28,50,51 Famciclovir has weak activity against HBV replication and is no longer used.

In 1995, early reports of lamivudine, a reverse-transcriptase inhibitor (3′-thiacytidine), which results in suppression of HBV replication by causing early chain termination, appeared promising for the treatment of chronic hepatitis B.52In vitro studies found lamivudine to have a relatively benign side effect profile without significant rates of haematopoietic toxicity in the setting of HBV reactivation following chemotherapy or immunosuppression.53,54 In 1997, the first clinical trials were published demonstrating inhibition and reduction of serum HBV DNA levels in patients with chronic, as well as acute, hepatitis B.55,56 Just prior to this, a case series had shown efficacy of lamivudine in treating HIV-infected patients coinfected with HBV.57 Additional case series provided in vivo evidence that lamivudine is efficacious in treating HBV infection in immunosuppressed patients and safe for patients with trilineage cytopenias secondary to chemotherapy.52,58,59 The role of lamivudine in the treatment of HBV reactivation was further defined in 1998 in two studies that documented resolution of reactivation in one case of fulminant hepatitis following chemotherapy for lymphoma, and acute icteric hepatitis in an allogeneic bone marrow transplant patient receiving immunosuppression for graft-vs.-host disease.60,61 Though lamivudine response occurred in the majority of patients, 18–40% of patients did not improve with lamivudine therapy.27,35,62–64 A trend among the patients who failed to respond to lamivudine indicated that these patients had delays in starting lamivudine therapy. Based on this finding combined with the low side effect profile, tolerability, and once-a-day dosing of lamivudine, therapy for chronic HBsAg carriers receiving immunosuppression or chemotherapy shifted from treatment after the diagnosis of reactivation towards prophylaxis with the initiation of chemotherapy.

Prophylactic lamivudine was first applied as a continuation therapy in which patients who had responded to lamivudine were continued on therapy to prevent future reactivation during immunosuppressive therapy. A series of patients receiving immunosuppression for bone marrow transplant demonstrated markedly low rates of reactivation without adverse effects of prophylaxis with lamivudine.41,65–67 The first case series of primary prophylaxis was published in 2001 involving 20 patients with haematological malignancies and a variety of chemotherapy regimens, the majority of which also included glucocorticoids.42 With a rate of HBV reactivation of 5%, the role of lamivudine for prophylaxis among HBsAg carriers appeared to be indicated. However, subsequent studies have raised concern regarding emergence of lamivudine-resistant mutants and increased mortality among this subset of patients treated with lamivudine.68–70 It is also unclear whether or not patients who are HBsAg-negative and anti-HBc-positive with detectable HBV DNA levels should receive prophylaxis.71 At this time, there remains no consensus on the role of lamivudine in primary prophylaxis for HBV reactivation. Our aim was to review the current randomized-controlled trials, randomized trials and prospective case series to provide an evidence-based recommendation that can be applied to chronic HBsAg carriers at risk of reactivation because of immunosuppression, chemotherapy, or other cytotoxic agents.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Conclusions
  7. Conclusion and recommendation
  8. Acknowledgements
  9. References

A thorough literature search was performed using MEDLINE/PubMed search engines with secondary review of cited publications. All prospective studies that included lamivudine for prophylaxis against HBV reactivation were reviewed and included in our data. One randomized-controlled trial, four prospective trials with historical controls, and five prospective case series were identified.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Conclusions
  7. Conclusion and recommendation
  8. Acknowledgements
  9. References

Patient selection and study protocol

Since the first prospective trial of lamivudine prophylaxis for HBV reaction in 2001 by Rossi et al.,42 four additional prospective trials without controls (prospective case series), four prospective trials with historical controls and one randomized-controlled trial have been published (Table 1).31,32,42,71–77 A total of 173 patients in 10 trials received lamivudine prophylaxis per trial protocol. Nine of 10 trials were performed in the adult population, and six of 10 trials enrolled subjects with haematological malignancies including leukaemia, lymphoma, multiple myeloma, aplastic anaemia and Waldenstrom macroglobulinaemia. A variety of chemotherapy regimens were administered, with subjects in eight of 10 studies receiving glucocorticoids. Five studies enrolled subjects with solid tumours, the majority (four of five studies) enrolling patients with breast cancer and one trial enrolling patients with nasopharyngeal carcinoma. In each trial, other than the paediatric-based investigation published by el-Sayed et al.76 in 2004, the dosage of lamivudine used was 100 mg/day. el-Sayed et al. dosed lamivudine according to body weight (3 mg/kg) in the paediatric population.76 Lamivudine was started 7–19 days prior to initiation of chemotherapy in seven studies, and on the first day of chemotherapy in the remaining three trials. Termination of prophylaxis was variable with one study discontinuing lamivudine on the last day of chemotherapy, seven studies continuing lamivudine from 1 to 3 months following completion of chemotherapy, and two studies continuing lamivudine either for 1 year or indefinitely after completion of chemotherapy. Likewise, the follow-up period was variable with patients followed for as short a period as 2 months following completion of chemotherapy to as long as more than 2 years.

Table 1.   Trials of prophylactic lamivudine therapy for prevention of hepatitis B reactivation – protocol
AuthorPrimary disease (n in lamivudine group/n in control group)Chemotherapy regimenPatients (n)Lamivudine
Lamivudine groupControl group (placebo)Dose (mg daily)Duration
  1. CDDP, cisplatin; AC, doxorubicin, cyclophosphamide; TAC, docetaxel, doxorubicin, cyclophosphamide; CMF, cyclophosphamide, methotrexate, fluorouracil; CAF, cyclophosphamide, doxorubicin, fluorouracil; NA, vinorelbine, doxorubicin; NE, vinorelbine, epirubicin; TF, docetaxel, tegafur-uracil; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; 2-CdA, 2-chlorodeoxyadenosine, cladribine; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; IDA, idarubicin; ARA-C, cytosine arabinoside; hyper-CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone, high-dose methotrexate, cytarabine; VAD, vincristine, doxorubicin, dacarbazine; F, fludarabine; CEOP, cyclophosphamide, epirubicin, vincristine, prednisolone; COPP, cyclophosphamide, vincristine, procarbazine, prednisolone; MTX, methotrexate; COMP, cyclophosphamide, oncovin, methotrexate, prednisone; ACVBP, intensified modified-CHOP regimen; HD-CY, high-dose cyclophosphamide; FLAG-IDA, fludarabine, cytarabine, filgrastin, idarubicin; CHL, chlorambucil; CY, cyclophosphamide; CT, chemotherapy; NR, not reported; UD, undetectable.

  2. * All patients in study <18 years of age.

Randomized-controlled trials
 Lau et al.77Lymphoma (15/15)CEOP, ABVD, CHOP, COPP1515100Initiation – 7 days prior to CT Completion – 43 days following CT
Prospective trials with historical controls
 Dai et al.32Breast CA (11/9)AC, TAC, CAF, CMF, CDDP, NA, NE, TF119100Initiation – 7 days prior to CT Completion – 28 days following CT
 Idilman et al.72Leukaemia (3/6), lymphoma (4/3), breast CA (0/1), multiple myeloma (1/0)IDA, ARA-C, ABVD, CHOP, 2-CdA, Hyper-CVAD, VAD, AC, F810100Initiation – day 1 of CT Completion – 365 days following CT
 Yeo et al.74Breast CA (31/61)Anthracyclines (97%), corticosteroids (74%)3161100Initiation – 7 days prior to CT Completion – 45 days following CT
 Yeo et al.73Nasopharyngeal CA (16/21)Cisplatin, platinum-based, corticosteriods1621100Initiation – 7 days prior to CT Completion – 45 days following CT
Prospective trials
 Dai et al.31Breast CA (6)TAC, AC, CMF, CAF, NA, NE, TF60100Initiation – 7 days prior to CT Completion – 28 days following CT
 el-Sayed et al.76*Leukaemia (7), lymphoma (3)CHOP/MTX, COEP/ABVD, COMP1003 mg/kg body weight dailyInitiation – day 1 of CT Completion – last day of CT
 Hui et al.75Leukaemia (8), lymphoma (35), multiple myeloma (3)Anthracyclines (76%), corticosteroids (78%)460100Initiation – 7 days prior to CT Completion – 90 days following CT
 Rossi et al.42Leukaemia (5), lymphoma (14), multiple myeloma (1)ACVBP, CHOP/HD-CY, CHOP, FLAG-IDA, CHL, F, HD-CY, CY, 2-CdA, corticosteroids (65%)200100Initiation – day 1 of CT Completion – 28 days following CT
 Vassiliadis et al.71Leukaemia (5), lymphoma (3), aplastic anaemia (1), Waldenstrom macroglobulinaemia (1)NR, corticosteroids (90%)100100Initiation – 19 days prior to CT Completion – continued throughout follow-up period

Efficacy and safety of lamivudine prophylaxis

The results of baseline serological tests of patients in nine of 10 studies were similar with all subjects positive for HBsAg (Table 2). Vassiliadis et al. enrolled 10 subjects without controls, seven patients who were HBsAg-positive, and three who were HBsAg-negative and anti-HBc-positive with detectable serum HBV DNA.71 Initial liver function tests, as assessed by alanine aminotransferase (ALT) levels, were normal or mildly elevated in all studies. The majority of patients receiving lamivudine and controls had undetectable HBV DNA levels at the onset of prophylaxis. Hepatitis was reported using the definition proposed by Lok et al., i.e. a greater than threefold increase in baseline ALT levels exceeding the upper limit of normal (ULN; 58 IU/L) or an absolute increase compared with baseline value of at least 100 IU/L.17 Among trials including controls, the rate of hepatitis among patients receiving placebo ranging from 33% to 67%, totalling 63 patients of 116 controls (average rate of 54%).32,72–74,77 Though the highest median ALT levels among these five studies was under 400 IU/L, maximum individual ALT levels were over 1000 IU/L and led to acute liver failure in a limited number of cases.72 The rate of hepatitis among subjects receiving lamivudine prophylaxis ranging from 0% to 20% from data of all 10 prospective trials (average of 9.2%).

Table 2.   Trials of prophylactic lamivudine therapy for prevention of hepatitis B reactivation – outcomes
AuthorPatients (n)HBV statusInitial ALT (median; IU/L)Initial HBV DNA level (median)Follow-up duration (months)Hepatitis*, n (%)Peak ALT (median; IU/L)HBV reactivation†, n (%)Peak HBV DNA level (median)HBV-related mortality, n (%)
Lamivudine groupControl group (placebo)
  1. * As defined by Lok et al.,17 a threefold or greater increase in ALT exceeding the ULN (58 IU/L) or an absolute increase of ALT to over 100 IU/L.

  2. † Defined as an increase in HBV DNA levels of 10-fold or greater relative to baseline or an absolute increase exceeding 1000 × 106 genome equivalents/mL.

  3. ‡ Patient developing hepatitis and recurrence was not compliant with lamivudine therapy.

  4. § All patients in study <18 years of age.

  5. CT, chemotherapy; NL, within upper limit of normal; UD, undetectable; NR, not reported; ALT, alanine aminotransferase; ULN, upper limit of normal.

Randomized-controlled trials
 Lau et al.771515HBsAg+/ HBeAg+ (4/4)Nl vs. Nl0 vs. 0 pg/mLCT + 33 (20) vs. 10 (66.7)Nl vs. 2750 vs. 8 (53.3)UD vs. 1 × 106  copies/mL0 vs. 0
Prospective trials with historical controls
 Dai et al.32119HBsAg+14 vs. 153.11 vs. 2.57 copies/mL19 vs. 102 (18.2) vs. 5 (55.6)26 vs. 1130 vs. 5 (55.6)UD vs. 1.2 × 103  copies/mL0 vs. 1 (11.1)
 Idilman et al.72810HBsAg+/ HBeAg−/ HBcAb (IgM/G)−/+29 vs. 25UD vs. UD120 vs. 5 (50)Nl vs. 3720 vs. 5 (50)UD vs. 30 pg/mL0 vs. 0
 Yeo et al.743161HBsAg+28 vs. 27NRCT + 24 (12.9) vs. 36 (59)Nl vs. 872 (6.5) vs. 19 (31.1)NR0 vs. 0
 Yeo et al.731621HBsAg+/ HBeAg+ (1/4)45 vs. 29UD vs. UDCT + 21 (6.3) vs. 7 (33.3)Nl vs. Nl0 vs. 6 (28.6)NR0 vs. 1 (4.8)
Prospective trials
 Dai et al.3160HBsAg+201000 copies/mLCT + 71 (16.7)‡501 (16.7)‡1000  copies/mL0
 el-Sayed et al.76§100HBsAg+302NR100Nl0NR0
 Hui et al.75460HBsAg+NlUDCT + 263 (8.7)NR11 (23.9)NR1 (2.2)
 Rossi et al.42200HBsAg+NlUD62 (10)Nl1 (5)UD0
 Vassiliadis et al.71100HBsAg+ (7)/ HBcAb+ and HBV DNA+ (3)Nl1100 copies/mL150Nl0UD0

Serum HBV DNA levels were undetectable in the majority of subjects and controls at the onset of each trial (Table 2). HBV reactivation was defined by an increase in HBV DNA levels 10-fold compared with baseline or an absolute increase of HBV DNA level exceeding 1000 × 106 genome equivalents/mL (an absolute increase of HBV DNA that exceeds 109 copies/mL).17,78 Rate of reactivation among controls during chemotherapy or the follow-up period ranged from 28.6% to 55.6% (43 of 116, 37%), with 53.3% of controls in the randomized trial developing HBV reactivation with 3 months of follow-up after completion of chemotherapy.32,72–74,77 Fifteen of 173 (8.7%) subjects between 10 studies receiving lamivudine prophylaxis developed HBV reactivation, with the majority of cases reported upon completion of chemotherapy and prophylaxis or within the follow-up after completion of treatment (a three- to sevenfold reduced rate of reactivation compared with controls). Six of 10 studies found no HBV reactivation among patients on prophylaxis. The greatest risk of reactivation among patients receiving prophylaxis corresponded to the trial with the longest follow-up duration (rate of reactivation of 23.9% with median follow-up of 26 months following completion of chemotherapy and 23 months following completion of lamivudine prophylaxis).75

Among all subjects in the 10 trials, only three HBV reactivation-related mortalities were reported. Two of the three were among control subjects who did not receive prophylaxis.32,73 The one HBV reactivation-related mortality among patients receiving prophylaxis was related to bleeding oesophageal varices and hepatic encephalopathy.75 This subject developed HBV reactivation 16 months after initiation of chemotherapy and almost 8 months after termination of lamivudine prophylaxis.

Minor adverse effects that were reported, none of which was dose-limiting or required cessation of lamivudine therapy, included elevations in amylase, lipase, creatine kinase, nausea, headache, dizziness and pancreatitis (Table 3). Only three of 10 prospective lamivudine trials monitored for emergence of YMDD mutations during prophylactic therapy. Of these three studies, in only one by Hui et al. were two mutant strains identified among 46 subjects (4.9%).75

Table 3.   Trials of prophylactic lamivudine therapy for prevention of hepatitis B reactivation – complications of lamivudine therapy
AuthorLamivudineToxicityDisruption of chemotherapy due to lamivudine toxicity, n (%)Early withdrawal due to lamivudine toxicity, n (%)YMDD lamivudine-resistant HBV mutant, n (%)
Dose (mg daily)Duration
  1. * All patients in study <18 years of age.

  2. † Two patients with YMDD mutants with prior lamivudine therapy and excluded from prospective trial. No enrolled patients developed new YMDD mutants.

  3. CT, chemotherapy; NR, not reported.

Randomized-controlled trials
 Lau et al.77100Initiation – 7 days prior to CT Completion – 43 days following CTNone00NR
Prospective trials with historical controls
 Dai et al.32100Initiation – 7 days prior to CT Completion – 28 days following CTNone000
 Idilman et al.72100Initiation – day 1 of CT Completion – 365 days following CTNone00NR
 Yeo et al.74100Initiation – 7 days prior to CT Completion – 45 days following CTNone00NR
 Yeo et al.73100Initiation – 7 days prior to CT Completion – 45 days following CTNone00NR
Prospective trials
 Dai et al.31100Initiation – 7 days prior to CT Completion – 28 days following CTNone000
 el-Sayed et al.76*3 mg/kg body weight dailyInitiation – day 1 of CT Completion – last day of CTNausea, headache, dizziness00NR
 Hui et al.75100Initiation – 7 days prior to CT Completion – 90 days following CTNone002 (4.9)†
 Rossi et al.42100Initiation – day 1 of CT Completion – 28 days following CTPancreatitis00NR
 Vassiliadis et al.71100Initiation – 19 days prior to CT Completion – continued throughout follow-up periodNone00NR

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Conclusions
  7. Conclusion and recommendation
  8. Acknowledgements
  9. References

Lamivudine, based on review of 10 prospective trials including a total of 173 patients, is clinically efficacious as prophylaxis to prevent HBV reactivation among patients receiving chemotherapy. From data of all 10 trials, the rate of hepatitis among subjects receiving lamivudine prophylaxis ranging from 0% to 20% (16 of 173, 9.2%), compared with 33–67% among controls (63 of 116, 54%). Of patients receiving lamivudine prophylaxis, 0–24% (15 of 173, 8.7%) developed HBV reactivation, compared with 29–56% of controls (43 of 116, 37%). Despite the universal efficacy of lamivudine prophylaxis, the optimal dose and duration, adverse effects and risk of inducing lamivudine-resistant mutants, and most appropriate patient population to receive lamivudine prophylaxis merit further discussion.

Dose and duration of lamivudine prophylaxis

All prospective adult trials have used equivalent daily doses of lamivudine, i.e. 100 mg daily.31,32,42,71–75,77 Three studies using higher doses of lamivudine have shown similar and not superior efficacy in preventing HBV reactivation.79–81 Little data exist to recommend dosing lamivudine on a regimen other than 100 mg/day. In contrast, duration of lamivudine therapy prior to, and even more significantly, after completion of chemotherapy, is widely variable. No single, multiarmed study with variable length of lamivudine prophylaxis has been conducted. However, based on the 10 prospective studies and prior cases series, HBV reactivation increases in incidence following withdrawal of chemotherapy and lamivudine prophylaxis. The highest HBV reactivation rate was observed in the prospective trials with the longest follow-up, i.e. a median of 26 months after completion of chemotherapy.75 Further, the only HBV reactivation-related mortality among the prospective trials occurred following discontinuation of lamivudine.75 Idilman et al. continued lamivudine for 1 year following chemotherapy and reported no events of HBV reactivation or reactivation-related mortality.72 Vassiliadis et al. in a prospective trial without controls have continued lamivudine prophylaxis indefinitely and have also observed no events of HBV reactivation or reactivation-related mortality.71 Clearly lamivudine prophylaxis should be continued through the course of chemotherapy. Given HBV reactivation has been reported >1 year after completion of chemotherapy, and lamivudine therapy is well tolerated, an argument can be made to continue lamivudine therapy indefinitely, or switch to another oral anti-viral agent with a lower rate of resistance.9,10

Adverse effects of lamivudine prophylaxis

Preliminary studies demonstrated a relatively benign toxicity profile of lamivudine when used as treatment for HBV infection and reactivation.52,57 Use of lamivudine for treatment of HBV reactivation in a number of studies confirmed the lack of toxicities or comorbidities, specifically among patients on chemotherapy or other immunosuppressive agents.44,60,66,79,82,83 However, one notable exception is patients with the acquired immune deficiency syndrome (AIDS) receiving both lamivudine and zidovudine, among whom five cases of pure red cell aplasia and anaemia have been reported.84–86 No evidence of clinically significant inhibition of haematopoiesis has been observed among oncology patients, even those high risk receiving stem cell transplant.61,87 As expected, when lamivudine was used as prophylaxis rather than for treatment of HBV, it also displayed a benign side effect profile.31,42,44,47,65,76,79

A major clinical concern regarding prophylactic therapy with lamivudine, and an area of substantial controversy, is development of lamivudine-resistant mutant strains of HBV.58,68,88 Evidence originally was based on case series of HBV infection treated with lamivudine for >1 year. Lai et al. identified a mutation rate of HBV, specifically within the YMDD motif, of 12–20% at 12 months.89 A follow-up analysis at 4 years (among the longest longitudinal studies currently published) found that of 58 Chinese patients with chronic HBV infection treated with lamivudine for up to 5 years, 39 patients (67%) developed YMDD mutant strains of HBV.90 Interestingly, despite emergence of YMDD mutants, the clinical outcomes were equivalent among chronic HBV carriers with and without YMDD mutant HBV. A similar percentage of HBsAg carriers achieved normalization of ALT levels at 4 years, i.e. 68% and 73% of patients with vs. without YMDD mutants, respectively. At 4 years, all patients, regardless of YMDD status, had decreased levels of HBV DNA following lamivudine therapy. In contrast to this study, Lok et al. published a 5-year follow-up of 998 HBeAg-positive patients who received lamivudine as treatment for up to 6 years.91 Lamivudine-resistant YMDD mutations were found in 23% of patients at year 1 of therapy and 65% at year 5. Within this patient population, an increased incidence of hepatitis flares as well as increased rates of serious adverse events in years 5 and 6 of follow-up were associated with the presence of lamivudine-resistant mutations. Prior to the fifth year of lamivudine treatment; however, rates of serious adverse events were similar in patients with and without YMDD mutations.

The incidence of lamivudine-resistant YMDD mutations among chronic HBsAg carriers receiving lamivudine as prophylaxis rather than treatment has not been well established. Rates reported in retrospective case series are conflicting. Caccamo et al. actually report a decreased prevalence of YMDD mutations after lamivudine prophylaxis among 17 patients, with YMDD mutants detected in 44% of patients at baseline and 17% after 24 months of prophylaxis.92 Dai et al.31 and Nagamatsu et al.,83 given their limited duration of follow-up and small sample sizes, found that no patients who were receiving lamivudine prophylaxis developed YMDD mutants.31,83 Lamivudine treatment of patients receiving chemotherapy for haematological malignancies was associated with a low rate (3.1%) of YMDD mutations.93 Among case series of HBsAg carriers following liver transplantation or receiving stem cell transplantation, emergence of YMDD mutants was significantly increased by lamivudine prophylaxis, observed in 21% of patients at 1 year and 34% at 2 years.69,94 A limited number of studies also suggest an increased rate of HBV reactivation and mortality associated with development of lamivudine-resistant YMDD mutations during prophylaxis.69,95

Among the 10 prospective trials, only three included this end point, with two observing no mutants, and only a single study by Hui et al., reporting development of mutant strains with a rate of 4.9%.75 However, both subjects were found to have YMDD mutants prior to enrolment in the trial and were excluded; though, each had received lamivudine prior to identification of the YMDD mutants. The Hui et al.75 trial also continued observation for mutant strains during a median follow-up of 26 months after completion of chemotherapy, and did not observe the emergence of any lamivudine-resistant mutants.

The implications of the emergence of YMDD mutants during lamivudine therapy or prophylaxis are not well defined. A recent investigation by Pallier et al. determined that despite a YMDD-variant mutation rate of 53–76% at 3 years of lamivudine therapy, the rate of actual viral replication lags significantly behind detection of genetic mutation within the YMDD catalytic motif.96 Not only does this suggests that additional mutations likely occur outside the YMDD motif which help restore HBV replicative potential, but also additionally that it may be possible to detect initial mutations in the HBV DNA and alter therapy before HBV reactivation occurs. A limited number of studies suggest that transition to adefovir dipivoxil following development of lamivudine-resistant HBV variants is safe and efficacious.97–100 Further clinical trials are still required to validate these findings. A multidrug, tiered strategy of HBV reactivation prophylaxis and/or treatment, would allow indefinite lamivudine prophylaxis to be recommended if routine monitoring for YMDD mutants is performed with transition in anti-viral therapy, including adefovir or entecavir, if detected. These drugs could then be continued long-term with hopefully lower rates of resistance.

Areas requiring continued research

Patient selection for lamivudine prophylaxis

Ideally, lamivudine prophylaxis would only be provided to patients at a significant risk for reactivation and also likely to respond to therapy. Multivariate analyses of risk factors for HBV reactivation have concluded the single greatest risk factor is a high HBV DNA level prior to initiation of lamivudine prophylaxis and either chemotherapy or other immunosuppression.18,47,75,101–105 However, chronic HBV carriers with evidence of HBV replication >104 copies/mL, require anti-viral treatment and should not be considered for prophylactic anti-viral therapy. Other identified risk factors include positive tests for both HBsAg and HBeAg, male gender, younger age, presence of a precore region mutation prior to initiation of lamivudine and chemotherapy with glucocorticoid-containing regimens.18,30,75,95,103

No patient characteristics have been defined to identify a population of chronic HBsAg carriers who have no risk of reactivation. Though only a limited population of patients who are HBsAg-negative but anti-HBc-positive at time of chemotherapy have been included in lamivudine prophylaxis trials, reactivation in this population has been observed.15,19,61,71,82 Kawatani et al.15 found that three of eight HBV-infected patients, despite being initially HBsAg-negative, developed severe liver dysfunction and became HBsAg-positive, with two of the three dying of fulminant hepatitis after beginning chemotherapy for haematological malignancies. These findings support screening for the presence of HBV DNA prior to chemotherapy.

Only a limited number of studies have investigated if patient or viral characteristics predict response to lamivudine. This area has been restricted to investigation whether HBV genotype predicts response. Data thus far suggest lamivudine response is not correlated with HBV genotype given no difference in rate or percentage of patients achieving normalization of ALT, reduction in HBV DNA levels and rate of HBeAg seroconversion between chronic HBV patients with genotype B or C.106,107

Glucocorticoid use and lamivudine prophylaxis

Glucocorticoid-containing chemotherapy regimens are known to increase the risk of HBV reactivation.45,108,109 A series of 50 HBsAg-positive patients with non-Hodgkin's lymphoma were randomized to chemotherapy treatment including epirubicin, cyclophosphamide and etoposide either with or without prednisolone.108 Incidence of HBV reactivation at 9 months after initiation of chemotherapy was 38% for patients not receiving glucocorticoids and 73% for those on prednisolone. Elevations in ALT levels diagnostic of hepatitis (defined by a greater than threefold increase in baseline ALT levels exceeding the ULN, or an absolute increase of at least 100 IU/L) occurred in 44% of patients receiving prednisolone, compared to only 13% of patients not receiving glucocorticoids. However, removal of glucocorticoids from the chemotherapy regimen significantly decreased survival, despite improving HBV status. Overall survival rate at 46 months in the prednisolone group was 68% vs. 36% in the glucocorticoid-free group.

An increased rate of HBV reactivation among HBsAg carriers receiving high-dose or chronic glucocorticoid therapy without chemotherapy has been presumed, but epidemiological evidence supporting this is lacking. If further research confirms both the in vitro data and clinical assumption regarding glucocorticoid therapy, a considerable number of patients will be candidates for lamivudine prophylaxis. Given the favourable safety and tolerability profile of lamivudine, it would be reasonable to provide prophylaxis as well to HBsAg carriers that require long-term, high-dose glucocorticoid treatment, pending formal study of this indication.

Conclusion and recommendation

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Conclusions
  7. Conclusion and recommendation
  8. Acknowledgements
  9. References

Hepatitis B virus reactivation in HBsAg carriers receiving chemotherapy has significant morbidity and potentially fatal complications. While more randomized-controlled trials are needed, the available data clearly support the use of lamivudine as prophylaxis in these subjects. In our review of 10 trials, lamivudine prophylaxis provided a four- to sevenfold decrease in rates of both hepatitis and HBV reactivation, when compared with controls. Patients receiving chemotherapy regimens that include glucocorticoids appear to have the highest rates of HBV reactivation. Whether glucocorticoid therapy independent of chemotherapy leads to HBV reactivation requires further investigation. However, pending study and given the favourable safety and tolerability profile of lamivudine, it would be reasonable to provide prophylaxis as well to HBsAg carriers that require long-term, high-dose glucocorticoid treatment.

Based on these data and on the protocols for the various trials, it is recommended that all HBsAg carriers receive lamivudine prophylaxis (100 mg/day) starting 7 days prior to the initiation of chemotherapy or high-dose glucocorticoids. While the optimal duration for prophylaxis is unclear, HBV reactivation has been reported more than 1 year after completion of chemotherapy. Therefore, lamivudine prophylaxis for at least 1 year following the completion of chemotherapy, if not longer, should be administered. While the risk of the development of lamivudine-resistant YMDD mutants is worrisome in the setting of long-term prophylaxis, it appeared to be of little clinical significance in the three trials that monitored for its development. Further studies will be needed to help delineate the need for monitoring for these mutants and possible transition to alternative anti-viral therapy, such as adefovir or entecavir with lower rates of resistance.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Conclusions
  7. Conclusion and recommendation
  8. Acknowledgements
  9. References

Drs Kohrt and Ouyang have declared no conflicts of interest. Dr Keeffe has served on advisory boards and is a member of speakers’ bureaus for GlaxoSmithKline, Gilead and Bristol-Myers Squibb. No independent sources funded this study.

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  5. Results
  6. Conclusions
  7. Conclusion and recommendation
  8. Acknowledgements
  9. References
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