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Lamivudine for the Prevention of Hepatitis B Virus Reactivation in Hepatitis B s-Antigen Seropositive Cancer Patients Undergoing Cytotoxic Chemotherapy

From the Department of Clinical Oncology and Department of Microbiology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong

Address reprint requests to Winnie Yeo, MD, MRCP, Department of Clinical Oncology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong; e-mail: winnieyeo{at}cuhk.edu.hk

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: For cancer patients receiving cytotoxic chemotherapy, hepatitis B virus (HBV) reactivation is a well described complication resulting in varying degrees of liver damage. The objectives of this study were to assess the efficacy of the antiviral agent lamivudine in reducing the incidence of HBV reactivation and diminishing morbidity and mortality of cancer patients with chronic HBV infection during chemotherapy.

PATIENTS AND METHODS: Two groups were compared in this nonrandomized study. The prophylactic lamivudine group consisted of 65 patients in a phase II study who were treated with lamivudine before and until 8 weeks after discontinuing chemotherapy. The historical controls consisted of 193 consecutive patients who underwent chemotherapy without prophylactic lamivudine. Significant prognosticators for the development of HBV reactivation were determined based on data from the controls. Potential confounding factors were identified between the two groups. The outcomes were compared.

RESULTS: In the controls, lymphoma and anthracycline usage were factors identified to be associated with reactivation. The two groups were comparable in most baseline characteristics, although in the prophylactic lamivudine group, there were significantly more patients with lymphoma and receiving anthracyclines. In the prophylactic lamivudine group, there was significantly less HBV reactivation (4.6% v 24.4% in the controls; P < .001), fewer incidences of hepatitis (17.5% v 44.6%; P < .0001) that were less severe (4.8% v 18.7%; P = .0005), and less disruption of chemotherapy (15.4% v 34.6%; P = .0029). The reduction in overall mortality was not statistically different.

CONCLUSION: Prophylactic lamivudine significantly reduced the incidence of HBV reactivation and the overall morbidity of cancer patients undergoing chemotherapy.

	INTRODUCTION

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More than a third of the world's population has been infected with the hepatitis B virus (HBV), and it is estimated conservatively that there are 350 million carriers. Seventy-five percent of HBV carriers live in Southeast Asia and the Western Pacific regions, where more than 8% of the population are chronic carriers [1,2]. For chronic carriers of HBV who undergo cytotoxic chemotherapy as part of anticancer treatment, reactivation of the hepatitis B virus has become a well-recognized complication [3]. The condition is characterized by raised levels of serum HBV DNA, abnormal liver function tests, and clinical hepatitis of varying degrees of severity that may result in death. Early reports of HBV reactivation involved mainly patients with hematologic malignancies [3-9], but more recent reports have described reactivation in patients with solid tumors [10-12], albeit at a lower rate of approximately 20%. With the increasing incidence of neoplastic diseases [13] and the more widespread use of cytotoxic chemotherapy, the incidence of HBV reactivation in adult patients in HBV endemic areas is likely to rise further.

The antiviral agent lamivudine has been reported to have a role in controlling HBV reactivation during chemotherapy [14-17]. However, despite treatment with lamivudine, fatal reactivation has been reported, [12,16,18] and for those who do recover from the consequent hepatic impairment, the prognosis of cancer may be adversely affected because of the disruption of chemotherapeutic administration.

Based on serial monitoring of HBV DNA and liver function (ALT), we have reported that viral replication occurs before clinical evidence of hepatitis, with peak HBV DNA preceding peak ALT activity by 1 to 2 weeks [19]. Because increased viral replication is the key event in this condition, it raises the possibility of adopting lamivudine in the prevention of HBV reactivation—that is, the use of the antiviral in a prophylactic manner, before the administration of chemotherapy.

In October 1997, we initiated a prospective cohort study of consecutive cases of hepatitis B s-antigen (HbsAg)–positive individuals undergoing cytotoxic chemotherapy, with a goal of assessing the incidence, risk factors, morbidity, and mortality of HBV reactivation. The results of the first 78 cases, which reported an HBV reactivation rate of 20% among HBsAg-positive cancer patients receiving cytotoxic chemotherapy, have been published [12]. In 2000, it became apparent that a number of centers were treating HBsAg carriers undergoing cytotoxic chemotherapy, either prophylactically or at the time of viral reactivation, with lamivudine. However, reports on the prophylactic use of lamivudine were based on retrospective data collection on small numbers of lymphoma patients [20-21]. Reports on patients with other malignancies, in whom HBV reactivation have been increasingly reported, have been lacking. We therefore decided to initiate a formal prospective study of lamivudine. Because of the recognized safety profile of lamivudine, its wide availability, and the morbidity and mortality reported in published studies, [12,16,18] we were aware that local physicians would be reluctant to enter patients onto a randomized trial that consisted of a control arm that did not have lamivudine treatment. We therefore designed a formal phase II nonrandomized study using prophylactic lamivudine, which followed directly from the original cohort that had, by then, reached a total of 193 patients; this latter group of patients was used as a historical control population. Apart from the fact that no prophylactic lamivudine was given in the controls, the clinical management was identical in both groups.

The objectives of the present study were to assess the efficacy of prophylactic lamivudine in reducing the incidence of HBV reactivation, and diminishing the morbidity and mortality in HBV carriers who underwent chemotherapy.

	PATIENTS AND METHODS

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We studied two groups of patients in this nonrandomized study. One group comprised patients who were entered onto the phase II study and were treated with prophylactic lamivudine between September 2000 and November 2001. The other group consisted of historical controls who were consecutive patients receiving no prophylactic lamivudine between October 1997 and August 2000. The protocol was approved by the Clinical Research Ethics Committee of the Chinese University of Hong Kong.

Entry and Exclusion Criteria
Cancer patients who were HBsAg positive were eligible if they were otherwise fit for intravenous (IV) chemotherapy according to the standard international guidelines, and if they were able to give written informed consent and attend clinic at least every 10 days during the study. For both groups, exclusion criteria excluded patients with hepatocellular carcinoma or head and neck cancers—these patients were under investigational protocols at the time and were thus excluded from the study—those who had decompensated liver disease at screening (as indicated by any of the following: prothrombin time > 4 seconds prolonged, albumin < 20 g/L, total bilirubin > 50 µmol/L, history of ascites, variceal hemorrhage, hepatic encephalopathy, or ALT > 10 x upper limit of normal [ULN; ie, > 580 iu/L]), those who had been treated with chronic antiviral therapy known to have activity against HBV (eg, interferon alfa, famciclovir, ganciclovir, or adefovir) within the previous 6 months, those who had acute fulminant hepatitis, those who were recipient of any investigational new drug (new chemical entity) within 30 days of the first dose of study drug, and those who were pregnant, lactating, or had pancreatitis.

Investigations
Before study entry, both groups of patients undertook the following investigations: HBsAg, hepatitis B e-antigen/antibody (HBeAg/anti-HBe), HBV DNA level, complete blood picture (hemoglobin, platelet count, white cell count, and differential), renal function test (sodium, potassium, urea, creatinine and creatinine clearance), liver function test (total protein, albumin, total bilirubin, ALT, and alkaline phosphatase) and clotting profile.

During the course of chemotherapy, on day 1 and day 10 of each cycle, the complete blood picture, clotting profile, renal function test, and liver function test were monitored with clinical signs and symptoms in all patients. Monitoring of these parameters was continued for 8 weeks after completion of chemotherapy.

When a patient was found to have developed hepatitis (as defined in the Definitions section) during the course of chemotherapy, HBV DNA was performed, with investigations for hepatitis A, C, and delta viruses, antinuclear factor, and other investigations as clinically indicated.

Hepatitis Serology and HBV DNA Assay
Hepatitis A, B, and delta markers were detected by commercial enzyme immunoassays (Cobas Core Anti-HAV IgM EIA, Roche Diagnostics GmbH, Germany, for hepatitis A; Auszyme MC Dynamic [HBsAg], Abbott Laboratories, Abbott Park, IL; Cobas Core Anti-HBc IgM EIA, Roche; MONOLISA HBe, Sanofi Diagnostics Pasteur, Chaska, MN; Abbott Anti-Delta EIA, Abbott). Hepatitis C RNA was detected by reverse transcription polymerase chain reaction using primers 209, 211, 939, and 940 as previously described [22]. HBV DNA level was measured by using the branched DNA hybridization assay (Quantiplex HBV DNA assay, Chiron Diagnostics, Emeryville, CA), which has a lower detection limit of 0.7 x 10⁶ genomic equivalent (ge)/mL.

Definitions
Based on a definition initially described by Lok et al [6] and subsequently modified by us, [12] hepatitis was defined as threefold or more increase in ALT that exceeded the upper limit of normal (< 58 U/L) or an absolute increase of ALT to more than 100 U/L when compared with baseline prechemotherapy value. Hepatitis attributable to HBV reactivation was defined as an increase in HBV DNA levels of tenfold or more when compared with baseline level or an absolute increase of HBV DNA level that exceeded 1,000 x 10⁶ ge/mL, in the absence of other systemic infection.

The severity of hepatitis was defined as mild when the rise in ALT was 2 x ULN or less; moderate, ALT more than 2 x and up to 5 x UNL; and severe, ALT more than 5 x ULN. Disruptions of chemotherapy were defined as either a premature termination of chemotherapy or a delay of more than 8 days of chemotherapy in between cycles.

Use of Lamivudine
For the prophylactic lamivudine group, treatment with lamivudine 100 mg orally daily commenced within 7 days before the start of chemotherapy. For patients with renal insufficiency, the daily lamivudine dose was adjusted according to creatinine clearance. Treatment was then continued throughout the course of chemotherapy for 8 weeks after discontinuation of chemotherapy.

Patients were withdrawn from the study if there was undue toxicity from lamivudine, if the patient was found to be pregnant at any point during the study, or if the patient requested to be withdrawn.

Historical Controls
Prophylactic lamivudine has historically not been administered. Therapeutic intervention for HBV reactivation with lamivudine became available in mid-1998. Thus, since then, for an individual who develops hepatitis, appropriate investigations were conducted, and the individual was started on the antiviral before the investigative results becoming available. With proven HBV reactivation, lamivudine was continued until 8 weeks after the discontinuation of chemotherapy; for patients subsequently proven not to have viral reactivation, the antiviral was stopped.

Statistical Methods
Based on the reported HBV reactivation rate of 20% among the first 78 patients in the controls [12], the present study aimed to detect a difference of 15% absolute reduction in the rate of reactivation. Because we had 193 patients in the historical control group who did not receive prophylactic lamivudine, our sample size was planned using a 3:1 ratio for control and prophylactic lamivudine groups, respectively, to minimize the duration required to obtain enough patients receiving prophylactic lamivudine to achieve adequate statistical power for the final analysis. The planned sample size called for a 90% power of detecting a 15% reduction in reactivation using a two-sided 5% level test, and a total of 258 patients were planned; as a result, the target number of accrual for the prophylactic lamivudine group in the phase II study was 65. All patients had been followed until completion of treatment before the final analysis.

Factors that were assessed for association with HBV reactivation included age, sex, baseline liver function (ALT, bilirubin, and albumin levels), HBeAg positivity, HBV DNA level, type of chemotherapy used, and type of malignancy. Prognostic factors for HBV reactivation in the controls were determined using a stepwise logistic regression model, with a significance level of less than 0.1 for a factor to enter into the logistic model in a stepwise fashion. Potential confounding factors were determined and took into account any difference between the two groups.

The primary outcome of this study was the proportion of patients with reactivation, as defined in the Definitions section. Fisher's exact test was used to compare the reactivation rates and outcomes between the two groups. The effect of prophylactic lamivudine was confirmed under a final logistic regression model adjusted for potential confounding factors as well as significant prognostic factors determined in the stepwise procedure. The Hosmer and Lemeshow Goodness-of-Fit test was used to evaluate the adequacy of the logistic model [23].

	RESULTS

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Patient Background Characteristics in the Two Groups
In this nonrandomized comparison, a total of 258 consecutive patients were studied; 193 patients were included in the historical controls and 65 in the prophylactic lamivudine group that belonged to the phase II study. Five patients were excluded during the study period, three from the controls (due to hyperbilirubinemia in two individuals and the use of oral cytotoxic in one) and two from the prophylactic lamivudine group (due to hyperbilirubinemia and the administration of lamivudine after initiation of chemotherapy, respectively). The characteristics of both groups are given in Table 1.

Biochemical, Virologic, and Clinical Outcomes in the Two Groups of Patients
The prophylactic lamivudine group. The median duration of lamivudine therapy was 161 days (range, 56 to 367 days). Patients received lamivudine at 100 mg daily, except for one patient, who receieved lamivudine at 50 mg daily because of renal insufficiency. The median number of chemotherapy cycles the patients received was six (range, one to 10 cycles). Of eleven patients (17.5%) who developed hepatitis during chemotherapy, three were found to have developed HBV reactivation, giving an HBV reactivation rate during cytotoxic chemotherapy of 4.6% (95% CI, 1% to 14%). The severity of hepatitis was mild in five patients (in two with hepatitis due to HBV reactivation), moderate in three patients (in one with hepatitis due to HBV reactivation) and severe in three patients (none with hepatitis due to HBV reactivation). Disruption in chemotherapy occurred in 10 patients (15.4%). Six patients had premature termination of chemotherapy, and four completed chemotherapy with interval delays; none of these 10 patients had hepatitis due to viral reactivation.

For the 54 patients who did not develop hepatitis during chemotherapy and lamivudine therapy, 10 had raised baseline viral DNA that fell to an undetectable level after a median time of 12 days of lamivudine (range, 11 to 21 days).

Five patients (7.7%) died during the study period because of progressive malignant disease; there was no mortality associated with HBV reactivation. The antiviral was well tolerated and was not associated with any unexpected or additional toxicity to chemotherapy.

Historical controls. The median number of chemotherapy cycles was five (range, one to 13 cycles). Eighty-six of the 193 patients (44.6%) developed hepatitis, of whom 47 had cases attributable to HBV reactivation, giving an HBV reactivation rate of 24.4% (95% CI, 19% to 31%). The severity of hepatitis was mild in 22 patients (nine with hepatitis due to HBV reactivation), moderate in 28 patients (13 with hepatitis due to HBV reactivation) and severe in 36 patients (25 with hepatitis due to HBV reactivation). Disruption in chemotherapy occurred in 67 patients (34.6%); 37 had premature termination of chemotherapy (19 with hepatitis due to HBV reactivation) whereas 30 had prolonged interval delays in between cycles (nine with hepatitis due to HBV reactivation).

Of the 47 patients who developed HBV reactivation, 32 received lamivudine as a therapeutic measure at the time of HBV reactivation. Despite this, five patients (11% of those who experienced reactivation) died, 22 had disruptions of chemotherapy, and only five managed to complete chemotherapy as planned.

Twenty-three patients (11.9%) died during the study period. Apart from five who died as a result of viral reactivation, 17 died as a result of progressive malignant disease, and one died as a result of chest infection.

Comparison of Outcomes Between the Two Groups
In the prophylactic lamivudine group, there was significantly less HBV reactivation (4.6% v 24.4% in the controls; P < .001), fewer incidences of hepatitis (17.5% v 44.6%; P < .0001) that were less severe (4.8% v 18.7%; P = .0005), and less disruption of chemotherapy (15.4% v 34.6%; P = .0029). The reduction in overall mortality was not statistically different.

The decrease in the reactivation rate was 19.8% (24.4% and 4.6% in the prophylactic lamivudine and control groups, respectively; 95% CI, 11% to 29%, P < .001). The number needed to treat to avoid an HBV reactivation by using prophylactic lamivudine is five patients (95% CI, 4 to 8). The number of patients needed to treat to save one life from death as a result of HBV reactivation using prophylactic lamivudine is 38 (95% CI, 21 to 282).

The final model was adjusted for the significant prognostic factors as well as the potential confounders, which include lymphoma and anthracycline-containing chemotherapy. The prophylactic lamivudine effect remained highly significant, as illustrated by an odds ratio of 11.1 (95% CI, 3.2 to 39.3) in favor of prophylactic lamivudine.

Prognostic Factors for HBV Reactivation in the Historical Controls
Potential prognostic factors are listed in Table 3 . Univariate analysis showed a higher rate of HBV reactivation in patients who received steroids than in those who did not (26% v13%, respectively; P = .011), anthracyclines (30% who received anthracyclines v 12% who did not; P < .001), and vinca alkaloids (39% who received vinca alkaloids v 15% who did not; P = .001), as well as those with a diagnosis of lymphoma (36% of lymphoma patients v 16% of patients with other malignancies; P = .006). On the other hand, patients with gastrointestinal cancers had a lower proportion of reactivation (24% patients with other malignancies v 6% patients with gastrointestinal cancers developed reactivation; P = .001). However, in the stepwise logistic regression analysis, only anthracycline-containing chemotherapy and lymphoma were significant factors in the model.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

For the controls, both investigations (to confirm the diagnosis of HBV reactivation during cytotoxic chemotherapy) and treatment (with lamivudine) were started on the detection of raised hepatic transaminase activity. This approach appeared ineffective, in that mortality was 11% among those who developed reactivation, with another 60% of patients having disruptions in chemotherapeutic treatment. This lack of efficacy may reflect the fact that viral replication proceeds, and may even end, before clinical hepatitis develops [19].

The use of prophylactic lamivudine in cancer patients undergoing chemotherapy has recently been reported in several small series in a retrospective manner, and these were based only on patients with lymphoma [21,24-26]. In one of the earlier reports by Silvestri et al [21], four lymphoma patients were described. All had previously recovered spontaneously from HBV reactivation during chemotherapy, and prophylactic lamivudine usage during subsequent chemotherapy prevented the recurrence of the condition while allowing the completion of the planned chemotherapy without compromising the prognosis from their lymphomas. A case-control study compared 16 HBsAg-positive patients who received prophylactic lamivudine during chemotherapy with 19 matched controls who did not; the result revealed that while HBV reactivation occurred in seven controls (36.8%), none occurred in the prophylactic group [25]. Shibolet et al [26] conducted a small retrospective study and reported that none of the 13 patients treated with prophylactic lamivudine developed HBV reactivation. In the only prospective study on prophylactic lamivudine, which was also based on lymphoma patients, the administration of lamivudine from the start of chemotherapy until 1 month after the end of chemotherapy in 20 patients has prevented the occurrence of HBV reactivation in all but one patient [27]. In a study with case matched historical controls, prophylactic lamivudine has also been shown to reduce HBV reactivation in a separate clinical entity that involved high-dose chemotherapy and transplantation in patients with hematologic malignancies [28].

Despite the potential benefits of the prophylactic approach, careful clinical monitoring is still required. In the case of chronic HBV infection, prolonged lamivudine therapy that exceeds 6 months' duration has been associated with an increased likelihood of treatment-emergent HBV variants with YMDD mutations [29-30], and they appeared in up to 66% after 4 years of lamivudine treatment [31-32]. For cancer patients undergoing a typical course of chemotherapy, there has been no consensus on the optimal duration of lamivudine therapy. Based on reported series, the continuation of lamivudine for a variable period of 1 to 6 months on completion of chemotherapy were shown to be equally effective in reducing viral reactivation [21,24-27]. In the present study, lamivudine administration for up to 8 weeks from discontinuation of chemotherapy has limited the antiviral therapy to less than 6 months in the majority (69%) of the patients. The cause of HBV reactivation in three patients in the current study is unclear, although in one patient there was strong evidence of poor compliance to lamivudine. For the other two patients, the emergence of a lamivudine-resistant mutant after 4 months of antiviral therapy could not be excluded.

Another concern with the use of lamivudine has been the occurrence of withdrawal hepatitic flares on stopping the antiviral [33]. Two studies have reported follow-up of patients who completed the cytotoxic as well as the antiviral treatments; although one reported no incidence of postlamivudine hepatitis flare in its three cases [24], the other study reported one such case among 20 patients treated, and this was associated with the premature stopping of lamivudine 1 month before [27]. In the present series, all patients treated with prophylactic lamivudine were additionally monitored for another 8 weeks after they had completed the study. On completion of chemotherapy and the antiviral, four of the 65 patients developed hepatitis (ALT range, 103 to 337 U/L), of whom two were found to have detectable viral DNA (1.438 x 10⁶ and 1.618 x 10⁶ ge/mL respectively). The conditions were self-limiting, and both patients had spontaneous resolution of the hepatitis within 2 weeks on first noticing the flare-up.

In summary, the current study has demonstrated that the use of lamivudine before commencing chemotherapy in HBsAg-positive cancer patients has significantly reduced the incidence of HBV reactivation. Although improvement in survival was not observed in this study, the benefit of prophylactic lamivudine, having allowed more patients to receive adequate anticancer therapy, may translate into survival advantage that may only become evident with long-term follow-up. The treatment should be considered for cancer patients who are known to be HBsAg positive and planned for cytotoxic chemotherapy, particularly lymphoma patients and those receiving anthracyclines.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	NOTES

Presented in part at the 2002 American Society of Clinical Oncology Annual Meeting, May18-21, 2002, Orlando, FL.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted May 23, 2003; accepted December 16, 2003.

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