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Potential conflict of interest: Nothing to report.
Reactivation of hepatitis B virus (HBV) during chemotherapy is well documented. However, there are limited data on this complication in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemotherapy. The aim of this study was to evaluate the efficacy of preemptive lamivudine therapy in reducing hepatitis due to HBV reactivation in patients with HCC undergoing transarterial chemo-lipiodolization (TACL) and to seek predictors of this event. A total of 73 consecutive HCC patients undergoing TACL using epirubicin 50 mg/m2 and cisplatin 60 mg/m2 at monthly intervals were prospectively and randomly assigned to receive lamivudine 100 mg daily from the start of TACL (preemptive group) or not (control group). During the study, 11 (29.7%) of 37 patients in the control group and 1 (2.8%) of 36 patients in the preemptive group developed hepatitis due to HBV reactivation (P = .002). In addition, there were significantly more incidences of overall hepatitis (P = .021) and severe grade of hepatitis (P = .035) in the control group. With multivariate Cox regression model, a baseline HBV DNA level of more than 104 copies/mL was the only independent predictor of hepatitis due to HBV reactivation during chemo-lipiodolization (P = .046). In conclusion, preemptive lamivudine therapy demonstrated excellent efficacy in reducing hepatitis due to HBV reactivation and hepatic morbidity during TACL. Preemptive therapy should be considered in HCC patients with an HBV DNA level of more than 104 copies/mL. Further studies are needed to confirm the value of this approach in patients with low-level viremia. (HEPATOLOGY 2006;43:233–240.)
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Evidence indicates that chronic hepatitis B virus (HBV) carriers have a higher incidence of hepatic complications during cytotoxic therapy, primarily in association with HBV reactivation. The reactivation of HBV replication has been reported to occur in 19%–55% of patients undergoing cytotoxic chemotherapy,1–3 with a variety of clinical signs ranging from asymptomatic hepatitis to fatal hepatic decompensation.1, 2, 4–6 This phenomenon remains a particularly important medical concern in areas such as Korea, where chronic HBV infection is endemic.
Most of the earlier reports on HBV reactivation have been documented in patients with hematological malignancies.1, 2, 5 Recently, with the more widespread use of cytotoxic chemotherapy and organ transplantation, data on this complication are now emerging in the setting of solid tumors.7–9 We have previously shown that HBV reactivation can occur in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemotherapy, leading to hepatic decompensation in some cases.10 Although rare, some patients with this complication develop severe hepatitis and ultimately die despite the use of lamivudine.2, 4, 5 These deaths are probably due to the late institution of lamivudine and highlight the need for the preemptive use of antiviral agents. Earlier studies have suggested that preemptive antiviral therapy significantly reduced the risk of HBV reactivation during cytotoxic chemotherapy.4, 6, 8, 11 Although the concept of preemptive therapy appears appealing, it has never been investigated prospectively in HCC patients. Moreover, transarterial chemotherapy seems to be different from systemic chemotherapy in terms of the route of administration and the toxicity of the treatment itself. The identification of patients most at risk for hepatitis due to HBV reactivation is also yet to be fully resolved.
This prospective randomized study investigated the efficacy of preemptive lamivudine in patients with unresectable HCC undergoing transarterial chemo-lipiodolization (TACL) compared with no antiviral treatment. The incidence of HBV reactivation, the grade of hepatitis, and subsequent interruption or premature termination of treatment courses due to HBV reactivation were compared between the 2 groups. In addition, using a more sensitive assay to measure serum HBV DNA, we identified candidates, according to baseline viral loads, who were likely to benefit most from preemptive lamivudine therapy in the setting of TACL.
HBV, hepatitis B virus; HCC, hepatocellular carcinoma; TACL, transarterial chemo-lipiodolization; AFP, α-fetoprotein; ALT, alanine aminotransferase; ULN, upper limit of normal.
Patients and Methods
This was a prospective single-center, randomized, open-label study. From January 2004 to February 2005, consecutive patients at our liver unit (Kangnam St. Mary's Hospital, The Catholic University of Korea) with newly diagnosed HBV-related unresectable HCC were eligible for enrollment. The diagnosis of HCC was based on histological evidence or elevated serum α-fetoprotein (AFP) levels (>400 ng/mL) with typical radiological findings.
Treatment assignment for unresectable HCC was done according to a standard protocol developed by the Barcelona Clinic Liver Cancer Group.12 Briefly, patients with a single nodule less than 5 cm in diameter or up to 3 nodules less than 3 cm in diameter were considered candidates for radiofrequency ablation, percutaneous ethanol injection therapy, or liver transplantation as available. For patients with HCC beyond this tumor extent, transarterial chemotherapy was performed for Child–Pugh classification A, while suboptimal or conservative management was given for Child–Pugh classification B or C.
Patients were excluded from the study if they fulfilled any of the following criteria: a previous history of antiviral therapy; a baseline serum alanine aminotransferase (ALT) level 2.5 times the upper limit of normal (ULN) or higher; a serum HBV DNA level greater than 107 copies/mL; extrahepatic metastasis; main portal vein thrombosis; underlying cardiac or renal diseases; positive tests for antibody to hepatitis C virus or human immunodeficiency virus; Child–Pugh classification B or C; or preexisting evidence of hepatic decompensation, including encephalopathy, ascites, a bilirubin level more than 2 times the ULN, or a prolonged prothrombin time of more than 3 seconds.
Patients were randomly assigned in a 1:1 ratio via computer-generated allocation to either the preemptive or control groups. Patients in the preemptive group received lamivudine 100 mg/d orally from the start of TACL; those in the control group did not. The study was approved by the Ethics Committee of the Catholic University of Korea, and study enrollment began after written informed consent was obtained from each patient.
The TACL regimen used was a combination of epirubicin (50 mg/m2) and cisplatin (60 mg/m2) in a mixture of lipiodol (5–10 mL) without gelfoam embolization. The treatment was administered at monthly intervals, and the doses of chemotherapeutic agents were adjusted as previously described.13 TACL was continued, without any limit on the number of courses, until the achievement of radiological disappearance or complete necrosis of viable tumor with normalization of AFP levels on 2 consecutive occasions. No patients received glucocorticoid therapy. All patients were tested at baseline for hepatitis B surface antigen, antibody to hepatitis B surface antigen, hepatitis B e antigen, antibody to hepatitis B e antigen (Abbott Laboratories, Abbott Park, IL), serum ALT, aspartate aminotransferase, albumin, bilirubin, prothrombin time, AFP, and HBV DNA (VERSANT 3.0, branched DNA assay, Bayer HealthCare LLC, Tarrytown, NY; detection range: 2 × 103 to 1 × 108 copies/mL).14 Complete blood cell counts and liver biochemical tests were performed biweekly until week 8 and monthly thereafter. Serum HBV DNA, hepatitis B e antigen/antibody to hepatitis B e antigen, and AFP levels were monitored monthly or more frequently if necessary. Genotyping of HBV was performed via ELISA (Institute of Immunology, Tokyo, Japan) using monoclonal antibodies to preS2 region as previously described.15 Emergence of lamivudine-resistant mutants was detected via restriction fragment length polymorphism and DNA sequence analysis as previously described.16 Preemptive lamivudine was initiated from the start of TACL and continued for 12 months after the completion of TACL. For patients in the control group who developed hepatitis due to HBV reactivation, lamivudine treatment was started immediately. If HBV reactivation occurred, the regular chemotherapy schedule was resumed once serum ALT levels returned to 3 times the ULN or less and serum bilirubin levels returned to 2 times the ULN or less. The chemo-lipiodolization was prematurely terminated if evidence of hepatic decompensation was observed for longer than 1 month.
The definitions of HBV reactivation and hepatitis were based on previous reports.10, 11, 17 HBV reactivation was defined as a greater than 10-fold increase in serum HBV DNA compared with the baseline level. Hepatitis due to HBV reactivation was defined as a threefold or greater increase in serum ALT to a level that exceeded 100 IU/L (reference range <33 IU/L) in patients with HBV reactivation in the absence of clinical features of tumor progression, hepatotoxic drugs, treatment-related hepatic damage, or other systemic infections. The grade of overall hepatitis during the follow-up was defined as moderate when ALT elevation was 3 to 5 times the ULN and severe when ALT elevation was more than 5 times the ULN. Hepatic decompensation was defined as newly developed encephalopathy, ascites, variceal bleeding, bilirubin level more than 2.5 times the ULN, or prolongation of prothrombin time by more than 3 seconds. Treatment disruption was defined as either a premature termination or a delay of at least 8 days in the regular chemo-lipiodolization schedule.
The primary end point was the occurrence of hepatitis due to HBV reactivation. Secondary end points included hepatic decompensation, treatment disruption due to HBV reactivation, and grade of hepatitis.
Based on previous data,10 it was estimated that approximately 25% of patients in the control group would develop hepatitis due to HBV reactivation, and the corresponding rate was likely to be 0% in the preemptive treatment group. Consequently, a sample size of 38 patients in each group was calculated using α of 0.05 and 90% power. Of these, 2 patients (1 in each group) were lost after the first chemotherapy session, and the transarterial approach was not possible for 1 patient in the preemptive group because of vascular insufficiency. Thus, a total of 3 patients were lost from the study and 73 were included.
Analyses were conducted using the independent sample t test, Mann-Whitney U test, chi-square test, and Fisher exact test when appropriate. Two-tailed P values less than .05 were considered significant. The incidence of hepatitis due to HBV reactivation in the 2 groups was compared using the log rank test. For the control group, univariate Cox regression analysis was performed to evaluate factors associated with occurrence of hepatitis due to HBV reactivation during TACL. Continuous variables were transformed into 2-level categorical data to have the greatest statistical power, based on the preliminary analysis of different cutoff values for each variable. Independent predictors of hepatitis due to HBV reactivation were analyzed using a multivariate Cox regression model with stepwise selection of variables. Data were analyzed using SPSS version 12.0 software (SPSS, Chicago, IL).
In this study, a total of 73 consecutive patients were enrolled: 36 in the preemptive group and 37 in the control group (Fig. 1). There were no significant differences in sex, age, ALT, bilirubin, HBeAg seropositivity, HBV DNA, Child-Turcotte-Pugh score, AFP, or other tumor characteristics between the 2 groups. All patients had HBV genotype C. Nine (25%) patients in the preemptive group and 10 (27%) patients in the control group had undetectable HBV DNA in serum (<2 × 103 copies/mL) before treatment. The baseline characteristics of each group are provided in Table 1.
Table 1. Baseline Characteristics of All 73 Patients
Preemptive Group (n = 36)
Control Group (n = 37)
Abbreviations: HBeAg, hepatitis B e antigen; ALT, alanine aminotransferase; PT, prothrombin time; INR, international normalized ratio; AFP, α-fetoprotein.
Age (yr), mean ± SD
52.5 ± 8.4
53.2 ± 9.0
HBV DNA (×103 copies/mL), median (range)
ALT (IU/L), mean ± SD
50.9 ± 21.0
51.8 ± 22.9
Total bilirubin (mg/dL), mean ± SD
0.92 ± 0.39
0.85 ± 0.35
Albumin (g/dL), mean ± SD
3.89 ± 0.33
3.81 ± 0.39
PT (INR), mean ± SD
1.04 ± 0.24
1.07 ± 0.30
AFP (ng/mL), median (range)
Tumor size (cm), mean ± SD
6.4 ± 3.7
7.1 ± 3.8
Multinodular or diffuse
Portal vein thrombosis
Child-Pugh score (5/6)
Differences in Clinical Outcomes Between the Two Groups.
The details of the clinical outcomes in the two groups are provided in Table 2. Overall, 16 (43.2%) patients in the control group and 6 (16.7%) patients in the preemptive group developed clinical hepatitis during a median follow-up of 5.8 months (P = .021). When the 22 cases of hepatitis were categorized by grade of hepatitis, there was a significantly higher incidence of severe hepatitis in the control group than in the preemptive group (11/37 [29.7%] vs. 3/36 [8.3%]; P = .035).
Table 2. Clinical Outcomes in Preemptive and Control Groups
Preemptive Group (n = 36)
Control Group (n = 37)
NOTE. P values were derived from the Fisher exact test.
All cases of HBV reactivation, n (%)
Hepatitis of all causes, n (%)
Grade of hepatitis
Hepatic decompensation, n (%)
Disruptions in treatment schedule, n (%)
Total number of cycles, mean ± SD
4.6 ± 2.1
4.1 ± 1.9
With regard to HBV reactivation, 15 (40.5%) patients in the control group and 1 (2.8%) patient in the preemptive group experienced viral reactivation (P < .001). For the control group, 11 (73.3%) of 15 with viral reactivation developed hepatitis. For the preemptive group, the 1 (2.8%) patient developed viral resistance 9 months after the initiation of lamivudine therapy, but resumed TACL after switching to adefovir (Fig. 2). As a result, hepatitis due to HBV reactivation occurred in 11 (29.7%) patients in the control group and 1 (2.8%) patient in the preemptive group (P = .002, log rank test) (Fig. 3). For the control group, the median time to onset of hepatitis due to HBV reactivation was 3.5 months (range, 1–6.0) after initiation of TACL. Viral reactivation preceded the onset of hepatitis by a median of 3.3 weeks (range, 0–6.0). After administration of lamivudine, 8 of 11 patients with hepatitis due to HBV reactivation resumed further courses of TACL, with a median delay of 24 days (range, 12–35). However, the remaining 3 (8.1%) patients eventually had hepatic decompensation despite the initiation of lamivudine, and stopped TACL prematurely. One of these patients ultimately died of variceal bleeding 53 days after HBV reactivation. The clinical details of the 11 patients with and without hepatic decompensation after viral reactivation are provided in Table 3. In total, hepatic decompensation was noted in 5 (13.5%) control group patients, compared with 1 (2.8%) patient in the preemptive group (P = .199). Of these, 3 cases in the control group were due to viral reactivation, while the remaining 2 cases occurred 3 and 5 days after the last TACL course and were attributed to treatment-related liver toxicity.
Table 3. Clinical Details Between Patients in Control Group With and Without Hepatic Decompensation After Developing Hepatitis Owing to HBV Reactivation
Patients With Hepatic Decompensation (n = 3)
Patients Without Hepatic Decompensation (n = 8)
Abbreviations: HBeAg, hepatitis B e antigen; ALT, alanine aminotransferase.
Age (yr), median (range)
ALT (IU/L), median (range)
HBV DNA (×103 copies/mL), median (range)
Total bilirubin (mg/dL), median (range)
Albumin (g/dL), median (range)
Child–Pugh score (5/6)
At time of HBV reactivation
ALT (IU/L), median (range)
HBV DNA (×103 copies/mL), median (range)
Time interval between reactivation Hepatitis and lamivudine administration (d), median (range)
There were 7 deaths in our study. Of these, 3 patients in the preemptive group and 1 in the control group died of tumor progression. The other 3 deaths were caused by sepsis in 1 patient in each group and by HBV reactivation in the remaining patient in the control group.
During the study period, treatment disruptions were noted in 8 (22.2%) patients in the preemptive group and in 15 (40.5%) patients in the control group (P = .092). In the control group, 4 (10.8%) patients terminated TACL prematurely, 3 with HBV reactivation and 1 with post-TACL hepatitis. In the preemptive group, only one patient terminated treatment prematurely due to post-TACL hepatitis (P = .358). There were 7 cases of complete tumor necrosis with TACL in the preemptive group, but no patient had discontinued preemptive lamivudine at the time of analysis, owing to ongoing TACL treatment or the short duration of follow-up after completion of TACL.
Predictors of Hepatitis Due to HBV Reactivation in the Control Group.
To identify predictors of hepatitis due to HBV reactivation in the control group, 9 potential variables were appropriately dichotomized as listed in Table 4. Of these, only baseline serum HBV DNA level was significantly associated with hepatitis due to HBV reactivation in the univariate analysis (P = .044). With multivariate analysis using Cox proportional hazard regression model, a serum HBV DNA level of more than 104 copies/mL at baseline was identified as the only independent predictor of hepatitis due to HBV reactivation (OR = 4.22; 95% CI 1.03–17.56; P = .046).
Table 4. Univariate Analysis of Factors Related to Hepatitis Due to HBV Reactivation During Chemo-lipiodolization in Control Group
Abbreviations: HBeAg, hepatitis B e antigen; ALT, alanine aminotransferase; PT, prothrombin time; INR, international normalized ratio.
HBV DNA (copies/mL)
Total bilirubin (mg/dL)
When the 37 patients in the control group were categorized into baseline viral load of more than 104 copies/mL and 104 copies/mL or less, there was a significantly increased rate of hepatitis due to HBV reactivation in patients with the higher viral load (P = .038) (Fig. 4). The median time to hepatitis due to HBV reactivation was 3.4 months in patients with a HBV DNA level of more than 104 copies/mL and 6 months in those with a HBV DNA level of 104 copies/mL or less (P = .018).
To investigate the benefit of preemptive lamivudine therapy according to the baseline viral load, all 73 patients from both groups were recategorized based on an HBV DNA level of more than 104 copies/mL and 104 copies/mL or less at baseline. There was a significantly higher rate of hepatitis due to HBV reactivation in the control group than in the preemptive group among the 45 patients with an HBV DNA level of more than 104 copies/mL (P = .001, log rank test), whereas there was no difference in its occurrence between the 2 groups among 28 patients with an HBV DNA level of 104 copies/mL or less (P = .353, log rank test).
In this prospective randomized study, we evaluated the efficacy of preemptive lamivudine therapy for the prevention of HBV reactivation in patients with HCC. Although HBV reactivation is a well-known complication during chemotherapy, very few cases have been observed in the setting of HCC. In the non-HCC population, there is a growing body of evidence to support the preemptive use of lamivudine during cytotoxic chemotherapy.4, 6, 8, 18, 19 If the same effects were seen in the HCC population undergoing transarterial chemotherapy, then preemptive antiviral therapy would effectively reduce liver-related morbidity attributable to HBV reactivation and would allow more prolonged chemotherapy. However, it is very important to note which patients will benefit the most from preemptive antiviral therapy, because universal application of the strategy would be costly and burdensome. A previous study has indicated that viral load is an independent predictor of hepatitis due to HBV reactivation.20 However, an earlier study from our institution failed to identify the viral load as a predictor of HBV reactivation.10 This failure most likely resulted from the use of an insensitive detection methodology, whereas in the current study a more sensitive assay was used to detect serum HBV DNA.
This study demonstrated that preemptive administration of lamivudine significantly reduced hepatic complications attributable to HBV reactivation, as well as the consequent treatment disruptions, in patients undergoing TACL. Our data support the suggestion that lamivudine should be initiated preemptively or at the time of starting chemotherapy.18 Of note, when hepatitis due to HBV reactivation occurred, three patients in this study had evidence of hepatic decompensation and eventually stopped further courses of TACL, despite an early initiation of lamivudine therapy once reactivation was detected. These cases of hepatic decompensation and subsequent disruptions to the scheduled chemotherapy further emphasize the importance of preemptive antiviral therapy against HBV reactivation in patients undergoing TACL.
Our study also suggests that preemptive lamivudine therapy decreases the severity of clinical hepatitis if it develops during TACL. This finding is in agreement with the findings of a retrospective study in which lamivudine prophylaxis prevented a deterioration in hepatic functions in HBeAg-positive HCC patients undergoing intra-arterial infusion chemotherapy.21 The beneficial effects of preemptive therapy on the severity of hepatitis most probably result from an elimination of any potential risk arising from viral reactivation. Whether preemptive antiviral therapy would reduce hepatic adverse events during TACL irrespective of viral reactivation remains an issue that should be evaluated further.
Another key finding of this study is the identification of a candidate group for preemptive antiviral therapy in HCC patients undergoing TACL. Despite the general awareness of chemotherapy-induced viral reactivation, predictors for this complication have not been conclusively identified. Recently, a baseline HBV DNA level of more than 105 copies/mL independently predicted hepatitis due to HBV reactivation in breast cancer and transplant patients.7, 20 In the current study, however, a lower cutoff level of more than 104 copies/mL was identified as the best predictor of hepatitis. One possible reason for the discrepancy is the use of different methods of HBV DNA quantification. In general, serum HBV DNA levels gradually decrease over time during the course of chronic HBV infection. However, for HCC patients, even a lower level of viremia does not seem to exclude the potential risk of viral reactivation, as reflected in the present data, and this may represent one of the unique characteristics of HBV reactivation in HCC patients. In addition, considering the underlying cirrhosis in HCC patients, it would be desirable to maintain the viral load at a lower level to offer more protection against worsening liver function. As a result, a lower cutoff would be reasonable as a threshold for starting preemptive therapy in these settings. The use of a highly sensitive assay to detect and measure serum HBV DNA before the initiation of TACL should be encouraged to identify patients most at risk for HBV reactivation.
Although the results of the current study show that a serum HBV DNA level of more than 104 copies/mL was predictive of hepatitis due to HBV reactivation during TACL, and that preemptive therapy did not appear to benefit those with a viral load below this level, it should not be overlooked that HBV reactivation can occur in patients with lower levels of viremia. In this study, 3 of 15 patients with HBV DNA of 104 copies/mL or less did develop hepatitis due to HBV reactivation. However, the time to hepatitis appeared to be longer in these cases when compared with patients who had higher levels of viremia. Taken together, our results suggest that preemptive antiviral therapy should be considered in patients with HBV DNA of more than 104 copies/mL, while virological and biochemical changes should be closely monitored in those with a viremia below this level, particularly in patients undergoing repetitive chemotherapeutic courses.
A major concern with preemptive lamivudine therapy is the emergence of viral resistance. From earlier reports in patients with chronic hepatitis B,22, 23 the chance of viral resistance emerging increases with prolonged lamivudine therapy. However, with the availability of rescue drugs, including adefovir, it no longer remains such a significant limitation. It could be argued that the therapeutic gain with this policy could be equivocal in other institutions employing different chemotherapy regimens because there is no standardized regimen for unresectable HCC. The issue of whether to stop antiviral therapy after completion of chemotherapy is another consideration that requires further study.
In conclusion, this study demonstrated the excellent efficacy of preemptive lamivudine therapy in HCC patients undergoing chemo-lipiodolization. Compared with the control group, the preemptive use of lamivudine significantly reduced the occurrence of hepatitis due to HBV reactivation. Furthermore, this therapy was found to lessen the severity of any clinical hepatitis that developed during the treatment. Based on our data with a small number of patients, a serum HBV DNA level of more than 104 copies/mL was the most important predictor of the occurrence of hepatitis due to HBV reactivation during chemo-lipiodolization. Thus, viral suppression through the use of preemptive antivirals should be considered in HCC patients with serum HBV DNA above this level. Nevertheless, the present results also demonstrate that lower levels of viremia remain associated with an approximately 30% risk of viral reactivation, and thus, these patients should also be closely monitored for its occurrence during treatment. Further studies with a large number of patients are needed to confirm the value of a preemptive approach to populations with lower levels of viremia. This study did not address the potential survival benefit in the preemptive lamivudine group. Given that preemptive antiviral therapy ameliorates the hepatic morbidity seen during transarterial chemotherapy and facilitates further chemotherapy without disruptions in treatment schedules, the expectation would be for an increased chance of survival with this approach. Future studies with a longer duration of follow-up will address this issue.