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Preliminary Communication | ONLINE FIRST

Association Between Nucleoside Analogues and Risk of Hepatitis B Virus–Related Hepatocellular Carcinoma Recurrence Following Liver Resection FREE

Chun-Ying Wu, MD, PhD, MPH; Yi-Ju Chen, MD, PhD; Hsiu J. Ho, PhD; Yao-Chun Hsu, MD, MS; Ken N. Kuo, MD; Ming-Shiang Wu, MD, PhD; Jaw-Town Lin, MD, PhD
[+] Author Affiliations

Author Affiliations: School of Medicine, National Yang-Ming University, Taipei, Taiwan (Drs Chun-Ying Wu and Chen); Division of Gastroenterology (Dr Chun-Ying Wu) and Department of Dermatology (Dr Chen), Taichung Veterans General Hospital, Taichung, Taiwan; Department of Public Health and Graduate Institute of Clinical Medicine, China Medical University, Taichung (Drs Chun-Ying Wu and Hsu); Department of Life Sciences, National Chung-Hsing University, Taichung (Dr Chun-Ying Wu); Division of Gastroenterology, National Taiwan University Hospital, Taipei (Drs Ho, Ming-Shiang Wu, and Lin); Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan (Drs Hsu and Lin); College of Medicine, Taipei Medical College, Taipei (Dr Kuo); Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan (Drs Kuo and Lin); and School of Medicine, Fu Jen Catholic University, Taipei (Dr Lin).


JAMA. 2012;308(18):1906-1913. doi:10.1001/2012.jama.11975.
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Published online

Context Tumor recurrence is a major issue for patients with hepatocellular carcinoma (HCC) following curative liver resection.

Objective To investigate the association between nucleoside analogue use and risk of tumor recurrence in patients with hepatitis B virus (HBV)−related HCC after curative surgery.

Design, Setting, and Participants A nationwide cohort study between October 2003 and September 2010. Data from the Taiwan National Health Insurance Research Database. Among 100 938 newly diagnosed HCC patients, we identified 4569 HBV-related HCC patients who received curative liver resection for HCC between October 2003 and September 2010.

Main Outcome Measures The risk of first tumor recurrence was compared between patients not taking nucleoside analogues (untreated cohort, n = 4051) and patients taking nucleoside analogues (treated cohort, n = 518). Cumulative incidences and hazard ratios (HRs) were calculated after adjusting for competing mortality.

Results The treated cohort had a higher prevalence of liver cirrhosis when compared with the untreated cohort (48.6% vs 38.7%; P < .001), but lower risk of HCC recurrence (n = 106 [20.5%] vs n = 1765 [43.6%]; P < .001), and lower overall death (n = 55 [10.6%] vs n = 1145 [28.3%]; P < .001). After adjusting for competing mortality, the treated cohort had a significantly lower 6-year HCC recurrence rate (45.6%; 95% CI, 36.5%-54.6% vs untreated, 54.6%; 95% CI, 52.5%-56.6%; P < .001). Six-year overall mortalities for treated cohorts were 29.0% (95% CI, 20.0%-38.0%) and for untreated 42.4% (95% CI, 40.0%-44.7%; P < .001). On modified Cox regression analysis, nucleoside analogue use (HR, 0.67; 95% CI, 0.55-0.81; P < .001), statin use (HR, 0.68; 95% CI, 0.53-0.87; P = .002), and nonsteroidal anti-inflammatory drugs or aspirin use (HR, 0.80; 95% CI, 0.73-0.88; P < .001) were independently associated with a reduced risk of HCC recurrence. Multivariable stratified analyses verified the association in all subgroups of patients, including those who were noncirrhotic (HR, 0.56; 95% CI, 0.42-0.76) and diabetic (HR, 0.52; 95% CI, 0.31-0.89).

Conclusion Nucleoside analogue use was associated with a lower risk of HCC recurrence among patients with HBV-related HCC after liver resection.

Figures in this Article

Surgery is considered the standard curative treatment option for hepatocellular carcinoma (HCC). However, the rate of long-term disease-free survival after liver resection remains unsatisfactory due to persistent high incidences of HCC recurrence.1 Many factors affect HCC recurrence risk after liver resection, including tumor size and stage, serum α-fetoprotein level, cirrhosis, hepatitis B e antigen (HBeAg) status, and hepatitis B virus (HBV) viral load.24 Among these factors, HBV viral load is the most clinically controllable.

Higher HBV viral load has been reported to be an independent risk factor for HCC recurrence in patients with HBV-related HCC.5,6 Nucleoside analogues are effective in suppressing HBV replication and in ameliorating HBV-related liver disease.7,8 They have been shown to be associated with a lower risk of HCC and other cirrhosis-related complications in those with chronic hepatitis9,10 and cirrhosis.11 However, studies on the effectiveness of nucleoside analogue use in HCC recurrence have been relatively limited and have yielded conflicting results.1214 In Taiwan, under the National Health Insurance (NHI) program, reimbursement for nucleoside analogues for HBV patients meeting certain criteria began on October 1, 2003 (eTable 1 and eTable 2).

The purpose of this study was to examine the association between use of nucleoside analogues and risk of HCC recurrence among patients with HBV-related HCC after curative liver resection. We also examined this association among different subpopulations and calculated the number needed to be treated (NNT) for 1 less HCC recurrence.

Study Design

We conducted a nationwide cohort study by retrieving all patients receiving curative liver resection for HCC from Taiwan's National Health Insurance Research Database (NHIRD). The NHIRD has been described in detail in previous studies.1517 In brief, it consists of detailed health care data from more than 25 million enrollees, representing more than 99% of Taiwan's entire population. The accuracy of diagnosis of major diseases in the NHIRD, such as stroke and acute coronary syndrome, has been validated.17,18 This study has been approved by the ethical review board of the National Health Research Institutes, Taiwan.

Study Population

We identified all hospitalized patients who were admitted with a primary diagnosis of HCC (International Classification of Diseases, Ninth Revision [ICD-9 ] codes 155.0, 155.2) for the first time and who received curative liver resection between October 1, 2003, and September 30, 2010. The diagnostic accuracy of HCC was confirmed by both specific admission ICD-9 codes and inclusion in the Registry for Catastrophic Illness Patient Database (RCIPD), a subpart of the NHIRD.15,16 Surgical pathological confirmation or typical image presentation of HCC is required for patients to be registered in the RCIPD.

Only HCC patients with HBV infection (ICD-9 codes 070.2, 070.3, and V02.61) were included in our study cohorts. Patients were excluded if diagnosed with hepatitis C (ICD-9 codes 070.41, 070.44, 070.51, 070.54, and V02.62), other viral hepatitis (ICD-9 code V02.69), malignant tumor (ICD-9 codes 104-208), or if they received antiviral treatments for more than 3 months before the index admission. Patients were also excluded if they received liver resection, transarterial chemoembolization, percutaneous ethanol injection, radiofrequency ablation, or liver transplantation before the index hospitalization.

Study Cohorts

Patients who were newly diagnosed with HBV-related HCC and who received curative liver resection were divided into 2 cohorts based on their use of nucleoside analogues. The untreated cohort comprised patients who never received nucleoside analogues and the treated cohort was patients who received nucleoside analogues for at least 90 days. Those receiving antiviral treatments for less than 90 days during the observation period or prior to the observation period were excluded. Information regarding patients' medications was retrieved from the pharmacy prescription database. Reliability of the retrieved information was verified independently by 2 statisticians. Nucleoside analogues included lamivudine, entecavir, and telbivudine. For each nucleoside analogue prescription, the number of days of use was calculated. Then, the numbers of days of use for each prescription were added together to determine the total number of days of nucleoside analogue use.

Main Outcome Measurements

Hepatocellular carcinoma recurrence was defined as rehospitalization with a primary diagnosis of HCC after the index admission date and a treatment modality for HCC recurrence, such as surgery, transarterial chemoembolization, percutaneous ethanol injection, radiofrequency ablation, or liver transplantation during the study period. Patients with HCC recurrence in the first 3 months after the index hospitalization for liver resection were excluded. We used the incident user design with follow-up for each patient beginning on the date of first prescription of nucleoside analogue in the treated cohort.19,20 The follow-up for the untreated cohort began on the first day after the index hospitalization for liver resection. Both cohorts were followed up until the date of HCC recurrence, death, or the end of 2010. Death was defined as withdrawal of the patient from the NHI program. Causes of death were defined according to the primary diagnosis of hospitalization in the 3 months preceding death.

Covariate Assessment

Propensity score was calculated using logistic regression as proposed by Rosenbaum and Rubin21,22 to estimate the probabilities of assigning a patient to the treated cohort given the background variables including age, sex, extent of resection, liver cirrhosis, other comorbidities listed in Table 1, and use of statins, nonsteroidal anti-inflammatory drugs (NSAIDs), and metformin. The mean and median propensity scores were compared between the 2 cohorts.

Table Graphic Jump LocationTable 1. Study Cohorts Following Liver Resection

Since the chance of HCC recurrence can be confounded by competing risk of mortality, we identified comorbidities that may be associated with mortality based on diagnostic codes from both outpatient and inpatient datasets prior to the outcome of interest. All diseases included in the Charlson Comorbidity Index were analyzed except for human immunodeficiency virus, metastatic solid tumor, and cancer, because patients with these conditions were excluded from the present study.23 Comorbidities, listed by ICD-9 code, included acute coronary syndrome (410-414), cerebrovascular accident (430-438), chronic obstructive pulmonary disease (490-496), diabetes mellitus (250), liver cirrhosis (571.5), liver failure (570), renal failure (584-586), hypertension (401-405), hyperlipidemia (272.0-272.2), and peptic ulcer disease (531-534).

Certain drugs, including statins, aspirin, NSAIDs, and metformin, which might alter the risk of recurrent HCC, were analyzed. Exposure to these drugs was defined as frequency of use of more than 1 tablet per month during the observation period. Liver resection modalities for treatment of the original HCC, including major resection (extensive and partial hepatic lobectomy with at least 3 segmental resections of liver parenchyma) and minor resection (extensive and partial hepatectomy with 2 or fewer segmental resections of liver), were also analyzed.

Statistical Analysis

Death prior to tumor recurrence was considered a competing risk event. The death-adjusted cumulative incidences of HCC recurrence were calculated using a 2-step process and tested for equality among the study cohorts. Calculation and comparison of cumulative incidences in competing risk data ratios were conducted using modified Kaplan-Meier method24 and Gray method.25 We tested differences in the full time-to-event distributions between the study groups using log-rank test.

To determine the independent risk factors for HCC recurrence, multivariable analyses and stratified analyses using hazard ratios (HRs) were carried out with modified Cox proportional hazards models in the presence of competing risk event after adjusting for age, sex, resection modality, liver cirrhosis, diabetes, propensity score, and use of statins, NSAIDs or aspirin, and metformin.24 To assess the dose-dependent association of recurrence with nucleoside analogue use, we further conducted multivariable analysis with nucleoside analogue use as a continuous variable. On multivariable stratified analyses, the association between nucleoside analogue use and the risk of HCC recurrence was examined in different subgroups. All subgroup comparisons were preplanned to control for potential confounding factors reported in previous studies.

The NNT represented the number of patients who needed to be treated for 1 less HCC recurrence or mortality; it was calculated by the inverse of the absolute risk reduction. All results in the present study originated from a nationwide registry database. Hepatocellular carcinoma is defined as a major disease and HCC patients can apply for a catastrophic illness certificate, which grants exemption from co-payment. It is nearly impossible for these HCC patients to withdraw from the NHI program before death. Therefore, there were no missing data or loss of follow-up in our study population.

All data management was performed using SAS 9.2 software (SAS Institute Inc). Calculations of cumulative incidences and Cox models in the competing risk analysis were carried out using the “cmprsk” package of R (http://cran.r-project.org/web/packages/cmprsk/index.html). Calculated results were expressed as the estimated number together with the 95% confidence interval. Based on statistical power at 0.9, type I error rate at .05, and our case numbers in both cohorts, the detectable risk difference was estimated to be 0.02.

Demographic Characteristics of the HCC Cohort

We first identified 100 938 potentially eligible HCC patients admitted for the first time and registered in the RCIPD. We excluded 78 948 patients who did not receive liver resection and 8173 patients who received liver resection before October 1, 2003. In addition, 7870 patients without HBV infection or coinfection with hepatitis C or other hepatitis were excluded. Those using antiviral agents 3 months before liver resection or for less than 3 months were also not enrolled. There were 1019 patients who received other liver therapy or with another type of tumor before liver resection who were excluded. Another 359 patients with follow-up for less than 3 months were not included in the study. Therefore, 4569 patients were enrolled into the study cohorts (untreated, 4051 patients; treated, 518 patients) (Figure 1). In the treated cohort, 487 patients received only 1 nucleoside analogue, including 159 patients who received lamivudine, 292 patients who received entecavir, and 36 patients who received telbivudine. The remaining patients received more than 1 nucleoside analogue.

Place holder to copy figure label and caption
Figure 1. Selection of Study Patients
Graphic Jump Location

HBV indicates hepatitis B virus; HCC, hepatocellular carcinoma.aNumbers for exclusions may not sum because of patients fulfilling more than 1 criterion.

Demographic characteristics, confounding drugs, comorbidities, and follow-up durations of the study cohorts are presented in Table 1. The follow-up durations for the untreated cohort were a mean (SD) of 2.18 (1.77) years and a median (interquartile range [IQR]) of 1.57 (0.77-3.15) years, and for the treated cohort, a mean (SD) of 2.64 (1.74) years and a median (IQR) of 2.18 (1.21-3.69) years. The mean (SD) interval to start of antiviral therapy after liver resection was 1.19 (1.38) years and the median (IQR) was 0.66 (0.14-1.84) years. The mean (SD) duration of nucleoside analogue use in treated patients was 1.45 (1.38) years and the median (IQR) was 0.95 (0.48-1.94) years. The mean (SD) propensity score for the untreated cohort was 0.11 (0.03) and the median (IQR) was 0.11 (0.09-0.14), and for the treated cohort, the mean (SD) was 0.12 (0.03) and the median (IQR) was 0.12 (0.10-0.15). The treated cohort had a significantly higher prevalence of liver cirrhosis (48.6%) when compared with the untreated cohort (38.7%) (P < .001).

Six-Year Cumulative Incidences of HCC Recurrence and Overall Mortality

Among the 359 patients excluded with follow-up of less than 3 months there were 226 HCC recurrences and 93 deaths. During the observation period, 1765 patients in the untreated cohort (43.6%) and 106 patients in the treated cohort (20.5%) developed HCC recurrence. Death before the recurrence of HCC was defined as competing mortality. Compared with the untreated cohort (451 deaths; 11.1%), only 26 patients (5.0%) died before HCC recurrence in the treated cohort. The major identifiable causes of competing mortality in the untreated cohort were HCC or HCC treatment–related mortality (314 patients), liver cirrhosis (14), pneumonia (12), sepsis (9), and gastrointestinal bleeding (7). The identifiable causes of competing mortality in the treated cohort included HCC or HCC treatment–related mortality (20 patients), pneumonia (2), liver cirrhosis (1), and sepsis (1). During the follow-up period, overall deaths for the untreated and treated cohorts were 1145 (28.3%) and 55 (10.6%), respectively. For overall mortality, the major identifiable causes of death in the untreated cohort were HCC or HCC treatment–related mortality (832 patients), liver cirrhosis (47), sepsis (28), pneumonia (22), and gastrointestinal bleeding (21). The major identifiable causes of overall mortality in the treated cohort were HCC or HCC treatment–related mortality (38 patients), liver cirrhosis (5), pneumonia (5), and sepsis (3).

In Figure 2, cumulative incidences of HCC recurrence after adjustment for competing mortality are shown. The risk of HCC recurrence was significantly lower for patients in the treated cohort (6-year cumulative incidence, 45.6%; 95% CI, 36.5%-54.6%) than for patients in the untreated cohort (54.6%; 95% CI, 52.5%-56.6%) (P < .001). The difference in 6-year cumulative incidence was 9%. The unadjusted NNT associated with 1 less HCC recurrence within 6 years was 12 (95% CI, 7.4-22.6). This implies that use of nucleoside analogues in 12 HCC patients after liver resection is associated with 1 less HCC recurrence within 6 years.

Place holder to copy figure label and caption
Figure 2. Cumulative Incidences of HCC Recurrence and Overall Mortality Following Liver Resection
Graphic Jump Location

Data were compiled after adjustment for competing mortality. For cumulative incidences of hepatocellular carcinoma (HCC), calculation and comparison in competing risk data ratios were conducted using modified Kaplan-Meier and Gray methods. For overall mortality, Kaplan-Meier method was used. Recurrences (for cumulative incidences of HCC) and deaths (for overall mortality) during the first 3 months were excluded. Treated and untreated categories indicate patients with hepatitis B virus who are receiving nucleoside analogues, and those who are not, respectively.

In the eFigure, we stratified patients by liver cirrhosis and NSAID use. We found that nucleoside analogue use was associated with lower risk of HCC recurrence in noncirrhotic patients, but not in cirrhotic patients. For NSAID users and nonusers, use of nucleoside analogues was associated with reduced risk of HCC recurrence.

Likewise, the risk of overall mortality was significantly lower in patients in the treated cohort (6-year cumulative incidence, 29.0%; 95% CI, 20.0%-38.0%) than in patients in the untreated cohort (42.4%; 95% CI, 40.0%-44.7%) (P < .001) (Figure 2). The difference in 6-year overall mortality was 13.4%. The unadjusted NNT associated with 1 less death within 6 years was 8 (95% CI, 5.7-11.0). This implies that use of nucleoside analogues in 8 HCC patients after liver resection is associated with 1 less death within 6 years.

Multivariable Analysis

Compared with the untreated cohort, the treated cohort was associated with a significantly lower risk of HCC recurrence (HR, 0.67; 95% CI, 0.55-0.81; P < .001). Use of statins (HR, 0.68; 95% CI, 0.53-0.87; P = .002) and use of NSAIDs or aspirin (HR, 0.80; 95% CI, 0.73-0.88; P < .001) were significantly associated with lower risk of tumor recurrence. Liver cirrhosis was found to be an independent risk factor for HCC recurrence (HR, 1.23; 95% CI, 1.12-1.35; P < .001) (Table 2). Each incremental year of use of nucleoside analogues was associated with reduced risk of HCC recurrence (HR, 0.59; 95% CI, 0.51-0.68; P < .001) (eTable 2).

Table Graphic Jump LocationTable 2. Risk of HCC Recurrence After Adjusting for Competing Mortalitya
Multivariable Stratified Analysis

The treated cohort was found to be associated with a reduced risk of HCC recurrence on all stratified analyses, including for noncirrhotic patients (HR, 0.56; 95% CI, 0.42-0.76) and diabetic patients (HR, 0.52; 95% CI, 0.31-0.89) (Figure 3). These observations further confirmed the association between nucleoside analogue use and attenuated risk of HCC recurrence in HBV-related HCC patients after liver resection.

Place holder to copy figure label and caption
Figure 3. Multivariable Stratified Analyses for the Association Between Nucleoside Analogue Use and HCC Recurrence
Graphic Jump Location

Among hepatitis B virus–related patients with hepatocellular carcinoma (HCC), nucleoside analogue use (treated cohort) was found to be associated with reduced risk of HCC recurrence on nearly all analyses (stratified by age, sex, extent of liver resection, liver cirrhosis, diabetes, and use of statins, nonsteroidal anti-inflammatory drugs [NSAIDs], and metformin). Some hazard ratios were not statistically significant due to a small number of cases. Recurrences during the first 3 months were excluded. Treated and untreated categories indicate patients with hepatitis B virus who are receiving nucleoside analogues, and those who are not, respectively. Major resection indicates extensive and partial hepatic lobectomy with at least 3 segmental resections of liver parenchyma; minor resection indicates extensive and partial hepatectomy with 2 or fewer segmental resections of liver.

The roles of HBV in HCC recurrence have been widely investigated. Kubo et al5 first reported that high viral load is an independent risk factor for HCC recurrence after liver resection in HBV-related HCC patients. Hung et al6 found that HBV viral load of greater than 2000 IU/mL is associated with an odds ratio as high as 22.3 for HCC recurrence after liver resection. The association between serum HBV loads and risk of HCC recurrence after liver resection or transcatheter arterial embolization has been confirmed in previous studies.3,26,27

In the present study, we did not have data regarding a patient's HBV viral load or liver function. However, Taiwan's NHI program has strict regulations regarding reimbursement for nucleoside analogues. Reimbursement is granted only to patients in high-risk populations (eTable 1). Under such regulations, patients in the treated cohort should have a higher baseline HBV viral load, higher ALT level, or higher prevalence of liver decompensation than those in the untreated cohort to be eligible for reimbursement. In the present study, the treated cohort had higher prevalence of liver cirrhosis. If higher HBV viral load is associated with higher risk of HCC recurrence, higher baseline HBV viral load in the treated patients may have led to a more conservative estimation of the association in the present study.

Although it is generally accepted that HBV viral load plays an important role in HCC recurrence, studies regarding the effectiveness of nucleoside analogues in HCC recurrence have been very limited and have produced conflicting results.28 Based on a study of 14 patients receiving lamivudine and 10 control participants, Kubo et al13 found a lower 5-year HCC disease-free survival rate after surgery in the lamivudine-treated patients. Chan et al14 reported that the 5-year tumor free survival rates in the lamivudine or entecavir-treated group (42 participants; 51.4%) were significantly higher than in the control group (94 participants; 33.8%). In contrast, Li et al29 found no significant differences in the 1-year tumor-free survival after curative hepatectomy between the lamivudine (43 participants; 23.3%) and control (36 participants; 8.3%) groups. Kuzuya et al12 demonstrated that 5-year cumulative recurrence rates of HCC do not differ in a study of 16 patients receiving lamivudine and 33 control participants. In the present study, we confirmed the association between nucleoside analogue use and reduced risk of HCC recurrence in HBV patients after liver resection based on a nationwide database. However, reimbursement for oral antiviral agents for HBV infection is strictly limited to specified indications in Taiwan, and HCC does not qualify as an indication. Therefore, most of the HBV-infected HCC patients in the present study did not fulfill the NHI criteria for oral antiviral therapy.

In previous studies, HCC with cirrhosis has been associated with decreased overall survival compared with HCC without cirrhosis after curative liver resection.2 However, the outcome of patients with HBV-related compensated cirrhosis has not been shown to be worse than that of noncirrhotic patients.4 In the present study, nucleoside analogue use was not only associated with improved disease-free survival, but also with improved overall survival in HBV-related HCC after liver resection. The higher prevalence of cirrhosis in the treated cohort was the main reason that the absolute difference in HCC recurrence rates (54.6% vs 45.6%) was much smaller than the HR (0.67) observed on multivariable analysis.

On multivariable analysis, we found that statin and NSAID or aspirin use were associated with a lower risk of HCC recurrence. The protective role of statins in HBV-infected HCC has been reported in a recent study.30 The potential mechanisms involve AMP-activated protein kinase, p21 expression, endoplasmic reticulum stress, and autophagy.31 The association between the use of NSAIDs or aspirin and a lower risk of HCC recurrence is a novel finding. Aspirin has been reported to induce cell cycle arrest and apoptosis, mediated by increased metabolic and oxidative stress.32 An in vivo study showed that aspirin results in tumor growth inhibition.33 More recently, Sitia et al demonstrated that aspirin diminishes the number of intrahepatic HBV-specific CD8(+) T cells and HBV-nonspecific inflammatory cells, the severity of liver fibrosis, and the development of HCC in an HBV transgenic mouse model.34 Based on prior studies and our results, we postulated that NSAIDs, including aspirin, may be beneficial for reducing tumor recurrence in HCC patients. Future randomized controlled trial studies are necessary to clarify this issue.

There are several limitations to the present study. First, a causal association between a drug of interest and risk of HCC recurrence cannot be inferred based on an observational study. Confounding by indication may exist and account for differences in outcomes. The patients in the study cohorts may differ in many measured and unmeasured ways. We did not have personal information for our patients such as lifestyle, family history of malignant diseases, body mass index, or laboratory parameters including HBV DNA viral load, which may contribute to tumor recurrence risk. To avoid these biases, we selected only patients receiving curative liver resection because resectable patients are comparable in terms of disease extent and remnant liver function. We analyzed propensity scores and Charlson scores to examine the comparability of these 2 cohorts. Multivariable analysis was performed to adjust for potential confounders. Furthermore, we conducted multivariable stratified analysis to examine the risk of HCC recurrence after liver resection for the study cohorts in different strata. Although unmeasured confounders may still exist, we believe the methodology used in the present study is solid and robust.

Second, coding error is possible in a database. We were unable to check the accuracy of nucleoside analogue use in the NHIRD. However, the information regarding insurance-paid nucleoside analogues was accurate because every prescription is strictly regulated and only patients fitting specific criteria are eligible to receive reimbursement.

Third, some patients may have used self-paid nucleoside analogues and thus may have been inappropriately classified into the untreated cohort. Conversely, nucleoside analogue users in the treated cohort may have poor compliance. These potential misclassifications may have led to an underestimation of the association.

Fourth, HCC recurrence was defined as rehospitalization with a primary diagnosis of HCC and further HCC therapy. It is possible that some incidence of HCC recurrence might have been missed, for example if a patient did not receive therapy for the recurrence. Since all enrolled participants were able to undergo curative resection, the majority of them were unlikely to give up therapy for a recurrence. Furthermore, such misclassification would have underestimated the incidence of recurrent HCC in both cohorts and biased the results toward null difference.

Fifth, information about adverse events of nucleoside analogues was not available from the NHIRD. However, there is evidence of excellent short-term safety profiles for the available nucleoside analogues for chronic hepatitis B.35 Therefore, adverse events associated with oral anti-HBV therapy were very unlikely to substantially influence clinical outcomes in the present study. Sixth, we did not treat nucleoside analogue use as a time-dependent variable in the Cox model. Instead, we used the incident user design in this study, in which exposure time begins with the start of new antiviral agents. This minimizes the potential for immortal person-time bias prior to treatment exposure, which may result in a downward trend toward underestimation of the risk rate ratios.

In conclusion, nucleoside analogue use was associated with a lower risk of HCC recurrence among patients with HBV-related HCC after liver resection.

Corresponding Author: Chun-Ying Wu, MD, PhD, MPH, LLM, School of Medicine, National Yang-Ming University, No. 155, Section 2, Linong Street, Taipei 11221, Taiwan (chun@vghtc.gov.tw).

Published Online: November 12, 2012. doi:10.1001/2012.jama.11975

Author Contributions: Dr C.-Y. Wu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs C.-Y. Wu and Chen contributed equally to this article as first authors; Drs C.-Y. Wu and Lin are both corresponding authors.

Study concept and design: Chun-Ying Wu, Chen, Kuo, Lin.

Acquisition of data: Chun-Ying Wu, Ho, Lin.

Analysis and interpretation of data: Chun-Ying Wu, Chen, Ho, Hsu, Ming-Shiang Wu, Lin.

Drafting of the manuscript: Chun-Ying Wu, Chen.

Critical revision of the manuscript for important intellectual content: Chun-Ying Wu, Chen, Ho, Hsu, Kuo, Ming-Shiang Wu, Lin.

Statistical analysis: Chun-Ying Wu, Chen, Ho, Hsu.

Obtained funding: Chun-Ying Wu, Kuo.

Administrative, technical, or material support: Chun-Ying Wu, Chen, Kuo, Ming-Shiang Wu, Lin.

Study supervision: Chun-Ying Wu, Kuo, Lin.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: The National Health Research Institutes provided access to the National Health Insurance Research Database (NHIRD) and financial support for the hiring of a research assistant. This work was supported by Taiwan's National Health Research Institute (PH-101-PP-23). This study is based on data from the NHIRD provided by the Bureau of National Health Insurance, Department of Health, and managed by the NHIRD, Taiwan.

Role of the Sponsor: The NHRI had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Disclaimer: The interpretations and conclusions contained in this article do not represent those of the Bureau of National Health Insurance, Department of Health, or the NHRI. National Health Insurance Research Database, Taiwan. http://www.nhri.org.tw/nhird/en/index.htm.

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Kuzuya T, Katano Y, Kumada T,  et al.  Efficacy of antiviral therapy with lamivudine after initial treatment for hepatitis B virus-related hepatocellular carcinoma.  J Gastroenterol Hepatol. 2007;22(11):1929-1935
PubMed   |  Link to Article
Kubo S, Tanaka H, Takemura S,  et al.  Effects of lamivudine on outcome after liver resection for hepatocellular carcinoma in patients with active replication of hepatitis B virus.  Hepatol Res. 2007;37(2):94-100
PubMed   |  Link to Article
Chan AC, Chok KS, Yuen WK,  et al.  Impact of antiviral therapy on the survival of patients after major hepatectomy for hepatitis B virus-related hepatocellular carcinoma.  Arch Surg. 2011;146(6):675-681
PubMed   |  Link to Article
Wu CY, Wu MS, Kuo KN, Wang CB, Chen YJ, Lin JT. Effective reduction of gastric cancer risk with regular use of nonsteroidal anti-inflammatory drugs in Helicobacter pylori-infected patients.  J Clin Oncol. 2010;28(18):2952-2957
PubMed   |  Link to Article
Wu CY, Kuo KN, Wu MS, Chen YJ, Wang CB, Lin JT. Early Helicobacter pylori eradication decreases risk of gastric cancer in patients with peptic ulcer disease.  Gastroenterology. 2009;137(5):1641-1648
PubMed   |  Link to Article
Wu CY, Chan FK, Wu MS,  et al.  Histamine2-receptor antagonists are an alternative to proton pump inhibitor in patients receiving clopidogrel.  Gastroenterology. 2010;139(4):1165-1171
PubMed   |  Link to Article
Cheng CL, Kao YH, Lin SJ, Lee CH, Lai ML. Validation of the National Health Insurance Research Database with ischemic stroke cases in Taiwan.  Pharmacoepidemiol Drug Saf. 2011;20(3):236-242
PubMed   |  Link to Article
Suissa S. Immortal time bias in pharmaco-epidemiology.  Am J Epidemiol. 2008;167(4):492-499
PubMed   |  Link to Article
Suissa S. Immortal time bias in observational studies of drug effects.  Pharmacoepidemiol Drug Saf. 2007;16(3):241-249
PubMed   |  Link to Article
Rosenbaum PR, Rubin D. The central role of the propensity score in observational studies for causal effects.  Biometrika. 1983;70(1):41-55Link to Article
Link to Article
Rosenbaum PR, Rubin D. Reducing bias in observational studies using subclassification on the propensity score.  J Am Stat Assoc. 1984;79(387):516-524Link to Article
Link to Article
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies.  J Chronic Dis. 1987;40(5):373-383
PubMed   |  Link to Article
Wu CY, Wu MS, Kuo KN, Wang CB, Chen YJ, Lin JT. Long-term peptic ulcer rebleeding risk estimation in patients undergoing haemodialysis.  Gut. 2011;60(8):1038-1042
PubMed   |  Link to Article
Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk.  Ann Stat. 1988;16(3):1141-1154
Link to Article
Kim BK, Park JY, Kim do Y,  et al.  Persistent hepatitis B viral replication affects recurrence of hepatocellular carcinoma after curative resection.  Liver Int. 2008;28(3):393-401
PubMed   |  Link to Article
Jang JW, Choi JY, Bae SH,  et al.  The impact of hepatitis B viral load on recurrence after complete necrosis in patients with hepatocellular carcinoma who receive transarterial chemolipiodolization.  Cancer. 2007;110(8):1760-1767
PubMed   |  Link to Article
Omata M, Lesmana LA, Tateishi R,  et al.  Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma.  Hepatol Int. 2010;4(2):439-474
PubMed   |  Link to Article
Li N, Lai EC, Shi J,  et al.  A comparative study of antiviral therapy after resection of hepatocellular carcinoma in the immune-active phase of hepatitis B virus infection.  Ann Surg Oncol. 2010;17(1):179-185
PubMed   |  Link to Article
Tsan YT, Lee CH, Wang JD, Chen PC. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection.  J Clin Oncol. 2012;30(6):623-630
PubMed   |  Link to Article
Yang PM, Liu YL, Lin YC, Shun CT, Wu MS, Chen CC. Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies.  Cancer Res. 2010;70(19):7699-7709
PubMed   |  Link to Article
Raza H, John A, Benedict S. Acetylsalicylic acid-induced oxidative stress, cell cycle arrest, apoptosis and mitochondrial dysfunction in human hepatoma HepG2 cells.  Eur J Pharmacol. 2011;668(1-2):15-24
PubMed   |  Link to Article
Hossain MA, Kim DH, Jang JY,  et al.  Aspirin induces apoptosis in vitro and inhibits tumor growth of human hepatocellular carcinoma cells in a nude mouse xenograft model.  Int J Oncol. 2012;40(4):1298-1304
PubMed
Sitia G, Aiolfi R, Di Lucia P,  et al.  Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B.  Proc Natl Acad Sci U S A. 2012;109(32):E2165-E2172
PubMed   |  Link to Article
Kwon H, Lok AS. Hepatitis B therapy.  Nat Rev Gastroenterol Hepatol. 2011;8(5):275-284

Figures

Place holder to copy figure label and caption
Figure 1. Selection of Study Patients
Graphic Jump Location

HBV indicates hepatitis B virus; HCC, hepatocellular carcinoma.aNumbers for exclusions may not sum because of patients fulfilling more than 1 criterion.

Place holder to copy figure label and caption
Figure 2. Cumulative Incidences of HCC Recurrence and Overall Mortality Following Liver Resection
Graphic Jump Location

Data were compiled after adjustment for competing mortality. For cumulative incidences of hepatocellular carcinoma (HCC), calculation and comparison in competing risk data ratios were conducted using modified Kaplan-Meier and Gray methods. For overall mortality, Kaplan-Meier method was used. Recurrences (for cumulative incidences of HCC) and deaths (for overall mortality) during the first 3 months were excluded. Treated and untreated categories indicate patients with hepatitis B virus who are receiving nucleoside analogues, and those who are not, respectively.

Place holder to copy figure label and caption
Figure 3. Multivariable Stratified Analyses for the Association Between Nucleoside Analogue Use and HCC Recurrence
Graphic Jump Location

Among hepatitis B virus–related patients with hepatocellular carcinoma (HCC), nucleoside analogue use (treated cohort) was found to be associated with reduced risk of HCC recurrence on nearly all analyses (stratified by age, sex, extent of liver resection, liver cirrhosis, diabetes, and use of statins, nonsteroidal anti-inflammatory drugs [NSAIDs], and metformin). Some hazard ratios were not statistically significant due to a small number of cases. Recurrences during the first 3 months were excluded. Treated and untreated categories indicate patients with hepatitis B virus who are receiving nucleoside analogues, and those who are not, respectively. Major resection indicates extensive and partial hepatic lobectomy with at least 3 segmental resections of liver parenchyma; minor resection indicates extensive and partial hepatectomy with 2 or fewer segmental resections of liver.

Tables

Table Graphic Jump LocationTable 1. Study Cohorts Following Liver Resection
Table Graphic Jump LocationTable 2. Risk of HCC Recurrence After Adjusting for Competing Mortalitya

References

Cho YK, Rhim H, Noh S. Radiofrequency ablation versus surgical resection as primary treatment of hepatocellular carcinoma meeting the Milan criteria: a systematic review.  J Gastroenterol Hepatol. 2011;26(9):1354-1360
PubMed
Grazi GL, Cescon M, Ravaioli M,  et al.  Liver resection for hepatocellular carcinoma in cirrhotics and noncirrhotics.  Aliment Pharmacol Ther. 2003;17:(suppl 2)  119-129
PubMed   |  Link to Article
Wu JC, Huang YH, Chau GY,  et al.  Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma.  J Hepatol. 2009;51(5):890-897
PubMed   |  Link to Article
Poon RT, Fan ST, Lo CM, Liu CL, Ng IO, Wong J. Long-term prognosis after resection of hepatocellular carcinoma associated with hepatitis B-related cirrhosis.  J Clinical Oncol. 2000;18(5):1094-1101
PubMed
Kubo S, Hirohashi K, Tanaka H,  et al.  Effect of viral status on recurrence after liver resection for patients with hepatitis B virus-related hepatocellular carcinoma.  Cancer. 2000;88(5):1016-1024
PubMed   |  Link to Article
Hung IF, Poon RT, Lai CL, Fung J, Fan ST, Yuen MF. Recurrence of hepatitis B-related hepatocellular carcinoma is associated with high viral load at the time of resection.  Am J Gastroenterol. 2008;103(7):1663-1673
PubMed   |  Link to Article
Liaw YF. Antiviral therapy of chronic hepatitis B: opportunities and challenges in Asia.  J Hepatol. 2009;51(2):403-410
PubMed   |  Link to Article
Yuen MF, Lai CL. Treatment of chronic hepatitis B: evolution over two decades.  J Gastroenterol Hepatol. 2011;26:(suppl 1)  138-143
PubMed   |  Link to Article
Tong MJ, Sun SC, Schaeffer BT, Chang NK, Lo KJ, Peters RL. Hepatitis-associated antigen and hepatocellular carcinoma in Taiwan.  Ann Intern Med. 1971;75(5):687-691
PubMed   |  Link to Article
Liaw YF, Sung JJ, Chow WC,  et al; Cirrhosis Asian Lamivudine Multicentre Study Group.  Lamivudine for patients with chronic hepatitis B and advanced liver disease.  N Engl J Med. 2004;351(15):1521-1531
PubMed   |  Link to Article
Chen CJ, Yang HI, Su J,  et al.  Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.  JAMA. 2006;295(1):65-73
PubMed   |  Link to Article
Kuzuya T, Katano Y, Kumada T,  et al.  Efficacy of antiviral therapy with lamivudine after initial treatment for hepatitis B virus-related hepatocellular carcinoma.  J Gastroenterol Hepatol. 2007;22(11):1929-1935
PubMed   |  Link to Article
Kubo S, Tanaka H, Takemura S,  et al.  Effects of lamivudine on outcome after liver resection for hepatocellular carcinoma in patients with active replication of hepatitis B virus.  Hepatol Res. 2007;37(2):94-100
PubMed   |  Link to Article
Chan AC, Chok KS, Yuen WK,  et al.  Impact of antiviral therapy on the survival of patients after major hepatectomy for hepatitis B virus-related hepatocellular carcinoma.  Arch Surg. 2011;146(6):675-681
PubMed   |  Link to Article
Wu CY, Wu MS, Kuo KN, Wang CB, Chen YJ, Lin JT. Effective reduction of gastric cancer risk with regular use of nonsteroidal anti-inflammatory drugs in Helicobacter pylori-infected patients.  J Clin Oncol. 2010;28(18):2952-2957
PubMed   |  Link to Article
Wu CY, Kuo KN, Wu MS, Chen YJ, Wang CB, Lin JT. Early Helicobacter pylori eradication decreases risk of gastric cancer in patients with peptic ulcer disease.  Gastroenterology. 2009;137(5):1641-1648
PubMed   |  Link to Article
Wu CY, Chan FK, Wu MS,  et al.  Histamine2-receptor antagonists are an alternative to proton pump inhibitor in patients receiving clopidogrel.  Gastroenterology. 2010;139(4):1165-1171
PubMed   |  Link to Article
Cheng CL, Kao YH, Lin SJ, Lee CH, Lai ML. Validation of the National Health Insurance Research Database with ischemic stroke cases in Taiwan.  Pharmacoepidemiol Drug Saf. 2011;20(3):236-242
PubMed   |  Link to Article
Suissa S. Immortal time bias in pharmaco-epidemiology.  Am J Epidemiol. 2008;167(4):492-499
PubMed   |  Link to Article
Suissa S. Immortal time bias in observational studies of drug effects.  Pharmacoepidemiol Drug Saf. 2007;16(3):241-249
PubMed   |  Link to Article
Rosenbaum PR, Rubin D. The central role of the propensity score in observational studies for causal effects.  Biometrika. 1983;70(1):41-55Link to Article
Link to Article
Rosenbaum PR, Rubin D. Reducing bias in observational studies using subclassification on the propensity score.  J Am Stat Assoc. 1984;79(387):516-524Link to Article
Link to Article
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies.  J Chronic Dis. 1987;40(5):373-383
PubMed   |  Link to Article
Wu CY, Wu MS, Kuo KN, Wang CB, Chen YJ, Lin JT. Long-term peptic ulcer rebleeding risk estimation in patients undergoing haemodialysis.  Gut. 2011;60(8):1038-1042
PubMed   |  Link to Article
Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk.  Ann Stat. 1988;16(3):1141-1154
Link to Article
Kim BK, Park JY, Kim do Y,  et al.  Persistent hepatitis B viral replication affects recurrence of hepatocellular carcinoma after curative resection.  Liver Int. 2008;28(3):393-401
PubMed   |  Link to Article
Jang JW, Choi JY, Bae SH,  et al.  The impact of hepatitis B viral load on recurrence after complete necrosis in patients with hepatocellular carcinoma who receive transarterial chemolipiodolization.  Cancer. 2007;110(8):1760-1767
PubMed   |  Link to Article
Omata M, Lesmana LA, Tateishi R,  et al.  Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma.  Hepatol Int. 2010;4(2):439-474
PubMed   |  Link to Article
Li N, Lai EC, Shi J,  et al.  A comparative study of antiviral therapy after resection of hepatocellular carcinoma in the immune-active phase of hepatitis B virus infection.  Ann Surg Oncol. 2010;17(1):179-185
PubMed   |  Link to Article
Tsan YT, Lee CH, Wang JD, Chen PC. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection.  J Clin Oncol. 2012;30(6):623-630
PubMed   |  Link to Article
Yang PM, Liu YL, Lin YC, Shun CT, Wu MS, Chen CC. Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies.  Cancer Res. 2010;70(19):7699-7709
PubMed   |  Link to Article
Raza H, John A, Benedict S. Acetylsalicylic acid-induced oxidative stress, cell cycle arrest, apoptosis and mitochondrial dysfunction in human hepatoma HepG2 cells.  Eur J Pharmacol. 2011;668(1-2):15-24
PubMed   |  Link to Article
Hossain MA, Kim DH, Jang JY,  et al.  Aspirin induces apoptosis in vitro and inhibits tumor growth of human hepatocellular carcinoma cells in a nude mouse xenograft model.  Int J Oncol. 2012;40(4):1298-1304
PubMed
Sitia G, Aiolfi R, Di Lucia P,  et al.  Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B.  Proc Natl Acad Sci U S A. 2012;109(32):E2165-E2172
PubMed   |  Link to Article
Kwon H, Lok AS. Hepatitis B therapy.  Nat Rev Gastroenterol Hepatol. 2011;8(5):275-284

Letters

February 27, 2013
Ching-Sheng Hsu, MD, PhD
JAMA. 2013;309(8):765. doi:10.1001/jama.2013.568.
February 27, 2013
Yi-Chun Yeh, MS; Pei-Jer Chen, MD, PhD; Mei-Shu Lai, MD, PhD
JAMA. 2013;309(8):765-767. doi:10.1001/jama.2013.571.
February 27, 2013
Chun-Ying Wu, MD, PhD, MPH; Yao-Chun Hsu, MD, MS
JAMA. 2013;309(8):765-767. doi:10.1001/jama.2013.574.
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Multimedia

Supplemental Content

Wu CY, Chen YJ, Ho HJ, et al. Association between nucleoside analogues and risk of hepatitis B virus–related hepatocellular carcinoma following liver resection. JAMA. doi: 10.1001/2012.jama.11975.

eTable 1. Regulations of the Taiwan National Health Insurance Program Regarding First-Line Oral Antiviral Therapy for Chronic Viral Hepatitis B

eTable 2. Regulations of Taiwan National Health Insurance Program Regarding Rescue Oral Antiviral Therapy for Chronic Viral Hepatitis B

eTable 3: Multivariable Cox Proportional Hazards Model Analysis for Risk of HCC Recurrence After Adjusting for Competing Mortality (Treating Nucleoside Analogues Use as a Continuous Variable According to the Total Number of Days of Nucleoside Analogues Use)

eFigure 1. Cumulative incidences of HCC recurrence following liver resection in untreated cohort and treated cohort after adjustment for competing mortality

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