Hsu et al., 1
Postoperative peg-interferon plus ribavirin associated with reduced
recurrence of hepatitis C virus-related hepatocellular carcinoma
Short title: Postoperative Peg-IFN plus RBV and recurrent HCC
Yao-Chun Hsu, MSc, MD1,2, Hsiu J. Ho, PhD3, Ming-Shiang Wu, MD, PhD 4,
Jaw-Town Lin, MD, PhD 2,3,5, Chun-Ying Wu, MD, PhD, MPH, LL.M1,6-9
1
Graduate Institute of Clinical Medicine, China Medical University, Taichung;
2
Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung;
3
School of Medicine, Fu Jen Catholic University, New Taipei;
4
Department of Internal Medicine, National Taiwan University Hospital, Taipei;
5
Center for Health Policy Research and Development, National Health Research
Institutes; Miaoli;
6
Division of Gastroenterology, Taichung Veterans General Hospital, Taichung;
7
Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei;
8
College of Public Health, China Medical University, Taichung;
9
Department of Life Sciences, National Chung-Hsing University, Taichung; all in
Taiwan
* Correspondence:
Hsu et al., 2
Chun-Ying Wu, MD, MPH, PhD
Faculty of Medicine, School of Medicine, National Yang-Ming University
No. 155, Section 2, Linong Street, Taipei 11221, Taiwan
E-mail: chun@vghtc.gov.tw; Tel: +886-4-23592525 # 3304; Fax: +886-4-23741331
Jaw-Town Lin, MD, PhD, Chair Professor
School of Medicine, Fu Jen Catholic University
No. 510, Zhongzheng Rd., Xinzhuang Dist., New Taipei City, 24205, Taiwan
E-mail: jawtown@gmail.com; Tel: +886-2-23562246; Fax: +886-2-23947899
Wu CY and Lin JT contributed to this work as corresponding authors.
Financial support: This work was supported in part by Taiwan National Health
Research Institutes (PH-100-PP-54, PH-101-PP-23).
Word Counts: 266 in the abstract; 4664 in the main text (including references)
Preliminary results of this study was presented at the 63rd annual meeting of the
American Association for the Study of Liver Diseases (the Liver Meeting ® 2012) on
November 12, 2012; Boston, MA.
Hsu et al., 3
ABSTRACT
Hepatocellular carcinoma (HCC) frequently recurs after surgical resection. This
population-based research aimed to investigate the association between postoperative
antiviral treatment and risk of recurrent HCC in patients with hepatitis C virus (HCV)
infection. By analyzing the Taiwan National Health Insurance Research Database, we
initially screened a total of 100,938 patients diagnosed with HCC for the first time
between October 2003 and December 2010. Among 2,237 antiviral-naïve
HCV-infected patients who curatively resected HCC, there were 213 patients receiving
antiviral treatment with pegylated interferon plus ribavirin for 16 weeks or more after
surgery (treated cohort). These treated patients were matched 1:4 with 852 controls
who never treated HCV infection (untreated cohort), in age, gender, cirrhosis, and the
elapsed time between surgery and antiviral therapy. Cumulative incidences of and
hazard ratios for recurrent HCC were calculated after adjusting for competing mortality.
The recurrence rate of HCC was significantly lower in the treated than untreated cohort,
with 52.1% (95% confidence interval [CI], 42.0-62.2%) and 63.9% (95% CI,
58.9-68.8%) after 5 years of follow-up, respectively (p=0.001). The number needed to
treat for one fewer recurrent HCC at 5 years was 8. The association between
postoperative antiviral treatment and risk of recurrent HCC was independent to
adjustment for multiple covariates, with an adjusted hazard ratio of 0.64 (95% CI,
Hsu et al., 4
0.50-0.83). Stratified analyses revealed that the attenuation in recurrence risk was
greater in patients younger than 60 years and those without cirrhosis or diabetes.
Conclusion: Postoperative pegylated interferon plus ribavirin is associated with
reduced recurrence of HCC in patients with HCV infection. Age, liver cirrhosis, and
diabetes mellitus appear to modify this association.
Keywords: hepatocellular carcinoma, chronic viral hepatitis C, antiviral therapy
Hsu et al., 5
Hepatocellular carcinoma (HCC) is the 3rd most lethal cancer worldwide, causing
approximately 600,000 deaths every year. The incidence is highest in Eastern Asia and
sub-Saharan Africa, but appears to rise in North America (1, 2). Almost all HCCs occur
in the background of chronic liver diseases that include viral hepatitis, alcoholic liver
disease, and steatohepatitis (3). Chronic infection with hepatitis B virus (HBV) or
hepatitis C virus (HCV) accounts for most HCCs; chronic hepatitis C (CHC) is the
leading etiology in countries where prevalence of HBV infection is low (4, 5).
Surgical resection is potentially curative for HCC and has been recommended as
the treatment of choice if the hepatic reserve permits complete resection (6, 7).
Nevertheless, recurrence is very common and strikes 50~60% of patients 3 years after
operation (8, 9). In addition to insidious intra-hepatic spreading prior to surgery, a large
proportion of recurrent HCCs originate from de novo tumor clones distinct to the
resected ones (10, 11). This may result from the underlying liver disease that
continuously promotes hepatocellular carcinogenesis despite removal of the primary
tumor. There remains a huge unmet need for effective therapy to prevent postoperative
recurrence (6, 7).
Antiviral therapy may reduce the risk of HCC in patients with chronic viral
hepatitis through elimination of viral oncoprotein, resolution of hepatic inflammation,
and amelioration of the carcinogenic microenvironment (12-14). A growing body of
Hsu et al., 6
evidence has indicated that interferon-based antiviral regimen may decrease
development of HCC in CHC patients, particularly in those achieving sustained
virological response (15, 16). Nonetheless, viral clearance cannot prevent all HCCs,
especially in those with old age or severe liver fibrosis (17), implicating that antiviral
therapy may be too late to halt hepatocarcinogenesis in patients with advanced disease.
The recurrence rate after HCC resection remained unknown in CHC patients receiving
postoperative pegylated interferon (peginterferon) plus ribavirin, the standard anti-HCV
regimen for a decade (18). Moreover, it has not been clarified whether this antiviral
regimen administered postoperatively was associated with fewer HCC recurrences.
Therefore, we aimed in this population-based study to determine the recurrence rate of
surgically resected HCC after postoperative administration of peginterferon plus
ribavirin, and to elucidate whether this antiviral therapy was associated with reduced
recurrence of HCC in CHC patients.
PATIENTS AND METHODS
Study design and patient population
This open-cohort research utilizes population-based data from the Taiwan National
Health Insurance Research Database (NHIRD). Since the National Health Insurance is
a compulsory universal program for all residents in Taiwan, NHIRD is a comprehensive
Hsu et al., 7
healthcare database that nearly covers the entire 23.7 million population of this country.
Details regarding the NHIRD have been reported in our previous investigations (19-21).
The present study was approved by the Research Ethics Committee of the National
Health Research Institutes, Taiwan (EC1010303-E).
We firstly screened all patients who had a first-time diagnosis of HCC from
October 1, 2003 to December 31, 2010, and then identified the study population as
those with CHC who underwent curative surgery. This research defined disease status
principally on the basis of admission diagnoses, which were coded according to the
International Classification of Diseases, 9th Revision, Clinical Modification
(ICD-9-CM). Apart from the specific ICD-9-CM code (155.0), the diagnosis of HCC
had to be certified in the Registry for Catastrophic Illness Patient Database (RCIPD), a
subpart of NHIRD. Given that all enrolled patients resected their HCC,
histopathological confirmation was required for registry in the RCIPD. All enrolled
patients received liver resection as the sole HCC treatment. Those who underwent liver
transplantation, local ablation (ethanol injection, radiofrequency ablation, or microwave
coagulation), or trans-arterial chemoembolization before or during the index admission
were excluded.
Patients with metastasis or any other malignant disease were excluded. We
enrolled exclusively patients coded with CHC at admission (ICD-9-CM codes: 070.41,
Hsu et al., 8
070.44, 070.51, 070.54, V02.62) to ascertain validity of the diagnosis. Those with HBV
infection or other viral hepatitis were excluded (ICD-9-CM codes: 070.2, 070.3,
V02.61, V02.69).
Antiviral therapy and definition of study cohorts
The antiviral regimen consisted of peginterferon alpha (either 2a or 2b) plus
ribavirin, which has been reimbursed for HCV infection in Taiwan since October 1,
2003. Generally, treatment was initiated at 180 µg per week irrespective of body weight
for peg-interferon alpha 2a, 1.5µg/kg per week for 2b, and 800 to 1,200 mg per day for
ribavirin, but it was individualized at the treating physician’s discretion and frequently
adjusted along the course. The reimbursed duration ranged from 16 weeks to 48 weeks,
depending on the date of administration, viral genotype, serum viral load, on-treatment
virological response, and patient tolerability (18).
The treated cohort comprised antiviral-naïve patients who received peginterferon
and ribavirin for a minimum of 16 weeks after surgery. Each treated patient was
matched in age, gender, and cirrhosis with 4 untreated counterparts randomly selected
from those who never used interferon or ribavirin. Furthermore, the untreated controls
were deliberately matched for the time period between surgery and administration of
antiviral therapy in treated patients, in order to eliminate the immortal time bias (22,
23).
Hsu et al., 9
Postoperative follow-up and definition of HCC recurrence
The treated and untreated cohorts were followed up after initiation of antiviral
regimen and matched postoperative duration, respectively, until recurrence of HCC,
death, or December 31, 2010; whichever occurred first. Recurrence of HCC was
defined as repeated cancer treatment for HCC during the follow-up period. Treatment
modalities for HCC recurrence included liver transplantation, surgical resection, focal
ablation, trans-arterial chemoembolization, radiotherapy, and chemotherapy. HCC that
recurred within 3 months of the index surgery was not included because it might arise
from incomplete primary resection.
Assessment of and adjustment for confounding factors
All comorbidities listed in the Charlson’s index were considered as important
covariates that might confound outcomes (24). The age-unadjusted Charlson scores
were computed for both the treated and untreated cohorts. Certain medications
including statin, non-steroidal anti-inflammatory drug (NSAID), aspirin, and metformin
were also assessed as potential confounders because they might modify the risk of
cancer (19-21). Users of these drugs were defined as those who took them on a regular
basis with frequency of more than one tablet per month during the study period. The
extent of hepatic surgery, namely major (at least 3 segments of hepatic parenchyma) or
minor resection (2 or fewer segments of liver), was also analyzed.
Hsu et al., 10
Data analysis and statistical test
The primary and secondary outcomes were HCC recurrence and mortality,
respectively. Death occurring prior to HCC recurrence, which could lead to informative
censoring, was regarded as a competing risk event in estimating the incidence of
recurrent HCC. The number needed to treat (NNT) represented the number of patients
needed to be treated in association with one fewer recurrent HCC or death. NNT was
calculated by the inverse of the absolute risk reduction. The modified Kaplan-Meier
method and the Gray's method were used to calculate and to compare the cumulative
incidences in data with competing risks (25). After confirming the assumption of
proportional hazards by plotting the graph of the survival function versus the survival
time and the graph of the log (-log(survival)) versus the log of survival time, we
applied the modified multivariate-adjusted Cox proportional hazard model in the
presence of competing risks to examine the independent risk factors for HCC
recurrence (26). The influence of antiviral therapy on HCC recurrence was further
explored in stratified analyses according to age, gender, cirrhosis, comorbidity,
medications, and extent of resection. All data was managed with the SAS software 9.2
version (SAS Institute., Cary, NC, USA). The cumulative incidence and hazard ratio
(HR) in the competing risk analysis were calculated by using the R software with the
“cmprsk_2.1-4” package (by Gray; http://biowww.dfci.harvard.edu/~gray/). Calculated
Hsu et al., 11
results were expressed with the estimated numbers alongside their 95% confidence
intervals (CIs). All statistical tests were two-sided with significance set at a p value
<0.05.
RESULTS
Baseline characteristics of the study population
We screened a total of 100,938 patients diagnosed with HCC for the first time
during the study period and finally identified 2,237 CHC patients who underwent
curative resection for HCC (Figure 1). Among the 239 patients who ever received
peginterferon plus ribavirin after surgery, 213 patients (89.1%) were treated for a
minimum of 16 weeks and formed the treated cohort, whose mean (± standard
deviation) duration of antiviral regimen was 25.99 ± 8.13 weeks and that of follow-up
was 2.01 ± 1.67 years. The matched controls accordingly comprised 852 untreated
patients randomly selected from those not receiving antiviral therapy. The untreated
cohort was followed up for 1.51 ± 1.28 years. These two cohorts were generally
comparable in baseline characteristics (Table 1).
HCC recurrence and mortality between the study cohorts
HCC recurred cumulatively in 16.2% (95% CI, 10.9-21.4%), 41.8% (95% CI,
33.2-50.4%), and 52.1% (95% CI, 42.0-62.2%) of the treated cohort after 1, 3, and 5
Hsu et al., 12
years of follow-up, respectively (Figure 2). The corresponding 1-, 3-, and 5-year
cumulative incidences in the untreated cohort were 24.5% (95% CI, 21.4-27.5%),
54.3% (95% CI, 50.0-58.6%), and 63.9% (95% CI, 58.9-68.8%), respectively.
Therefore, patients receiving postoperative anti-HCV regimen had a significantly lower
recurrence rate (p=0.001). The unadjusted NNT associated with one fewer HCC
recurrences after 1, 3, and 5 years were 12, 8, and 8, respectively (Table 2).
The treated cohort also had a significantly lower mortality rate as compared with
the untreated counterpart (p<0.001). The 1-, 3-, and 5-year cumulative incidences of
mortality were 2.8% (95% CI, 0.4-5.2%), 10.8% (95% CI, 4.9-16.6%), and 15.4%
(95% CI, 7.7-23.1%) in the treated patients, and 6.9% (95% CI, 5.1-8.7%), 24.8 (95%
CI, 20.9-28.6%), and 47.0% (95% CI, 40.7-53.2%) in the untreated controls (Figure 3).
The unadjusted NNT associated with one less mortality at 1, 3, and 5 years after
antiviral treatment were 24, 7, and 3, respectively (Table 2).
Multivariate-adjusted association of antiviral therapy with HCC recurrence
The modified Cox proportional hazard model demonstrated that postoperative
antiviral therapy was independently associated with 36% reduction in hazard of HCC
recurrence (adjusted HR, 0.64; 95% CI, 0.50-0.83; p=0.001) (Table 3). Besides, major
surgical resection as compared with a minor one (adjusted HR, 0.76; 95% CI, 0.59-0.97;
p=0.027) and regular NSAID or aspirin use (adjusted HR, 0.80; 95% CI, 0.66-0.97;
Hsu et al., 13
p=0.026) were also linked to reduction of recurrent HCC.
Stratified analyses for recurrent HCC in association with antiviral therapy
The association between postoperative antiviral therapy and reduced HCC
recurrence was generally consistent across different patient subgroups, since the
estimated HRs favored antiviral treatment in all strata (Figure 4). The reduction of
hazard, however, differed in magnitude among patients according to age, liver cirrhosis,
diabetes mellitus, and use of metformin. The association was more pronounced in
patients younger (adjusted HR, 0.47; 95% CI, 0.30-0.73) versus older than 60 years
(adjusted HR, 0.80; 95% CI, 0.59-1.09), without (adjusted HR, 0.56; 95% CI, 0.40-0.80)
versus with cirrhosis (adjusted HR, 0.82; 95% CI, 0.56-1.20), and without (adjusted HR,
0.60; 95% CI, 0.45-0.81) versus with diabetes (adjusted HR, 0.86; 95% CI, 0.51-1.44).
DISCUSSION
This nationwide population-based study unraveled a significantly lower risk of
recurrent HCC in CHC patients who treated their HCV infection postoperatively with
peginterferon plus ribavirin, as compared with those whose CHC was left untreated.
The hazard was reduced by 36% (adjusted HR 0.64; 95% CI, 0.50-0.83; p=0.001)
after adjustment for possible confounding. The unadjusted NNT in association with
one patient free of recurrent HCC at 1, 3, and 5 years after antiviral treatment were 12,
Hsu et al., 14
8, and 8, respectively. Nevertheless, the magnitude of association appeared to differ
among patient subgroups, in that the attenuated risk of HCC recurrence was more
apparent in younger patients without cirrhosis or diabetes. These findings not only
implicate that antiviral treatment may still ameliorate hepatocellular carcinogenesis
even when HCV infection has progressed to the stage of HCC, but also characterize
those who are more likely to benefit from this management.
To date, there has been no adjuvant therapy approved for HCC after curative
resection (6, 7). Conventional interferon alpha has been tested for this indication, but
the results from randomized trials involving CHC patients were conflicting (27-30).
Kubo et al. reported in a small trial (N=30) that postoperative administration of
interferon for 2 years decreased recurrence of resected HCC (27), whereas Mazzaferro
et al. concluded that adjuvant interferon for 48 weeks could not prevent HCC
recurrence in 150 HCV-infected cirrhotic patients (28). The other two randomized
trials, which recruited predominantly HBV-infected patients along with some CHC
patients, also conflicted in the efficacy for secondary prevention of HCC (29, 30). In
addition, therapeutic agent, dosing protocol, patient characteristic, and study endpoint
also varied remarkably across these trials. Therefore, conventional interferon cannot
be accepted as the standard care following HCC resection in CHC patients (7), despite
a positive result from meta-analyses (31).
Hsu et al., 15
Peginterferon alpha plus ribavirin has become the standard anti-HCV regimen
for a decade (32, 33), but its efficacy in preventing recurrence of curatively treated
HCC remains undetermined. Two previous studies addressing this issue did not find
peginterferon-based therapy was associated with fewer recurrences (34, 35). In a
cohort study consisting of 182 patients predominantly receiving radiofrequency
ablation, Hagihara et al. reported HCC recurred similarly between 37 treated and 145
untreated patients (58% versus 70% at 5 years; p=0.17) (34). By taking a propensity
score approach, Tanimoto et al. showed that recurrence did not differ between patients
with and without postoperative peginterferon-based treatment (55.3% versus 44.7%;
p=0.36; n=38 in both groups) (35). Both studies were probably underpowered because
of the small number of participants. Besides, differences in demographics, HCC
treatment, antiviral medication, outcome definition, and follow-up duration might also
factor in the discrepancy between their results and ours. Based on our data, it needs a
large sample comprising representative subgroups to uncover the association between
postoperative antiviral treatment and HCC recurrence, in that the recurrence rate
among treated patients may be lower but remains substantial and that certain patient
characteristics can modify the association.
Peg-interferon plus ribavirin is highly effective in achieving HCV eradication in
Taiwan (36, 37), where a favorable genetic variation in IL28B is prevalent (38), and
Hsu et al., 16
has been validated among Taiwanese patients with HCC in a multicenter trial (39).
However, this study in and of itself could not delineate how virological response
might have influenced the association. Because linking from the NHIRD to individual
patients’ laboratory results was forbidden for privacy protection, we were unable to
determine whether viral elimination mediated this association. Nevertheless, a large
body of evidence has indicated that sustained virological response to antiviral
treatment appears essential to reduce risk of developing HCV-related HCC (15,16).
The large-scale randomized and placebo-controlled HALT-C trial has also refuted
antitumor efficacy of peg-interferon in CHC patients who failed to eradicate HCV
(40). In our opinion, antiviral efficacy was more likely than anti-proliferative property
to account for the observed association in our study, although further research is
clearly required to clarify the underlying mechanism. Furthermore, different viral
clearance rate could plausibly explain why age, cirrhosis, and diabetes modified the
association with recurrent HCC, since these were all validated host features predictive
of therapeutic response (41-43). In consistence with our previous study which focused
on recurrent HCC in patients with HBV infection (21), this study also uncovered an
inverse association between use of aspirin or NSAID and risk of HCC recurrence. The
mechanism of this intriguing finding may involve induction of cell cycle arrest and
apoptosis in HCC cells (44, 45), and should inspire more investigation.
Hsu et al., 17
This study has applied a number of methodological procedures to avoid a biased
or confounded result, in addition to adjusting for multiple parameters in the
multivariate analyses. First, enrollment was explicitly restricted to patients who could
tolerate and recover from liver resection; whose performance status as well as hepatic
reserve was therefore unlikely to contraindicate use of interferon and ribavirin.
Second, in order to ensure comparability of the study cohorts, enrolled patients were
matched in age, gender and cirrhosis. The treated and untreated cohorts were
consequently similar in their baseline characteristics including the comorbidity index,
i.e., the Charlson’s score. Moreover, matching in the time period from surgery to
administration of antiviral therapy prevented the immortal time bias (23). Third, the
universal coverage of Taiwan National Health Insurance, which fully reimbursed
peginterferon and ribavirin for treating HCV infection, precluded healthcare
accessibility or financial disparity as a determinant for receiving treatment or not. Last
but not the least, we recognized how mortality might have confounded the estimation
of the association with HCC recurrence (46). Since antiviral treatment could have
affected survival by ameliorating the background liver disease, without relation to any
effect on HCC, the higher mortality in the untreated patients would have
overestimated their HCC recurrence rate and spuriously exaggerated the difference
between the study cohorts, had the censoring caused by death been simply dismissed
Hsu et al., 18
as non-informative (47, 48). Therefore, we believe these data valuable for physicians
and surgeons who need to weigh up the benefits and risks of using peginterferon and
ribavirin after resection of HCC, even though the observational nature of this study
forestalled definite ascertainment of the causal relationship.
Several limitations warrant discussion. First, lack of direct laboratory results in
the Taiwan NHIRD prohibited exploration in terms of virological response, viral
genotype, baseline viral load, size and number of tumors, and histological
differentiation. Second, we were unable to determine the adverse reactions related to
peginterferon and ribavirin. Nevertheless, nearly 90% of those who ever started
postoperative antiviral therapy eventually completed a minimum of 16-week course,
indicating tolerability of this regimen in these patients. Besides, a multicenter trial
from Taiwan has confirmed its applicability in HCC patients (39). Finally, for the
purpose of internal validity, we deliberately matched the postoperative period prior to
antiviral treatment and restricted enrollment in patients free of recurrence within 3
months of surgery. Given that the time pattern of recurrence has been shown to
correlate with its pathogenesis (49), recurrent HCC in this study might more likely
result from de novo carcinogenesis instead of preexistent micro-metastasis. We
accordingly suggest caution be exercised before extrapolating our findings in the
setting of immediate recurrence following resection.
Hsu et al., 19
In summary, recurrence of HCV-related HCC after surgical resection is reduced in
patients who receive postoperative antiviral therapy with peginterferon plus ribavirin,
as compared with those who never treat their HCV infection. Moreover, greater risk
reduction of recurrent HCC is observed in younger patients (<60 years) and those
without cirrhosis or diabetes. These results implicate that antiviral therapy appears
better late than never in CHC patients with curable HCC. How to improve outcomes
when the current therapy is either intolerable or ineffective warrants further research.
ACKNOWLEDGEMENT
This work is supported by Taiwan’s National Health Research Institutes
(PH-101-PP-23) and based on data from the National Health Insurance Research
Database provided by the Bureau of National Health Insurance, Department of Health
and managed by the National Health Research Institutes. The interpretations and
conclusions contained herein do not represent those of the Bureau of National Health
Insurance, Department of Health or the National Health Research Institutes. Citation of
URL: http://www.nhri.org.tw/nhird/en/index.htm. Yao-Chun Hsu reports having
received lecture fees from Merck Sharp & Dohme (Taiwan), Roche (Taiwan), and
Bristol-Myers Squibb (Taiwan). There is no other potential conflict of interest to
declare.
Hsu et al., 20
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FIGURE LEGENDS
Figure 1. Flow diagram of identification and enrollment of the study subjects;
CHC, chronic hepatitis C; HCC, hepatocellular carcinoma
Figure 2. Recurrence of surgically resected hepatocellular carcinoma in patients
treated with postoperative antiviral therapy (treated cohort, blue line) and
matched controls without antiviral treatment (untreated cohort, red line); death
prior to recurrence is adjusted as a competing cause of risk.
Figure 3. The mortality rates between the treated (blue line) and untreated
cohorts (red line).
Figure 4. Multivariate stratified analyses for the association between
postoperative antiviral therapy and recurrence of hepatocellular carcinoma after
resection. All subgroup analyses are adjusted for confounders and accounted for death
as the competing cause of risk. CI, confidence interval; HR, hazard ratio; NSAID,
Hsu et al., 29
non-steroidal anti-inflammatory drug