Research Article
Trends in hepatocellular carcinoma among people with HBV or
HCV notification in Australia (20002014)
Reem Waziry1,, Jason Grebely1, Janaki Amin1, Maryam Alavi1, Behzad Hajarizadeh1,
Jacob George2, Gail V. Matthews1, Matthew Law1, Gregory J. Dore1
1
The Kirby Institute, UNSW Australia, Sydney, Australia; 2Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital,
University of Sydney, Sydney, Australia
Background & Aims: This study evaluates trends in hepatocellu-
lar carcinoma (HCC) among people with hepatitis B virus (HBV)
or hepatitis C virus (HCV) infection in New South Wales (NSW),
Australia between 2000 and 2014.
Methods: Data on HBV and HCV notifications between January
1993 and December 2012 were linked to the NSW Admitted
Patients Data Collection database between July 2000 and June
2014 and NSW Registry of Births Deaths and Marriages. The bur-
den, crude and age-standardised incidence of HCC based on first
hospitalization were calculated.
Results: In NSW between 20002014, there were 54,399, 93,099
and 3,809 individuals notified with HBV, HCV and HBV/HCV coin-
fection respectively. There were 725 (1.3%) with HCC among
those with HBV notification as compared to 1,309 with HCC
(1.4%) in those with HCV notification. The population-level bur-
den of new HCC cases per year has stabilised in the HBV cohort
(53 in 2001 and 44 in 2013), but increased markedly in the
HCV cohort (49 in 2001 to 151 in 2013). The age-standardised
incidence rates of HCC (per 1,000 person-years) declined from
2.3 (95% confidence interval (CI) 1.4, 3.1) in 2001 to 0.9 (95% CI
0.6, 1.2) in 2012 among those with HBV and remained stable
between 2001 (1.4; 95% CI 0.8, 1.9) and 2012 (1.5; 95% CI 1.2,
1.7) in those with HCV. Main factors associated with HCC in those
with HBV included later study period (20052009; 20102014)
(hazard ratio (HR) = 0.54, 95% CI 0.42, 0.70), male gender
(HR = 4.50, 95% CI 3.6, 5.6), Asia-Pacific country of birth
(HR = 3.84, 95% CI 2.58, 5.71) and alcohol dependency
(HR = 2.84, 95% CI 1.95, 4.13). Main factors associated with HCC
in those with HCV included male gender (HR = 2.56, 95% CI
2.20, 2.98), rural place of residence (HR = 0.73, 95% CI 0.62,
0.86), Asia-Pacific country of birth (HR = 2.37, 95% CI 1.99, 2.82)
and alcohol dependency (HR = 3.90, 95% CI 3.39, 4.49).
Keywords: Australia; Data linkage; Epidemiology; Hepatitis B virus; Hepatitis C
virus; Hepatocellular carcinoma.
Received 28 April 2016; received in revised form 23 June 2016; accepted 4 August
2016; available online 26 August 2016
Corresponding author. Address: Viral Hepatitis Clinical Research Program, The
Kirby Institute for Infection and Immunity in Society, University of New South
Wales, Australia. Tel.: +61 2 9385 9273.
E-mail address: rwaziry@kirby.unsw.edu.au (R. Waziry).
Journal of Hepatology 2016 vol. 65 j 10861093
Conclusions: Individual-level risk of HBV-related HCC has
declined, suggesting an impact of more effective antiviral therapy
from mid-2000s. In contrast, the interferon-containing HCV treat-
ment era had no impact on individual-level HCV-related HCC risk
and has seen escalating population-level HCC burden.
Lay summary: Individual-level risk of HBV-related HCC has
declined, suggesting an impact of more effective antiviral therapy
from mid-2000s. In contrast, the interferon-containing HCV treat-
ment era had no impact on individual-level HCV-related HCC risk
and has seen escalating population-level HCC burden.
2016 European Association for the Study of the Liver. Published
by Elsevier B.V. All rights reserved.
Introduction
Hepatocellular carcinoma (HCC) is the third leading cause of can-
cer death worldwide [14]. Chronic hepatitis B virus (HBV) and
hepatitis C virus (HCV) infections are the major causes of HCC
[58], responsible for around 80% of cases [9]. The prognosis of
HCC is extremely poor [3,10], with curative strategies such as
liver resection and liver transplantation feasible only in a small
minority of cases [3,4,11,12].
Increasing chronic viral hepatitis prevalence, ageing popula-
tions of those infected and sub-optimal treatment uptake and
outcomes (particularly for HCV) have led to escalating HCC bur-
den and mortality globally [2,10,12,13]. Improved antiviral ther-
apy for chronic HBV (from mid-2000s) and HCV (more recent
development of direct acting antiviral agents) may have impacted
HCC at the individual-level (age-adjusted risk) and population-
level (disease burden).
The mandatory notification of HBV and HCV diagnoses in Aus-
tralia and well-established surveillance systems provide the
opportunity to evaluate HCC burden at the individual and popu-
lation levels, including temporal trends and factors associated
with HCC. The aims of this study were: 1) to assess trends in
HCC incidence and burden among people with HBV or HCV infec-
tion, and 2) identify factors associated with HBV- and HCV-
related HCC.

Patients and methods
Study population and data sources
The study population included all persons notified with HBV or HCV infection as
recorded on the New South Wales (NSW) Notifiable Conditions Information Man-
agement System (NCIMS) between 1 January 1993 and 31 December 2012, and
alive at commencement of study period on 1 July 2000. Under the Public Health
Act 1991, all new HBV and HCV diagnoses are notifiable to the NSW department
of health [14,15]. A notifiable HBV case requires detection of HBV surface antigen
or HBV DNA. A notifiable HCV case requires detection of anti-HCV antibody or
HCV RNA. Personal identifiers were first recorded in the NCIMS in 1992.
To ascertain HCC cases and potential factors associated with HCC, HBV/HCV
notifications were linked to several administrative databases.
HCC ascertainment and case definition
A case of HCC was defined by hospitalization with a HCC code (C22.0) as principal
or additional diagnosis. Hospital admissions were obtained from the NSW Admit-
ted Patient Data Collection (APDC), which includes in-patient hospitalizations
from all public and private hospitals in NSW between 1 July 2000 and 30 June
2014. Data on each hospitalization is recorded at separation and includes demo-
graphic and administrative data, the principle and any additional diagnoses coded
according to the 10th revision of the International Classification of Diseases-
Australian Modification (ICD-10-AM). The validity of ascertainment of HCC cases
through hospitalization-based codes was assessed by linkage to the NSW Cancer
Council Registry (CCR), with data available for the period between 1 Jan 1994 to
31 Dec 2009.
Other data sources and definitions
Data on HIV was obtained from the National HIV Registry (NHR) that includes all
individuals notified with HIV between 1 January 1993 and 31 December 2013.
Data on deaths among those with HBV or HCV notification was obtained from
the NSW Registry for Births, Deaths and Marriages (RBDM) between 1 January
1993 and 18 June 2014. HCV and HBV mono-infections were defined according
to the earliest notification record available. HBV/HCV co-infections were defined
according to date of notification of the latest infection and included in the HCV
cohort. Alcohol dependency was defined according to hospitalization with any
of the following principal or additional ICD-10 codes: alcohol abuse counselling
and surveillance (Z71.4), alcoholic cardiomyopathy (I42.6), alcohol-induced
pseudo-Cushings syndrome (E24.4), alcoholic myopathy (G72.1), alcoholic
polyneuropathy (G62.1), alcohol rehabilitation (Z50.2), degeneration of nervous
system due to alcohol (G31.2) or mental and behavioural disorders due to alcohol
(F10). For HCC and alcohol dependency diagnoses, the first hospitalization as
principle or additional diagnosis was used.
Linkage process
Data linkage was completed in two stages. First, HBV and HCV notifications were
linked internally to identify people with HBV/HCV coinfection. All notifications
were then matched to other datasets (hospitalizations, cancer registry, death reg-
istry) using probabilistic record linkage methods based on matching demographic
data, using ChoiceMaker software [15,16]. The second stage involved HBV and
HCV notifications linkage to the HIV notifications using deterministic methods
based on 100% match on name code, sex and date of birth. Data linkage was com-
pleted by the Centre for Health Record Linkage (CHeReL) [15,16].
Statistical analysis
Baseline characteristics were summarized as median [Interquartile range (IQR)]
for continuous variables and frequencies and percentages for categorical vari-
ables. Two types of analysis were undertaken. First, burden was assessed as tem-
poral trends in HBV-HCC and HCV-HCC cases per year. Second, incidence was
analysed as time from HBV or HCV diagnosis to HCC. For incidence analysis, data
were additionally censored at date of death or end of follow-up (31 June 2014),
whichever occurred first. Age-standardised incidence rates for HCC were calcu-
lated per 1000 person-years and according to the age distribution in the standard
Australian population in 2001 using five-year age groups. Records of HBV and or
Journal of Hepatology 2016 vol. 65 j 10861093
JOURNAL OF HEPATOLOGY
HCV notification with missing date of birth, missing age at notification and HCC
hospitalizations within six months of HCV or HBV notification were excluded
from the incidence analyses. The latter exclusion was to reduce the potential
impact of advanced HBV and HCV-related HCC on incidence rates and to be con-
sistent with earlier studies done on the same population [16]. Accordingly, the
follow-up time was shortened by six months. This resulted in exclusion of 311
HCC cases. This exclusion was not applied to the crude trends.
Log-rank tests and Cox proportional hazards regression analysis was used to
assess the strength of association between HCC and explanatory variables. Kaplan
Meier graphs were used to assess the cumulative risk of HCC. The main explana-
tory variables included: study period, updated age, gender, place of residence
based on the statistical local area (SLA) that was further grouped into rural,
metropolitan and outer-metropolitan SLAs, HIV, and alcohol dependency hospi-
talization. Variables with a p value of 0.25 or less in the univariate analysis were
kept in the final model. Time-log variables and Schoenfeld residuals were used to
assess violation of the proportional hazards assumption. Analyses were per-
formed using the Stata v14.0 (StataCorp, College Station, Texas) and SAS software
version 9.4 (SAS Institute, Cary, NC).
Ethics approval
Ethics approval for the study was granted by the NSW Population and Health Ser-
vices Research Ethics Committee.
Results
Participant characteristics
A total of 151,307 individuals were notified with HBV or HCV
infections in NSW between 1993 and 2012, including 54,399 with
HBV, 93,099 with HCV and 3809 with HBV/HCV coinfection. Par-
ticipant characteristics are shown in Table 1. Compared to people
with HCV, people notified with HBV were younger (median year
of birth = 1966 vs. 1965), more often female (45% vs. 37%), and
more often born in Asia (30% vs. 5%) (Table 1).
Burden and incidence of HCC in people with HBV and HCV
notification in NSW 20002014
Between 2000 and 2014, the total number of people with HCC
was 1309 (1.4%) among those with an HCV notification and 725
(1.3%) among those with an HBV notification. Among people with
HBV, HCC cases per year remained relatively stable between 2001
(n = 53) and 2013 (n = 44). In comparison, among people with
HCV, HCC cases per year increased from 49 in 2001, to 151 in
2013 (Fig. 1A, B).
Among people with HBV, age-standardised HCC incidence
decreased from 2.3 (95% confidence interval (CI) 1.4, 3.1) per
1000 person-years in 2001 to 0.9 (95% CI 0.6, 1.2) per 1000
person-years in 2012. Among people with HCV, age-
standardised HCC incidence remained relatively constant at 1.4
(95% CI 0.8, 1.9) per 1000 person-years in 2001 and 1.5 (95% CI
1.2, 1.7) in 2012 (Fig. 1C, D).
Factors associated with HCC in people with HBV
In adjusted Cox proportional hazards analyses, time to HCC
among people with HBV was associated with study period, age,
gender, country of birth and alcohol dependency-related hospi-
talization. There was no association with place of residence or
HIV coinfection (Table 2).
1087
Research Article
Table 1. Characteristics of people notified with HBV or HCV in NSW (Jan 1st through 2013. In contrast, data on HCC cases recorded on the
1993Dec 31st 2012). NSW CCR was only available through 2009. The availability of
HBV HCV HBV/HCV the two data sources for the period 2001 to 2009 provided the
(n = 54,399) (n = 93,099) (n = 3809) opportunity to validate the hospitalization data. Over this period
Year of birth, median (IQR) 1966 (20) 1965 (15) 1967 (16) the vast majority of HCC cases among individuals with HBV
Year of notification, median 2001 (9) 2000 (9) 2001 (8) (89.9%) and HCV (91.3%) were recorded on both datasets
(IQR) (Fig. 2). A small proportion of cases (6.2%, HBV; 5.4%, HCV) on
Year of birth the hospitalization dataset were not present on the CCR.
>1965 27,934 (51) 43,449 (47) 2084 (55)
1956-1965 13,820 (25) 32,388 (35) 1144 (30)
<1956 12,634 (23) 17,235 (18) 581 (15) Discussion
Gender
Female 24,524 (45) 34,765 (37) 1097 (28) This study presents contrasting trends in HBV- and HCV-related
Male 29,595 (54) 58,037 (62) 2709 (71) HCC in NSW, Australia. Population-level burden of HBV-HCC is
Missing/unknown 280 (0.5) 297 (0.3) 3 (0.1) stable and individual-level HBV-HCC risk has declined markedly
Place of residence over the period 20012013. During the same period, HCV-HCC
Metro 24,299 (44) 29,629 (31) 1116 (29) population-level burden has risen markedly, and individual-
Outer-metro 24,730 (46) 29,955 (32) 1671 (44) level HCV-HCC risk has been stable. Although linkage to
Rural 4850 (9) 31,742 (34) 968 (25) individual-level HBV and HCV treatment data was not possible,
Missing/unknown 520 (1) 1773 (2) 54 (1) the contrasting trends suggest a favourable impact of improving
Country of birth HBV antiviral therapy since the mid-2000s and no significant
Australia 4269 (8) 48,257 (52) 1949 (51) impact of interferon (IFN)-based HCV therapy. The availability
Asia Pacific 16,440 (30) 4794 (5) 460 (12) of data on mandatory HBV and HCV notifications and the capacity
Europe 1581 (3) 4614 (5) 210 (6) for regular linkage to other administrative databases provides the
Other 944 (2) 1563 (2) 113 (3) opportunity for ongoing evaluation of strategies to further
Missing 31,165 (57) 33,871 (36) 1077 (28) enhance HBV diagnosis and antiviral therapy uptake, and the
HIV positive 391 (1) 1000 (2) 67 (2) recent introduction of government-subsidized broad access to
Alcohol related 1138 (2) 15,495 (17) 802 (21)
IFN-free direct-acting antiviral agent (DAA) HCV therapy in
hospitalization Australia.
Died 2636 (5) 10,277 (11) 554 (15) The individual-level risk of HCC among people with HBV in
Age at death, median (IQR) 62 (24) 51 (21) 48 (17) NSW has more than halved over the period 2001 to 2013. The
Numbers in parentheses represent percentage (column percentage) unless introduction of entecavir (2005) and tenofovir (2007) have pro-
mentioned otherwise; yPlace of residence based on statistical local area (SLA). vided access to highly effective HBV antiviral therapy in Australia.
These improvements in antiviral therapy efficacy were accompa-
nied by considerable increases in uptake, with the estimated
Factors associated with HCC in people with HCV number of people dispensed HBV antiviral drugs increasing from
about 1800 in the first quarter of 2006 [17] to more than 11,000
In adjusted Cox proportional hazards analyses, time to HCC in the last quarter of 2014 [18]. Although, this represents only
among people with HCV was associated with gender, place of res- 11% of an estimated 104,000 people diagnosed with chronic
idence, country of birth and alcohol dependency-related hospital- HBV [19,20], at the population-level, a small minority (possibly
ization. There was no association with study period, HIV or HBV 1015%) of the chronic HBV population would be recommended
coinfection (Table 3). for treatment based on consensus guidelines [21,22]. While other
factors, including lifestyle modifications (such as reduced alcohol
Validation of HCC cases intake and weight loss), could potentially ameliorate HCC risk,
improvements in HBV antiviral therapy efficacy and uptake are
Utilisation of hospitalization coding data for diagnosis of HCC a more likely explanation for declining individual-level HCC risk.
among people with HBV and HCV was based on its availability Further improvements in HBV screening, diagnosis, and

A B C HBV-HCC age
D HCV-HCC age
Age standardised incidence rates

HBV-HCC burden HCV-HCC burden standardised incidence rates standardised incidence rates
(per 1000 person-years)

200 4 4
First hospitalizations, n

200

150 150 3 3

100 100 2 2

50 50 1 1

0 0 0 0
01 0 3 05 07 0 9 11 13 01 0 0 3 0 0 5 007 0 0 9 0 1 1 013
01

03

05

07

09

11

13

01

03

05

07

09

11

13

20 2 0 20 20 2 0 20 20 20
20

20

20

20

20

20

20

20

20

20

20

20

20

20

2 2 2 2 2 2

Fig. 1. First hospitalization for HCC. Data shown for patients with (A) HBV notification, (B) HCV notification and age-standardized incidence rates for first HCC
hospitalization among those with (C) HBV notification, and (D) HCV notification.

1088 Journal of Hepatology 2016 vol. 65 j 10861093

 JOURNAL OF HEPATOLOGY
Table 2. Cox proportional hazards analysis of factors associated with time to first hospitalization with hepatocellular carcinoma among people notified with HBV.y

Person-years HCC (n = 552) Rate (/1000 person-years) HR (95% CI) Adjusted HR (95% CI) p value
Study period
2000-2004 126,501 134 1.1 1.00 1.00 --
2005-2009 196,827 195 0.9 0.94 (0.74, 1.18) 0.75 (0.59, 0.94) 0.01
2010-2014 219,230 223 1.0 0.99 (0.78, 1.26) 0.54 (0.42, 0.70) <0.001
Age -- -- -- 1.06 (1.06, 1.07) 1.06 (1.05, 1.06) <0.001
Gender
Female 248,993 94 0.4 1.00 1.00
Male 290,337 458 1.6 4.17 (3.34, 5.21) 4.50 (3.6, 5.6) <0.001
Place of residence
Metro 243,626 257 1.1 1.00 1.00 --
Outer-metro 247,880 263 1.1 1.01 (0.84, 1.19) 0.94 (0.79, 1.13) 0.54
Rural 46,993 32 0.6 0.64 (0.45, 0.93) 0.85 (0.57, 1.27) 0.44
Country of birth
Australia 42,674 31 0.7 1.00 1.00 --
Asia Pacific 159,955 400 2.5 3.44 (2.38, 4.96) 3.84 (2.58, 5.71) <0.001
Europe 15,246 52 3.4 4.69 (3.01, 7.32) 2.14 (1.34, 3.39) <0.01
Other 7724 12 1.6 2.13 (1.09, 4.15) 2.91 (1.48, 5.74) <0.01
Not specified 3737 21 5.6 7.75 (4.45, 13.48) 7.02 (3.96, 12.43) <0.001
HIV
No 539,652 545 1.0 1.00 1.00 --
Yes 2907 7 2.4 2.38 (1.13, 5.02) 2.25 (0.99, 5.10) 0.05
Alcohol-related hospitalization
No 533,353 514 0.9 1.00 1.00 --
Yes 9206 38 4.1 4.27 (3.07, 5.94) 2.84 (1.95, 4.13) <0.001
y
Includes people co-infected with HBV/HIV and excluding HCC hospitalizations within 6 months after HBV notification; HCC, Hepatocellular carcinoma; The overall p
value for place of residence = 0.06, country of birth <0.001 and study period <0.001; Age is calculated based on 5-year interval.

treatment uptake could lead to pronounced declines in HBV-HCC
cases per year, given that 43% of people living with chronic HBV
in Australia are estimated to remain undiagnosed [19,20]. Thus,
there is potential to further reduce the individual-level HCC risk
for the estimated 183,000 people with chronic HBV in Australia
and to reduce the population-level burden [20].
The individual-level risk of HCC among people with HCV in
NSW has remained stable over the period 2001 to 2013, while
the population-level HCV-HCC burden continues to escalate. This
is despite the improvements in IFN-based therapy during the
2000s and early 2010s, including the addition of first generation
protease inhibitors [23,24]. However, HCV treatment rates in
Australia have remained low and IFN-based therapy has
remained particularly problematic for many people with
advanced liver disease [5,25,26]. Thus, the apparent lack of an
impact of HCV antiviral therapy on individual-level HCC risk
relates to sub-optimal treatment outcomes, particularly in those
with cirrhosis [27,28] and low HCV treatment uptake. Although
the estimated number of people receiving treatment increased
from about 1,100 in 1997 to 2,800 in 2014 [29], the latter fig.
remains less than 2% of the estimated 230,000 people with
chronic HCV infection [30].
The recent development of highly effective IFN-free DAA ther-
apy, and Australian Government subsidization of several regi-
mens from March 2016 (without disease stage or drug and
alcohol restrictions) provides the opportunity to rapidly scale-
up HCV antiviral therapy and provide individual-level and
population-level benefits in terms of HCC and other liver disease
burden reductions. The relatively high HCV diagnosis rate in Aus-
tralia, and the particularly enhanced efficacy and tolerability of
these regimens in the setting of advanced liver disease [3134]
provides considerable optimism for a major impact on HCV-
HCC burden.
Although later study period (20052009, 20102014) was
associated with reduced risk of HBV-HCC, other factors associated
with HCC were similar among those with HBV and HCV. These
included older age, male gender, Asia-Pacific and other non-
Australian countries of birth, and hospitalization for alcohol-
related disorder (surrogate for alcohol dependency). Older age,
male gender and alcohol dependency are all associated with
accelerated fibrosis progression or more advanced fibrosis, and
have been clearly associated with HCC development in prior
studies [9,10,35,36]. It is unclear why non-Australian country of
birth is associated with development of both HBV-HCC and
HCV-HCC. Recent evidence suggests that Asian ethnicity may be
associated with fibrosis progression through a higher prevalence
of IFNk3 gene polymorphisms [37,38]. Among people with HCV-
related cirrhosis, reported rates of HCC development are consis-
tently higher in Asian settings, particularly Japan [36]. It is also
unclear why risk of HCV-HCC is reduced in rural areas. Differen-
tial HCC screening or hospitalization coding in different areas
could influence HCC diagnosis, however, the latter seems unlikely
given the high concordance with cancer registry.
The apparent chemoprevention of HCC through improved
HBV antiviral therapy has important implications for public
health policy and clinical management. The specific impact needs
to be further evaluated through linkage to individual-level HBV
treatment data. Such linkage should be possible in NSW in the

Journal of Hepatology 2016 vol. 65 j 10861093 1089

Research Article
Table 3. Cox proportional hazards analysis of factors associated with time to first hospitalization with hepatocellular carcinoma among people notified with HCV.y

Person-years HCC (n = 1168) Rate (/1000 person-years) HR (95% CI) Adjusted HR (95% CI) p value
Study period
2000-2004 249,848 184 0.7 1.00 1.00 --
2005-2009 360,922 350 0.9 1.29 (1.07, 1.56) 0.86 (0.71, 1.04) 0.12
2010-2014 373,389 634 1.6 2.20 (1.83, 2.65) 0.85 (0.69, 1.03) 0.10
Age -- -- -- 1.07 (1.06, 1.07) 1.1 (1.08, 1.09) <0.001
Gender
Female 372,446 231 0.6 1.00 1.00 --
Male 608,106 937 1.5 2.49 (2.15, 2.88) 2.56 (2.20, 2.98) <0.001
Place of residence
Metro 323,233 440 1.4 1.00 1.00 --
Outer-metro 323,048 445 1.4 1.04 (0.91, 1.19) 0.91 (0.79, 1.05) 0.20
Rural 327,573 280 0.8 0.64 (0.55, 0.74) 0.73 (0.62, 0.86) <0.001
Country of birth
Australia 503,627 569 1.1 1.00 1.00 --
Asia Pacific 49,684 236 4.7 4.30 (3.69, 5.1) 2.37 (1.99, 2.82) <0.001
Europe 46,998 188 4.0 3.49 (2.96, 4.13) 1.59 (1.33, 1.90) <0.001
Other 16,174 60 3.7 3.38 (2.59, 4.42) 2.00 (1.52, 2.64) <0.001
Not specified 16,307 12 0.7 0.59 (0.34, 1.06) 0.64 (0.35, 1.13) 0.12
HBV
No 948,235 1104 1.2 1.00 1.00 --
Yes 35,925 64 1.8 1.58 (1.22, 2.03) 1.3 (0.97, 1.65) 0.07
HIV
No 975,577 1161 1.2 1.00 1.00 --
Yes 8584 7 0.8 0.71 (0.34, 1.49) 0.76 (0.36, 1.62) 0.48
Alcohol-related hospitalization
No 845,590 779 0.9 1.00 1.00 --
Yes 138,570 389 2.8 3.12 (2.76, 3.52) 3.90 (3.39, 4.49) <0.001
y
Includes HCV/HBV co-infections and excluding HCC hospitalizations within 6 months after HCV notification; HCC, Hepatocellular carcinoma; The overall p value for place
of residence <0.001, country of birth <0.001 and study period = 0.1; Age is calculated based on 5-year interval.

near future, following procedures to enable access to
government-subsidized treatment (vast majority of treatment
in Australia) datasets. These procedures will also enable evalua-
tion of individual-level HCV treatment impact, following the
anticipated rapid scale-up of DAA therapy.
Our findings are likely relevant to other settings. In Taiwan,
enhanced therapeutic intervention through the national hepatitis
treatment program (for HBV and HCV) appears to have reduced
HCC incidence from the early 2000s to recent years, although
the separate impact of HBV and HCV was not analysed [35].
The low HCV treatment uptake in the IFN-containing era is con-
sistent with most settings [5,3941], and the limited
population-level impact of therapy on HCV-HCC incidence has
been previously described. Among a population of US veterans,
IFN-containing HCV therapy had a negligible impact on the inci-
dence of HCC related to HCV, even though the majority of HCV
patients have been diagnosed (80%) and about 23% have
received treatment [5,42].
This study has several limitations. First, HCV diagnosis for
surveillance reporting is generally based on anti-HCV antibody
detection and does not require HCV RNA confirmation. Thus, an
estimated 25% of HCV notifications would have undergone spon-
taneous HCV clearance. The lack of confirmation of chronic HCV
infection should, however, not have a major impact on the study
findings, given the surveillance definition and systems in NSW
have been stable throughout the study period. Second, the use
of hospitalization coding data for diagnosis of HCC could intro-
duce misclassification (over-diagnosis) or missed cases (under-
diagnosis). Some patients with HCC, particularly those with early
stage disease, do not require hospitalization for HCC manage-
ment. However, the availability of data on HCC through the Cen-
tral Cancer Registry allowed for validation of HCC cases captured
through hospitalization data for most of the study period (2000
2009). Around 90% of HCC cases were recorded on both datasets,
providing confidence that hospitalization-based HCC burden and
trends are valid measures at the population-level. Third, symp-
tomatic presentation of HCC could inflate incidence rates, partic-
ularly among people with HBV in whom a considerable
proportion remain undiagnosed. This is less an issue for HCV,
where an estimated 75% are diagnosed [20,29]. Further, cases of
HCC within six months of HBV or HCV diagnosis were excluded
for the analyses of incidence. Finally, the use of alcohol hospital-
izations likely underestimates the real burden of alcohol depen-
dency in this cohort. However, the use of ICD diagnostic
definitions from hospital databases has shown great validity with
physicians diagnoses and has been extensively used in epidemi-
ological studies [5,12,4347].
In conclusion, this population-level data linkage study in
NSW, Australia provides evidence for declining risk of HBV-
HCC, a likely result of improving HBV antiviral therapy. The
surveillance system we have developed, particularly with the
addition of individual-level HBV and HCV treatment data will

1090 Journal of Hepatology 2016 vol. 65 j 10861093

 JOURNAL OF HEPATOLOGY
A HCC diagnosis, proportion 100
HBV (FP7/2007-2013) under REA grant agreement No PCOFUND-GA-
2012-600181. Jacob George is supported by the Robert W. Storr
Bequest to the Sydney Medical Foundation, University of Sydney;
80 a National Health and Medical Research Council of Australia
(NHMRC) program grant (1053206), Project grants
60 (APP1107178 and APP1108422) and a Cancer Institute Transla-
tional Cancer Research Centre award. Behzad Hajarizadeh is a
40
recipient of an NHMRC early career fellowship (#1112512). Gre-
gory Dore is supported by a National Health and Medical
20
Research Council practitioner research fellowships.
0
01

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05

06

07

08

09
20

20

20

20

20

20

20

20

20
Conflict of interest
Year of HCC diagnosis

B 100
HCV Jason Grebely has received research support and is a consultant
for Gilead Sciences and Merck. Jason Grebely has received
HCC diagnosis, proportion

80
research support from Bristol-Myers Squibb and Abbvie. Jacob
George is on the speakers bureau for Gilead Sciences, Merck,
60 Janssen, Roche and Pharmaxis. Jacob George is a member of advi-
sory board for Gilead Sciences, Merck, Janssen, Bristol-Myers
40 Squibb, Abbvie, Roche, GlaxoSmithKline and Pharmaxis. Jacob
George has received travel support from Gilead Sciences, Merck,
20 Bristol-Myers Squibb, Abbvie and Roche. Gail V Matthews has
received advisory board payments from Gilead, speaker fees
0 and honoraria from Gilead, Bristol-Myers Squibb and Abbvie
01

02

03

04

05

06

07

08

09

and research grant funding from Janssen, Gilead and Abbvie. Mat-
20

20

20

20

20

20

20

20

20

Year of HCC diagnosis
Admitted Patient Data Collection only Central Cancer Registry only
Fig. 2. Agreement between the Central Cancer Registry and the Admitted
Patients Data Collection. Data shown for patients with (A) HBV and (B) HCV
notification.
be a valuable tool for evaluation of enhanced strategies for viral
hepatitis diagnosis and treatment in the future. It will also pro-
vide the opportunity to compare population and individual-
level impacts in different settings, particularly those with manda-
tory HBV and HCV notification and capacity for data linkage to a
range of administrative datasets.
thew G Law has received research support and is a consultant for
Both
Gilead Sciences. Matthew G Law has received research support
from Merck, Bristol-Myers Squibb, Boehringer Ingelheim,
Janssen-Cilag and ViiV HealthCare. Matthew G Law has received
Data Safety Monitoring Board Committee fees from Sirtex Pty
Ltd. Gregory J Dore has received research support and is a consul-
tant for Gilead Sciences, Merck and Janssen. Gregory J Dore has
received research support from Bristol-Myers Squibb, Abbvie
and Roche. Gregory J Dore is on the speakers bureau for Gilead
Sciences, Merck, Janssen and Roche. Gregory J Dore is a member
of advisory board for Gilead Sciences, Merck, Janssen, Bristol-
Myers Squibb, Abbvie, Roche, GlaxoSmithKline and Abbott Diag-
nostics. Gregory J Dore has received travel support from Gilead
Sciences, Merck, Bristol-Myers Squibb, Abbvie and Roche. Other
authors have no commercial relationships that might pose a con-
flict of interest in connection with this manuscript.

Financial support

The Kirby Institute is funded by the Australian Government Authors contributions

Department of Health, under the agreement ID number 2-
D3X513. The views expressed in this publication do not necessar-
ily represent the position of the Australian Government. This
publication is part of the blood borne viruses and sexually trans-
missible infections research, strategic interventions and evalua-
tion (BRISE) program, funded by the NSW Ministry of Health.
This publication has received funding from the Sydney West
Translational Cancer Research Centre (SW-TCRC) program
HOTTer-West: HCC outcome improvements through transla-
tional research in Western Sydney. Jason Grebely is supported
by a National Health and Medical Research Council Career Devel-
opment Fellowship. Maryam Alavi is the recipient of a CASCADE
international fellowship. The research leading to these results has
received funding from the People Programme (Marie Curie
Actions) of the European Unions Seventh Framework Programme
Reem Waziry contributed to the study design, statistical analyses,
interpretation of data and drafting the article; Jason Grebely con-
tributed to the acquisition and interpretation of the data, the
study design and drafting the article; Janaki Amin contributed
to the study design, the statistical analysis and interpretation of
data; Maryam Alavi contributed to the statistical analyses and
the acquisition and interpretation of the data; Behzad Hajariza-
deh contributed to drafting the article and the statistical analy-
ses; Jacob George and Gail Matthews contributed to
interpretation of the data; Matthew Law contributed to the sta-
tistical analyses and interpretation of the data; Gregory Dore con-
tributed to the study design, interpretation of the data and
drafting the article. All authors revised and approved the final
version for publication.

Journal of Hepatology 2016 vol. 65 j 10861093 1091

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