ABSTRACT
Background
Chronic hepatitis B virus (HBV) remains a major cause of hepatocellular carcinoma (HCC) in Australia, despite the availability of effective, subsidized antiviral therapy. We aimed to describe the clinical characteristics, HBV care cascade, and outcomes among people with HBV‐related HCC in Victoria, Australia.
Methods
We conducted a multicenter cohort study of all incident HCC cases across eight tertiary health networks in Victoria, Australia. Cases were identified retrospectively (January 1, 2018 to December 31, 2019) and prospectively (January 1, 2020 to October 17, 2022). The primary outcome was the proportion of incident HCC attributable to HBV. Secondary outcomes included uptake of guideline‐based antiviral therapy and surveillance and overall survival from HCC diagnosis. Multivariable logistic regression was used to identify factors associated with treatment and surveillance uptake.
Results
Among 1203 incident HCC cases, 219 (18.2%) were HBV related. Most patients were male (89%) and of Asian ethnicity (60%). While 61% were aged 56–75 years, 25% were 36–55 years. Cirrhosis was present in 141 (64%), although 57 (26%) were newly diagnosed with cirrhosis at HCC presentation. The 121 (60%) patients were eligible for antiviral therapy. Linkage to specialist care was associated with treatment uptake (adjusted OR 8.4, 95% CI 4.3–16.1; p < 0.001). Surveillance enrolment at diagnosis was higher among HBV‐related HCC compared with non‐HBV HCC (48% vs. 40%).
Conclusion
HBV remains a substantial contributor to HCC in Australia. Gaps in antiviral treatment and cirrhosis recognition persist, highlighting missed opportunities for prevention and early detection. Interventions to improve linkage to care and delivery of guideline‐based HBV management are urgently needed.
1. Introduction
Hepatitis B virus (HBV) is a leading cause of cirrhosis and hepatocellular carcinoma (HCC), contributing significantly to global liver‐related morbidity and mortality despite the availability of effective antiviral therapies [1]. Chronic HBV infection affects over 254 million people worldwide and accounts for more than 50% of HCC cases globally [2]. The global burden of HBV is concentrated in the Asia‐Pacific and sub‐Saharan African regions, where prevalence remains high despite ongoing vaccination efforts [3]. In Australia, HBV is a significant public health concern: Approximately 200 000 Australians are living with chronic HBV infection, with an estimated 500 new HBV‐related HCC cases annually [4]. Prevalence is highest among people born in endemic countries, including migrants from Asia and Africa, and Aboriginal and Torres Strait Islander Peoples [4].
Effective management of HBV includes timely diagnosis, regular assessment for liver inflammation and fibrosis, initiation of antiviral therapy when eligible, and enrolment in HCC surveillance for those at increased risk of HCC. Treatment with antiviral therapy significantly reduces the risk of cirrhosis, HCC, and liver‐related mortality [5, 6]. In people with chronic HBV, treatment resulted in a significant reduction in HCC risk by 30% in people with cirrhosis and up to 80% in people without cirrhosis [5, 6]. Furthermore, early diagnosis of cirrhosis and identification of other risk factors that warrant engagement in surveillance is critical for the early detection of HCC when it is potentially amenable to curative therapies that significantly improve long‐term survival [7, 8].
Substantial gaps remain in the cascade of HBV care despite established guidelines [9, 10, 11, 12, 13] both globally and within Australia. These gaps include delays in diagnosis, suboptimal treatment uptake even among eligible individuals, under‐recognition of cirrhosis and low uptake of HCC surveillance. These deficiencies can result in late‐stage presentation of HCC and poor outcomes, despite the availability of effective interventions. Addressing these gaps is critical to reducing HBV‐related HCC incidence and improving survival outcomes [14].
To date, little is known about the cascade of care among people with HBV‐related HCC in Australia, and how gaps in care may contribute to adverse outcomes. In this study, we aimed to describe the HBV care cascade and clinical outcomes among people with HBV‐related HCC in Victoria, Australia. We examined factors associated with uptake of guideline‐based HBV treatment at HCC diagnosis. These findings are intended to inform targeted interventions to improve HBV care delivery and reduce HCC‐related mortality in Australia.
2. Methods
2.1. Study Design
We conducted a multicenter observational cohort study with retrospective and prospective components, including incident HCC cases across the eight public tertiary hospital networks in Victoria, Australia. Newly diagnosed incident HCC cases in individuals who had not previously had HCC were identified retrospectively between January 1, 2018 to December 31, 2019 from prospectively collected data, then prospectively from January 1, 2020 to October 17, 2022. The cases were followed to death or until November 30, 2023.
2.2. Study Population and Setting
The study included all eight major tertiary hospital networks with primary liver cancer services in the Greater Melbourne area (population 5.5 million), including The Royal Melbourne Hospital, Austin Health, Eastern Health, Western Health, Alfred Health, Northern Health, Monash Health, and St Vincent's Hospital. All consecutive incident HCC cases in adults aged 18 years and older were identified from each health service's clinical HCC multidisciplinary meetings (MDTs), cross‐referenced with prospectively entered data from HCC clinical databases and electronic medical records at each health network. All patients presenting to a participating MDT with a new diagnosis of HCC between January 1, 2018 and October 17, 2022 were eligible for inclusion, regardless of residential postcode. The date of HCC diagnosis was defined as the day that consensus diagnosis of HCC was made at the MDT. All HCC cases were diagnosed using standard international radiological criteria and/or liver biopsy [7, 8, 10]. Liver Imaging Reporting And Data System (LI‐RADS) criteria were used across all centers in the study [8]. Exclusion criteria included children under 18 years, those residing outside Greater Melbourne, and people with mixed cholangiocarcinoma—HCC phenotype primary liver cancer.
2.3. Study Aims and Outcomes
The primary aims of the study were to describe uptake of the steps in the cascade of care and overall survival from HCC diagnosis among people with HBV‐related HCC, compared to those with HCC due to other chronic liver diseases. Secondary aims were to identify factors associated with timely uptake of the cascade of care and overall survival. The primary outcomes were the number (proportion) of people with incident HCC who were diagnosed with cirrhosis prior to HCC diagnosis, enrolled in HCC surveillance, and on HBV treatment if eligible.
2.4. Study Definitions
HCC stage of disease was defined using Barcelona Clinic Liver Cancer (BCLC) stages 0–D [15]; early‐stage HCC was defined as BCLC Stage 0 or A disease, with advanced stage disease being defined as BCLC Stage B, Stage C, or Stage D.
Active hepatitis B infection status was determined by a positive hepatitis B surface antigen test (HBsAg). Where individuals were listed in HCC MDT records as having had past chronic hepatitis B infection and were documented as being HBsAg negative, hepatitis B core antibody positive (HBcAb) and anti‐hepatitis B surface antibody positive (anti‐HBsAb) during the study period, hepatitis B was documented as a potential past contributing chronic liver disease.
Cirrhosis was diagnosed using vibration‐controlled transient elastography (VCTE), liver histopathology, shearwave elastography, and/or radiologic findings of cirrhosis and portal hypertension on cross‐sectional imaging. In patients with cirrhosis, severity of liver disease was defined using Child–Turcot–Pugh class and score. The presence of clinically significant portal hypertension was defined by the presence of varices or splenomegaly on imaging or at endoscopy and/or a low platelet count and elevated VCTE (Fibroscan), per Baveno VII criteria [16].
As per national guidelines [10, 11], HCC surveillance was defined as 6 monthly liver ultrasound, with or without alpha‐fetoprotein (AFP) at the clinician's discretion. Optimal HCC surveillance was defined as having four surveillance liver ultrasounds within the 24 months preceding diagnosis, consistent with the recommended six‐monthly interval suggested in HCC surveillance guidelines [11]. Suboptimal adherence was one to three liver ultrasounds within the 12 months preceding HCC diagnosis. HCC cases were defined as diagnosed through surveillance if HCC was initially detected on surveillance imaging.
Hepatitis B treatment eligibility was determined using EASL 2017 criteria [17], which were used locally during the study period. This includes patients with HBV DNA thresholds > 2000 IU/mL with elevated ALT, or > 20 000 IU/mL irrespective of ALT, ALT cut‐offs used locally (above the upper limit of normal, with the EASL‐recommended lower ALT threshold of 30 U/L for men and 19 U/L for women applied where available) and the criterion that all patients with cirrhosis and any detectable HBV DNA were considered treatment‐eligible regardless of ALT or HBV DNA level. Eligibility was assessed using the most recent virological and biochemical data available prior to HCC diagnosis, as recorded in the MDT and electronic medical record (EMR).
Individuals with HCC were assigned one or more causes of underlying liver disease based on meeting standard international criteria, including Metabolic Dysfunction‐Associated Steatotic Liver Disease (MASLD) criteria [18], as documented by their treating clinician, with confirmation using medical records.
2.5. Data Collection
Clinical and demographic variables, including age, etiology of liver disease, BCLC stage, and Child–Turcot–Pugh class, were prospectively and retrospectively collected from HCC multidisciplinary team meetings (MDTs), prospectively collected HCC clinical databases, and corroborated with electronic medical records. Data were de‐identified after assigning a unique study ID number and entered into a secure password‐protected, encrypted data repository (REDCap).
This study was approved by the St Vincent's Hospital Melbourne Human Research Ethics Committee (LRR 322/21) and all methods were performed in accordance with the relevant guidelines and regulations, including the Declaration of Helsinki. As this study used de‐identified data extracted from HCC multidisciplinary team meeting records and electronic medical records for both the retrospective and prospective components, the approving ethics committee granted a waiver of the requirement to obtain individual participant informed consent. Individual patient informed consent was therefore not obtained.
2.6. Statistical Analysis
Distribution of socio‐demographic and clinical variables were described overall and stratified by HBV status. Mean ± standard deviation (std) was used for continuous parametric variables and median interquartile range (IQR) for non‐parametric variables. Bivariable proportions were compared using Chi‐square test and continuous data were compared between groups using Student's t‐test and Wilcoxon rank sum test as appropriate.
For the purposes of this analysis, “uptake of guideline‐based HBV treatment at HCC diagnosis” was defined as being established on a guideline‐recommended antiviral agent (entecavir or tenofovir‐based regimen) at the time of HCC diagnosis among those meeting EASL 2017 treatment eligibility criteria; treatment initiated de novo following HCC diagnosis was not counted as prior uptake. The number (proportion) of people with uptake of each step of the cascade of care (diagnosis of HBV, cirrhosis, HBV treatment, and HCC surveillance) was described overall and stratified by HBV status. Mantel–Haenzel odds ratios were calculated for bivariable associations with uptake of each step of the cascade of care. Logistic multivariable models were built to identify factors associated with uptake of guideline‐based HBV treatment at HCC diagnosis, diagnosis of cirrhosis, and enrolment in HCC surveillance respectively, using stepwise backward elimination and likelihood ratio testing and model fit confirmed by post‐estimation Hosmer–Lemeshow goodness of fit testing.
Overall survival was compared between groups using Logrank testing and Kaplan Meier curves. Hazard ratios for associations between survival and clinic‐demographic factors were determined and a multivariable Cox proportional hazards model was built using backward elimination and likelihood ratio testing to determine survival by HBV status, controlled for factors associated with overall survival, with proportional hazards assumption confirmed by Nelson‐Aalen plots.
Missing data were handled using complete‐case analysis. For each variable, the relevant denominator is stated in the accompanying table or text (indicated by the notation N = X in each table header or row where data were incomplete). Missing data for most clinical variables was low (typically < 5%), with the exception of ethnicity/country of birth, for which site‐level variation in data capture practices contributed to a higher proportion of missing values. We acknowledge that complete‐case analysis may introduce bias if data are not missing at random and this is noted as a limitation.
3. Results
3.1. Epidemiology of Hepatitis B–related HCC in Victoria
During the 5‐year study period, 1203 HCC cases were diagnosed, of which 219 HCC cases (18.2%) were due to chronic hepatitis B infection. The number and proportion of HBV‐related HCC cases peaked in 2019 (N = 52, 24% of HBV‐related HCC cases).
The distribution of socio‐demographic variables across the cohort is outlined in Table 1. Most people with HBV‐related HCC were male (N = 195, 89%) and of Asian ethnicity (N = 131, 60%). Compared to people with HCC due to other aetiologies, people with HBV‐related HCC were more likely to be younger (p < 0.001); notably, 25% of people with HBV‐HCC were less than 55 years of age (Table 1). More people with HBV‐HCC were of non‐English speaking background (47% vs. 10%, p < 0.001) and had a family history of HCC (7% vs. 1%, p < 0.001). Furthermore, people with HBV‐related HCC were less likely to have been exposed to other risks for chronic liver disease progression, such as smoking (31% vs. 41% p = 0.018), alcohol misuse (23% vs. 54%, p < 0.001), type 2 diabetes (28% vs. 39%, p = 0.003), or obesity (6% vs. 15%, p = 0.001).
TABLE 1.
Distribution of socio‐demographic variables among people with HCC, with and without hepatitis B.
| HBV (N = 219) |
Non HBV (N = 984) |
χ 2 p | |
|---|---|---|---|
| Age category | < 0.001 | ||
| ≤ 35 years | 0 | 9 (1%) | |
| 36–45 years | 17 (8%) | 12 (1%) | |
| 46–55 years | 38 (17%) | 99 (11%) | |
| 56–65 years | 72 (33%) | 320 (33%) | |
| 66–75 years | 61 (28%) | 330 (34%) | |
| > 75 year | 31 (14%) | 214 (22%) | |
| Male | 195 (89%) | 773 (79%) | < 0.001 |
| Ethnic background (N = 1193) | < 0.001 | ||
| African | 9 (4%) | 5 (1%) | |
| Asian | 131 (60%) | 101 (10%) | |
| ATSI | 1 (1%) | 13 (1%) | |
| Caucasian | 76 (35%) | 857 (88%) | |
| Non‐English speaking background | 100 (47%) | 101 (10%) | < 0.001 |
| T2DM (N = 1193) | 61 (28%) | 383 (39%) | 0.003 |
| Obesity (N = 1165) | 13 (6%) | 138 (15%) | 0.001 |
| Mental health (N = 1172) | 16 (8%) | 149 (16%) | 0.001 |
| Smoking status (N = 1166) | 0.018 | ||
| Current | 33 (16%) | 217 (23%) | |
| Past | 31 (15%) | 168 (18%) | |
| Non‐smoker | 148 (70%) | 569 (60%) | |
| Harmful alcohol use (N = 1183) | < 0.001 | ||
| Current | 28 (13%) | 300 (31%) | |
| Past | 22 (10%) | 226 (23%) | |
| None | 162 (76%) | 445 (46%) | |
| Intravenous drug use (IVDU) (N = 1157) | 0.295 | ||
| Current | 6 (3%) | 24 (3%) | |
| Past | 14 (7%) | 95 (10%) | |
| None | 192 (91%) | 826 (87%) | |
| Family history HCC | 15 (7%) | 12 (1%) | < 0.001 |
| Year of HCC diagnosis | 0.742 | ||
| 2018 | 42 (19%) | 220 (22%) | |
| 2019 | 52 (24%) | 200 (20%) | |
| 2020 | 47 (21%) | 204 (21%) | |
| 2021 | 45 (21%) | 203 (21%) | |
| 2022 | 33 (15%) | 157 (16%) |
Diagnosis period was not independently associated with overall survival (aHR 1.32, 95% CI 0.77–2.26, p = 0.314) or with early BCLC stage at diagnosis (aOR 0.95, 95% CI 0.47–1.92, p = 0.883) after adjustment for other covariates. Estimates for specialist hepatology care, surveillance enrolment and ECOG score were materially unchanged by the inclusion of diagnosis year, suggesting that temporal changes in HCC management practice did not substantially confound the observed associations. Year of HCC diagnosis was added to Table 1 and included as a covariate in multivariable models evaluating overall survival and BCLC stage at diagnosis, grouped as 2018–2019 (retrospective period) versus 2020–2022 (prospective period), to account for potential secular trends in HCC management over the study period.
3.2. Clinical Presentation of Hepatitis B–Related HCC
The distribution of clinical variables across the HBV‐HCC cohort is shown in Table 2. Though most HBV‐related HCC cases occurred in people with cirrhosis (N = 141/219, 64%), the proportion with cirrhosis was lower than in people with non‐HBV HCC (86%, p < 0.001). Those with HBV‐related HCC and cirrhosis were more likely to have Child–Pugh Class A compensated disease than those with other liver diseases (77% vs. 64%, p < 0.001). Performance status was higher among those with HBV‐related HCC: 148/219 (69%) of people with HBV HCC were Eastern Oncology Collaborative Group (ECOG) stage 0 at presentation compared with 544/984 (57%) of those with non‐HBV HCC (p = 0.004).
TABLE 2.
Clinical characteristics and cascade of care uptake in people with HBV‐HCC compared to people with non‐HBV HCC.
| HBV (N = 219) | Non HBV (N = 984) | χ 2 p | |
|---|---|---|---|
| Referral source (N = 1170) | 0.061 | ||
| GP | 26 (12%) | 105 (11%) | |
| Hepatology specialist | 114 (53%) | 435 (46%) | |
| Non‐liver specialist a | 30 (14%) | 204 (21%) | |
| Inpatient | 44 (21%) | 212 (22%) | |
| Cirrhosis | 141 (64%) | 851 (86%) | < 0.001 |
| New diagnosis of cirrhosis at HCC diagnosis | 57 (26%) | 302 (31%) | < 0.001 |
| Portal hypertension | 69 (32%) | 498 (51%) | < 0.001 |
| Child–Pugh Class | < 0.001 | ||
| A | 169 (77%) | 634 (64%) | |
| B | 32 (15%) | 266 (27%) | |
| C | 18 (8%) | 84 (9%) | |
| ECOG | 0.004 | ||
| 0 | 148 (69%) | 544 (57%) | |
| 1 | 48 (23%) | 238 (25%) | |
| 2 | 12 (6%) | 104 (11%) | |
| 3 | 5 (2%) | 53 (6%) | |
| 4 | 0 | 10 (1%) | |
| Enrolled in surveillance (N = 1178) | 103 (48%) | 388 (40%) | 0.029 |
| Portal vein thrombus (N = 1193) | 40 (18%) | 196 (21%) | 0.581 |
| Metastases | 17 (8%) | 61 (6%) | 0.394 |
| BCLC stage | 0.003 | ||
| 0 | 29 (13%) | 104 (11%) | |
| A | 97 (44%) | 339 (35%) | |
| B | 26 (12%) | 188 (19%) | |
| C | 38 (17%) | 150 (15%) | |
| D | 29 (13%) | 199 (20%) | |
| BCLC early stage (0/A) | 126 (58%) | 443 (45%) | < 0.001 |
| Stage according to surveillance? | |||
| First treatment curative intent b | 100 (46%) | 324 (33%) | < 0.001 |
Including surgical services and private and public non‐hepatologist specialist services.
Liver transplantation, surgical resection, microwave ablation (laparoscopic or percutaneous), and radiofrequency ablation.
Of the 219 people with HBV‐related HCC, 208 had viral load data available at the time of HCC diagnosis. The 165 (79%) had a viral load < 2000 IU/mL at the time of diagnosis of HCC; 49 with cirrhosis and 115 without cirrhosis. Of the 165 with viral load < 2000 IU/mL, 88 (53%) were on treatment (62 on Entecavir, 32 on Tenofovir disoproxil fumarate, four on other treatment combinations), while the remainder with a low viral load had chronic eAg negative hepatitis B infection (Phase 3). In the 134 individuals with HBV with HBeAg data available, most (92%) were HBeAg negative, though 10 (12%) with cirrhosis were HBeAg positive. A greater proportion of HBV‐HCC were diagnosed at early BCLC 0/A stage (58% compared with 45%, p < 0.001) and received curative therapy compared to non‐HBV related HCC (46% compared to 33%, p < 0.001).
The relationship between HBV viral suppression (DNA < 2000 IU/mL) at HCC diagnosis and both BCLC stage and overall survival was examined. On univariable analysis, viral suppression was associated with a higher rate of early BCLC stage HCC at diagnosis (66% in suppressed vs. 35% in unsuppressed, p < 0.001). However, on multivariable logistic regression, including engagement in specialist hepatology care and surveillance enrolment, viral suppression was no longer independently associated with early BCLC stage (aOR 2.00, 95% CI 0.89–4.53, p = 0.095), suggesting that this association is largely mediated through receipt of guideline‐based care more broadly. On univariable analysis, patients with viral suppression had longer overall survival (median 19.5 vs. 13.9 months, logrank p = 0.030). Unlike BCLC stage, viral suppression remained independently associated with improved survival after adjustment for specialist care, surveillance enrolment and ECOG score (aHR 0.56, 95% CI 0.33–0.96, p = 0.035), suggesting that beyond its relationship with engagement in care, viral suppression may confer an independent survival benefit in patients with established HBV‐related HCC.
3.3. Cascade of Care Among People With HBV‐Related HCC
A comparison of the uptake of each step of the cascade of liver disease care between people with HBV‐HCC and HCC due to other aetiologies is presented in Table 2.
3.4. Cirrhosis Diagnosis Prior to HCC Diagnosis
Among those with HBV‐HCC, 141/219 (64%) had known cirrhosis, while 57 (26%) were diagnosed with cirrhosis for the first time when they were diagnosed with HCC. Of these, eight (16%) were referred by liver specialists, (N = 20, 36%) were referred from non‐liver specialists and (N = 22, 40%) presented through hospitalization with symptoms. Five people (10%) were not recognized to have cirrhosis until their first review by a liver specialist, or had cirrhosis diagnosed histologically at the time of HCC treatment. Of the 57 patients newly diagnosed with cirrhosis at HCC presentation, 23 (40%) would independently have met guideline‐based HCC surveillance criteria on demographic grounds alone (i.e., as Asian men aged ≥ 40 years, Asian women aged ≥ 50 years, or African patients aged ≥ 20 years), irrespective of their unrecognized cirrhosis. The remaining 34 (60%) did not meet any non‐cirrhotic surveillance criteria and therefore relied exclusively on cirrhosis recognition to qualify for surveillance. Earlier diagnosis of cirrhosis in this group would have directly enabled surveillance enrolment.
On univariable analysis, being linked into specialist hepatology care was associated with increased odds of cirrhosis diagnosis prior to HCC diagnosis, whereas having poor performance status was associated with reduced odds of cirrhosis diagnosis prior to HCC diagnosis (Table S1). On multivariable analysis (including referral source, ecog score and non‐English speaking background; Table S1), being linked into specialist hepatology care was the only significant factor associated with timely cirrhosis diagnosis (adjusted OR 9.23, 95% CI 3.8–22.3, p < 0.001) among people with HBV‐HCC, whereas people from non‐English speaking backgrounds had 58% lower odds of diagnosis of cirrhosis prior to HCC diagnosis (adjusted OR 0.42, 95% CI 0.18–0.98, p = 0.045) compared to people of english‐speaking background.
3.5. Comparison of Cirrhotic and Non‐Cirrhotic HBV‐HCC
Among the 219 patients with HBV‐related HCC, 141 (64%) had cirrhosis and 78 (36%) did not. There was no significant difference in median age between cirrhotic and non‐cirrhotic patients (63 vs. 64 years, p = 0.891), rates of HCC surveillance enrolment (49% vs. 48%, p = 0.947), or viral load suppression at HCC diagnosis (79% vs. 79%, p = 0.940). Non‐cirrhotic patients were more likely to be diagnosed at early BCLC stage (68% vs. 52%, p = 0.020), though overall survival was similar between groups (median 17.0 vs. 16.8 months, logrank p = 0.185). Full characteristics are provided in Table S5.
3.6. Enrolment in HCC Surveillance
A higher proportion of people with HBV were enrolled in surveillance at the time of HCC diagnosis compared to those with HCC due to other aetiologies (48% compared with 40%, p = 0.029). With increased surveillance uptake, more people with HBV‐related HCC were diagnosed with early BCLC stage (0/A) disease (58% compared with 45%, p < 0.001) and more received first line curative treatment (46% compared with 33%, p < 0.001) than those with non‐HBV HCC.
Among people with HBV‐HCC, on univariable analysis being engaged in specialist liver care was associated with 50% higher odds of enrolment in HCC surveillance, whereas being male, of non‐English speaking background and having a higher ECOG score were associated with lower odds of enrolment in HCC surveillance (Table S2). On multivariable analysis (including referral source, non‐English speaking background, and ECOG status; Table S2), being in specialist hepatology care was associated with 4‐fold higher odds of enrolment in surveillance (adjusted OR 4.01, 95% CI 2.10–7.69, p < 0.001), while odds of enrolment in surveillance fell by 45% for every point increase in ECOG score above 0 (adjusted OR 0.55, 95% CI 0.31–0.97, p = 0.04).
3.7. Treatment Eligibility and Uptake Among People With Hepatitis B–Related HCC
Overall, 88 (40%) of 219 people with available data were on treatment at the time of HCC diagnosis and all but one person on treatment had a completely suppressed viral load (one patient had a HBV DNA level of 88 IU/mL). Eighty‐eight of 165 (53%) people with low viral load < 2000 IU/mL were on treatment (62 on ETV, 32 on TDF, four on other treatment combinations), while the remainder with a low viral load had chronic eAg negative hepatitis B infection.
As per EASL 2017 criteria, 180 of 219 (82%) with available data were eligible for HBV treatment at the time of HCC diagnosis, of whom 49% (N = 88, 49%) were on treatment. Among those with cirrhosis, only 55/141 (39%) were on antiviral therapy at the time of HCC diagnosis, 34 (24%) of whom were known to be cirrhotic but not on treatment. Among those without cirrhosis who were eligible for treatment, 33/39 (85%) were on antiviral treatment at the time of diagnosis of HCC. Notably, 39 (18%) people with HBV‐related HCC were not eligible for treatment per EASL 2017 guidelines.
On univariable analysis, not being linked into specialist hepatology care was associated with higher odds of receiving guideline‐based antiviral therapy, whereas poor performance status and hazardous or harmful alcohol intake were associated with lower odds of being on antiviral therapy (Table S3). However, on multivariable analysis only linkage to specialist hepatology care was associated with receiving guideline‐based hepatitis B treatment (adjOR 6.25, 95% CI 2.98–13.11, p < 0.001; Table S3).
3.8. Factors Associated With Survival in People With HBV‐Related HCC
Overall survival from time of diagnosis among those with HBV‐related HCC was higher than those with non‐HBV‐related HCC (Figure 1). Median survival was 51 months (IQR 10.8 months, no upper bound) for those with HBV‐HCC and 33 months (979 days; IQR 7.9, 68.5 months) for those with non‐HBV HCC.
FIGURE 1.
Overall survival among people with hepatitis B–related HCC (HBV‐HCC) compared to other aetiologies (non‐HBV HCC); logrank p < 0.001.
On univariable analysis, high ECOG score, hazardous or harmful alcohol use, high Child–Pugh class and presence of portal hypertension were associated with greater mortality, whereas early‐stage HCC at diagnosis was associated with greater survival (Table 3). Being in specialist hepatology care, being enrolled in surveillance and being on HBV antiviral therapy were also associated with prolonged survival (Table 3 and Figures S1 and S2, all log‐rank p < 0.001).
TABLE 3.
Factors associated with overall survival since diagnosis of hepatitis B–related HCC on univariable and adjusted multivariable analysis (N = 219).
| Crude HR (95% CI) | p | Adjusted HR (95% CI) | p | |
|---|---|---|---|---|
| Age category | ||||
| 36–45 years | Ref | |||
| 46–55 years | 1.10 (0.44–2.73) | 0.833 | ||
| 56–65 years | 0.96 (0.42–2.19) | 0.919 | ||
| 66–75 years | 0.93 (0.39–2.18) | 0.872 | ||
| > 75 year | 1.42 (0.58–3.49) | 0.443 | ||
| Male | 0.97 (0.45–2.11) | 0.940 | ||
| Ethnic background | ||||
| Caucasian | Ref | |||
| African | 0.49 (0.12–2.04) | 0.327 | ||
| Asian | 0.66 (0.42–1.02) | 0.063 | ||
| ATSI | 4.13 (0.56–30.62) | 0.166 | ||
| Non‐English speaking background | 0.90 (0.58–1.38) | 0.624 | ||
| ECOG a | 2.26 (1.81–2.83) | < 0.001 | 1.80 (1.37–2.37) | < 0.001 |
| T2DM | 0.98 (0.61–1.59) | 0.949 | ||
| Obesity | 1.17 (0.51–2.68) | 0.717 | ||
| Mental health condition | 1.36 (0.66–2.82) | 0.408 | ||
| Smoking status | 0.68 (0.35–1.32) | 0.256 | ||
| Hazardous or harmful alcohol use | 2.53 (1.46–4.39) | 0.001 | 2.12 (1.20–3.75) | 0.009 |
| IVDU | 0.71 (0.17–2.90) | 0.635 | ||
| Family history HCC | 0.43 (0.14–1.36) | 0.149 | ||
| Cirrhosis | 1.48 (0.93–2.37) | 0.164 | ||
| Portal hypertension | 1.88 (1.21–2.94) | 0.005 | 1.75 (1.10–2.79) | 0.019 |
| Child–Pugh Class | ||||
| A | Ref | |||
| B | 4.24 (2.54–7.08) | < 0.001 | ||
| C | 6.47 (3.47–12.08) | < 0.001 | ||
| Early BCLC stage | 0.14 (0.09–0.23) | < 0.001 | 0.22 (0.13–0.37) | < 0.001 |
| Specialist liver care pre‐diagnosis | 0.37 (0.24–0.58) | < 0.001 | ||
| Enrolled in HCC surveillance | 0.48 (0.31–0.75) | 0.001 | ||
| On antiviral therapy at HCC diagnosis | 0.43 (0.27–0.69) | < 0.001 |
Note: Final Cox proportional hazards model included ECOG, hazardous or harmful alcohol use, portal hypertension, and early versus advanced BCLC stage.
Treated as an ordinal continuous variable, due to a positive test for linear trend.
Cox proportional hazards multivariable modeling for explanatory factors for overall survival in people with HBV‐HCC identified several intrinsic factors associated with overall survival (Table 3). There was a 2.3‐fold increase in mortality risk with every point increase in ECOG score (aHR 2.26, 95% CI 1.82–2.83, p < 0.001), double the mortality risk with hazardous or harmful alcohol use (aHR 2.12, 95% CI 1.20–3.75, p = 0.009) and almost double the mortality risk when portal hypertension was present (aHR 1.75, 95% CI 1.10–2.79, p = 0.019). However, early BCLC stage at diagnosis was associated with a 78% reduction in mortality risk (HR 0.22, 95% CI 0.13–0.37, p < 0.001; Table 3).
Several potentially modifiable factors associated with HCC diagnosis at early BCLC (0/A) stage were determined (Table 4). On univariable analysis, being engaged in specialist hepatology care, being enrolled in surveillance and being on HBV treatment were all associated with early BCLC stage HCC at diagnosis, whereas a poor performance status and hazardous or harmful alcohol use were associated with lower odds of early BCLC stage HCC. On logistic regression multivariable analysis, being enrolled in surveillance was associated with 5‐fold higher odds of diagnosis at early BCLC stage (aHR 4.80, 95% CI 1.81–12.74, p = 0.002), while being linked into specialist hepatology care was associated with three‐fold higher odds of early BCLC stage HCC at diagnosis (aHR 2.99, 95% CI 1.11–8.07, p = 0.03). In contrast, there was an 80% reduction in odds of diagnosis of early‐stage HCC for every one point increase in ECOG score above 0 (aHR 0.21, 95% CI 0.08–0.56, p 0.002; Table 4).
TABLE 4.
Factors associated with HCC diagnosis at early BCLC stage (0 and A) in people with HBV‐HCC (N = 219).
| Crude HR (95% CI) | p | Adjusted HR (95% CI) | p | |
|---|---|---|---|---|
| Age category | ||||
| 36–45 years | Ref | |||
| 46–55 years | 0.57 (0.17–1.95) | 0.373 | ||
| 56–65 years | 0.78 (0.25–2.48) | 0.677 | ||
| 66–75 years | 0.52 (0.16–1.67) | 0.275 | ||
| > 75 years | 0.23 (0.06–0.82) | 0.024 | ||
| Male | 1.70 (0.72–3.98) | 0.223 | ||
| Non‐English speaking background | 0.96 (0.56–1.66) | 0.895 | ||
| ECOG a | 0.20 (0.11–0.36) | < 0.001 | 0.21 (0.08–0.56) | 0.002 |
| Mental health | 1.62 (0.54–4.84) | 0.387 | ||
| Smoking status | 2.11 (0.93–4.79) | 0.075 | ||
| Harmful alcohol use | 0.34 (0.15–0.80) | 0.013 | ||
| Liver specialist | 3.69 (2.04–6.53) | < 0.001 | 2.99 (1.11–8.07) | 0.030 |
| Enrolled in surveillance | 6.55 (3.52–12.17) | < 0.001 | 4.80 (1.81–12.74) | 0.002 |
| On antiviral treatment | 5.77 (3.06–10.87) | < 0.001 |
Note: Final logistic regression model included ECOG score, enrolment in HCC surveillance, and linkage to specialist hepatology care.
Treated as an ordinal continuous single parameter variable in multivariable model.
4. Discussion
Our data from a large cohort of subjects with HBV‐related HCC show that gaps in the cascade of care persist for HBV treatment, cirrhosis diagnosis, and enrolment in HCC surveillance. Further, HBV remains a major cause of HCC in Victoria, despite national commitment to achieving hepatitis B elimination by 2030 [19]. This is consistent with trends seen in other high‐income settings with effective HBV vaccination programs and effective access to antiviral therapy [20, 21, 22, 23, 24].
Examination of the HBV cascade of care in this cohort highlights persistent gaps that are consistent with national findings from the Australian Hepatitis B Mapping Project, which has demonstrated suboptimal engagement at multiple stages of the care continuum [4]. We did not identify any differences in outcomes by gender, CALD status, or other markers of potential access to care barriers such as mental health conditions or IVDU. However, on an individual cascade of care level, harmful alcohol use and non‐English speaking background were barriers to accessing care. Furthermore, recognition of cirrhosis among people with HBV was suboptimal. Among the 57 patients first diagnosed with cirrhosis at the time of HCC presentation, 60% did not independently meet non‐cirrhotic demographic criteria for HCC surveillance, meaning that earlier cirrhosis diagnosis would have been the only pathway to surveillance eligibility in this subgroup. While this represents a proportion of the total newly diagnosed cirrhosis patients, it nonetheless highlights a real and preventable gap in early HCC detection, particularly given that enrolment in surveillance was independently associated with a 4.8‐fold higher odds of diagnosis at early BCLC stage.
Early diagnosis enables curative treatments which can markedly influence mortality in HCC [25]. Compared to people with HCC due to other aetiologies, individuals with HBV‐related disease had less metabolic and alcohol‐related comorbidities and less cirrhosis, which are positive prognostic factors for survival in HCC as they enable more curative therapeutic options. It is therefore vital that people with HBV are treated, evaluated for cirrhosis and enrolled in HCC surveillance to capitalize on the benefits of early diagnosis and curative treatments.
Our study found that linkage to hepatology specialist care was strongly associated with several cascade‐of‐care outcomes, including diagnosis of cirrhosis prior to HCC, enrolment in HCC surveillance, and uptake of guideline‐based antiviral therapy. These associations should, however, be interpreted with caution. Since our data are cross‐sectional in nature with respect to referral, we were unable to determine the temporal relationship between specialist referral and each cascade‐of‐care outcome. It is plausible that patients who had already been diagnosed with cirrhosis, commenced on antiviral therapy or enrolled in surveillance may have been more likely to be referred to and retained in specialist care, rather than specialist care being the primary driver of these outcomes. In the absence of referral‐timing data, we cannot distinguish this from a true causal effect of specialist care on cascade‐of‐care uptake. Notwithstanding this limitation, the consistency of the association across multiple outcomes, its magnitude, and its biological plausibility collectively support specialist hepatology engagement as an important enabler of guideline‐adherent HBV management. These findings reinforce that reliance on hepatology specialist‐led models is increasingly untenable given workforce limitations and inequitable access for culturally and linguistically diverse communities and those living outside metropolitan areas [26, 27]. Strengthening primary care‐led HBV management, supported by simplified guidelines, shared‐care frameworks and improved digital integration is therefore essential. Strategies to achieve this include targeted primary care and non‐hepatology specialist education, streamlined referral pathways and use of clinical decision support systems [27, 28, 29, 30].
At the time of HCC diagnosis, 18% were not eligible for treatment per guidelines used at the time of the study. This could be due to missing data on their viral loads in their EMR and notes. By the current EASL 2025 guidelines [31], this proportion could be lower. Antiviral therapy has been shown to significantly reduce the risk of cirrhosis, HCC, and liver‐related mortality [5, 6]. Notably, all but one person with HBV on antiviral treatment had an undetectable viral load, demonstrating high adherence at the time of HCC diagnosis. This shows that treatment is tolerated well and highly acceptable to people living with HBV, which is important to consider in the context of expanding HBV treatment eligibility in guidelines.
People with HBV‐HCC had higher adherence to HCC surveillance than people with non‐HBV HCC, reiterating that gaps in care are driven primarily by health system failures rather than lack of client acceptance and uptake. We identified several intrinsic factors associated with overall survival on multivariable analysis. These were early BCLC stage at diagnosis, ECOG score, harmful alcohol use, and portal hypertension. Age was not a factor, but frailty (performance status) was, suggesting that frailty could be a better guide than age to survival in HCC. We also identified several potentially modifiable factors associated with early BCLC stage HCC at diagnosis. These included liver specialist care, enrolment in surveillance, and ECOG score. Patients diagnosed at earlier BCLC stages had significantly improved survival, largely due to their eligibility for curative treatment options [15]. Taken together, data from these models suggest that diagnosis of HCC at early BCLC stage is a key determinant of mortality and the likelihood of this is increased by linkage to specialist care, through provision of hepatitis B treatment and HCC surveillance. In contrast, factors such as performance status (ECOG), which were independently associated with mortality, may be less amenable to intervention at the time of cancer diagnosis.
Several international studies report a declining contribution of HBV to overall HCC burden in settings with sustained vaccination and wider antiviral therapy. Population‐level analyses from Taiwan that examined the combined impact of universal infant vaccination (initiated in 1984) and subsequent antiviral programs show marked decreases in HCC incidence and end‐stage liver disease across birth cohorts exposed to these interventions, highlighting the complementary role of vaccination and treatment in reducing HBV‐related HCC at the population level [22, 23]. Similarly, country‐level data from South Korea demonstrate improvements in HCC outcomes and survival over successive cohorts that parallel enhanced HBV control measures and broadened access to effective antiviral agents [24]. Japan and other East Asian countries have reported analogous trends, with neonatal vaccination, national screening/surveillance initiatives, and greater use of potent antiviral therapy contributing to lower HBV‐attributable HCC incidence among younger cohorts [32]. Other studies further corroborate the protective effect of antiviral therapy against progression to cirrhosis and HCC, while acknowledging residual risk. Large observational analyses and systematic reviews have demonstrated that long‐term suppression of HBV replication with entecavir or tenofovir is associated with substantially reduced HCC incidence and liver‐related mortality compared with historical untreated cohorts, particularly in patients with established advanced fibrosis or cirrhosis [5, 6, 33]. In our study, HBV accounted for a similar proportion of incident HCC cases in 2018–2022 (18.2%) to what was described by Hong et al. in Victoria in 2012–2013 (22%), suggesting that there have been only modest improvements achieved in the hepatitis B cascade of care over the last decade [34].
The generalizability of our findings warrants consideration. The migrant‐dominant epidemiology of HBV‐related HCC in our Victorian cohort, with the majority of cases occurring in people of Asian ethnicity born in HBV‐endemic countries is consistent with patterns described in other high‐income, low‐endemicity countries with substantial migrant populations, including the United States and Canada. Comparable gaps in the HBV care cascade have been reported in these settings, including suboptimal treatment uptake, under‐recognition of cirrhosis and low HCC surveillance rates among migrant communities [35, 36]. For example, population‐level cohort studies from the United States have described treatment uptake rates of 40%–60% among HBV‐infected persons meeting treatment eligibility criteria, with lower rates among recent migrants and non‐English speaking individuals, findings that align closely with our own [35]. These parallels suggest that the cascade‐of‐care gaps identified in our study are not unique to the Victorian or Australian context and reflect systemic challenges in delivering guideline‐based HBV care to migrant‐dominant patient populations more broadly. Conversely, our cohort was ascertained exclusively through tertiary HCC MDTs in Greater Melbourne and likely under‐represents patients managed outside metropolitan specialist services, in regional and rural Victoria, and in health systems with different funding models for antiviral therapy or surveillance infrastructure. These factors should be considered when generalizing our findings to settings with different HBV care delivery models or patient population characteristics.
Notably, only one Aboriginal or Torres Strait Islander person was identified with HBV‐related HCC in our cohort. This marked under‐representation is unlikely to reflect true rates of HBV‐related HCC in the First Nations community, given the substantially higher prevalence of chronic HBV infection among Aboriginal and Torres Strait Islander Australians compared with the non‐Indigenous population (estimated at two to three times the national average in some jurisdictions) [37]. Several factors may contribute to this under‐ascertainment. First, our study was limited to Greater Melbourne tertiary centers and many First Nations Victorians reside in regional and rural areas outside our geographic catchment, rendering them ineligible for inclusion. Second, structural barriers to accessing tertiary hepatology and HCC MDT services, including geographic distance, limited culturally safe care and historical mistrust of health institutions may result in HBV‐related HCC being diagnosed and managed outside specialist MDT settings or not reaching a tertiary MDT before death. Third, HBV may be underdiagnosed or undertreated in some First Nations communities due to gaps in access to primary care and culturally appropriate chronic disease management programs. A dedicated analysis of HBV‐related HCC in Aboriginal and Torres Strait Islander Australians, drawing on population‐level data linkage and engagement with community‐controlled health services is an urgent priority.
This study has several limitations, including the relatively small subset of patients with HBV‐related HCC and incomplete capture of data for some variables, for example, basal metabolic index (BMI) at some sites. Since case ascertainment relied on presentation and formal discussion at an HCC MDT meeting, patients who died shortly after initial presentation before MDT review could occur may have been under‐captured. This could result in underestimation of the most severe end of the HCC severity and early mortality spectrum and should be considered when interpreting our survival findings. Although our cohort includes all incident HCC cases evaluated through HCC MDTs at all the main HCC health services in Greater Melbourne, which include many regional HCC patients, the findings may not be fully generalizable to regional Australia or other states and territories. While ethnicity carries transmission risk and genotype information, there were limited data on country of birth from most sites. We could not capture information on duration and adherence to hepatitis B therapy and surveillance outside of the timeframe of the study, which may have impacted HCC incidence, survival and engagement in care. Since this study relied on retrospectively and prospectively collected MDT and EMR data rather than direct patient or referrer interview, we were not able to systematically capture the reasons that individual patients were not linked to specialist hepatology care (e.g., lack of awareness among primary care providers, patient‐level barriers such as language, health literacy or engagement with care, service capacity constraints, or geographic access). Additionally, our dataset did not capture the timing of referral to specialist hepatology care relative to cirrhosis diagnosis, initiation of antiviral therapy or enrolment in HCC surveillance. The temporality of these relationships therefore cannot be established from our data, and the observed associations between specialist care and cascade‐of‐care outcomes may partly reflect reverse causation (whereby patients already engaged in care components were more likely to be referred to specialist services). Future prospective studies incorporating referral pathway data and time‐stamped care events would be required to better characterize the direction and magnitude of these effects. We were unable to obtain complete data on country of birth for many participants due to variation in data capture practices across sites. Ethnicity was used instead, which may not accurately reflect country of origin or duration of residence in Australia, all of which may independently influence HBV care engagement. Finally, this cohort only includes people with HCC, whereas the population living with hepatitis B without HCC may have considerable differences in their cascade of care. Nevertheless, the study provides prospective, granular data on the HBV care cascade and survival outcomes, offering valuable insights to inform targeted interventions aimed at improving HBV care, preventing HCC, and enhancing survival.
5. Conclusion
Gaps in guideline‐based HBV care must be urgently addressed to reduce HBV‐related HCC incidence and mortality in Australia. Linkage to specialist hepatology care was associated with receipt of antiviral treatment, recognition of cirrhosis, and enrolment in HCC surveillance, though the direction of these associations requires confirmation through prospective studies incorporating referral‐timing data. People from non‐English speaking backgrounds had significantly lower odds of cirrhosis diagnosis prior to HCC, representing a critical and preventable gap in care. Specific targets for cirrhosis assessment, treatment uptake and HCC surveillance within national viral hepatitis elimination frameworks would strengthen accountability and drive investment in the infrastructure needed to close these gaps. Interventions should include culturally and linguistically appropriate models of care encompassing professional interpreter services, bilingual health education materials, and community‐based outreach to migrant and First Nations communities as a core component of strategies to improve HBV care delivery. There is an urgent need to raise awareness among non‐hepatology specialists and people living with HBV of the importance of antiviral treatment and timely HCC surveillance to capitalize on the survival benefits of early cancer detection.
Funding
We are grateful for funding from Gilead Sciences, Eisai and NHMRC (Investigator grant J.H.).
Conflicts of Interest
J.E.F. is supported by a Gilead Australia Fellowship unrelated to this work. J.H. has received speaker fees from Roche and participated in Advisory boards for Astra‐Zeneca and Roche.
Supporting information
Table S1: Factors associated with being diagnosed with cirrhosis prior to HCC diagnosis among those with cirrhosis and HBV‐HCC (N = 141).
Table S2: Factors associated with being enrolled in HCC surveillance among people with HBV‐HCC who were eligible for HCC surveillance (N = 188).
Table S3: Factors associated with being on HBV treatment (N = 219).
Table S4: Factors associated with HCC diagnosis at early BCLC stage (0/A) (N = 202).
Figure S1: Comparison of overall survival from diagnosis in people with hepatitis B related HCC who were enrolled in HCC surveillance compared to those who were not at the time of diagnosis (logrank p = 0.001).
Figure S2: Overall survival among people with hepatitis B related HCC who were on HBV treatment with nucleos(t)ide analogs at the time of HCC diagnosis compared to those who were not (Logrank p < 0.001).
Acknowledgments
We gratefully acknowledge the patients with HCC whose data were included in this study and the multidisciplinary teams who care for them. Open access publishing facilitated by The University of Melbourne, as part of the Wiley ‐ The University of Melbourne agreement via the Council of Australasian University Librarians
Data Availability Statement
The datasets generated and/or analyzed during the current study are not publicly available as the data contain potentially re‐identifiable patient information collected under institutional ethics approval (LRR 322/21) but are available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Factors associated with being diagnosed with cirrhosis prior to HCC diagnosis among those with cirrhosis and HBV‐HCC (N = 141).
Table S2: Factors associated with being enrolled in HCC surveillance among people with HBV‐HCC who were eligible for HCC surveillance (N = 188).
Table S3: Factors associated with being on HBV treatment (N = 219).
Table S4: Factors associated with HCC diagnosis at early BCLC stage (0/A) (N = 202).
Figure S1: Comparison of overall survival from diagnosis in people with hepatitis B related HCC who were enrolled in HCC surveillance compared to those who were not at the time of diagnosis (logrank p = 0.001).
Figure S2: Overall survival among people with hepatitis B related HCC who were on HBV treatment with nucleos(t)ide analogs at the time of HCC diagnosis compared to those who were not (Logrank p < 0.001).
Data Availability Statement
The datasets generated and/or analyzed during the current study are not publicly available as the data contain potentially re‐identifiable patient information collected under institutional ethics approval (LRR 322/21) but are available from the corresponding author on reasonable request.