Background
The global burden of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is rising, with HBV and HCV-related deaths increasing from 0.8 to 1.4 million over the period 1990 to 2013 [
1]. Ageing populations with chronic HBV and HCV and limited uptake of effective antiviral therapy are driving this burden. Therapeutic advances, particularly the advent of direct-acting antiviral (DAA) therapy for chronic HCV, provide optimism that major reductions in population-level liver-related mortality are achievable [
2]. In fact, the World Health Organization (WHO) has recently set a target of a 65% reduction in HBV- and HCV-related mortality by 2030 [
3]. In this context, ongoing surveillance of mortality trends is crucial to evaluate the efficacy of implementation of public health strategies against these infections.
Evaluation of mortality among people with HBV and HCV should ideally involve characterisation of cause-specific mortality. Co-morbidities are particularly prevalent among HCV populations, related to ongoing drug and alcohol use [
4,
5], extrahepatic manifestations of HCV [
6], or ageing-related chronic disorders [
7]. Even within liver-related mortality there may be differential trends for decompensated cirrhosis (DC) and hepatocellular carcinoma (HCC) [
8]. Characterisation of these mortality patterns before the rapid scale-up of DAA therapies is a public health priority, providing a foundation for the evaluation of the impact of new treatments on the disease burden of HCV.
Globally, Australia is among the few settings with established national surveillance systems that enable ongoing monitoring of all people notified with HBV and HCV infections, by linking notifications, hospitalisation, and mortality databases. The aim of this study was to assess cause-specific mortality trends and liver-related mortality risk factors among people with an HBV and HCV notification in New South Wales (NSW), Australia.
Methods
Study population and data sources
The study population consisted of all people recorded in the NSW Notifiable Conditions Information Management System (NCIMS) with an HBV and HCV notification. NSW NCIMS holds records of all individuals with positive HBV and HCV serology tests, notified of diagnoses via mandatory notification procedures, since 1991 [
9]. Notifiable HBV and HCV cases require detection of HBV surface antigen or HBV DNA and anti-HCV antibody or HCV RNA, respectively.
People with HIV co-infection were identified through the National HIV Registry (NHR). NHR receives all notifications of HIV infection in Australia via mandatory notification procedures, since 1985 [
10].
Deceased people were identified through the NSW Registry of Births, Deaths and Marriages (RBDM) and Cause of Death Unit Record File (COD URF). All deaths in NSW are registered within the NSW RBDM (since 1993) and coded causes are held within the COD URF. Since 1997, deaths are coded using the 10th revision of the International Classification of Diseases and Related Health Problems (ICD-10) [
9].
Hospital admissions for alcohol-use disorder (AUD) and end-stage liver disease (ESLD) were identified through the NSW Admitted Patient Data Collection (APDC). Since 2001, NSW APDC holds inpatient admission information from all NSW hospitals, including diagnosis information coded at the time of discharge by ICD-10 [
9]. People with a history of opioid substitution therapy (OST) were identified through the Pharmaceutical Drugs of Addiction System (PHDAS). PHDAS is used by the NSW Ministry of Health to issue authorities for applicant prescribers to prescribe drugs of addiction, including methadone (since 1985) and buprenorphine (since 2001) under the NSW Opioid Treatment Program [
9].
Data linkage
Data linkage occurred in two stages. First, NSW NCIMS HBV and HCV notifications were matched internally, to identify people with co-infection. Second, records were linked deterministically and probabilistically between the NSW NCIMS and NHR, and the NSW NCIMS and APDC, PHDAS, and RBDM and COD URF, respectively. Demographic details used for record linkages included full name, name codes (only for NHR), gender, date of birth, and address. NSW Centre for Health Record Linkage undertook all the linkages. Probabilistic linkage procedures had an error rate of 0.5% or less (i.e. false positive and false negative rates of 5/1000) [
9].
Study period
HBV and HCV notifications and mortality records were extracted for the study period between 1 January 1993 and 31 December 2012, 1 January 1993 and 31 December 2013, respectively.
Study outcome
The primary outcome of interest was liver-related mortality, defined by multiple causes of death (i.e. coded in the underlying and/or contributing fields of a linked record, Additional file
1: Table S1). To improve the accuracy of this definition, contributing fields were included only if a prior ESLD-related hospitalisation was documented (defined by DC and/or HCC admissions, Additional file
1: Table S1). This definition was selected after considering a number of different classifications. Compared to those excluding secondary causes, a multiple-cause definition was believed to complement the routine description of liver-related mortality that would use only the underlying cause [
11]. In the sensitivity analyses, trends of liver-related mortality were evaluated using three alternative definitions, including underlying and/or contributing causes of death (definition 2); underlying causes (definition 3); and underlying causes with prior ESLD admission (definition 4).
Exclusion criteria
Records where date of death was prior to introduction of ICD-10 coding (calendar year 1997), and records where the date of HBV or HCV notification occurred after censoring were excluded.
Statistical analysis
Among people with an HBV and HCV notification, cause-specific mortality numbers were first described by chapters of ICD-10. Liver-related mortality numbers were compared between four definitions, defined over several chapters of ICD-10, and ranging from the most conservative (definition 4) to the least conservative estimates (definition 2). Trends in cause-specific mortality (liver-, circulatory system-, drug-, and cancer-related, excluding liver cancer) numbers, incidence rates, and age-standardised incidence rates [per 100 person-years (PY)] were evaluated. The Australian Standard Population 2001 was used for standardisation. The strength of the association between risk factors and liver-related mortality was assessed by unadjusted and adjusted Cox proportional hazards regressions. Risk factors included birth cohort, gender, country of birth, calendar period of hepatitis notification, HBV/HCV/HIV co-infection, geographical area of residence at the time of hepatitis notification, history of AUD, and history of OST. Following unadjusted analyses, multivariable regressions were performed to evaluate factors associated with liver-related mortality, considering factors significant at the 0.20 level in the unadjusted models.
A multiple-cause definition was not used for non-liver-related causes of death (circulatory system-, drug-, and cancer-related); i.e. in all analyses, only the underlying field of a linked record was used to define these deaths (Additional file
1: Table S1). Other cause-related mortality was defined excluding ICD-10 codes used in the definitions of liver-, circulatory system-, drug, and cancer-related mortality (excluding liver cancer). AUD was the label used to define continued drinking despite adverse mental and physical consequences [
12], and having at least one AUD-related hospital admission was referred to as history of AUD. AUD-related admissions were defined using the primary and/or secondary fields of linked hospitalisation records (Additional file
1: Table S1). In all analysis, having at least one episode of OST was referred to as history of OST.
To calculate all-cause and ICD-10 chapter-specific mortality numbers, all linked mortality records between 1997 and 2013 were included in analyses (including deaths that occurred within 6 months post the date of HCV notification). To calculate cause-specific mortality numbers and rates (liver-, circulatory system-, drug-, and cancer-related), and assess factors associated with liver-related mortality; linked mortality records between 2002 and 2013 were included in analyses. In all survival analyses, linked mortality records prior to 1 January 2002 were censored, given availability of hospitalisation data since 2001 (required to define liver-related mortality definition numbers one and four). In all survival analyses, people with a missing date of birth were excluded. Finally, in all survival analyses, observation time was defined to start 6 months post the date of HCV notification [
13], and to end at whichever occurred first; death, or end of follow-up. Statistical analyses were carried out in STATA versions 12.
Discussion
This study demonstrated opposing trends in liver-related mortality among people with an HBV and HCV notification in NSW, Australia. During 2002-2012, among people with HBV age-standardised risk of liver mortality has reduced significantly, while the population-level burden of liver mortality (total deaths per year) has remained relatively stable. By contrast, among people with HCV age-standardised risk of liver mortality has remained relatively stable, while population-level burden has markedly increased. The potential impact of improving HBV antiviral therapy since the mid-2000s is encouraging; however, these trends underline the relatively limited impact of interferon-based HCV treatment. Non-liver-related causes comprised the majority of HBV and HCV deaths throughout the study period, highlighting the need for a comprehensive strategy for reducing morbidity and mortality among people with HBV and HCV. Mandatory HBV and HCV notifications, availability of this data for research, and the capacity for regular linkages to other routinely collected administrative databases provides the opportunity for ongoing evaluation of HBV and HCV public health strategies, including the introduction of government-subsidized broad access to interferon-free DAA HCV treatment in Australia from 2016.
Among people with an HBV notification, proportions of DC-related mortality significantly declined between early 2000s and early 2010s; however, HCC-related mortality remained stable during this period. Improved HBV therapies have been shown to reduce the risks of hepatic events, HCC, liver-related, and all-cause mortality, particularly among people with cirrhosis [
14]. However, current regimens cannot completely prevent HCC, and regular surveillance is still required in at-risk groups (predominantly those with cirrhosis) even when HBV DNA is undetectable [
15]. In Australia, the number of people receiving HBV treatment has increased in recent years, from 8500 in 2006 to 11,000 in 2012 [
16,
17]; however, substantial gaps remain in the HBV cascade of care, given that up to two-thirds of eligible individuals are not receiving therapy [
17]. The potential to further reduce the mortality burden of HBV infection through enhanced diagnosis and treatment uptake is considerable.
Among people with an HCV notification, proportions of DC-related mortality were stable between early 2000s and early 2010s, while HCC-related mortality increased in this period. Despite improvements in HCV antiviral therapy, small numbers of individuals were treated during 2000s-early 2010s, and treatment outcomes were sub-optimal [
18]. Moving forward, a combination of enhanced treatment efficacy and increased treatment uptake is expected to have a greater impact on HCV-related mortality [
2]. In Australia, access to highly effective interferon-free DAA therapies has been provided via government subsidy from March 2016, regardless of disease stage or drug and alcohol use. This has enabled a rapid initial uptake of DAA therapy [
19], with the potential to reduce liver-related mortality. Importantly, entry into HCV care through diverse models including primary care and drug and alcohol services could improve engagement and retention along the HCV care cascade and optimise co-morbidity management [
20].
More recent notification periods (2001-2006, 2007-2012) were associated with increased risk of HBV and HCV liver-related mortality, an association that is likely to be driven by age (Additional file
1: Table S6). Other factors associated with liver-related mortality included older age, male gender, HBV/HCV/HIV co-infection, and history of AUD. Given the accelerated progression to advanced liver disease [
21‐
23], where appropriate, these characteristics could be used to constitute high-risk groups that may need to be prioritised in the era of improved antiviral therapies.
Drug-related mortality remained a major cause of death among people with an HCV notification during 2002-2012, which is not surprising given that the majority of HCV transmissions are among people who inject drugs. In Australia, this period was characterised by shifting heroin and methamphetamine markets, changing patterns of drug use (including poly drug use), and increases in extra-medical opioid use [
24‐
27]. In this context, the rising individual-level risk of drug-related mortality underlines the need for broader access to harm reduction and treatment programs that are responsive to the changing needs of people who use drugs. In addition to mortality from direct effects of drug use, this study showed a substantial number of deaths among people with HCV are due to suicide and accidental injuries. These results were sobering, in highlighting the importance of a multidisciplinary response to HCV that encompasses not only provision of antiviral therapy, but also strategies to improve mental health- and substance use-related outcomes [
28].
As populations with HBV and HCV age, mortality from non-communicable diseases increases in prominence [
7]. Circulatory system-related mortality remained a major cause of HBV and HCV deaths in early 2010s; however, declines in its individual-level risk (particularly among people with an HCV notification) is consistent with trends in other high income countries [
29]. Nevertheless, these trends are dynamic, given changes in the prevalence of risk factors and uncertainties about the impact of enhanced HCV treatment uptake [
6,
30], and should be closely monitored.
This study has several limitations. First, in Australia, HBV notifications are based on evidence of chronic infection. However, the number of people with active HBV replication could not be evaluated. Second, HCV diagnosis for surveillance does not necessitate HCV RNA confirmation, and is commonly based on anti-HCV antibody detection. Therefore, an estimated 25% of people with an HCV notification would have spontaneously cleared their HCV infection. Nevertheless, these limitations are not thought to have a significant impact on the findings of this study, given fixed surveillance definition and systems in NSW during the study period. Third, in the presence of multiple chronic diseases that are each potentially fatal, the decision about selecting the underlying cause of death can be subjective; however, where possible (i.e. liver-related mortality), a multiple cause definition was used to include important cause information that might have been overlooked otherwise [
11]. Fourth, in evaluation of the association between risk factors and liver-related mortality, a sensitivity analysis was performed using Fine and Gray regression, to account for competing risks. Period of HBV notification was not associated with liver-related mortality in the adjusted Fine and Gray model. This difference could be due to the potential impact of higher numbers of deaths among older people who had an HBV notification in recent time periods, and inclusion of these deaths in the risk set of a competing risk framework. Fifth, using administrative data to assess risk factors for HBV- and HCV-related liver mortality has clear limitations, including lack of sociodemographic and health risk information such as smoking, poor diet, physical inactivity, mental health problems, and low income. Sixth, DC-related hospitalisation and mortality were defined by a limited number of conditions that appear to be strong indicators of the decompensated stage of cirrhosis; however, this definition has not been validated against the clinical diagnosis of DC, and requires further validation studies. Finally, given lack of individual-level treatment data, in the analyses of factors associated with liver-related mortality, it was not possible to determine which associated factors were proxies for not receiving antiviral therapy. During the era of interferon-containing HCV treatments, factors including older age, advanced liver disease, and history of alcohol use could have been associated with lower HCV treatment uptake, given poorer response rates [
31].
Competing interests
J Grebely has received research support and is a consultant for Abbvie, Gilead Sciences and Merck. J Grebely has received research support from Bristol-Myers Squibb and Cepheid. ML has received research support from Merck, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen-Cilag, Gilead Sciences, and ViiV HealthCare. ML has received consultancy and workshop fees from Gilead Sciences. ML has received Data Safety Monitoring Board Committee fees from Sirtex Pty Ltd. J George is on the speaker’s bureau for Gilead Sciences, Merck, Janssen, Roche, and Pharmaxis. J George is a member of advisory board for Gilead Sciences, Merck, Janssen, Bristol-Myers Squibb, Abbvie, Roche, GlaxoSmithKline, and Pharmaxis. J George has received travel support from Gilead Sciences, Merck, Bristol-Myers Squibb, Abbvie, and Roche. SL and LD have received untied educational grant funding from Indivior to examine naloxone for opioid overdose reversal (2015-2017), and OST use among chronic pain patients (2015-2016). GD has received research support and is a consultant for Gilead Sciences, Merck, and Janssen. GD has received research support from Bristol-Myers Squibb, Abbvie, and Roche. GD is on the speaker’s bureau for Gilead Sciences, Merck, Janssen, and Roche. GD is a member of advisory board for Gilead Sciences, Merck, Janssen, Bristol-Myers Squibb, Abbvie, Roche, GlaxoSmithKline, and Abbott Diagnostics. GD has received travel support from Gilead Sciences, Merck, Bristol-Myers Squibb, Abbvie, and Roche. MA and BH are members of the BMC Infectious Diseases editorial board. Other authors have no commercial relationships that might pose a conflict of interest in connection with this manuscript.