Mortality among British Columbians testing for hepatitis C antibody

Hepatitis C virus (HCV) infection is associated with significant morbidity and mortality. World-wide, approximately 170 million people are infected with HCV, including 243,000 to 300,000 Canadians and 60,000 British Columbians [1–3]. About 25% of infected individuals spontaneously clear infection and 75% become chronically infected [4, 5]. Within 20 to 30 years of infection, approximately 10% to 40% of HCV-infected individuals will develop cirrhosis [6], and about 1% to 5% will develop hepatocellular carcinoma [7]. End stage liver disease caused by HCV infection is the primary reason for liver transplantation in Western Europe and North America [8–11]. Most new HCV infections occur in people who inject drugs (IDU) [1], whose risk activities may result in mortality unrelated to HCV infection, and for this population, the risk of death from drug related causes is greater than from liver related causes [12–15]. HCV treatment has been shown to significantly reduce morbidity and mortality [16–18]. Approximately 50% of individuals who are able to tolerate interferon/ribavirin therapies achieve sustained virological response. The addition of protease inhibitors improves curability to about 65% to 75% and the large number of antiviral agents in the therapeutic pipeline will likely result in cure rates of greater than 90% [18].

We examined the HCV-attributable disease burden by estimating all cause and disease specific mortality among individuals who underwent HCV serological testing between 1992 and 2004 in British Columbia (BC), Canada. We also differentiated mortality due to HCV infection from risk activities associated with HCV acquisition.

This study examined all cause and disease specific mortality among individuals tested for HCV antibody in BC from 1992 to 2004. A unique feature of the study was the use of a population based central laboratory database to identify HCV-tested individuals (both positive and negative results) and to correlate the risk of death with serological results and testing patterns. To our knowledge this is the first study to use time dependent HCV serological groups to help stratify infection status and mortality risks. While the risk of death among all individuals who underwent HCV antibody testing was significantly higher than the BC population, the serological groupings helped to differentiate mortality which was likely related to risk activities associated with HCV acquisition from mortality associated with HCV related chronic liver disease.

Our findings confirm that mortality among seroconverters was more likely to be drug related. This is consistent with other published studies which demonstrated no increase in liver related mortality among seroconverters during the first decade after infection [27, 28], whereas accidental deaths, including drug overdose, contributed significantly [27]. This is expected because acute HCV infection rarely results in fulminant liver failure [4], and decades are required to develop cirrhosis [6]. In contrast, individuals whose first anti-HCV test was reactive were more likely to have chronic HCV infection and had higher risk of liver related mortality, partly as a result of being older and having survived their substance use. Drug use was also an important mortality contributor in the REAC group, and in addition, both the REAC and SERO groups had increased HIV related mortality.

While it could be argued that the designation of SNR, MNR, REAC and SERO groups is arbitrary, the grouping assumptions are supported by the data. The SERO group was the best characterized group because the date of a previous negative anti-HCV test was known. The REAC group was likely heterogeneous and included persons who may have been infected in the past from contaminated blood products, past or present IDU or other risk factors [29]. The lack of previous serology prevents their identification as a seroconverter. Persons in the REAC group had the highest liver related death rate. However, it is recognized that about 25% of HCV-infected individuals will spontaneously clear infection and remain antibody reactive [4] and such individuals are not known to be at increased risk of HCV related liver disease [30]. In contrast, seronegative individuals who tested only once likely had some baseline risks which led to serological testing. Therefore, the SNR group represents a relatively conservative comparator group given that their mortality risks were only slightly higher than the general BC population. Multiple negative testers likely had ongoing risks. For example, they were more likely to die of renal failure, diabetes and both alcoholic and non-alcoholic liver disease.

A recent study in the United States by El-Kamary et al. [32] utilized data from the National Health and Nutrition Examination Survey (NHANES) to examine mortality among HCV-uninfected, HCV antibody positive/HCV RNA negative, and HCV chronically infected individuals. This study used mortality rate ratios that showed all cause mortality among chronically infected individuals was more than twice that of HCV negative individuals and that 57.8% of the mortality was attributable to HCV. While our study demonstrated an increased drug related mortality in association with HCV infection, El-Kamary et al. [32] did not find a significant association between HCV status and non-liver related deaths. This may reflect differences in the underlying risk factors in the populations studied, i.e., the NHANES-based study reflects a random population sample which was then tested for HCV, whereas our study involved individuals who underwent diagnostic HCV testing.

Co-infections with HIV and hepatitis B virus (HBV) are common in HCV-infected individuals, and co-infected individuals have increased mortality relative to HCV mono-infected individuals [12–15]. Although we were unable to differentiate HCV mono-infected individuals from those co-infected, the HCV positive group (REAC and SERO groups combined) would be expected to include HBV and HIV co-infected individuals. HIV and HCV prevalence rates among BC IDUs have been reported as 17% [33] and 83% [34] respectively, and among HIV positive individuals in BC, the HCV co-infection rate has been estimated to be between 27% and 53% [35]. Unfortunately, the HIV status was unknown unless the individual died of HIV related causes. The SMRs for all cause, liver and drug related mortality for our HCV positive group were, however, similar to other HIV co-infected populations [15].

The time dependent Cox proportional hazard modelling revealed an 83-fold higher HIV related mortality for women in the REAC group relative to SNR women, whereas REAC men displayed a 12-fold higher mortality relative to SNR men. This may reflect the lack of access to care by highly marginalized women who are then more likely to die of HIV related causes.

This study has important public health implications. In the short term, younger drug users, here represented by the seroconverters, would likely benefit more from harm reduction, including needle distribution and methadone maintenance programs to reduce the risk of drug related mortality, than from antiviral treatment when their risk of liver related mortality is low [36]. In contrast, individuals with chronic HCV infection would benefit from harm reduction programs and antiviral treatment to reduce the risk of drug related mortality and progressive liver disease. These findings are consistent with a recent HCV costing analysis in BC where substantial HCV related direct healthcare costs could be ascribed to mental health, addictions and associated risk activities which lead to HCV acquisition, as well as the consequences of progressive liver disease [21]. Of note, early treatment of IDUs has been shown to be cost-effective [37]. Since most onward HCV transmission involves IDU, virological cure could potentially reduce incident HCV infections.

The study has several limitations. Approximately 20% of individuals in the laboratory dataset had no PHN and could not be deterministically linked, which could lead to exclusion of vulnerable individuals, e.g., with no fixed address, who have been shown to have higher HCV prevalence and morbidity/mortality risks compared to the general population [1]. As with all administrative data linkages, the ability to control for confounders such as HCV transmission risks, co-morbidities or social determinants of health, which may impact access to testing, is limited. Misclassification of seroconverters within the REAC group would occur if a recently infected individual had no prior HCV test, but the SERO vs. REAC comparison was considered a reasonable surrogate for comparing incident vs. chronic HCV infection. All of these limitations could lead to underestimation of SMR and HR in our study. Seriously ill individuals or recipients of unscreened blood products in the past are more likely to be tested, and our attempt to compensate for potential notification bias by applying a twelve month lagging period to study enrolment may have been insufficient. We did not analyze HCV RNA results which were available for only a limited number of individuals. Therefore, individuals who had cleared their infection would have been classified as incident or chronic infections based on their anti-HCV test results. Since individuals who spontaneously clear their HCV infection are not known to be at risk of progressive liver disease [30], our SMR and HR estimates for mortality due to chronic HCV infection, especially for liver related mortality, are likely conservative. Different anti-HCV screening tests were used during the study period (second generation from 1992 to 1997 and third generation from 1997 to 2004). However, both assays have good sensitivity and specificity [38] so this is unlikely to significantly affect diagnostic accuracy. The death register data are considered reliable as registration is a mandatory requirement, subject to federal/provincial standards and coded according to ICD-10 classification. However, since only 7.1% of all deaths in BC (2009 data) had an autopsy [39], the listed underlying cause of death may not be completely reliable. Deaths attributable to viral hepatitis primarily result from chronic liver disease and liver failure, and viral hepatitis may not consistently be listed as the underlying cause of death, leading to underestimation of deaths due to chronic viral hepatitis. In addition, deaths which occurred outside of BC were not captured in the analysis.

The strengths of this study include the large sample size, cohort design, and longitudinal population based serological data. The large sample size allowed us to more precisely measure the effect of mortality attributable to HCV infection than smaller studies. The longitudinal serological data with HCV seropositive and seronegative results enabled the identification of incident HCV cases and multiple non-reactive testers. This information helped to differentiate HCV related mortality due to progressive liver disease from the risk behaviours/activities that are associated with HCV acquisition.

We found excess mortality due to progressive liver disease and risk activities related to HCV acquisition among individuals who test anti-HCV positive. From a policy perspective, reduction of HCV related mortality requires comprehensive prevention and harm reduction programming and improved treatment uptake to reduce the consequences of chronic HCV infection, which include progressive liver disease and other extra-hepatic illnesses.