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Background & Aims: We evaluated the effect of direct-acting antiviral (DAA)-induced sustained virologic response (SVR) on all-cause, liver- and drug-related mortality in a population-based cohort in British Columbia, Canada., Methods: We used data from the British Columbia Hepatitis Testers Cohort, which includes people tested for HCV since 1990, linked with data on medical visits, hospitalizations, prescription drugs and mortality. We followed people who received DAAs and people who did not receive any HCV treatment to death or December 31, 2019. We used inverse probability of treatment weighting to balance the baseline profile of treated and untreated individuals and performed multivariable proportional hazard modelling to assess the effect of DAAs on mortality., Results: Our cohort comprised 10,851 people treated with DAAs (SVR 10,426 [96%], no-SVR: 425) and 10,851 matched untreated individuals. Median follow-up time was 2.2 years (IQR 1.3-3.6; maximum 6.2). The all-cause mortality rate was 19.5/1,000 person-years (PY) among the SVR group (deaths = 552), 86.5/1,000 PY among the no-SVR group (deaths = 96), and 99.2/1,000 PY among the untreated group (deaths = 2,133). In the multivariable model, SVR was associated with significant reduction in all-cause (adjusted hazard ratio [aHR] 0.19; 95% CI 0.17-0.21), liver- (adjusted subdistribution HR [asHR] 0.22, 95% CI 0.18-0.27) and drug-related mortality (asHR 0.26, 95% CI 0.21-0.32) compared to no-treatment. Older age and cirrhosis were associated with higher risk of liver-related mortality while younger age, injection drug use (IDU), problematic alcohol use and HIV/HBV co-infections were associated with a higher risk of drug-related mortality., Conclusions: DAA treatment is associated with a substantial reduction in all-cause, liver- and drug-related mortality. The association of IDU and related syndemic factors with a higher risk of drug-related mortality calls for an integrated social support, addiction, and HCV care approach among people who inject drugs., Lay Summary: We assessed the effect of treatment of hepatitis C virus infection with direct-acting antiviral drugs on deaths from all causes, liver disease and drug use. We found that treatment with direct-acting antiviral drugs is associated with substantial lowering in risk of death from all causes, liver disease and drug use among people with hepatitis C virus infection., Competing Interests: Conflict of interest MK has received grant funding via his institution from Roche Molecular Systems, Boehringer Ingelheim, Merck, Siemens Healthcare Diagnostics and Hologic Inc. SB has advised and spoken for Gilead Sciences (all personal payments given as unrestricted donations to BC Centre for Disease Control Foundation for Public Health). Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: High HCV treatment uptake among people at most risk of transmission is essential to achieve elimination. We aimed to characterise subpopulations of people with HCV based on drug dependence, to estimate direct-acting antiviral (DAA) uptake in an unrestricted treatment era, and to evaluate factors associated with treatment uptake among people with recent drug dependence., Methods: HCV notifications in New South Wales, Australia (1995-2017) were linked to opioid agonist therapy (OAT), hospitalisations, incarcerations, HIV notifications, deaths, and prescription databases. Drug dependence was defined as hospitalisation due to injectable drugs or receipt of OAT, with indicators in 2016-2018 considered recent. Records were weighted to account for spontaneous clearance. Logistic regression was used to analyse factors associated with treatment uptake among those with recent drug dependence., Results: 57,467 people were estimated to have chronic HCV throughout the DAA era. Treatment uptake was highest among those with recent (47%), compared to those with distant (38%), and no (33%) drug dependence. Among those with recent drug dependence, treatment was more likely among those with HIV (adjusted odds ratio [aOR] 1.71; 95% CI 1.24-2.36), recent incarceration (aOR 1.10; 95% CI 1.01-1.19), and history of alcohol use disorder (aOR 1.22; 95% CI 1.13-1.31). Treatment was less likely among women (aOR 0.78; 95% CI 0.72-0.84), patients of Indigenous ethnicity (aOR 0.75; 95% CI 0.69-0.81), foreign-born individuals (aOR 0.86; 95% CI 0.78-0.96), those with outer-metropolitan notifications (aOR 0.90; 95% CI 0.82-0.98), HBV coinfection (aOR 0.69; 95% CI 0.59-0.80), and >1 recent hospitalisation (aOR: 0.91; 95% CI 0.84-0.98)., Conclusions: These data provide evidence of high DAA uptake among people with recent drug dependence, including those who are incarcerated. Enhancing this encouraging initial uptake among high-risk populations will be essential to achieve HCV elimination., Lay Summary: To facilitate HCV elimination, those at highest risk of infection and transmission are a treatment priority. This study shows the successes of Australia's universal provision of DAA therapy in reducing the barriers to treatment which have historically persisted among people who inject drugs. Despite higher DAA therapy uptake among those with recent drug dependence, gaps remain. Strategies which aim to reduce marginalisation and increase treatment uptake to ensure equitable HCV elimination must be advanced., Competing Interests: Conflict of interest GD reports grants from Gilead, Abbvie, Merck, and Bristol-Myers Squibb, personal fees from Gilead, Abbvie, and Merck, and non-financial support from Gilead, Abbvie, and Merck, outside the submitted work. JGrebely reports grants from Merck, grants from Cepheid, during the conduct of the study; grants and personal fees from Abbvie, grants and personal fees from Gilead Sciences, grants and personal fees from Merck, grants and personal fees from Cepheid, grants from Hologic, grants from Indivior, outside the submitted work. ML reports grants from Gilead, ViiV Healthcare and Janssen outside the submitted work. MK reports receiving grants from Boehringer Ingelheim, Hologic, Merck, Roche Molecular Systems, and Siemens Healthcare Diagnostics outside of the submitted work. JGeorge reports funding from MSD, Abbvie, BMS, Pharmaxis, Norvartis, Cincera, and Bayer outside the submitted work. BH reports grants from NSW Health and Cancer Council NSW. LD has received investigator-initiated untied educational grants for studies of opioid medications in Australia from Indivior, Mundipharma and Seqirus. All remaining authors have no potential conflicts to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: HCV infection is associated with several extrahepatic manifestations (EHMs). We evaluated the impact of sustained virological response (SVR) on the risk of 7 EHMs that contribute to the burden of extrahepatic disease: type 2 diabetes mellitus, chronic kidney disease or end-stage renal disease, stroke, ischemic heart disease, major adverse cardiac events, mood and anxiety disorders, and rheumatoid arthritis., Methods: A longitudinal cohort study was conducted using data from the British Columbia Hepatitis Testers Cohort, which included ~1.3 million individuals screened for HCV. We identified all HCV-infected individuals who were treated with interferon-based therapies between 1999 and 2014. SVR was defined as a negative HCV RNA test ≥24 weeks post-treatment or after end-of-treatment, if unavailable. We computed adjusted subdistribution hazard ratios (asHR) for the effect of SVR on each EHM using competing risk proportional hazard models. Subgroup analyses by birth cohort, sex, injection drug exposure and genotype were also performed., Results: Overall, 10,264 HCV-infected individuals were treated with interferon, of whom 6,023 (59%) achieved SVR. Compared to those that failed treatment, EHM risk was significantly reduced among patients with SVR for type 2 diabetes mellitus (asHR 0.65; 95%CI 0.55-0.77), chronic kidney disease or end-stage renal disease (asHR 0.53; 95% CI 0.43-0.65), ischemic or hemorrhagic stroke (asHR 0.73; 95%CI 0.49-1.09), and mood and anxiety disorders (asHR 0.82; 95%CI 0.71-0.95), but not for ischemic heart disease (asHR 1.23; 95%CI 1.03-1.47), major adverse cardiac events (asHR 0.93; 95%CI 0.79-1.11) or rheumatoid arthritis (asHR 1.09; 95% CI 0.73-1.64)., Conclusions: SVR was associated with a reduction in the risk of several EHMs. Increased uptake of antiviral therapy may reduce the growing burden of EHMs in this population., Lay Summary: We estimated the rates of chronic comorbidities other than liver disease between those who were cured and those who failed treatment for hepatitis C virus (HCV) infection. Our findings showed that the rates of these non-liver diseases were largely reduced for those who were cured with interferon-based treatments. Early HCV treatments could provide many benefits in the prevention of various HCV complications beyond liver disease., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Affordable point-of-care tests for hepatitis C (HCV) viraemia are needed to improve access to treatment in low- and middle-income countries. Our aims were to determine the target limit of detection (LOD) necessary to diagnose the majority of people with HCV eligible for treatment, and identify characteristics associated with low-level viraemia (LLV) (defined as the lowest 3% of the distribution of HCV RNA) to understand those at risk of being misdiagnosed., Methods: We established a multi-country cross-sectional dataset of first available quantitative HCV RNA measurements linked to demographic and clinical data. We excluded individuals on HCV treatment. We analysed the distribution of HCV RNA and determined critical thresholds for detection of HCV viraemia. We then performed logistic regression to evaluate factors associated with LLV, and derived relative sensitivities for significant covariates., Results: The dataset included 66,640 individuals with HCV viraemia from across the world. The LOD for the 95th and 99th percentiles were 3,311 IU/ml and 214 IU/ml. The LOD for the 97th percentile was 1,318 IU/ml (95% CI 1,298.4-1,322.3). Factors associated with LLV, defined as HCV RNA <1,318 IU/ml, were younger age 18-30 vs. 51-64 years (odds ratios [OR] 2.56; 95% CI 2.19-2.99), female vs. male sex (OR 1.32; 95% CI 1.18-1.49), and advanced fibrosis stage F4 vs. F0-1 (OR 1.44; 95% CI 1.21-1.69). Only the younger age group had a decreased relative sensitivity below 95%, at 93.3%., Conclusions: In this global dataset, a test with an LOD of 1,318 IU/ml would identify 97% of viraemic HCV infections among almost all populations. This LOD will help guide manufacturers in the development of affordable point-of-care diagnostics to expand HCV testing and linkage to care in low- and middle-income countries., Lay Summary: We created and analysed a dataset from 12 countries with 66,640 participants with chronic hepatitis C virus infection. We determined that about 97% of those with viraemic infection had 1,300 IU/ml or more of circulating virus at the time of diagnosis. While current diagnostic tests can detect as little as 12 IU/ml of virus, our findings suggest that increasing the level of detection closer to 1,300 IU/ml would maintain good test accuracy and will likely enable development of more affordable portable tests for use in low- and middle-income countries., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Direct-acting antiviral therapies (DAA) are an important tool for hepatitis C virus (HCV) elimination. However, reinfection among people who inject drugs (PWID) may hamper elimination targets. Therefore, we estimated HCV reinfection rates among DAA-treated individuals, including PWID., Methods: We analyzed data from the British Columbia Hepatitis Testers Cohort which included ∼1.7 million individuals screened for HCV in British Columbia, Canada. We followed HCV-infected individuals treated with DAAs who achieved a sustained virologic response (SVR) and had ≥1 subsequent HCV RNA measurement to April 22nd, 2018. Reinfection was defined as a positive RNA measurement after SVR. PWID were identified using a validated algorithm and classified based on recent (<3 years) or former (≥3 years before SVR) use. Crude reinfection rates per 100 person-years (PYs) were calculated. Poisson regression was used to model adjusted incidence rate ratios (IRRs) and 95% CIs., Results: Of 4,114 individuals who met the inclusion criteria, most were male (n = 2,692, 65%), born before 1965 (n = 3,411, 83%) and were either recent (n = 875, 21%) or former PWID (n = 1,793, 44%). Opioid-agonist therapy (OAT) was received by 19% of PWID. We identified 40 reinfections during 2,767 PYs. Reinfection rates were higher among recent (3.1/100 PYs; IRR 6.7; 95% CI 1.9-23.5) and former PWID (1.4/100 PYs; IRR 3.7; 95% CI 1.1-12.9) than non-PWID (0.3/100 PYs). Among recent PWID, reinfection rates were higher among individuals born after 1975 (10.2/100 PYs) and those co-infected with HIV (5.7/100 PYs). Only one PWID receiving daily OAT developed reinfection., Conclusions: Population-level reinfection rates remain elevated after DAA therapy among PWID because of ongoing exposure risk. Engagement of PWID in harm-reduction and support services is needed to prevent reinfections., Lay Summary: Direct-acting antivirals are an effective tool for the treatment of hepatitis C virus, enabling the elimination of the virus. However, some patients who have been successfully treated with direct-acting antivirals are at risk of reinfection. Our findings showed that the risk of reinfection was highest among people with recent injection drug use. Among people who inject drugs, daily use of opioid-agonist therapy was associated with a lower risk of reinfection., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: The advent of direct-acting antivirals (DAAs) has led to ambitious targets for hepatitis C virus (HCV) elimination. However, in the context of alcohol use disorder the ability of DAAs to achieve these targets may be compromised. The aim of this study was to evaluate the contribution of alcohol use disorder to HCV-related decompensated cirrhosis in three settings., Methods: HCV notifications from British Columbia, Canada; New South Wales, Australia, and Scotland (1995-2011/2012/2013, respectively) were linked to hospital admissions (2001-2012/2013/2014, respectively). Alcohol use disorder was defined as non-liver-related hospitalisation due to alcohol use. Age-standardised decompensated cirrhosis incidence rates were plotted, associated factors were assessed using Cox regression, and alcohol use disorder-associated population attributable fractions (PAFs) were computed., Results: Among 58,487, 84,529, and 31,924 people with HCV in British Columbia, New South Wales, and Scotland, 2,689 (4.6%), 3,169 (3.7%), and 1,375 (4.3%) had a decompensated cirrhosis diagnosis, and 28%, 32%, and 50% of those with decompensated cirrhosis had an alcohol use disorder, respectively. Age-standardised decompensated cirrhosis incidence rates were considerably higher in people with alcohol use disorder in New South Wales and Scotland. Decompensated cirrhosis was independently associated with alcohol use disorder in British Columbia (aHR 1.92; 95% CI 1.76-2.10), New South Wales (aHR 3.68; 95% CI 3.38-4.00) and Scotland (aHR 3.88; 95% CI 3.42-4.40). The PAFs of decompensated cirrhosis-related to alcohol use disorder were 13%, 25%, and 40% in British Columbia, New South Wales and Scotland, respectively., Conclusions: Alcohol use disorder was a major contributor to HCV liver disease burden in all settings, more distinctly in Scotland. The extent to which alcohol use would compromise the individual and population-level benefits of DAA therapy needs to be closely monitored. Countries, where appropriate, must develop strategies combining promotion of DAA treatment uptake with management of alcohol use disorders, if World Health Organization 2030 HCV mortality reduction targets are going to be achieved., Lay Summary: The burden of liver disease has been rising among people with hepatitis C globally. The recent introduction of highly effective medicines against hepatitis C (called direct-acting antivirals or DAAs) has brought renewed optimism to the sector. DAA scale-up could eliminate hepatitis C as a public health threat in the coming decades. However, our findings show heavy alcohol use is a major risk factor for liver disease among people with hepatitis C. If continued, heavy alcohol use could compromise the benefits of new antiviral treatments at the individual- and population-level. To tackle hepatitis C as a public health threat, where needed, DAA therapy should be combined with management of heavy alcohol use., (Copyright © 2017 European Association for the Study of the Liver. All rights reserved.)

Background & Aims: We measured the timing of hepatitis B virus (HBV) and hepatitis C virus (HCV) diagnoses relative to the detection of decompensated cirrhosis (DC) and hepatocellular carcinoma (HCC) as an indicator of late hepatitis diagnosis., Methods: HBV and HCV diagnoses were defined relative to the diagnosis of DC or HCC such that HBV/HCV diagnoses within two years prior, at the time of or after HCC or DC diagnosis were considered late. We performed multivariable logistic regression to assess factors associated with late HBV/HCV diagnoses among those with DC or HCC., Results: From 1990 to 2012, 778/32,664 HBV cases (2.4%) and 3,925/57,866 HCV cases (6.8%) developed DC while 628/32,644 HBV cases (1.9%) and 902/57,866 HCV cases (1.6%) developed HCC. Among HBV and HCV cases with DC, 49% and 40% respectively were late diagnoses, as were 46% and 31% of HBV and HCV cases with HCC, respectively. HBV late diagnosis declined from 100% in 1992 to 11% and 26% in 2011, while HCV late diagnosis declined from 100% in 1992 to 16% and 14% in 2011 for DC and HCC respectively. In multivariable modelling, late HBV diagnosis was associated with mental illness and a fewer number of physician visits in the five years prior to HBV diagnosis. Late HCV diagnosis was also associated with fewer physician visits, while those with illicit drug use were less likely to be diagnosed late., Conclusions: The proportion of late diagnoses has declined over time. People with better engagement with the healthcare system and with risk activities were diagnosed earlier. Lay summary: Late diagnosis of HBV and HCV represents a missed opportunity to reduce the risk of serious liver disease. Our results identify successes in earlier diagnosis over time using risk-based testing as well as groups that are being missed for screening such as those who do not see a physician regularly and those with serious mental illness., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Evidence is limited on hepatocellular carcinoma (HCC) risk after sustained virological response (SVR) to interferon-based treatment of hepatitis C virus (HCV) infection. We evaluated the effect of SVR on the risk of HCC and estimated its incidence in post-SVR HCV patients from a large population-based Canadian cohort., Methods: The British Columbia Hepatitis Testers Cohort includes individuals tested for HCV between 1990-2013 linked with data on their medical visits, hospitalizations, cancers, prescription drugs and mortality. Patients receiving interferon-based HCV treatments were followed from the end of treatment to HCC diagnosis, death or December 31, 2012. We examined HCC risk among those who did and did not achieve SVR using multivariable proportional hazard models with the Fine and Gray modification for competing risks., Results: Of 8147 individuals who received HCV treatment and were eligible for analysis, 4663 (57%) achieved SVR and 3484 (43%) did not. Each group was followed for a median of 5.6years (range: 0.5-12.9) for an HCC incidence rate of 1.1/1000 person-years (PY) among the SVR and 7.2/1000 PY among the no SVR group. The HCC incidence rate was higher among those with cirrhosis (SVR: 6.4, no SVR: 21.0/1000 PY). In the multivariable model, SVR was associated with a lower HCC risk (subdistribution hazard ratio [SHR]=0.20, 95% CI: 0.13-0.3), while cirrhosis (SHR=2.61, 95% CI: 1.68-4.04), age ⩾50years, being male and genotype 3 infection were associated with a higher HCC risk. Among those who achieved SVR, cirrhosis, age ⩾50years and being male were associated with a higher HCC risk., Conclusion: SVR after interferon-based treatment substantially reduces but does not eliminate HCC risk, which is markedly higher among those with cirrhosis and age ⩾50years at treatment initiation. Treatment of patients at an advanced fibrosis stage with new highly effective drugs will warrant continued surveillance for HCC post-SVR., Lay Summary: We assessed the effect of successful hepatitis C treatment with older interferon-based treatment on the occurrence of liver cancer (hepatocellular carcinoma) and found that successful treatment prevents liver cancer. However, more people with cirrhosis and older age continued to develop liver cancer after successful treatment. Thus, treatment with new drugs among those with cirrhosis will require continued monitoring for liver cancer., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Understanding HCV transmission among people who inject drugs (PWID) is important for designing prevention strategies. This study investigated whether HCV infection among younger injectors occurs from few or many transmission events from older injectors to younger injectors among PWID in Vancouver, Canada., Methods: HCV antibody positive participants at enrolment or follow-up (1996-2012) were tested for HCV RNA and sequenced (Core-E2). Time-stamped phylogenetic trees were inferred using Bayesian Evolutionary Analysis Sampling Trees (BEAST). Association of age with phylogeny was tested using statistics implemented in the software Bayesian Tip Significance (BaTS) testing. Factors associated with clustering (maximum cluster age: five years) were identified using logistic regression., Results: Among 699 participants with HCV subtype 1a, 1b, 2b and 3a infection (26% female, 24% HIV+): 21% were younger (<27years), and 10% had recent HCV seroconversion. When inferred cluster age was limited to <5years, 15% (n=108) were in clusters/pairs. Although a moderate degree of segregation was observed between younger and older participants, there was also transmission between age groups. Younger age (<27 vs. >40, AOR: 3.14; 95% CI: 1.54, 6.39), HIV (AOR: 1.97; 95% CI: 1.22, 3.18) and subtype 3a (AOR: 2.12; 95% CI: 1.33, 3.38) were independently associated with clustering., Conclusions: In this population of PWID from Vancouver, HCV among young injectors was seeded from many transmission events between HCV-infected older and younger injectors. Phylogenetic clustering was associated with younger age and HIV. These data suggest that HCV transmission among PWID is complex, with transmission occurring between and among older and younger PWID., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: People living with hepatitis C virus (HCV) are at increased risk of all-cause and liver-related mortality, although successful treatment has been shown to reduce this risk. The aim of this study was to provide baseline data on trends in cause-specific mortality and to establish an international surveillance system for evaluating the population level impact of HCV treatments., Methods: Population level HCV diagnosis databases from Scotland (1997-2010), Australia (New South Wales [NSW]) (1997-2006), and Canada (British Columbia [BC]) (1997-2003) were linked to corresponding death registries using record linkage. For each region, age-adjusted cause-specific mortality rates were calculated, and trends in annual age-adjusted liver-related mortality were plotted., Results: Of 105,138 individuals diagnosed with HCV (21,810 in Scotland, 58,484 in NSW, and 24,844 in BC), there were 7275 deaths (2572 in Scotland, 2655 in NSW, and 2048 in BC). Liver-related deaths accounted for 26% of deaths in Scotland, 21% in NSW, and 22% in BC. Temporal trends in age-adjusted liver related mortality were stable in Scotland (males p=0.4; females p=0.2) and NSW (males p=0.9; females p=0.9), while there was an increase in BC (males p=0.002; females p=0.04)., Conclusions: The risk of liver-related mortality after a diagnosis of HCV has remained stable or increased over time across three regions with well-established diagnosis databases, highlighting that HCV treatment programmes to-date have had minimal impact on population level HCV-related liver disease. With more effective therapies on the horizon, and greater uptake of treatment anticipated, the potential of future therapeutic strategies to reduce HCV-related mortality is considerable., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)