Testing and Treatment Interventions in Community Settings Key to Controlling a Recent Human Immunodeficiency Virus Outbreak Among People Who Inject Drugs in Glasgow: A Modeling Study.

BACKGROUND: A human immunodeficiency virus (HIV) outbreak was identified among people who inject drugs (PWID) in Glasgow in 2015, with >150 diagnoses by the end of 2019. The outbreak response involved scaling up HIV testing and improving HIV treatment initiation and retention. METHODS: We parameterized and calibrated a dynamic, deterministic model of HIV transmission among PWID in Glasgow to epidemiological data. We use this model to evaluate HIV testing and treatment interventions. We present results in terms of relative changes in HIV prevalence, incidence, and cases averted. RESULTS: If the improvements in both testing and treatment had not occurred, we predict that HIV prevalence would have reached 17.8% (95% credible interval [CrI], 14.1%-22.6%) by the beginning of 2020, compared to 5.9% (95% CrI, 4.7%-7.4%) with the improvements. If the improvements had been made on detection of the outbreak in 2015, we predict that peak incidence would have been 26.2% (95% CrI, 8.8%-49.3%) lower and 62.7% (95% CrI, 43.6%-76.6%) of the outbreak cases could have been averted. The outbreak could have been avoided if the improvements had already been in place. CONCLUSIONS: Our modeling suggests that the HIV testing and treatment interventions successfully brought the HIV outbreak in Glasgow under control by the beginning of 2020.

Impact of the COVID-19 Pandemic on HIV Test Uptake Among People Who Inject Drugs in the Context of an HIV Outbreak.

Glasgow, Scotland's largest city, has been experiencing an HIV outbreak among people who inject drugs (PWID) since 2015. A key focus of the public health response has been to increase HIV testing among those at risk of infection. Our aim was to assess the impact of COVID-19 on HIV testing among PWID in Glasgow. HIV test uptake in the last 12 months was quantified among: (1) PWID recruited in six Needle Exchange Surveillance Initiative (NESI) surveys (n = 6110); linked laboratory data for (2) people prescribed opioid agonist therapy (OAT) (n = 14,527) and (3) people hospitalised for an injecting-related hospital admission (IRHA) (n = 12,621) across four time periods: pre-outbreak (2010-2014); early-outbreak (2015-2016); ongoing-outbreak (2017-2019); and COVID-19 (2020-June 21). From the pre to ongoing period, HIV testing increased: the highest among people recruited in NESI (from 28% to 56%) and on OAT (from 17% to 54%) while the lowest was among people with an IRHA (from 15% to 42%). From the ongoing to the COVID-19 period, HIV testing decreased markedly among people prescribed OAT, from 54% to 37% (aOR 0.50, 95% CI 0.48-0.53), but increased marginally among people with an IRHA from 42% to 47% (aOR 1.19, 95% CI 1.08-1.31). In conclusion, progress in increasing testing in response to the HIV outbreak has been eroded by COVID-19. Adoption of a linked data approach could be warranted in other settings to inform efforts to eliminate HIV transmission.

Laying the foundations for hepatitis C elimination: evaluating the development and contribution of community care pathways to diagnostic efforts.

BACKGROUND: Hepatitis C Virus (HCV) is a public health threat which contributes substantially to the global burden of liver disease. There is much debate about effective approaches to scaling up diagnosis of HCV among risk groups. Tayside, a region in the East of Scotland, developed low-threshold community pathways for HCV to lay the foundations of an elimination strategy. In this retrospective study, we sought to: quantify the contribution of community pathways to increasing HCV diagnosis; understand if shifting diagnosis to community settings led to a higher proportion of individuals tested for HCV being actively infected; and describe functional characteristics of the care pathways. METHODS: Descriptive statistics were used to for analysis of routinely-collected HCV testing data from 1999 to 2017, and a review of the development of the care pathways was undertaken. Community-based testing was offered through general practices (GP); nurse outreach clinics; prisons; drug treatment services; needle and syringe provision (NSP) sites; community pharmacies; and mosques. RESULTS: Anti-HCV screening was undertaken on 109,430 samples, of which 5176 (4.7%) were reactive. Of all samples, 77,885 (71.2%) were taken in secondary care; 25,044 (22.9%) in GPs; 2970 (2.7%) in prisons; 2415 (2.2%) in drug services; 753 (0.7%) in NSPs; 193 (0.2%) pharmacies; and 170 (0.1%) in mosques. The highest prevalence of HCV infection among those tested was in NSP sites (26%), prisons (14%), and drug treatment centres (12%). CONCLUSIONS: Decentralised care pathways, particularly in harm reduction and other drug service settings, were key to increasing diagnosis of HCV in the region, but primary and secondary care remain central to elimination efforts.

Population-level estimates of hepatitis C reinfection post scale-up of direct-acting antivirals among people who inject drugs.

BACKGROUND & AIMS: Scale-up of highly effective direct-acting antivirals (DAAs) for HCV among people who inject drugs (PWID) in Scotland has led to a reduction in the prevalence of viraemia in this population. However, the extent of reinfection among those treated with DAAs remains uncertain. We estimated HCV reinfection rates among PWID in Scotland by treatment setting, pre- and post-introduction of DAAs, and the potential number of undiagnosed reinfections resulting from incomplete follow-up testing. METHODS: Through linkage of national clinical and laboratory HCV data, a retrospective cohort of PWID who commenced treatment between 2000-2018 and achieved a sustained virological response (SVR) were followed up for reinfection to December 2019. Reinfection was defined as a positive HCV antigen or RNA test. RESULTS: Of 5,686 SVRs among 5,592 PWID, 4,126 (73%) had an HCV RNA or antigen test post-SVR. Of those retested, we identified 361 reinfections (3.9/100 person-years [PY]). The reinfection rate increased from 1.5/100 PY among PWID treated in 2000-2009 to 8.8/100 PY in 2017-2018. The highest reinfection rates were observed among those treated in prison (14.3/100 PY) and community settings (9.5/100 PY). Among those treated in the DAA era (2015-2018), 68% were tested within the first year post-SVR but only 30% in the second year; while 169 reinfections were diagnosed in follow-up, an estimated 200 reinfections (54% of the estimated total) had gone undetected. CONCLUSIONS: HCV reinfection rates among PWID in Scotland have risen alongside the scale-up of DAAs and broadened access to treatment for those at highest risk, through delivery in community drug services. Promotion of HCV testing post-SVR among PWID is essential to ensure those reinfected are identified and retreated promptly. LAY SUMMARY: Increased rates of hepatitis C reinfection in Scotland were observed following the rapid scale-up of highly effective direct-acting antiviral (DAA) treatments among people who inject drugs. This demonstrates that community-based treatment pathways are reaching high-risk groups, regarded vital in efforts to eliminate the virus. However, we estimate that less than half of reinfections have been detected in the DAA era because of inadequate levels of retesting beyond the first year following successful treatment. Sustained efforts that involve high coverage of harm reduction measures and high uptake of annual testing are required to ensure prompt diagnosis and treatment of those reinfected if the goals of elimination are to be met.

Comparing Predicted Probability of Hepatocellular Carcinoma in Patients With Cirrhosis With the General Population: An Opportunity to Improve Risk Communication?

INTRODUCTION: Risk scores estimating a patient's probability of a hepatocellular carcinoma (HCC) diagnosis are abundant but are difficult to interpret in isolation. We compared the predicted HCC probability for individuals with cirrhosis and cured hepatitis C with the general population (GP). METHODS: All patients with cirrhosis achieving sustained viral response (SVR) in Scotland by April 2018 were included (N = 1,803). The predicted 3-year probability of HCC at time of SVR achievement was determined using the aMAP prognostic model. GP data on the total number of incident HCCs in Scotland, stratified by demographics, were obtained from Public Health Scotland. Predicted HCC risk of cirrhosis SVR patients was compared with GP incidence using 2 metrics: (i) incidence ratio: i.e., 3-year predicted probability for a given patient divided by the 3-year probability in GP for the equivalent demographic group and (ii) absolute risk difference: the 3-year predicted probability minus the 3-year probability in the GP. RESULTS: The mean predicted 3-year HCC probability among cirrhosis SVR patients was 3.64% (range: 0.012%-36.12%). Conversely, the 3-year HCC probability in the GP was much lower, ranging from <0.0001% to 0.25% depending on demographics. The mean incidence ratio was 410, ranging from 5 to >10,000. The mean absolute risk difference was 3.61%, ranging from 0.012% to 35.9%. An online HCC-GP comparison calculator for use by patients/clinicians is available at https://thrive-svr.shinyapps.io/RShiny/ . DISCUSSION: Comparing a patient's predicted HCC probability with the GP is feasible and may help clinicians communicate risk information and encourage screening uptake.

Declining incidence of hepatitis C related hepatocellular carcinoma in the era of interferon-free therapies: A population-based cohort study.

BACKGROUND & AIMS: The impact of interferon (IFN)-free therapies on the epidemiology of hepatitis C virus (HCV) related hepatocellular carcinoma (HCC) is not well understood at a population level. Our goal was to bridge this evidence gap. METHODS: This study included all patients in Scotland with chronic HCV and a diagnosis of cirrhosis during 1999-2019. Incident cases of HCC, episodes of curative HCC therapy, and HCC-related deaths were identified through linkage to nationwide registries. Three time periods were examined: 1999-2010 (pegylated interferon-ribavirin [PIR]); 2011-2013 (First-generation DAA); and 2014-2019 (IFN-free era). We used regression modelling to determine time trends for (i) number diagnosed and living with HCV cirrhosis, (ii) HCC cumulative incidence, (iii) HCC curative treatment uptake and (iv) post-HCC mortality. RESULTS: 3347 cirrhosis patients were identified of which 381 (11.4%) developed HCC. After HCC diagnosis, 140 (36.7%) received curative HCC treatment and there were 202 deaths from HCC. The average annual number of patients diagnosed and living with HCV cirrhosis was approximately seven times higher in the IFN-free versus the PIR era, whereas the number of incident HCCs was four times higher. However, the cumulative incidence of HCC was significantly lower in the IFN-free versus PIR era (sdHR: 0.65; 95%CI:0.47-0.88; P = .006). Among HCC patients, diagnosis in the IFN-free era was not associated with improved uptake of curative treatment (aOR:1.18; 95%CI:0.69-2.01; P = .54), or reduced post-HCC mortality (sdHR: 0.74; 95%CI:0.53-1.05; P = .09). CONCLUSIONS: The cumulative incidence of HCC is declining in HCV cirrhosis patients, but uptake of curative HCC therapy and post-HCC survival remains suboptimal.

A global investment framework for the elimination of hepatitis B.

BACKGROUND & AIMS: More than 292 million people are living with hepatitis B worldwide and are at risk of death from cirrhosis and liver cancer. The World Health Organization (WHO) has set global targets for the elimination of viral hepatitis as a public health threat by 2030. However, current levels of global investment in viral hepatitis elimination programmes are insufficient to achieve these goals. METHODS: To catalyse political commitment and to encourage domestic and international financing, we used published modelling data and key stakeholder interviews to develop an investment framework to demonstrate the return on investment for viral hepatitis elimination. RESULTS: The framework utilises a public health approach to identify evidence-based national activities that reduce viral hepatitis-related morbidity and mortality, as well as international activities and critical enablers that allow countries to achieve maximum impact on health outcomes from their investments - in the context of the WHO's 2030 viral elimination targets. CONCLUSION: Focusing on hepatitis B, this health policy paper employs the investment framework to estimate the substantial economic benefits of investing in the elimination of hepatitis B and demonstrates how such investments could be cost saving by 2030. LAY SUMMARY: Hepatitis B infection is a major cause of death from liver disease and liver cancer globally. To reduce deaths from hepatitis B infection, we need more people to be tested and treated for hepatitis B. In this paper, we outline a framework of activities to reduce hepatitis B-related deaths and discuss ways in which governments could pay for them.

The impact of direct-acting antivirals on hepatitis C viraemia among people who inject drugs in England; real-world data 2011-2018.

Direct-acting antiviral (DAA) therapy for anybody with viraemic HCV infection has been scaled-up in England since 2017. To assess early impacts, we investigated trends in, and factors associated with, HCV viraemia among people who inject drugs (PWID). We also examined trends in self-reported treatment access. Bio-behavioural data from an annual, national surveillance survey of PWID (2011-2018) estimated trends in viraemic prevalence among HCV antibody-positive PWID. Multivariable logistic regression identified characteristics independently associated with viraemia. Trends in treatment access were examined for PWID with known infection. Between 2011 and 2016, viraemic prevalence among antibody-positive PWID remained stable (2011, 57.7%; 2016, 55.8%) but decreased in 2017 (49.4%) and 2018 (50.4%) (both p < 0.001). After adjustment for demographic and behavioural characteristics, there remained significant reduction in viraemia in 2017 (adjusted odds ratio [aOR] 0.79, 95% CI 0.65-0.94) and 2018 (aOR 0.79, 95% CI 0.66-0.93) compared to 2016. Other factors associated with viraemia were male gender (aOR 1.68, 95% CI 1.53-1.86), geographical region, injecting in past year (aOR 1.26, 95% CI 1.13-1.41), imprisonment (aOR 1.14, 95% CI 1.04-1.31) and homelessness (aOR 1.17, 95% CI 1.04-1.31). Among non-viraemic PWID with known infection, the proportion reporting ever receiving treatment increased in 2017 (28.7%, p < 0.001) and 2018 (38.9%, p < 0.001) compared to 2016 (14.5%). In conclusion, there has been a small reduction in HCV viraemia among antibody-positive PWID in England since 2016, alongside DAA scale-up, and some indication that treatment access has improved in the same period. Population-level monitoring and focus on harm reduction is critical for achieving and evaluating elimination.

Uptake of interferon-free DAA therapy among HCV-infected decompensated cirrhosis patients and evidence for decreased mortality.

Interferon-free DAA therapies have recently been licensed for patients infected with hepatitis C virus (HCV) who have decompensated cirrhosis (DC). Our aim was to describe factors associated with uptake of IFN-free DAAs in DC patients and to compare mortality risk and hospital admission rates between pre-DAA and DAA eras. This observational study used record-linkage between Scotland's HCV Clinical Database and national inpatient hospitalization and mortality registers. For the DAA uptake analysis, the study population (n = 297) was restricted to patients alive on 1 November 2014, and Cox regression was used to estimate uptake associated with various covariates. For the Cox regression of mortality comparing pre-DAA and DAA eras, the study population (n = 624) comprised those diagnosed with DC in 2005-2018; follow-up was censored at two years. DAA uptake was 63% overall and was significantly higher for treatment-experienced patients (adjusted hazard ratio (aHR) = 1.64, 95% CI:1.14-2.34), genotype 1 vs. other genotypes (aHR = 1.55. 95% CI:1.15-2.10) and lower for persons diagnosed with DC pre-2014 (0.47, 95% CI:0.33-0.68) and in Greater Glasgow (0.64, 95% CI:0.47-0.88). The intention-to-treat SVR rate was 89% (95% CI:83-93%). All-cause and liver-related mortality risk were significantly reduced among patients diagnosed with DC in the DAA era (November 2014-December 2018) compared with the pre-DAA era (2005-October 2014) (aHRs of 0.68, 95% CI:0.49-0.93; 0.69, 95% CI:0.50-0.95, respectively); in contrast, hospital admission rates were higher in the DAA era (aRR = 1.14, 95% CI:1.04-1.26). The majority of HCV-infected DC patients engaged with specialist services can be treated with IFN-free DAAs. Improved survival among patients diagnosed with DC in the DAA era supports the beneficial impact of IFN-free therapies among those with advanced liver disease.

Population impact of direct-acting antiviral treatment on new presentations of hepatitis C-related decompensated cirrhosis: a national record-linkage study.

OBJECTIVE: Population-based studies demonstrating the clinical impact of interferon-free direct-acting antiviral (DAA) therapies are lacking. We examined the impact of the introduction of DAAs on HCV-related decompensated cirrhosis (DC) through analysis of population-based data from Scotland. DESIGN: Through analysis of national surveillance data (involving linkage of HCV diagnosis and clinical databases to hospital and deaths registers), we determined i) the scale-up in the number of patients treated and achieving a sustained viral response (SVR), and ii) the change in the trend of new presentations with HCV-related DC, with the introduction of DAAs. RESULTS: Approximately 11 000 patients had been treated in Scotland over the 8-year period 2010/11 to 2017/18. The scale-up in the number of patients achieving SVR between the pre-DAA and DAA eras was 2.3-fold overall and 5.9-fold among those with compensated cirrhosis (the group at immediate risk of developing DC). In the pre-DAA era, the annual number of HCV-related DC presentations increased 4.6-fold between 2000 (30) and 2014 (142). In the DAA era, presentations decreased by 51% to 69 in 2018 (and by 67% among those with chronic infection at presentation), representing a significant change in trend (rate ratio 0.88, 95% CI 0.85 to 0.90). With the introduction of DAAs, an estimated 330 DC cases had been averted during 2015-18. CONCLUSIONS: National scale-up in interferon-free DAA treatment is associated with the rapid downturn in presentations of HCV-related DC at the population-level. Major progress in averting HCV-related DC in the short-term is feasible, and thus other countries should strive to achieve the same.

aMAP risk score predicts hepatocellular carcinoma development in patients with chronic hepatitis.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is the leading cause of death in patients with chronic hepatitis. In this international collaboration, we sought to develop a global universal HCC risk score to predict the HCC development for patients with chronic hepatitis. METHODS: A total of 17,374 patients, comprising 10,578 treated Asian patients with chronic hepatitis B (CHB), 2,510 treated Caucasian patients with CHB, 3,566 treated patients with hepatitis C virus (including 2,489 patients with cirrhosis achieving a sustained virological response) and 720 patients with non-viral hepatitis (NVH) from 11 international prospective observational cohorts or randomised controlled trials, were divided into a training cohort (3,688 Asian patients with CHB) and 9 validation cohorts with different aetiologies and ethnicities (n = 13,686). RESULTS: We developed an HCC risk score, called the aMAP score (ranging from 0 to 100), that involves only age, male, albumin-bilirubin and platelets. This metric performed excellently in assessing HCC risk not only in patients with hepatitis of different aetiologies, but also in those with different ethnicities (C-index: 0.82-0.87). Cut-off values of 50 and 60 were best for discriminating HCC risk. The 3- or 5-year cumulative incidences of HCC were 0-0.8%, 1.5-4.8%, and 8.1-19.9% in the low- (n = 7,413, 43.6%), medium- (n = 6,529, 38.4%), and high-risk (n = 3,044, 17.9%) groups, respectively. The cut-off value of 50 was associated with a sensitivity of 85.7-100% and a negative predictive value of 99.3-100%. The cut-off value of 60 resulted in a specificity of 56.6-95.8% and a positive predictive value of 6.6-15.7%. CONCLUSIONS: This objective, simple, reliable risk score based on 5 common parameters accurately predicted HCC development, regardless of aetiology and ethnicity, which could help to establish a risk score-guided HCC surveillance strategy worldwide. LAY SUMMARY: In this international collaboration, we developed and externally validated a simple, objective and accurate prognostic tool (called the aMAP score), that involves only age, male, albumin-bilirubin and platelets. The aMAP score (ranged from 0 to 100) satisfactorily predicted the risk of hepatocellular carcinoma (HCC) development among over 17,000 patients with viral and non-viral hepatitis from 11 global prospective studies. Our findings show that the aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk among all the cohorts irrespective of aetiology and ethnicity.

Real-world utility of HCV core antigen as an alternative to HCV RNA testing: Implications for viral load and genotype.

Following positive serology, the gold standard confirmatory test of hepatitis C virus (HCV) infection is detection of HCV RNA by PCR. We assessed the utility of HCV core antigen testing to identify active infection among those positive for anti-HCV antibodies, when introduced to routine testing. We identified serum samples that were tested at a single laboratory in Scotland from June 2011to December 2017. Serum samples testing positive for HCV antibodies (HCV Ab positive) followed by reflex HCV core antigen (Ag) testing during the study period were identified. Those patients for whom a PCR test was requested on the baseline sample were also identified. For this group, the sensitivity and specificity of HCV Ag as a diagnostic tool were assessed using HCV PCR as gold standard. In our cohort of 744 patients, we demonstrated a sensitivity of 82.1% (95% CI 77.1%-86.2%) and a specificity of 99.8% (95% CI 98.6%-100%). Genotype 3 was associated with increased odds of a false-negative result (OR = 3.59, 95% CI: 1.32-9.71), and reduced odds of a false negative were associated with older age (odds ratio (OR)=0.92, 95% CI: 0.88-0.97 per year) and viral load (OR = 0.10, 95% CI: 0.05-0.21 per log10 IU/ml). While the implementation of HCV core antigen testing for diagnosis could lead to significant cost savings in national screening programmes, our data suggest that a significant proportion of HCV-infected individuals may be missed. These findings have implications for HCV diagnosis and determination of viral clearance after treatment, particularly in low- and middle-income regions, where genotype 3 is prevalent.

Real-world impact following initiation of interferon-free hepatitis C regimens on liver-related outcomes and all-cause mortality among patients with compensated cirrhosis.

Few studies have investigated clinical outcomes among patients with cirrhosis who were treated with interferon (IFN)-free direct-acting antiviral (DAA). We aimed to quantify treatment impact on first decompensated cirrhosis hospital admission, first hepatocellular carcinoma (HCC) admission, liver-related mortality and all-cause mortality among a national cohort of cirrhotic patients. Through record linkage between Scotland's HCV Clinical Database and inpatient/day-case hospitalization and deaths records, a study population comprising chronic HCV-infected patients with compensated cirrhosis and initiated on IFN-free DAA between 1 March 2013 and 31 March 2018 was analysed. Cox regression evaluated the association of each clinical outcome with time-dependent treatment status (on treatment, responder, nonresponder or noncompliant), adjusting for patient factors including Child-Pugh class. Among the study population (n = 1073) involving 1809 years of follow-up, 75 (7.0%) died (39 from liver-related causes), 47 progressed to decompensated cirrhosis, and 28 developed HCC. Compared with nonresponders, treatment response (96% among those attending their 12 weeks post-treatment SVR test) was associated with a reduced relative risk of decompensated cirrhosis (hazard ratio [HR] = 0.14; 95% CI: 0.05-0.39), HCC (HR = 0.17; 95% CI: 0.04-0.79), liver-related death (HR = 0.13; 95% CI: 0.05-0.34) and all-cause mortality (HR = 0.30; 95% CI: 0.12-0.76). Compared with responders, noncompliant patients had an increased risk of liver-related (HR = 6.73; 95% CI: 2.99-15.1) and all-cause (HR = 5.45; 95% CI: 3.07-9.68) mortality. For HCV patients with cirrhosis, a treatment response was associated with a lower risk of severe liver complications and improved survival. Our findings suggest additional effort is warranted to address the higher mortality among the minority of cirrhotic patients who do not comply with DAA treatment or associated RNA testing.

Hepatitis C test uptake among historic blood transfusion recipients following media coverage of the Penrose Inquiry and an awareness-raising campaign.

The final report of the Penrose Inquiry into historic transmission of HIV and hepatitis C (HCV) through blood transfusion/products in Scotland was published in March 2015 and recommended "everyone who had received a blood transfusion prior to 1991 and who had not had a test for HCV should be offered one." A targeted awareness-raising campaign to encourage such individuals to be tested was launched in October 2016. We examined HCV testing undertaken in 2015-2016 in three NHS boards in Scotland to evaluate impact of these events. Statistical process control was used to monitor trends in individuals tested and those mentioning transfusion. HCV positivity was calculated and multivariate logistic regression was used to examine factors associated with mention of transfusion. A total of 22 842 individuals received an HCV test in 2015-2016 and 3% of those with clinical information mentioned transfusion. The total number of HCV tests was significantly higher in the week following the Penrose Report and the number mentioning transfusion was significantly higher for three weeks. There was no significant increase following the awareness-raising campaign. Women and those aged over 50 years were the most likely to have mentioned transfusion. Overall HCV positivity was 3.7% and <1% for the transfusion group. The impact of both intense media coverage and the government-funded awareness-raising campaigns in terms of HCV test uptake was modest and short-lived. Our findings highlight the challenges of case-finding for HCV and the limited impact of awareness-raising. This can be used by other countries aiming to identify those infected through historic blood transfusion.

The contribution of health risk behaviors to excess mortality in American adults with chronic hepatitis C: A population cohort-study.

In resource-rich countries, chronic hepatitis C (CHC) infection is associated with a sizeable excess mortality risk. The extent to which this is due to (1) the biological sequelae of CHC infection versus (2) a high concomitant burden of health risk behaviors (HRBs) is unclear. We used data from the 1999-2010 U.S. National Health and Nutritional Examination Surveys (NHANES), which include detailed information on HRBs and CHC infection status. We calculated the prevalence of the five major HRBs-alcohol use; cigarette smoking, physical inactivity, unhealthy diet, and illicit drug use-according to CHC after adjusting for sociodemographic differences. Mortality status after survey interview was ascertained by linkage to the U.S. National Death Index. To assess the contribution of HRBs to the excess mortality risk, we determined the all-cause mortality rate ratio (MRR) for individuals with CHC relative to individuals without, and then calculated the attenuation in this MRR following adjustment for HRBs. This analysis included 27,468 adult participants of NHANES of which 363 tested positive for CHC. All HRBs were markedly more prevalent among individuals with CHC versus individuals without. CHC was associated with a 2.4-fold higher mortality rate after adjustment for sociodemographic factors (MRR, 2.36; 95% CI, 1.60-3.49). Subsequent adjustment for all five HRBs attenuated this ratio by 50.7% to MRR 1.67 (95% CI, 1.14-2.44). Higher levels of attenuation (69.1%) were observed among individuals aged 45-70 years, who form the target demographic for U.S. birth cohort screening. CONCLUSION: At least half the excess mortality risk for individuals with CHC in the United States may be attributed to HRBs rather than CHC. The remedial response to hepatitis C must not neglect action on HRBs if it is to fully resolve the high mortality problem in this population. (Hepatology 2018;67:97-107).

Innovative strategies for the elimination of viral hepatitis at a national level: A country case series.

Viral hepatitis is a leading cause of morbidity and mortality worldwide, but has long been neglected by national and international policymakers. Recent modelling studies suggest that investing in the global elimination of viral hepatitis is feasible and cost-effective. In 2016, all 194 member states of the World Health Organization endorsed the goal to eliminate viral hepatitis as a public health threat by 2030, but complex systemic and social realities hamper implementation efforts. This paper presents eight case studies from a diverse range of countries that have invested in responses to viral hepatitis and adopted innovative approaches to tackle their respective epidemics. Based on an investment framework developed to build a global investment case for the elimination of viral hepatitis by 2030, national activities and key enablers are highlighted that showcase the feasibility and impact of concerted hepatitis responses across a range of settings, with different levels of available resources and infrastructural development. These case studies demonstrate the utility of taking a multipronged, public health approach to: (a) evidence-gathering and planning; (b) implementation; and (c) integration of viral hepatitis services into the Agenda for Sustainable Development. They provide models for planning, investment and implementation strategies for other countries facing similar challenges and resource constraints.

The contribution of alcohol use disorder to decompensated cirrhosis among people with hepatitis C: An international study.

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.

The risk of hepatocellular carcinoma in cirrhotic patients with hepatitis C and sustained viral response: Role of the treatment regimen.

BACKGROUND & AIMS: Previous studies have reported a high frequency of hepatocellular carcinoma (HCC) occurrence in patients with advanced liver disease, after receipt of interferon (IFN)-free therapy for hepatitis C virus (HCV) infection. Our objective was to verify and account for this phenomenon using data from the Scottish HCV clinical database. METHODS: We identified HCC-naïve individuals with liver cirrhosis receiving a course of antiviral therapy in Scotland from 1997-2016 resulting in a sustained virologic response. Patients were followed-up from their treatment start date to the earliest of: date of death, date of HCC occurrence, or 31 January 2017. We used Cox regression to compare the risk of HCC occurrence according to treatment regimen after adjusting for relevant co-factors (including: demographic factors; baseline liver disease stage; comorbidities/health behaviours, virology, and previous treatment experience). HCC occurrence was ascertained through both the HCV clinical database and medical chart review. For our main analysis, treatment regimen was defined as IFN-free vs. IFN-containing. RESULTS: A total of 857 patients met the study criteria, of whom 31.7% received an IFN-free regimen. Individuals receiving IFN-free therapy were more likely to be: older; of white ethnicity, Child-Turcotte-Pugh B/C vs. Child-Turcotte-Pugh A; thrombocytopenic; non-genotype 3; and treatment experienced. HCC occurrence was observed in 46 individuals during follow-up. In univariate analysis, IFN-free therapy was associated with a significantly increased risk of HCC (HR: 2.48; p = 0.021). However, after multivariate adjustment for baseline factors, no significant risk attributable to IFN-free therapy persisted (aHR: 1.15, p = 0.744). CONCLUSION: These findings suggest that the higher incidence of HCC following sustained virologic response with IFN-free therapy relates to baseline risk factors/patient selection, and not the use of IFN-free therapy per se. LAY SUMMARY: We examined the risk of liver cancer in 857 patients with cirrhosis in Scotland who received hepatitis C antiviral therapy and achieved a cure. We compared the risk of first-time liver cancer in patients treated with the newest interferon-free regimens, to patients treated with interferon. After accounting for the different characteristics of these two treatment groups, we found no evidence that interferon-free therapy is associated with a higher risk of liver cancer.

HCV avidity as a tool for detection of recent HCV infection: Sensitivity depends on HCV genotype.

Accurate detection of incident hepatitis C virus (HCV) infection is required to target and evaluate public health interventions, but acute infection is largely asymptomatic and difficult to detect using traditional methods. Our aim was to evaluate a previously developed HCV avidity assay to distinguish acute from chronic HCV infection. Plasma samples collected from recent seroconversion subjects in two large Australian cohorts were tested using the avidity assay, and the avidity index (AI) was calculated. Demographic and clinical characteristics of patients with low/high AI were compared via logistic regression. Sensitivity and specificity of the assay for recent infection and the mean duration of recent infection (MDRI) were estimated stratified by HCV genotype. Avidity was assessed in 567 samples (from 215 participants), including 304 with viraemia (defined as ≥250 IU/mL). An inverse relationship between AI and infection duration was found in viraemic samples only. The adjusted odds of a low AI (<30%) decreased with infection duration (odds ratio [OR] per week of 0.93; 95% CI:0.89-0.97), and were lower for G1 compared with G3 samples (OR = 0.14; 95% CI:0.05-0.39). Defining recent infection as <26 weeks, sensitivity (at AI cut-off of 20%) was estimated at 48% (95% CI:39-56%), 36% (95% CI:20-52%), and 65% (95% CI:54-75%) and MDRI was 116, 83, and 152 days for all genotypes, G1, and G3, respectively. Specificity (≥52 weeks infection duration, all genotypes) was 96% (95% CI:90-98%). HCV avidity testing has utility for detecting recent HCV infection in patients, and for assessing progress in reaching incidence targets for eliminating transmission, but variation in assay performance across genotype should be recognized.