Epidemiology of SARS-CoV-2 during the first three waves in Scotland: a national record linkage study.

BACKGROUND: The early COVID-19 pandemic in Scotland-defined as the era before widespread access to vaccination and monoclonal antibody treatment-can be characterised into three distinct waves: March-July 2020, July 2020-April 2021 and May-August 2021. Each wave was met with various societal restrictions in an effort to reduce disease transmission and associated morbidity and mortality. Understanding the epidemiology of infections during these waves can provide valuable insights into future pandemic planning. METHODS: Scottish RT-PCR testing data reported up until 8 August 2021, the day prior to most restrictions being lifted in Scotland, were included. Demographic characteristics including age, sex and social deprivation associated with transmission, morbidity and mortality were compared across waves. A case-control analysis for each wave was then modelled to further compare risk factors associated with death over time. RESULTS: Of the 349 904 reported cases, there were 18 099, 197 251 and 134 554 in waves 1, 2 and 3, respectively. Hospitalisations, intensive care unit admissions and deaths appeared highest in wave 2, though risk factors associated with COVID-19 death remained similar across the waves. Higher deprivation and certain comorbidities were associated with higher deaths in all waves. CONCLUSIONS: Despite the higher number of cases reported in waves 2 and 3, case fatality rates were lower: likely a combination of improved detection of infections in younger age groups, introduction of social measures and vaccination. Higher social deprivation and comorbidities resulted in higher deaths for all waves.

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.

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.

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.

Hepatitis C reinfection following treatment induced viral clearance among people who have injected drugs.

BACKGROUND: Although people who inject drugs (PWID) are an important group to receive Hepatitis C Virus (HCV) antiviral therapy, initiation onto treatment remains low. Concerns over reinfection may make clinicians reluctant to treat this group. We examined the risk of HCV reinfection among a cohort of PWID (encompassing all those reporting a history of injecting drug use) from Scotland who achieved a sustained virological response (SVR). METHODS: Clinical and laboratory data were used to monitor RNA testing among PWID who attained SVR following therapy between 2000 and 2009. Data were linked to morbidity and mortality records. Follow-up began one year after completion of therapy, ending on 31st December, 2012. Frequency of RNA testing during follow-up was calculated and the incidence of HCV reinfection estimated. Cox proportional hazards regression was used to examine factors associated with HCV reinfection. RESULTS: Among 448 PWID with a SVR, 277 (61.8%) were tested during follow-up, median 4.5 years; 191 (69%) received one RNA test and 86 (31%) received at least two RNA tests. There were seven reinfections over 410 person years generating a reinfection rate of 1.7/100py (95% CI 0.7-3.5). For PWID who have been hospitalised for an opiate or injection related cause post SVR (11%), the risk of HCV reinfection was greater [AHR=12.9, 95% CI 2.2-76.0, p=0.002] and the reinfection rate was 5.7/100py (95% CI 1.8-13.3). CONCLUSION: PWID who have been tested, following SVR, for HCV in Scotland appear to be at a low risk of reinfection. Follow-up and monitoring of this population are warranted as treatment is offered more widely.

Liver mortality attributable to chronic hepatitis C virus infection in Denmark and Scotland--using spontaneous resolvers as the benchmark comparator.

UNLABELLED: Liver mortality among individuals with chronic hepatitis C (CHC) infection is common, but the relative contribution of CHC per se versus adverse health behaviors is uncertain. We explored data on spontaneous resolvers of hepatitis C virus (HCV) as a benchmark group to uncover the independent contribution of CHC on liver mortality. Using national HCV diagnosis and mortality registers from Denmark and Scotland, we calculated the liver mortality rate (LMR) for persons diagnosed with CHC infection (LMRchronic ) and spontaneously resolved infection (LMRresolved ), according to subgroups defined by age, sex, and drug use. Through these mortality rates, we determined subgroup-specific attributable fractions (AFs), defined as (LMRchronic - LMRresolved )/LMRchronic , and then calculated the total attributable fraction (TAF) as a weighted average of these AFs. Thus, the TAF represents the overall fraction (where 0.00 = not attributable at all; and 1.00 = entirely attributable) of liver mortality attributable to CHC in the diagnosed population. Our cohort comprised 7,005 and 21,729 persons diagnosed with HCV antibodies in Denmark and Scotland, respectively. Mean follow-up duration was 6.3-6.9 years. The TAF increased stepwise with age. It was lowest for death occurring at <45 years of age (0.21 in Denmark; 0.26 in Scotland), higher for death occurring at 45-59 years (0.69 in Denmark; 0.69 in Scotland), and highest for death at 60+years (0.92 in Denmark; 0.75 in Scotland). Overall, the TAF was 0.66 (95% confidence interval [CI]: 0.55-0.78) in Denmark and 0.55 (95% CI: 0.44-0.66) in Scotland. CONCLUSIONS: In Denmark and Scotland, the majority of liver death in the CHC-diagnosed population can be attributed to CHC-nevertheless, an appreciable fraction cannot, cautioning that liver mortality in this population is a compound problem that can be reduced, but not solved, through antiviral therapy alone.

Expansion of HCV treatment access to people who have injected drugs through effective translation of research into public health policy: Scotland's experience.

Seven years have elapsed since the Scottish Government launched its Hepatitis C Action Plan - a Plan to improve services to prevent transmission of infection, particularly among people who inject drugs (PWID), identify those infected and ensure those infected receive optimal treatment. The Plan was underpinned by industrial scale funding (around £100 million, in addition to the general NHS funding, will have been invested by 2015), and a web of accountable national and local multi-disciplinary multi-agency networks responsible for the planning, development and delivery of services. Initiatives ranged from the introduction of testing in specialist drug services through finger-prick blood sampling by non-clinical staff, to the setting of government targets to ensure rapid scale-up of antiviral therapy. The Plan was informed by comprehensive national monitoring systems, indicating the extent of the problem not just in terms of numbers infected, diagnosed and treated but also the more penetrative data on the number advancing to end-stage liver disease and death, and also through compelling modelling work demonstrating the potential beneficial impact of scaling-up therapy and the mounting cost of not acting. Achievements include around 50% increase in the proportion of the infected population diagnosed (38% to 55%); a sustained near two-and-a-half fold increase in the annual number of people initiated onto therapy (470 to 1050) with more pronounced increases among PWID (300 to 840) and prisoners (20 to 140); and reversing of an upward trend in the overall number of people living with chronic infection. The Action Plan has demonstrated that a Government-backed, coordinated and invested approach can transform services and rapidly improve the lives of thousands. Cited as "an impressive example of a national strategy" by the Global Commission on Drug Policy, the Scottish Plan has also provided fundamental insights of international relevance into the management of HCV among PWID.

Uptake of hepatitis C specialist services and treatment following diagnosis by dried blood spot in Scotland.

BACKGROUND: Dried blood spot (DBS) testing for hepatitis C (HCV) was introduced to Scotland in 2009. This minimally invasive specimen provides an alternative to venipuncture and can overcome barriers to testing in people who inject drugs (PWID). OBJECTIVES: The objective of this study was to determine rates and predictors of: exposure to HCV, attendance at specialist clinics and anti-viral treatment initiation among the DBS tested population in Scotland. STUDY DESIGN: DBS testing records were deterministically linked to the Scottish HCV Clinical database prior to logistic regression analysis. RESULTS: In the first two years of usage in Scotland, 1322 individuals were tested by DBS of which 476 were found to have an active HCV infection. Linkage analysis showed that 32% had attended a specialist clinic within 12 months of their specimen collection date and 18% had begun anti-viral therapy within 18 months of their specimen collection date. A significantly reduced likelihood of attendance at a specialist clinic was evident amongst younger individuals (<35 years), those of unknown ethnic origin and those not reporting injecting drug use as a risk factor. CONCLUSION: We conclude that DBS testing in non-clinical settings has the potential to increase diagnosis and, with sufficient support, treatment of HCV infection among PWID.

Rise in testing and diagnosis associated with Scotland's Action Plan on Hepatitis C and introduction of dried blood spot testing.

BACKGROUND: A key aim of the Hepatitis C Action Plan for Scotland was to reduce the undiagnosed population through awareness-raising activities, for general practitioners and those at risk, and the introduction of dried blood spot (DBS) sampling in community drug services to overcome barriers to testing. This study evaluates the impact of these activities on testing and diagnosis. METHODS: Data on hepatitis C virus (HCV) testing undertaken between January 1999 and December 2011 in Scotland's four largest health boards were analysed. Segmented regression analysis was used to examine changes in testing following the (1) launch of the Action Plan and (2) introduction of DBS testing. RESULTS: Between the pre-Action Plan and Action Plan periods, increases were observed in the average number of HCV tests (19 058-29 045), positive tests (1993-2405) and new diagnoses (1221-1367). Since July 2009, 26% of new diagnoses were made in drug services. The trend in the number of positive tests was raised during the Action Plan, compared to pre-Action Plan, particularly in drug services (rate ratio (RR)=1.4, p<0.001) and prisons (RR=1.2, p<0.001); no change was observed in general practice. Following introduction of DBS testing, there was a 3-fold increase in testing (RR=3.5, p<0.001) and 12-fold increase in positives (RR=12.1, p<0.001) in drug services. CONCLUSIONS: The introduction of DBS sampling in community drug services has made an appreciable contribution to efforts to diagnose the HCV-infected population in Scotland. These findings are important to other countries, with injecting-related HCV epidemics, needing to scale-up testing/case-finding initiatives.

The prevalence of hepatitis C virus among people of South Asian origin in Glasgow - results from a community based survey and laboratory surveillance.

BACKGROUND: South Asians often present late with HCV or HBV related liver disease which could have been avoided with early diagnosis and subsequent treatment; however the prevalence of HCV/HBV among South Asians in Glasgow is not known. Accordingly, to inform the need for case finding among this group we aimed to examine the prevalence of Hepatitis C virus (HCV) among South Asians living in Glasgow. METHODS: A community-based survey recruited individuals at six mosques and four community centres serving the South Asian community during 2009-2010; participants had predominantly never been HCV tested. Laboratory surveillance data involving all individuals tested for HCV during 1993-2009 were examined and South Asians were identified using Nam Pehchan software. RESULTS: In the community-based survey, 2.6% of 1288 participants tested HCV-antibody positive; the prevalence ranged from 0.6% among those born in the UK to 3.1% among those born in Pakistan. The odds of testing HCV-antibody positive were significantly raised among those who had surgery in South Asia (aOR: 5.0, 95% CI: 2.0-12.3) and had either medical/dental treatment or an injection in South Asia (aOR: 2.2, 95% CI: 1.0-5.0). Of 6404 South Asians identified from laboratory surveillance data, 9.3% tested HCV positive. An estimated 38% (330/870) of HCV-infected South Asians living in Glasgow remain undiagnosed. CONCLUSIONS: South Asians living in Glasgow, particularly those born outside the UK are at greater risk of HCV infection than the general population. Efforts to increase awareness and testing in this population are warranted.

Examination of the risk of reinfection with hepatitis C among injecting drug users who have been tested in Glasgow.

BACKGROUND: Unsafe injecting practices put injecting drug users (IDUs) at repeat exposure to infection with the hepatitis C virus (HCV). It has not yet been determined if spontaneously clearing one's primary infection influences the risk of reinfection; our aim was to estimate the relative risk of reinfection in IDUs who have cleared the virus. METHODS: We conducted a retrospective study using a large database of HCV test results covering Greater Glasgow Health Board during 1993-2007 to calculate rates of infection and reinfection in current/former IDUs. The relative risk of (re)infection in previously infected compared with never-infected IDUs was estimated using Poisson regression, adjusting for age at study entry, sex, and calendar period of test. RESULTS: Although the rate of reinfection in IDUs who were HCV antibody-positive, RNA-negative at baseline was lower (7/100 person-years, 95% CI: 5-9) than the rate of acute infection in IDUs who were HCV antibody-negative at baseline (10/100 person-years, 95% CI: 9-12), the risk of reinfection was not significantly different than the risk of initial infection (adjusted rate ratio=0.78, 95% CI: 0.57-1.08). CONCLUSION: We found only weak evidence for a reduced risk of HCV reinfection in IDUs who had cleared their previous infection. Further research among those who have cleared infection through antiviral therapy is needed to help inform decisions regarding treatment of IDUs.

Excess liver-related morbidity of chronic hepatitis C patients, who achieve a sustained viral response, and are discharged from care.

UNLABELLED: Our objective was to address two shortfalls in the hepatitis C virus (HCV) literature: (1) Few data exist comparing post-treatment liver-related mortality/morbidity in HCV-sustained virologic response (SVR) patients to non-SVR patients and (2) no data exist examining liver-related morbidity among treatment response subgroups,particularly among noncirrhotic SVR patients, a group who in the main are discharged from care without further follow-up. A retrospective cohort of 1,215 previously naïve HCV interferon patients (treated 1996-2007)was derived using HCV clinical databases from nine Scottish clinics. Patients were followed up post-treatment for a mean of 5.3 years. (1) By Cox-regression, liver-related hospital episodes (adjusted hazard ratio [AHR]:0.22; 95% confidence interval [CI]: 0.15-0.34) and liver-related mortality [corrected] (AHR: 0.22; 95% CI: 0.09-0.58)were significantly lower in SVR patients, compared to non-SVR patients. (2) Rates of liver-related hospitalization were elevated among all treatment subgroups compared to the general population: Among noncirrhotic SVR patients, adjusted standardized morbidity ratio (SMBR) up to 5.9 (95% CI: 4.5-8.0); among all SVR patients,SMBR up to 10.5 (95% CI: 8.7-12.9); and among non-SVR patients, SMBR up to 53.2 (95% CI: 49.4-57.2).Considerable elevation was also noted among patients who have spontaneously resolved their HCV infection(a control group used to gauge the extent to which lifestyle factors, and not chronic HCV, can contribute toliver-related morbidity), SMBR up to 26.8 (95% CI: 25.3-28.3). CONCLUSIONS: (1) Patients achieving an SVR were more than four times less likely to be hospitalized, or die for a liver-related reason, than non-SVR patients and (2) although discharged, noncirrhotic SVR patients harbor a disproportionate burden of liver-related morbidity; up to six times that of the general population. Further, alarming levels of liver-related morbidity in spontaneous resolvers is an important finding warranting further study..