Allan McLeod

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

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 (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 to liver‐related morbidity), with 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 (i.e., up to six times that of the general population). Furthermore, alarming levels of liver‐related morbidity in spontaneous resolvers is an important finding warranting further study. (HEPATOLOGY 2011;)

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 Scotlands 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.

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.

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.

Estimating the number of injecting drug users in Scotland's HCV-diagnosed population using capture–recapture methods

In countries maintaining national hepatitis C virus (HCV) surveillance systems, a substantial proportion of individuals report no risk factors for infection. Our goal was to estimate the proportion of diagnosed HCV antibody-positive persons in Scotland (1991-2010) who probably acquired infection through injecting drug use (IDU), by combining data on IDU risk from four linked data sources using log-linear capture-recapture methods. Of 25,521 HCV-diagnosed individuals, 14,836 (58%) reported IDU risk with their HCV diagnosis. Log-linear modelling estimated a further 2484 HCV-diagnosed individuals with IDU risk, giving an estimated prevalence of 83. Stratified analyses indicated variation across birth cohort, with estimated prevalence as low as 49% in persons born before 1960 and greater than 90% for those born since 1960. These findings provide public-health professionals with a more complete profile of Scotlands HCV-infected population in terms of transmission route, which is essential for targeting educational, prevention and treatment interventions.

Comparison of deaths related to Hepatitis C and AIDS in Scotland.

Summary.  In resource‐rich countries, the incidence of and mortality from AIDS has fallen dramatically since the introduction of combination antiretroviral therapy. In contrast, developed countries have observed increases in the public health burden associated with the hepatitis C virus (HCV). We compared past and current trends in mortality related to HCV sequelae and HIV/AIDS in Scotland by linking death records with national databases of persons diagnosed with HCV and HIV/AIDS. AIDS‐related deaths increased rapidly during the late‐1980s to mid‐1990s and declined dramatically after 1996. Deaths related to HCV (i.e., viral hepatitis, liver cancer, alcoholic liver disease, or non‐alcoholic liver disease) surpassed the number of AIDS‐related deaths in 1998 and increased at an average annual rate of 10.5% (95% confidence interval = 7–14%) during 1996–2005. The leading underlying cause of HCV‐related deaths was alcoholic liver disease (50% of deaths during 2001–2005). This study highlights the increasing public health burden, vis‐à‐vis mortality, of HCV, when compared with HIV/AIDS in developed countries. Increased diagnosis and treatment of eligible HCV‐infected individuals will be required if we wish to mitigate the future impact of HCV morbidity and mortality.

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 ones 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.

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

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. (Hepatology 2016;63:1506‐1516)

Uptake of hepatitis C antibody testing in patients with end-stage liver disease in Glasgow, 1993-2007

Summary.  Individuals infected with hepatitis C virus (HCV) need to be diagnosed well before developing end‐stage liver disease to benefit from treatment. We aimed to ascertain what proportion of cases had been tested for HCV to inform on the effectiveness of current guidelines. Record linkage between national databases of HCV tests, hospital discharges and deaths identified 10 645 persons who were hospitalized or had died with mention of end‐stage liver disease in Glasgow, Scotland, between 1993 and 2007. We estimated HCV test uptake and prevalence of HCV infection within the study population. The associations between both HCV test uptake and HCV‐antibody status and sex, age group and deprivation quintile were estimated using logistic regression. We found that 43% of those hospitalized (n = 9153) and 23% of those who otherwise died (n = 1492) with first‐time mention of end‐stage liver disease had been tested for HCV during this period. Test uptake in those hospitalized increased from 13 (95% CI: 12–14%) in 1993–1997 to 58% (56–59%) in 2003–2007. The adjusted odds of being tested for HCV were significantly higher for men (OR=1.3, 95% CI: 1.2–1.5), for ages 25–54 (25–34 years: 2.7, 95% CI: 2.1–3.4; 35–44 years: 2.3, 95% CI: 2.0–2.6; 45–54 years: 1.5, 95% CI: 1.4–1.7) compared with 55+ years, and for those residing in the two most deprived quintiles (1.1, 95% CI: 1.0–1.2). Twenty‐eight per cent of the HCV testees aged 25–44 years were HCV infected. These results highlight the continuing need for raising awareness among medical professionals for comprehensive HCV testing in patients with liver disease.