Scott A. McDonald

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;)

How preview space/time translates into preview cost/benefit for fixation durations during reading:

Eye-movement control during reading depends on foveal and parafoveal information. If the parafoveal preview of the next word is suppressed, reading is less efficient. A linear mixed model (LMM) reanalysis of McDonald (2006) confirmed his observation that preview benefit may be limited to parafoveal words that have been selected as the saccade target. Going beyond the original analyses, in the same LMM, we examined how the preview effect (i.e., the difference in single-fixation duration, SFD, between random-letter and identical preview) depends on the gaze duration on the pretarget word and on the amplitude of the saccade moving the eye onto the target word. There were two key results: (a) The shorter the saccade amplitude (i.e., the larger preview space), the shorter a subsequent SFD with an identical preview; this association was not observed with a random-letter preview. (b) However, the longer the gaze duration on the pretarget word, the longer the subsequent SFD on the target, with the difference between random-letter string and identical previews increasing with preview time. A third pattern—increasing cost of a random-letter string in the parafovea associated with shorter saccade amplitudes—was observed for target gaze durations. Thus, LMMs revealed that preview effects, which are typically summarized under “preview benefit”, are a complex mixture of preview cost and preview benefit and vary with preview space and preview time. The consequence for reading is that parafoveal preview may not only facilitate, but also interfere with lexical access.

Quantifying the fraction of cirrhosis attributable to alcohol among chronic hepatitis C virus patients: Implications for treatment cost‐effectiveness

A substantial baseline risk of liver cirrhosis exists for patients with chronic hepatitis C virus (HCV) infection. However, the extent to which this could be driven by heavy alcohol use is unclear. Therefore, our principal aim was to determine the fraction of cirrhosis attributable to heavy alcohol use among chronic HCV patients attending a liver clinic. The study population comprised chronic HCV patients who had attended one of five liver clinics in Scotland during 1996‐2010 and had (1) remained in follow‐up for at least 6 months, (2) acquired HCV through either injecting drugs or blood transfusion, and (3) an estimated date of acquiring infection. Predictors of cirrhosis were determined from multivariate logistic regression. Regression parameters were used to determine the fraction of cirrhosis attributable to heavy alcohol use. Among 1,620 patients, 9% were diagnosed with cirrhosis, and 34% had ever engaged in heavy alcohol use (>50 units/week for a sustained period). Significant predictors of cirrhosis were age, duration of infection, and ever heavy alcohol use. The fraction of cirrhosis attributable to ever heavy alcohol use was 36.1% (95% confidence interval [CI]: 24.4‐47.4). Moreover, among patients who had ever engaged in heavy alcohol use specifically, this attributable fraction exceeded 50% (61.6%; 95% CI: 47.0‐72.2). Conclusions: A substantial proportion of patients with chronic HCV develop liver cirrhosis as a consequence of heavy alcohol use. This has not been adequately acknowledged by cost utility analyses (CUAs). As such, estimates of cost‐effectiveness may be exaggerated. Thus, these data are important to guide forthcoming CUAs in terms of taking better account of the factors leading to cirrhosis among patients with chronic HCV. (HEPATOLOGY 2013)

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.

Decrease in health-related quality of life associated with awareness of hepatitis C virus infection among people who inject drugs in Scotland

BACKGROUND & AIMS Chronic hepatitis C virus (HCV) infection can significantly reduce health-related quality of life (QoL), but it is not clear if reduction is associated with the infection or with being aware of ones infection status. Understanding the impact of a HCV diagnosis on QoL is essential to inform decision-making regarding screening/testing and treatment. METHODS Using a cross-sectional design, we assessed QoL in 2898 people who inject drugs (PWID), surveyed in Scotland during 2010 using EQ-5D. Multifactorial regression compared self-reported QoL between PWID who were (i) chronically HCV-infected and aware of their infected status, (ii) chronically HCV-infected but unaware, and (iii) not chronically infected. RESULTS Median time since onset of injecting was 10years; not chronically infected PWID were younger and had shorter injecting careers than chronically infected PWID. Median EQ-5D was highest for the not chronically infected and the chronic/unaware groups (0.73) compared with the chronic/aware group (0.66). After adjustment for demographic and behavioural co-factors, QoL was significantly reduced in chronic/aware compared with chronic/unaware PWID (adjusted B=-0.09, p=0.005); there was no evidence for a difference in QoL between not chronically infected and chronic/unaware PWID (adjusted B=-0.03, p=0.13). CONCLUSIONS Awareness of ones chronic HCV status was associated with reduced health-related QoL, but there was no evidence for further reduction attributable to chronic infection itself after adjusting for important covariate differences.

Mortality in hepatitis C patients who achieve a sustained viral response compared to the general population

BACKGROUND & AIMS The number of people living with previous hepatitis C infection that have attained a sustained viral response (SVR) is expected to grow rapidly. So far, the prognosis of this group relative to the general population is unclear. METHODS Individuals attaining SVR in Scotland in 1996-2011 were identified using a national database. Through record-linkage, we obtained cause-specific mortality data complete to Dec 2013. We calculated standardised mortality ratios (SMRs) to compare the frequency of mortality in SVR patients to the general population. In a parallel analysis, we used Cox regression to identify modifiable patient characteristics associated with post-SVR mortality. RESULTS We identified 1824 patients, followed on average for 5.2years after SVR. In total, 78 deaths were observed. Overall, all-cause mortality was 1.9 times more frequent for SVR patients than the general population (SMR: 1.86; 95% confidence interval (CI): 1.49-2.32). Significant cause-specific elevations were seen for death due to primary liver cancer (SMR: 23.50; 95% CI: 12.23-45.16), and death due to drug-related causes (SMR: 6.58, 95% CI: 4.15-10.45). Together these two causes accounted for 66% of the total excess death observed. All of the modifiable characteristics associated with increased mortality were markers either of heavy alcohol use or injecting drug use. Individuals without these behavioural markers (32.8% of cohort) experienced equivalent survival to the general population (SMR: 0.70; 95% CI: 0.41-1.18) CONCLUSIONS: Mortality in Scottish SVR patients is higher overall than the general population. The excess was driven by death from drug-related causes and liver cancer. Health risk behaviours emerged as important modifiable determinants of mortality in this population. LAY SUMMARY Patients cured of hepatitis C through treatment had a higher mortality rate overall than the general population. Most of the surplus mortality was due to drug-related causes and death from liver cancer. A history of heavy alcohol and injecting drug use were associated with a higher mortality risk.

A record-linkage study of the development of hepatocellular carcinoma in persons with hepatitis C infection in Scotland.

We investigated trends in first-time hospital admissions and deaths attributable to hepatocellular carcinoma (HCC) in a large population-based cohort of 22 073 individuals diagnosed with hepatitis C viral (HCV) infection through laboratory testing in Scotland in 1991–2006. We identified new cases of HCC through record-linkage to the national inpatient hospital discharge database and deaths registry. A total of 172 persons diagnosed with HCV were admitted to hospital or died with first-time mention of HCC. Hepatocellular carcinoma incidence increased between 1996 and 2006 (average annual change of 6.1, 95% confidence interval (CI): 0.9–11.6%, P=0.021). The adjusted relative risk of HCC was greater for males (hazard ratio=2.7, 95% CI: 1.7–4.2), for those aged 60 years or older (hazard ratio=2.7, 95% CI: 1.9–4.1) compared with 50–59 years, and for those with a previous alcohol-related hospital admission (hazard ratio=2.5, 95% CI: 1.7–3.7). The risk of individuals diagnosed with HCV developing HCC was greatly increased compared with the general Scottish population (standardised incidence ratio=127, 95% CI: 102–156). Owing to the advancing age of the Scottish HCV-diagnosed population, the annual number of HCC cases is projected to increase, with a consequent increasing burden on the public healthcare system.

Attendance at specialist hepatitis clinics and initiation of antiviral treatment among persons chronically infected with hepatitis C: examining the early impact of Scotland's Hepatitis C Action Plan

Primary goals of the Hepatitis C Action Plan for Scotland Phase II (May 2008–March 2011) were to increase, among persons chronically infected with the hepatitis C (HCV) virus, attendance at specialist outpatient clinics and initiation on antiviral therapy. We evaluated progress towards these goals by comparing the odds, across time, of (a) first clinic attendance within 12 months of HCV diagnosis (n = 9747) and (b) initiation on antiviral treatment within 12 months of first attendance (n = 5736). Record linkage between the national HCV diagnosis (1996–2009) and HCV clinical (1996–2010) databases and logistic regression analyses were conducted for both outcomes. For outcome (a), 32% and 45% in the respective pre‐Phase II (before 1 May 2008) and Phase II periods attended a specialist clinic within 12 months of diagnosis; the odds of attendance within 12 months increased over time (OR = 1.05 per year, 95% CI: 1.04–1.07), but was not significantly greater for persons diagnosed with HCV in the Phase II era, compared with the pre‐Phase II era (OR = 1.1, 95% CI: 0.9–1.3), after adjustment for temporal trend. For outcome (b), 13% and 28% were initiated on treatment within 12 months of their first clinic attendance in the pre‐Phase II and Phase II periods, respectively. Higher odds of treatment initiation were associated with first clinic attendance in the Phase II (OR = 1.9, 95% CI: 1.5–2.4), compared with the pre‐Phase II era. Results were consistent with a positive impact of the Hepatitis C Action Plan on the treatment of chronically infected individuals, but further monitoring is required to confirm a sustained effect.

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.

What is the impact of a country-wide scale-up in antiviral therapy on the characteristics and sustained viral response rates of patients treated for hepatitis C?

BACKGROUND & AIMS The global burden associated with hepatitis C virus (HCV) infection has prompted a scale-up of antiviral therapy. Hitherto, no data exist on the impact of scaling-up, on the characteristics of treated populations, or on sustained viral response (SVR) rates. We assessed the country-wide scale-up of antiviral therapy in Scotland, a country which nationally monitors uptake of and response to HCV treatment. METHODS Data for patients, initiated on combined pegylated interferon and ribavirin therapy at 13 specialist HCV clinics in 2001-2010, were extracted from the Scottish HCV Clinical Database (n=3895). Patient characteristics included age, genotype, PWID (people who inject drugs) status, prison referral, and diagnosed cirrhosis. Temporal trends in covariates and adjusted effects on a SVR were examined via mixed-effects regression. RESULTS The number of patients starting treatment increased from 237 in 2001-2002 to 1560 in 2009-2010, with an increasing trend in SVR from 44% to 57% over this period. For a given clinic, between 2001/2 and 2010 there was a decrease in the odds of those treated being diagnosed with cirrhosis (odds ratio [OR]=0.84 per year), and increasing temporal trends for those treated being PWID (OR=1.08) and prison referrals (OR=1.06). Adjusting for covariates, the proportion of a given clinics patients achieving SVR was positively associated with the percentage of PWID (OR=1.01 per percent increase; 95% confidence interval [CI]: 1.00-1.02) and genotype 2/3 (OR=1.03; 95% CI: 1.02-1.04). CONCLUSIONS Despite changes in patient characteristics, a country-wide scale-up of antiviral therapy did not compromise SVR rates. Results are highly relevant to countries planning on scaling-up treatment, given the forthcoming availability of new interferon-free therapies.