Hamish Innes

Toward a more complete understanding of the association between a hepatitis C sustained viral response and cause-specific outcomes

Sustained viral response (SVR) is the optimal outcome of hepatitis C virus (HCV) therapy, yet more detailed data are required to confirm its clinical value. Individuals receiving treatment in 1996‐2011 were identified using the Scottish HCV clinical database. We sourced data on 10 clinical events: liver, nonliver, and all‐cause mortality; first hospitalisation for severe liver morbidity (SLM); cardiovascular disease (CVD); respiratory disorders; neoplasms; alcohol‐intoxication; drug intoxication; and violence‐related injury (note: the latter three events were selected a priori to gauge ongoing chaotic lifestyle behaviours). We determined the association between SVR attainment and each outcome event, in terms of the relative hazard reduction and absolute risk reduction (ARR). We tested for an interaction between SVR and liver disease severity (mild vs. nonmild), defining mild disease as an aspartate aminotransferase‐to‐platelet ratio index (APRI) <0.7. Our cohort comprised 3,385 patients (mean age: 41.6 years), followed‐up for a median 5.3 years (interquartile range: 3.3‐8.2). SVR was associated with a reduced risk of liver mortality (adjusted hazard ratio [AHR]: 0.24; P < 0.001), nonliver mortality (AHR, 0.68; P = 0.026), all‐cause mortality (AHR, 0.49; P < 0.001), SLM (AHR, 0.21; P < 0.001), CVD (AHR, 0.70; P = 0.001), alcohol intoxication (AHR, 0.52; P = 0.003), and violence‐related injury (AHR, 0.51; P = 0.002). After 7.5 years, SVR was associated with significant ARRs for liver mortality, all‐cause mortality, SLM, and CVD (each 3.0%‐4.7%). However, we detected a strong interaction, in that ARRs were considerably higher for individuals with nonmild disease than for individuals with mild disease. Conclusions: The conclusions are 3‐fold: (1) Overall, SVR is associated with reduced hazard for a range of hepatic and nonhepatic events; (2) an association between SVR and behavioral events is consistent with SVR patients leading healthier lives; and (3) the short‐term value of SVR is greatest for those with nonmild disease. (Hepatology 2015;62:355–364

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;)

Strategies for the treatment of Hepatitis C in an era of interferon-free therapies: what public health outcomes do we value most?

Objective The expense of new therapies for HCV infection may force health systems to prioritise the treatment of certain patient groups over others. Our objective was to forecast the population impact of possible prioritisation strategies for the resource-rich setting of Scotland. Design We created a dynamic Markov simulation model to reflect the HCV-infected population in Scotland. We determined trends in key outcomes (e.g. incident cases of chronic infection and severe liver morbidity (SLM)) until the year 2030, according to treatment strategies involving prioritising, either: (A) persons with moderate/advanced fibrosis or (B) persons who inject drugs (PWID). Results Continuing to treat the same number of patients with the same characteristics will give rise to a fall in incident infection (from 600 cases in 2015 to 440 in 2030) and a fall in SLM (from 195 cases in 2015 to 145 in 2030). Doubling treatment-uptake and prioritising PWID will reduce incident infection to negligible levels (<50 cases per year) by 2025, while SLM will stabilise (at 70–75 cases per year) in 2028. Alternatively, doubling the number of patients treated, but, instead, prioritising persons with moderate/advanced fibrosis will reduce incident infection less favourably (only to 280 cases in 2030), but SLM will stabilise by 2023 (i.e. earlier than any competing strategy). Conclusions Prioritising treatment uptake among PWID will substantially impact incident transmission, however, this approach foregoes the optimal impact on SLM. Conversely, targeting those with moderate/advanced fibrosis has the greatest impact on SLM but is suboptimal in terms of averting incident infection.

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)

Ranking predictors of a sustained viral response for patients with chronic hepatitis C treated with pegylated interferon and ribavirin in Scotland.

Objectives From the literature on the hepatitis C virus, the existence of a gap between a sustained virologic response (SVR) attainable in randomized clinical trials (RCTs) versus routine practice is not clear. Further, in terms of the pretreatment prediction of SVR, to date, studies have focused only on reporting the magnitude of association (MOA) between each predictor and an SVR. They fail to acknowledge that a predictor with a large MOA is of little value to clinicians if it has low variability in the treatment population. Methods Hepatitis C virus clinical databases were used to derive a large, representative cohort of Scottish pegylated interferon and ribavirin initiates. Results Overall, 39% [123/315, 95% confidence interval (CI) 34–45%] of genotype 1 and 70% (414/594, 95% CI 66–73%) of genotype 2/3 patients achieved an SVR; this compares with the pooled estimates of 47% for genotype 1 (95% CI 41–52%) and 80% for genotype 2/3 (95% CI 75–85%) RCT participants. Significant predictors of SVR identified from logistic regression were ranked on the basis of the akaike information criteria (reflecting an approach that will account for each predictor’s MOA and variability) as follows: (i) genotype, % increase in akaike information criteria of the final model when variables are excluded, 58.49%; (ii) &ggr;-glutamyl transferase, 18.64%; (iii) platelet count, 6.48%; (iv) alanine aminotransferase quotient, 4.63%; (v) ever infected with hepatitis B virus, 4.31% and (vi) sex, 3.10%. Conclusion (i) The proportion of patients attaining an SVR in Scottish routine practice is marginally lower than in RCTs and (ii) other than genotype, &ggr;-glutamyl transferase emerges as a valuable predictor of an SVR in routine practice. Further, we demonstrate an approach to more clearly discern the predictive value of response predictors.

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.

Trends in mortality after diagnosis of hepatitis C virus infection: An international comparison and implications for monitoring the population impact of treatment

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

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.

Review and meta-analysis of the association between self-reported sharing of needles/syringes and hepatitis C virus prevalence and incidence among people who inject drugs in Europe

BACKGROUND Although sharing needles/syringes (N/S) is a recognised risk factor for the hepatitis C virus (HCV), epidemiological studies have shown inconsistent associations between self-reported N/S sharing and biological markers of HCV infection. This review aims to summarise, and explore factors that may explain the variation in, the measure of association between self-reported sharing of N/S and HCV prevalence/incidence among people who inject drugs (PWID). METHODS Studies undertaken in Europe during 1990-2011 were identified through an electronic literature search. Eligible studies reported HCV prevalence (or incidence) among those who reported ever/never (or recent/non-recent) sharing of N/S. Meta-analysis was undertaken to generate a pooled estimate of the association and heterogeneity was explored using stratified analyses. RESULTS Sixteen cross-sectional studies and four longitudinal studies were included. Pooled prevalence and incidence of HCV was 59% and 11% among PWID who reported never and not recently sharing N/S, respectively. Random effects meta-analysis generated a pooled odds ratio (OR) of 3.3 (95% CI 2.4-4.6), comparing HCV infection among those who ever (or recently) shared N/S relative to those who reported never (or not recently) sharing. There was substantial heterogeneity between the study effect sizes (I(2)=72.8%). Differences in pooled ORs were found when studies were stratified by recruitment setting (prison vs. drug treatment sites), recruitment method (outreach vs. non-outreach), sample HCV prevalence and sample mean/median time since onset of injecting. CONCLUSION We found high incidence/prevalence rates among those who did not report sharing N/S during the risk period, which may be due to a combination of unmeasured risk factors and reporting bias. Study design and population are likely to be important modifiers of the size and strength of association between HCV and N/S sharing.