Hepatocellular Carcinoma Risk Scores Predict Patients Under Surveillance at Low Risk of Benefit and High Risk of Harm.

AIMS: Surveillance for hepatocellular carcinoma (HCC) is recommended for patients with cirrhosis. Multiple risk scores aim to stratify HCC risk, potentially allowing individualized surveillance strategies. We sought to validate four risk scores and quantify the consequences of surveillance via the calculation of numbers needed to benefit (NNB) and harm (NNH) according to classification by risk score strata. METHODS: Data were collected on 482 patients with cirrhosis during 2013-2014, with follow-up until 31/12/2019. Risk scores (aMAP, Toronto risk index, ADRESS HCC, HCC risk score) were derived from index clinic results. The area under the receiving operating characteristic curve (AUC) was calculated for each. Additionally, per-risk strata, NNB was calculated as total surveillance ultrasounds per surveillance diagnosed early HCC (stage 0/A) and NNH as total ultrasounds performed per false positive (abnormal surveillance with normal follow-up imaging). RESULTS: 22 (4.6%) patients developed HCC. 77% (17/22) were diagnosed through surveillance, of which 13/17 (76%) were early stage. There were 88 false positives and no false negatives (normal surveillance result however subsequent HCC detection). Overall NNB and NNH were 241 and 36, respectively. No score was significantly superior using AUC. Patients classified as low risk demonstrated no surveillance benefit (AMAP, THRI) or had a high NNB of > 300/900 (ADRESS HCC, HCC risk score), with low NNH (24-38). CONCLUSION: Given the lack of benefit and increased harm through false positives in low-risk groups, a risk-based surveillance strategy may have the potential to reduce patient harm and increase benefit from HCC surveillance. CLINICAL TRIALS REGISTRATION: This was not a clinical trial and the study was not pre-registered.

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.

Positive predictive value of sustained virologic response 4 weeks posttreatment for achieving sustained virologic response 12 weeks posttreatment in patients receiving glecaprevir/pibrentasvir in Phase 2 and 3 clinical trials.

Sustained virologic response at posttreatment Week 12 (SVR12) is the widely accepted efficacy endpoint for direct-acting antiviral agents. Those with hepatitis C virus (HCV) are presenting younger with milder liver disease, potentially reducing need for long-term liver posttreatment monitoring. This analysis aimed to determine the positive predictive value (PPV) of SVR at posttreatment Week 4 (SVR4) for achieving SVR12 in patients with HCV, without cirrhosis or with compensated cirrhosis, receiving glecaprevir/pibrentasvir (G/P) in clinical trials. An integrated dataset from 20 Phase 2 and 3 clinical trials of G/P was evaluated in patients with 8-, 12- or 16-week treatment duration consistent with the current label (label-consistent group), and in all patients regardless of treatment duration consistency with the current label (overall group). Sensitivity analyses handled missing data either by backward imputation or were excluded. SVR4 PPV, negative predictive value (NPV), sensitivity and specificity were calculated for achieving SVR12 in both groups, and by treatment duration in the label-consistent group. SVR was defined as HCV ribonucleic acid 99% in both groups regardless of treatment duration. Not achieving SVR4 had 100% NPV and sensitivity for all groups. SVR4 measure had 79.5% specificity for identifying patients who did not achieve SVR12. Across 20 Phase 2/3 clinical trials of G/P, SVR4 was highly predictive of SVR12. Long-term follow-up to confirm SVR may not be necessary for certain populations of patients with HCV.

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.

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.

Eight weeks of sofosbuvir/velpatasvir for genotype 3 hepatitis C in previously untreated patients with significant (F2/3) fibrosis.

Twelve weeks sofosbuvir/velpatasvir (SOF/VEL) is a highly effective pan-genotypic regimen for hepatitis C. Phase 2 data suggest 8 weeks of treatment may be sufficient for previously untreated noncirrhotic patients with genotype 3 (GT3) infection. To maximize the number of patients potentially cured within a fixed treatment budget, we elected to treat such patients locally eligible for treatment (F2/3), with 8 weeks of SOF/VEL. By local protocol, treatment-naive patients with F2 (LSM > 6.9kPa < 9.5kPa) or F3 fibrosis (≥9.5kPa < 12.5kPa) were eligible for 8-week SOF/VEL treatment. Patients commencing treatment before 1 Oct 2017 were identified from the Scottish HCV database. Baseline and treatment outcome data obtained. Ninety patients were included for analysis (72 (80%) male, mean age 45 (IQR ± 8.4), 28 (31.1%) F3 fibrosis). Opioid agonist therapy (OAT) was prescribed in 82 (91.1%) patients. Of 49 patients attending Glasgow city Alcohol and Drug Services, 27 (55.1%) had evidence of recent drug use (< 3 months) including 8 (16.3%) with self-reported intravenous drug use. On an intention-to-treat basis, SVR rates were 86/90 (95.6%, 95% CI 89.0-98.8). Excluding those who prematurely discontinued treatment (n = 4), died prior to SVR testing (n = 1) or whom experienced reinfection (n = 1), per-protocol SVR rate was 84/84 (100%, 95% CI 95.7-100.0). In conclusion, eight-week SOF/VEL is highly effective in treatment-naive GT3 patients with significant fibrosis. This offers a non-protease inhibitor-based 8-week regimen which may be useful for complex drug interactions or where time-limited opportunity for treatment. In limited resource settings, reduction in drug acquisition costs may help achieve progress towards the goal of HCV elimination.

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.

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.

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.

Broad Anti-Hepatitis C Virus (HCV) Antibody Responses Are Associated with Improved Clinical Disease Parameters in Chronic HCV Infection.

UNLABELLED: During hepatitis C virus (HCV) infection, broadly neutralizing antibody (bNAb) responses targeting E1E2 envelope glycoproteins are generated in many individuals. It is unclear if these antibodies play a protective or a pathogenic role during chronic infection. In this study, we investigated whether bNAb responses in individuals with chronic infection were associated with differences in clinical presentation. Patient-derived purified serum IgG was used to assess the breadth of HCV E1E2 binding and the neutralization activity of HCV pseudoparticles. The binding and neutralization activity results for two panels bearing viral envelope proteins representing either an intergenotype or an intragenotype 1 group were compared. We found that the HCV load was negatively associated with strong cross-genotypic E1E2 binding (P= 0.03). Overall, we observed only a modest correlation between total E1E2 binding and neutralization ability. The breadth of intergenotype neutralization did not correlate with any clinical parameters; however, analysis of individuals with genotype 1 (gt1) HCV infection (n= 20), using an intragenotype pseudoparticle panel, found a strong association between neutralization breadth and reduced liver fibrosis (P= 0.006). A broad bNAb response in our cohort with chronic infection was associated with a single nucleotide polymorphism (SNP) in theHLA-DQB1 gene (P= 0.038), as previously reported in a cohort with acute disease. Furthermore, the bNAbs in these individuals targeted more than one region of E2-neutralizing epitopes, as assessed through cross-competition of patient bNAbs with well-characterized E2 antibodies. We conclude that the bNAb responses in patients with chronic gt1 infection are associated with lower rates of fibrosis and host genetics may play a role in the ability to raise such responses. IMPORTANCE: Globally, there are 130 million to 150 million people with chronic HCV infection. Typically, the disease is progressive and is a major cause of severe liver cirrhosis and hepatocellular carcinoma. While it is known that neutralizing antibodies have a role in spontaneous clearance during acute infection, little is known about their role in chronic infection. In the present work, we investigated the antibody response in a cohort of chronically infected individuals and found that a broadly neutralizing antibody response is protective and is associated with reduced levels of liver fibrosis and cirrhosis. We also found an association between SNPs in class II HLA genes and the presence of a broadly neutralizing response, indicating that antigen presentation may be important for the production of HCV-neutralizing antibodies.

Factors associated with spontaneous clearance of chronic hepatitis C virus infection.

BACKGROUND & AIMS: Spontaneous clearance of chronic hepatitis C virus (HCV) infection (CHC) is rare. We conducted a retrospective case-control study to identify rates and factors associated with spontaneous clearance of CHC. METHODS: We defined cases as individuals who spontaneously resolved CHC, and controls as individuals who remained chronically infected. We used data obtained on HCV testing between 1994 and 2013 in the West of Scotland to infer case/control status. Specifically, untreated patients with ⩾2 sequential samples positive for HCV RNA ⩾6months apart followed by ⩾1 negative test, and those with ⩾2 positive samples ⩾6months apart with no subsequent negative samples were identified. Control patients were randomly selected from the second group (4/patient of interest). Case notes were reviewed and patient characteristics obtained. RESULTS: 25,113 samples were positive for HCV RNA, relating to 10,318 patients. 50 cases of late spontaneous clearance were identified, contributing 241 person-years follow-up. 2,518 untreated, chronically infected controls were identified, contributing 13,766 person-years follow-up, from whom 200 controls were randomly selected. The incidence rate of spontaneous clearance was 0.36/100 person-years follow-up, occurring after a median 50months' infection. Spontaneous clearance was positively associated with female gender, younger age at infection, lower HCV RNA load and co-infection with hepatitis B virus. It was negatively associated with current intravenous drug use. CONCLUSIONS: Spontaneous clearance of CHC occurs infrequently but is associated with identifiable host and viral factors. More frequent HCV RNA monitoring may be appropriate in selected patient groups. LAY SUMMARY: Clearance of hepatitis C virus infection without treatment occurs rarely once chronic infection has been established. We interrogated a large Scottish patient cohort and found that it was more common in females, patients infected at a younger age or with lower levels of HCV in the blood, and patients co-infected with hepatitis B virus. Patients who injected drugs were less likely to spontaneously clear chronic infection.

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

UNLABELLED: 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.

Viral genotype correlates with distinct liver gene transcription signatures in chronic hepatitis C virus infection.

BACKGROUND: Chronic hepatitis C virus (HCV) infection of the liver with either genotype 1 or genotype 3 gives rise to distinct pathologies, and the two viral genotypes respond differently to antiviral therapy. METHODS: To understand these clinical differences, we compared gene transcription profiles in liver biopsies from patients infected with either gt1 or gt3, and uninfected controls. RESULTS: Gt1-infected biopsies displayed elevated levels of transcripts regulated by type I and type III interferons (IFN), including genes that predict response to IFN-α therapy. In contrast, genes controlled by IFN-γ were induced in gt3-infected biopsies. Moreover, IFN-γ levels were higher in gt3-infected biopsies. Analysis of hepatocyte-derived cell lines confirmed that the genes upregulated in gt3 infection were preferentially induced by IFN-γ. The transcriptional profile of gt3 infection was unaffected by IFNL4 polymorphisms, providing a rationale for the reduced predictive power of IFNL genotyping in gt3-infected patients. CONCLUSIONS: The interactions between HCV genotypes 1 and 3 and hepatocytes are distinct. These unique interactions provide avenues to explore the biological mechanisms that drive viral genotype-specific differences in disease progression and treatment response. A greater understanding of the distinct host-pathogen interactions of the different HCV genotypes is required to facilitate optimal management of HCV infection.

Patient-important benefits of clearing the hepatitis C virus through treatment: a simulation model.

BACKGROUND & AIMS: Given an appreciable risk of adverse-effects, current therapies for chronic hepatitis C virus (HCV) infection pose a dilemma to patients. We explored, via simulation modelling, patient-important benefits of attaining a sustained viral response (SVR). METHODS: We created the HCV Individualised Treatment-decision model (the HIT-model) to simulate, on a per patient basis, the lifetime course of HCV-related liver disease according to two distinct scenarios: (i) SVR attained, and (ii) SVR not attained. Then, for each model subject, the course of liver disease under these alternative scenarios was compared. The benefit of SVR was considered in terms of two patient-important outcomes: (1) the percent-probability that SVR confers additional life-years, and (2) the percent-probability that SVR confers additional healthy life-years, where "healthy" refers to years spent in compensated disease states (i.e., the avoidance of liver failure). RESULTS: The benefit of SVR varied strikingly. It was lowest for patients aged 60 years with initially mild fibrosis; 1.6% (95% CI: 0.8-2.7) and 2.9% (95% CI: 1.5-4.7) probability of gaining life-years and healthy life-years, respectively. Whereas it was highest for patients with initially compensated cirrhosis aged 30 years; 57.9% (95% CI: 46.0-69.0) and 67.1% (95% CI: 54.1-78.2) probability of gaining life-years and healthy life-years, respectively. CONCLUSIONS: For older patients with less advanced liver fibrosis, SVR is less likely to confer benefit when measured in terms of averting liver failure and premature death. These data have important implications. Foremost, it may inform the contemporary patient dilemma of immediate treatment with existing therapies (that have poor adverse effect profiles) vs. awaiting future regimens that promise better tolerability.

Utility of a buccal swab point-of-care test for the IFNL4 genotype in the era of direct acting antivirals for hepatitis C virus.

BACKGROUND: The CC genotype of the IFNL4 gene is known to be associated with increased Hepatitis C (HCV) cure rates with interferon-based therapy and may contribute to cure with direct acting antivirals. The Genedrive® IFNL4 is a CE marked Point of Care (PoC) molecular diagnostic test, designed for in vitro diagnostic use to provide rapid, real-time detection of IFNL4 genotype status for SNP rs12979860. METHODS: 120 Participants were consented to a substudy comparing IFNL4 genotyping results from a buccal swab analysed on the Genedrive® platform with results generated using the Affymetix UK Biobank array considered to be the gold standard. RESULTS: Buccal swabs were taken from 120 participants for PoC IFNL4 testing and a whole blood sample for genetic sequencing. Whole blood genotyping vs. buccal swab PoC testing identified 40 (33%), 65 (54%), and 15 (13%) had CC, CT and TT IFNL4 genotype respectively. The Buccal swab PoC identified 38 (32%) CC, 64 (53%) CT and 18 (15%) TT IFNL4 genotype respectively. The sensitivity and specificity of the buccal swab test to detect CC vs non-CC was 90% (95% CI 76-97%) and 98% (95% CI 91-100%) respectively. CONCLUSIONS: The buccal swab test was better at correctly identifying non-CC genotypes than CC genotypes. The high specificity of the Genedrive® assay prevents CT/TT genotypes being mistaken for CC, and could avoid patients being identified as potentially 'good responders' to interferon-based therapy.

Mortality rates among patients successfully treated for hepatitis C in the era of interferon-free antivirals: population based cohort study.

OBJECTIVES: To quantify mortality rates for patients successfully treated for hepatitis C in the era of interferon-free, direct acting antivirals and compare these rates with those of the general population. DESIGN: Population based cohort study. SETTING: British Columbia, Scotland, and England (England cohort consists of patients with cirrhosis only). PARTICIPANTS: 21 790 people who were successfully treated for hepatitis C in the era of interferon-free antivirals (2014-19). Participants were divided into three liver disease severity groups: people without cirrhosis (pre-cirrhosis), those with compensated cirrhosis, and those with end stage liver disease. Follow-up started 12 weeks after antiviral treatment completion and ended on date of death or 31 December 2019. MAIN OUTCOME MEASURES: Crude and age-sex standardised mortality rates, and standardised mortality ratio comparing the number of deaths with that of the general population, adjusting for age, sex, and year. Poisson regression was used to identify factors associated with all cause mortality rates. RESULTS: 1572 (7%) participants died during follow-up. The leading causes of death were drug related mortality (n=383, 24%), liver failure (n=286, 18%), and liver cancer (n=250, 16%). Crude all cause mortality rates (deaths per 1000 person years) were 31.4 (95% confidence interval 29.3 to 33.7), 22.7 (20.7 to 25.0), and 39.6 (35.4 to 44.3) for cohorts from British Columbia, Scotland, and England, respectively. All cause mortality was considerably higher than the rate for the general population across all disease severity groups and settings; for example, all cause mortality was three times higher among people without cirrhosis in British Columbia (standardised mortality ratio 2.96, 95% confidence interval 2.71 to 3.23; P<0.001) and more than 10 times higher for patients with end stage liver disease in British Columbia (13.61, 11.94 to 15.49; P<0.001). In regression analyses, older age, recent substance misuse, alcohol misuse, and comorbidities were associated with higher mortality rates. CONCLUSION: Mortality rates among people successfully treated for hepatitis C in the era of interferon-free, direct acting antivirals are high compared with the general population. Drug and liver related causes of death were the main drivers of excess mortality. These findings highlight the need for continued support and follow-up after successful treatment for hepatitis C to maximise the impact of direct acting antivirals.

Characterisation of a Hepatitis C Virus Subtype 2a Cluster in Scottish PWID with a Suboptimal Response to Glecaprevir/Pibrentasvir Treatment.

Direct-acting antivirals (DAAs) have revolutionised the treatment of Hepatitis C virus (HCV), allowing the World Health Organisation (WHO) to set a target of eliminating HCV by 2030. In this study we aimed to investigate glecaprevir and pibrentasvir (GP) treatment outcomes in a cohort of patients with genotype 2a infection. METHODS: Clinical data and plasma samples were collected in NHS Greater Glasgow & Clyde. Next generation whole genome sequencing and replicon assays were carried out at the MRC-University of Glasgow Centre for Virus Research. RESULTS: 132 cases infected with genotype 2a HCV were identified. The SVR rate for this group was 91% (112/123) following treatment with GP. An NS5A polymorphism, L31M, was detected in all cases of g2a infection, and L31M+R353K in individuals that failed treatment. The results showed that R353K was present in 90% of individuals in the Glasgow genotype 2a phylogenetic cluster but in less than 5% of all HCV subtype 2a published sequences. In vitro efficacy of pibrentasvir against sub-genomic replicon constructs containing these mutations showed a 2-fold increase in IC50 compared to wildtype. CONCLUSION: This study describes a cluster of HCV genotype 2a infection associated with a lower-than-expected SVR rate following GP treatment in association with the NS5A mutations L31M+R353K.