Development and validation of a nomogram for assessing hepatocellular carcinoma risk after SVR in hepatitis C patients with advanced fibrosis and cirrhosis.

BACKGROUND: Hepatitis C patients with advanced fibrosis or cirrhosis are at high risk of developing hepatocellular carcinoma (HCC), even after sustained virological response (SVR). Clinical recommendations impose a significant burden on patients by recommending lifelong screening for HCC every six months. The goals of this study were to develop a nomogram that accurately stratifies risk of HCC and improve the screening approach that is currently in use. METHOD: Risk factors for HCC were identified using univariate and multivariate analyses in this prospective study. We developed and validated a nomogram for assessing hepatocellular carcinoma risk after SVR in patients with advanced fibrosis and cirrhosis. RESULTS: During the median follow-up period of 61.00 (57.00-66.00) months in the derivation cohort, 37 patients (9.61%) developed HCC. Older age (HR = 1.08, 95% CI 1.02-1.14, p = 0.009), male gender (HR = 2.38, 95% CI 1.10-5.13, p = 0.027), low serum albumin levels (HR = 0.92, 95% CI 0.86-1.00, p = 0.037), and high liver stiffness measurement (LSM) (HR = 1.03, 95% CI 1.01-1.06, p = 0.001) were found to be independent predictors of HCC development. Harrell's C-index for the derivation cohort was 0.81. The nomogram's 3-, 5- and 7-years time-dependent AUROCSs were 0.84 (95% CI 0.80-0.88), 0.83 (95% CI 0.79-0.87), and 0.81 (95% CI 0.77-0.85), respectively (all p > 0.05). According to the nomogram, patients are categorized as having low, intermediate, or high risk. The annual incidence rates of HCC in the three groups were 0.18%, 1.29%, and 4.45%, respectively (all p < 0.05). CONCLUSIONS: Older age, male gender, low serum albumin levels, and high LSM were risk factors for HCC after SVR in hepatitis C patients with advanced fibrosis and cirrhosis. We used these risk factors to establish a nomogram. The nomogram can identify a suitable screening plan by classifying hepatitis C patients according to their risk of HCC.

Sofosbuvir (+) daclatasvir (+) ribavirin in Egyptian patients with hepatitis C virus: Therapeutic outcomes and the prognostic role of natural killer cells.

BACKGROUND: One of the prominent causes of chronic liver disease worldwide is the hepatitis C virus (HCV). HCV believed that innate immunity contributes to a sustained virological response (SVR) to the treatment of Sofosbuvir (SOF) (+) Daclatasvir (DCV) (+) Ribavirin (RBV). This study aimed to evaluate the impact of SOF (+) DCV (+) RBV therapy and persistent HCV infection on the subset of natural killer cells (NK) in HCV genotype four patients from Egypt. MATERIALS AND METHODS: One hundred and ten patients with persistent HCV infections requiring SOF (+) DCV (+) RBV therapy were grouped, and a flow cytometry (FCM) study of the NK cell subset in peripheral blood was performed. The assessment was performed before and after three and/or six months of the cessation of viral suppression therapy when a patient had a long-term viral response (SVR). One hundred and ten volunteers from the National Liver Institute's (NLI) blood bank were selected as controls. RESULTS: Patients with chronic HCV infection before therapy had considerably lower CD16+ and CD3- CD56+ cells than controls. Their levels increase during SOF (+) DCV (+) RBV therapy. In patients with SVR during treatment, CD16+ and CD3- CD56+ cells increased significantly compared to those who did not get SVR. Furthermore, CD56+ cells were significantly higher in patients with persistent infection before treatment than controls but diminished with the response to treatment. CONCLUSION: NK cell activation following SOF (+) DCV (+) RBV therapy and polarization to cytotoxicity occurred early in HCV antiviral therapy and was elevated in the respondents. Our data illustrated that establishing an inhibitory cytotoxic NK profile is related to therapeutic outcomes.

Post-treatment LSM rather than change during treatment predicts decompensation in patients with cACLD after HCV cure.

BACKGROUND & AIMS: Baveno VII has defined a clinically significant (i.e., prognostically meaningful) liver stiffness measurement (LSM)-decrease in cACLD by ≥20% associated with a final LSM<20 kPa, or any decrease to <10 kPa. However, these rules have not yet been validated against direct clinical endpoints. METHODS: We retrospectively analysed cACLD patients (LSM≥10 kPa) with paired liver stiffness measurement (LSM) before (BL) and after (FU) HCV-cure by interferon-free therapies from 15 European centers. The cumulative incidence of hepatic decompensation was compared according to these criteria, considering hepatocellular carcinoma and non-liver-related death as competing risks. RESULTS: 2335 patients followed for a median of 6 years were analysed. Median BL-LSM was 16.6 kPa with 37.1% having ≥20 kPa. After HCV-cure, FU-LSM decreased to a median of 10.9 kPa (<10 kPa: 1002 [42.9%], ≥20 kPa: 465 [19.9%]) translating into a median LSM-change of -5.3 (-8.8-[-2.4])kPa corresponding to -33.9 (-48.0-[-15.9])%. Patients achieving a clinically significant decrease (65.4%) had a significantly lower risk of hepatic decompensation (subdistribution hazard ratio [SHR]: 0.12 [95%CI: 0.04-0.35], p<0.001). However, these risk differences were primarily driven by a negligible risk in patients with FU-LSM <10 kPa (5y-cumulative incidence: 0.3%) compared to a high risk in patients with FU-LSM ≥20 kPa (16.6%). Patients with FU-LSM 10-19.9 kPa (37.4%) also had a low risk of hepatic decompensation (5y-cumulative incidence: 1.7%), and importantly, the risk of hepatic decompensation did not differ between those with/without an LSM-decrease ≥20% (p=0.550). CONCLUSIONS: FU-LSM is key for risk stratification after HCV-cure and should guide clinical decision-making. LSM dynamics do not hold significant prognostic information in patients with FU-LSM 10-19.9 kPa, and thus, their consideration is not of sufficient incremental value in the specific context of HCV-cure.

Updated Clinical Guidelines on the Management of Hepatitis C Infection in Children.

Children represent only a small proportion of those infected with the hepatitis C virus (HCV) compared to adults. Nevertheless, a substantial number of children have chronic HCV infection and are at risk of complications including cirrhosis, portal hypertension, hepatic decompensation with hepatic encephalopathy, and hepatocellular carcinoma in adulthood. The overall prevalence of the HCV in children was estimated to be 0.87% worldwide. The HCV spreads through the blood. Children born to women with chronic hepatitis C should be evaluated and tested for HCV due to the known risk of infection. The course of treatment for hepatitis C depends on the type of HCV. Currently, there are two pan-genotype HCV treatments (Glecaprevir/pibrentasvir and Sofosbuvir/velpatasvir) for children. We aim to review the updated clinical guidelines on the management of HCV infection in children, including screening, diagnosis, and long-term monitoring, as well as currently published clinical trials and ongoing research on direct acting antiviral hepatitis C treatment in children.

mADRES predicts hepatocellular carcinoma development in patients with hepatitis C virus who achieved sustained virological response.

BACKGROUND AND AIM: The study aims to develop a novel predictive model including the fibrosis (FIB)-3 index for hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C virus (HCV) who achieved sustained virological response (SVR) with direct-acting antiviral (DAA) therapy. METHODS: This study included 2529 patients in whom HCV was eradicated with DAA therapy. The after DAA recommendation for surveillance (ADRES) score, which is based on sex, FIB-4 index, and α-fetoprotein, was used to predict HCC development. We developed a modified ADRES (mADRES) score, in which the FIB-4 index was replaced by the FIB-3 index, and evaluated its usefulness in predicting HCC development compared with the ADRES score. RESULTS: In the training set (n = 1770), multivariate analysis with Cox proportional hazards modeling showed that male sex (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.48-3.01), FIB-3 index (HR, 1.36; 95% CI, 1.28-1.45), and α-fetoprotein (HR, 1.05; 95% CI, 1.03-1.07) are independently associated with HCC development. The incidence of HCC differed significantly by ADRES or mADRES score in multiple comparisons. Univariate Cox proportional hazards models showed that compared with the mADRES score 0 group, the HR for HCC development was 2.07 (95% CI, 1.02-4.19) for the mADRES score 1 group, 11.37 (95% CI, 5.80-22.27) for the mADRES score 2 group, and 21.95 (95% CI, 10.17-47.38) for the mADRES score 3 group. Similar results were obtained for mADRES score but not for ADRES score in the validation set (n = 759). CONCLUSION: The mADRES score is useful for predicting HCC development after SVR.

Sustained virologic response improved the long-term health-related quality of life in patients with chronic hepatitis C: a prospective national study in China.

BACKGROUND: To investigate the trends in health-related quality of life (HRQoL) among hepatitis C virus (HCV) patients and to assess the longitudinal impact of antiviral therapy on their well-being. METHODS: In this prospective multicenter observational study in adults with HCV infection, sociodemographic, clinical characteristics and EQ-5D questionnaires were collected. Generalized estimating equation (GEE) models were used to assess the associations between these variables and changes in HRQoL over time. RESULTS: 456 patients were included, with a median age of 46.5 (36.5-57.0) years, of which 262 (57.5%) were males and 44 (9.6%) had cirrhosis. 335 patients (73.5%) receiving antiviral therapy and 61.8% achieved sustained virologic response (SVR). The baseline EQ-5D utility and EQ-VAS were 0.916 ± 0.208 and 80.6 ± 13.0. In multivariable analysis of GEE estimation, achieving SVR24 was positively associated with EQ-5D utility (p = 0.000) and EQ-VAS (p = 0.000) over time. Age and income were shown to be significant predictors of EQ-5D utility, while gender, age and genotype were associated with EQ-VAS over time. CONCLUSIONS: SVR improved long-term HRQoL in HCV patients in the first few years following viral clearance. Certain sociodemographic factors, such as gender, age, income as well as genotype, significantly influenced long-term changes in patients' quality of life. TRIAL REGISTRATION: NCT01594554. Registration date: 09/05/2012.

Evolution of spontaneous portosystemic shunts over time and following aetiological intervention in patients with cirrhosis.

Background & Aims: Spontaneous portosystemic shunts (SPSS) develop frequently in cirrhosis. Changes over time and the effect of aetiological interventions on SPSS are unknown, so we aimed to explore the effect of these variables on SPSS evolution. Methods: Patients with cirrhosis from the Baveno VI-SPSS cohort were selected provided a follow-up abdominal CT or MRI scan was available. Clinical and laboratory data were collected at baseline and follow-up. Imaging tests were reviewed to evaluate changes in the presence and size of SPSS (large (L)-SPSS was ≥8 mm) over time. Regarding alcohol- or HCV-related cirrhosis, two populations were defined: cured patients (abstinent from alcohol or successful HCV therapy), and non-cured patients. Results: A total of 617 patients were included. At baseline SPSS distribution was 22% L-SPSS, 30% small (S)-SPSS, and 48% without (W)-SPSS. During follow-up (median follow-up of 63 months), SPSS distribution worsened: L-SPSS 26%, S-SPSS 32%, and W-SPSS 42% (p <0.001). Patients with worse liver function during follow-up showed a simultaneous aggravation in SPSS distribution. Non-cured patients (n = 191) experienced a significant worsening in liver function, more episodes of liver decompensation and lower transplant-free survival compared to cured patients (n = 191). However, no differences were observed regarding SPSS distribution at inclusion and at follow-up, with both groups showing a trend to worsening. Total shunt diameter increased more in non-cured (52%) than in cured patients (28%). However, total shunt area (TSA) significantly increased only in non-cured patients (74 to 122 mm2, p <0.001). Conclusions: The presence of SPSS in cirrhosis increases over time and parallels liver function deterioration. Aetiological intervention in these patients reduces liver-related complications, but SPSS persist although progression is decreased. Impact and implications: There is no information regarding the evolution of spontaneous portosystemic shunts (SPSS) during the course of cirrhosis, and especially after disease regression with aetiological interventions, such as HCV treatment with direct-acting antivirals or alcohol abstinence. These results are relevant for clinicians dealing with patients with cirrhosis and portal hypertension because they have important implications for the management of cirrhosis with SPSS after disease regression. From a practical point of view, physicians should be aware that in advanced cirrhosis with portal hypertension, after aetiological intervention, SPSS mostly persist despite liver function improvement, and complications related to SPSS may still develop.

Occult hepatitis C virus infection in hemodialysis patients who achieved a sustained virological response to directly acting antiviral drugs: is it a concern?

PURPOSE: Hepatitis C virus infection is a major health problem in hemodialysis patients. Occult HCV infection is defined as the presence of HCV-RNA in hepatocytes or peripheral blood mononuclear cells without the detection of HCV-RNA in the serum. We aimed to evaluate the prevalence and predictors of occult HCV infection among hemodialysis patients after treatment with direct-acting antiviral agents. METHODS: This research is a cross-sectional study that included 60 HCV patients maintained on regular HD patients who achieved 24 weeks of sustained virological response after treatment with direct-acting antiviral agents. Real-time PCR was performed to detect HCV-RNA in peripheral blood mononuclear cells. RESULTS: HCV-RNA was detected in peripheral blood mononuclear cells of three patients (5%). Occult HCV infection cases were treated by Interferon/ribavirin before direct-acting antiviral agents and two of them had raised pre-treatment alanine aminotransferase levels. Logistic regression analyses revealed that high pre-treatment viral load and raised pre-treatment alanine aminotransferase were associated with an increased risk of occult HCV infection with p value of 0.041 and 0.029, respectively. CONCLUSIONS: Occult HCV infection in hemodialysis patients who achieved sustained virological response after treatment with direct-acting antiviral agents may occur, and this may necessitate dual testing for HCV in both serum and peripheral blood mononuclear cells to ensure viral clearance. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT04719338.

Comparison of postoperative outcomes in cases achieving sustained virological response with direct-acting antiviral and interferon therapy.

BACKGROUND/PURPOSE: The effect of direct-acting antiviral agents (DAAs) on hepatocellular carcinoma (HCC) recurrence after curative hepatectomy remains uncertain. This retrospective study aimed to evaluate the effect of sustained virological response (SVR) with DAAs or interferon (IFN) therapy on recurrence and overall survival (OS) after hepatectomy. METHODS: We enrolled 593 patients who underwent curative resections between January 2010 and December 2017. Among them, 186 achieved SVR before hepatectomy: a total of 51 (27.4%) in the DAA-SVR group and 132 (72.6%) in the IFN-based SVR group. RESULTS: SVR before hepatectomy was an independent predictor of OS, and the 5-year OS rate was significantly higher in the SVR group than that in the non-SVR group (82.2% vs. 63.9%). There were no significant differences in the recurrence rates or OS between DAA and IFN treatments in achieving SVR before hepatectomy, regardless of poor hepatic function in the DAA therapy group. CONCLUSIONS: There was no significant difference in OS and recurrence-free survival (RFS) between the preoperative SVR achieved with DAA and IFN groups in this study, although liver function was significantly worse at the time of surgery in the DAA group compared to the IFN group.

VFMAP predicted hepatocellular carcinoma development in patients with chronic hepatitis C who were treated with direct-acting antiviral and achieved sustained virologic response.

PURPOSE: Risk factors for the development of hepatocellular carcinoma (HCC) remain unclear in patients with hepatitis C virus (HCV) who achieve sustained virological response (SVR) after direct-acting antiviral (DAA) therapy. This study investigated the usefulness of the VFMAP scoring system for predicting the development of HCC in these patients. METHODS: This study included 358 patients with HCV who achieved SVR after DAA treatment. The VFMAP system defines and scores cutoff values for virtual touch quantification (VTQ), fasting plasma glucose, sex, age, and alpha-fetoprotein values. All patients were grouped according to their VFMAP scores as follows: 0 or 1 point, low-score group; 2 or 3 points, intermediate-score group; and 4 or 5 points, high-score group. RESULTS: Nineteen patients developed HCC. The median follow-up duration was 3.2 (1.5-4.0) years. The respective cumulative incidence rates of HCC at 12, 24, and 36 months were as follows in different subgroups: all study patients, 3.0%, 4.8%, and 6.6%; low-score group, 0.96%, 0.96%, and 0.96%; intermediate-score group, 2.6%, 4.5%, and 6.8%; and high-score group, 10.0%, 15.3%, and 18.5%. The cumulative incidence rates of HCC in the high-score group were significantly higher than those in the low- and intermediate-score groups (p < 0.001 and < 0.05, respectively). CONCLUSION: VFMAP accurately predicted the development of HCC in HCV patients who achieved SVR following treatment with DAAs.

A Synopsis of Hepatitis C Virus Treatments and Future Perspectives.

Hepatitis C virus (HCV) infection is a worldwide public health problem. Chronic infection with HCV can lead to liver cirrhosis or cancer. Although some immune-competent individuals can clear the virus, others develop chronic HCV disease due to viral mutations or an impaired immune response. IFNs type I and III and the signal transduction induced by them are essential for a proper antiviral effect. Research on the viral cycle and immune escape mechanisms has formed the basis of therapeutic strategies to achieve a sustained virological response (SVR). The first therapies were based on IFNα; then, IFNα plus ribavirin (IFN-RBV); and then, pegylated-IFNα-RBV (PEGIFNα-RIV) to improve cytokine pharmacokinetics. However, the maximum SVR was 60%, and several significant side effects were observed, decreasing patients' treatment adherence. The development of direct-acting antivirals (DAAs) significantly enhanced the SVR (>90%), and the compounds were able to inhibit HCV replication without significant side effects, even in paediatric populations. The management of coinfected HBV-HCV and HCV-HIV patients has also improved based on DAA and PEG-IFNα-RBV (HBV-HCV). CD4 cells are crucial for an effective antiviral response. The IFNλ3, IL28B, TNF-α, IL-10, TLR-3, and TLR-9 gene polymorphisms are involved in viral clearance, therapeutic responses, and hepatic pathologies. Future research should focus on searching for strategies to circumvent resistance-associated substitution (RAS) to DAAs, develop new therapeutic schemes for different medical conditions, including organ transplant, and develop vaccines for long-lasting cellular and humoral responses with cross-protection against different HCV genotypes. The goal is to minimise the probability of HCV infection, HCV chronicity and hepatic carcinoma.

Hepatocellular Carcinoma Prevention in the Era of Hepatitis C Elimination.

The hepatitis C virus (HCV), a single-stranded RNA virus belonging to the Flaviviridae family, is a major cause of hepatocellular carcinoma (HCC) worldwide. Tumors caused by HCC have an increased mortality rate globally, which is more accentuated in Western countries. The carcinogenic potential of this virus is mediated through a wide range of mechanisms, spanning from the induction of chronic inflammation to oxidative stress and deregulation of cellular pathways by viral proteins. As the number of new infections continues unabated, HCC-related mortality should be prioritized through early detection, continued prevention of HCV transmission, and treatment of HCV with safe and efficacious direct antiviral agents (DAAs). People who inject drugs (PWID) are a significant reservoir of new HCV infections globally, and in order to eliminate hepatitis C as a global health threat, as set out by the World Health Organization, an integrated approach based on the optimization of care delivery and increased access to harm reduction and treatment for PWID is needed. Thanks to the development of safe and effective antiviral agents, eradication of the infection is now possible in almost all treated patients, leading to a significant reduction but not the elimination of the risk for HCC in cured patients. This is particularly relevant among aged populations who have cofactors of morbidity known to accelerate HCC progression, such as diabetes, obesity, and excessive alcohol consumption. Given the restless accumulation of individuals with cured HCV infection, the implementation of risk-stratified surveillance programs becomes impellent from a cost-effectiveness perspective, whereas the availability of a performant biomarker to predict HCC in cured patients remains an unmet clinical need.

Combining the age-male-albumin-bilirubin-platelets score and shear wave elastography stratifies carcinogenic risk in hepatitis C patients after viral clearance.

BACKGROUND: The treatment of hepatitis C with direct-acting antiviral agents (DAAs) produces a high rate of sustained virological response (SVR) with fewer adverse events than interferon (IFN) therapy with a similar effect in inhibiting carcinogenesis as IFN therapy. The age-male-albumin-bilirubin-platelets (aMAP) score is useful for stratifying the risk of hepatocellular carcinoma in chronic hepatitis patients, and the velocity of shear waves (Vs) measured by shear wave elastography has also been shown to be useful for diagnosing the level of fibrotic progression in hepatitis C and predicting carcinogenic risk. Combining these two may improve the prediction of carcinogenic risk. AIM: To determine whether combining the aMAP score with Vs improves carcinogenic risk stratification in medium-to-high-risk hepatitis C patients. METHODS: This retrospective, observational study involved hepatitis C patients treated with DAAs who achieved SVR. Vs was measured before treatment (baseline), at the end of treatment (EOT), and 12 wk (follow-up 12) and 24 wk (follow-up 24) after treatment. The patients were followed for at least six months after EOT to determine whether cancer developed. Multiple regression analysis was used to identify factors contributing to hepatic carcinogenesis. The diagnostic performances of clinical parameters for predicting the presence of hepatocellular carcinoma were evaluated using receiver-operating characteristic (ROC) curve analyses. RESULTS: A total of 279 patients (mean age 65.9 years, 118 males, 161 females) were included in the analysis. Multiple regression analysis was performed with carcinogenesis as the target variable and alanine aminotransferase, platelets, α-fetoprotein, Vs, and the Fib-4 index as explanatory variables; only Vs was found to be significant (P = 0.0296). The cut-off value for Vs for liver carcinogenesis calculated using the ROC curve was 1.53 m/s. Carcinoma developed in 2.0% (3/151) of those with Vs < 1.53 m/s and in 10.5% (9/86) of those with Vs ≥ 1.53 m/s. CONCLUSION: In hepatitis C patients after SVR, combining the aMAP score and Vs to stratify the risk of carcinogenesis is more efficient than uniform surveillance of all patients.

Hepatitis C virus treatment with glecaprevir and pibrentasvir in patients co-prescribed carbamazepine: Three case reports.

BACKGROUND: Highly effective and well-tolerated direct-acting antiviral (DAA) therapies have revolutionised the management of hepatitis C virus (HCV); however, niche populations face treatment barriers. DAAs co-prescribed with several first-generation anti-epileptic drugs (AEDs) are contraindicated due to drug-drug interactions. A common example is carbamazepine whereby steady-state carbamazepine reduces the maximum concentration and area under the curve of velpatasvir, glecaprevir and pibrentasvir due to potent cytochrome P450 (CYP) 3A4 induction. Carbamazepine also induces P-glycoprotein which reduces glecaprevir and pibrentasvir's area under curve to infinite time. Sofosbuvir-velpatasvir and glecaprevir-pibrentasvir are contraindicated in patients who are co-prescribed carbamazepine due to the risk of reduced DAA therapeutic effect and consequently, virological treatment failure. This presents a challenge for patients in whom carbamazepine substitution is medically unfeasible, impractical or unacceptable. However, the properties of current generation DAA therapies, including high-potency non-structural protein 5A inhibitory effect, may be sufficient to overcome reduced bioavailability arising from carbamazepine related CYP 3A4 and P-glycoprotein induction. CASE SUMMARY: We present a case series of three patients with non-cirrhotic, treatment-naïve, genotype 1a, 1b, and 3a HCV who were treated with a 12 wk course of glecaprevir-pibrentasvir, while co-prescribed carbamazepine for seizure disorders. Glecaprevir-pibrentasvir combination therapy was chosen due to its potent in vitro activity and low barrier to pan-genotypic resistance associated variants. DAA therapy was dose-separated from carbamazepine to maximise time to peak concentration, and taken with meals to improve absorption. Sustained virological response at 12 wk was achieved in each patient with no adverse outcomes. CONCLUSION: DAA therapies, including glecaprevir-pibrentasvir, warrant consideration as a therapeutic agent in people with HCV who are co-prescribed carbamazepine, particularly if AED substitution is not feasible.

Treatment Outcomes of Sofosbuvir/Velpatasvir/Voxilaprevir in Direct-Acting Antiviral-Experienced Hepatitis C Virus Patients: A Systematic Review and Meta-Analysis.

About 5% of chronic hepatitis C (CHC) patients experienced treatment failure with direct-acting antiviral (DAA) treatment. The global data on the practice and treatment outcomes of Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) in DAA-experienced CHC patients remains sparse. We performed a systematic review and meta-analysis to evaluate the efficacy and safety of SOF/VEL/VOX as a salvage treatment in DAA-experienced CHC patients. We searched five electronic databases from inception to 31 January 2023. The study outcomes were SVR12 and treatment-related adverse effects, with subgroup analysis performed based on genotype, cirrhosis, HCC, prior SOF/VEL exposure, and region. We identified and analyzed data from 24 studies (2877 DAA-experienced CHC patients); 17.2% had prior SOF/VEL exposure, 25% received ribavirin with SOF/VEL/VOX, and 42% had pre-treatment resistance-associated substitution (RAS) testing performed. Eastern Mediterranean had a higher pooled SVR12 than the America and Europe regions (p < 0.05). Predictors of SOF/VEL/VOX failure were genotype 3, active HCC, baseline cirrhosis, and prior SOF/VEL. Baseline RAS mutation and ribavirin supplementation were not associated with higher SVR12. Treatment discontinuation because of drug-related adverse events was uncommon (10 studies, 0.2%). In summary, SOF/VEL/VOX is efficacious and safe for retreatment in DAA-experienced CHC patients, even with RAS mutation. Our findings support SOF/VEL/VOX as a first-line rescue treatment for DAA-experienced CHC patients.

Dynamic Changes in Non-Invasive Markers of Liver Fibrosis Are Predictors of Liver Events after SVR in HCV Patients.

Objectives: The course of progressive liver damage after achieving sustained virological response (SVR) with direct-acting antivirals (DAAs) remains undetermined. We aimed to determine risk factors associated with the development of liver-related events (LREs) after SVR, focusing on the utility of non-invasive markers. Methods: An observational, retrospective study that included patients with advanced chronic liver disease (ACLD) caused by hepatitis C virus (HCV), who achieved SVR with DAAs between 2014 and 2017. Patients were followed-up until December 2020. LREs were defined as the development of portal hypertension decompensation and the occurrence of hepatocellular carcinoma (HCC). Serological markers of fibrosis were calculated before treatment and one and two years after SVR. Results: The study included 321 patients, with a median follow-up of 48 months. LREs occurred in 13.7% of patients (10% portal hypertension decompensation and 3.7% HCC). Child-Pugh [HR 4.13 (CI 95% 1.74; 9.81)], baseline FIB-4 [HR 1.12 (CI 95% 1.03; 1.21)], FIB-4 one year post-SVR [HR 1.31 (CI 95% 1.15; 1.48)] and FIB-4 two years post-SVR [HR 1.42 (CI 95% 1.23; 1.64)] were associated with portal hypertension decompensation. Older age, genotype 3, diabetes mellitus and FIB-4 before and after SVR were associated with the development of HCC. FIB-4 cut-off values one and two years post-SVR to predict portal hypertension decompensation were 2.03 and 2.21, respectively, and to predict HCC were 2.42 and 2.70, respectively. Conclusions: HCV patients with ACLD remain at risk of developing liver complications after having achieved SVR. FIB-4 evaluation before and after SVR may help to predict this risk, selecting patients who will benefit from surveillance.

Necessity for surveillance for hepatocellualr carcinoma in older patients with chronic hepatitis C who achieved sustained virological response.

Background and Aim: Hepatocellular carcinoma (HCC) surveillance in low-risk patients (annual incidence <1.5%) is not recommended per the American Association for the Study of Liver Diseases guidelines. Because patients with chronic hepatitis C with non-advanced fibrosis who have achieved sustained virological response (SVR) have a low risk of HCC, HCC surveillance is not recommended for them. However, aging is a risk factor for HCC; threfore, the necessity for HCC surveillance in older patients with non-advanced fibrosis needs to be verified. Methods: This multicenter, prospective study enrolled 4993 patients with SVR (1998 patients with advanced fibrosis and 2995 patients with non-advanced fibrosis). The HCC incidence was examined with particular attention to age. Results: The 3-year incidence of HCC in patients with advanced and non-advanced fibrosis was 9.2% (95% CI: 7.8-10.9) and 2.9% (95% CI: 2.1-3.7), respectively. HCC incidence was significantly higher in patients with advanced fibrosis (P < 0.001). HCC incidence stratified by age and sex was investigated in patients with non-advanced fibrosis. The HCC incidence in the 18-49, 50s, 60s, 70s, and ≥80 age groups were 0.26, 1.3, 1.8, 1.7, and 2.9 per 100 person-years in men, and 0.00, 0.32, 0.58, 0.49, and 0.57 per 100 person-years in women, respectively. Conclusions: Male patients with non-advanced fibrosis aged ≥60 years have a higher risk of developing HCC and, thus, require HCC surveillance.

Development, implementation, and feasibility of site-specific hepatitis C virus treatment workflows for treating vulnerable, high-risk populations: protocol of the Erase Hep C study - a prospective single-arm intervention trial.

BACKGROUND: Hepatitis C virus (HCV) is the leading indication for liver transplantation and liver-related mortality. The development of direct-acting antivirals (DAA) and a simplified treatment algorithm with a > 97% cure rate should make global elimination of HCV an achievable goal. Yet, vulnerable populations with high rates of HCV still have limited access to treatment. By designing locally contextualized site-specific HCV treatment workflows, we aim to cure HCV in vulnerable, high-risk populations, including people experiencing homelessness (PEH) and people who inject drugs (PWID), in Austin, TX, USA. METHODS: Our implementation science study will utilize a qualitative and design thinking approach to characterize patient and systemic barriers and facilitators to HCV treatment in vulnerable, high-risk populations seeking care across seven diverse primary care clinics serving PEHs and PWIDs. Qualitative interviews guided by the Practical, Robust Implementation and Sustainability Model (PRISM) framework will identify barriers and facilitators by leveraging knowledge and experience from both clinic staff and patients. Data synthesized using thematic analysis and design thinking will feed into workshops with clinic stakeholders for idea generation to design site-specific HCV treatment workflows. Providers will be trained on the use of a simplified HCV treatment algorithm with DAAs and clinic staff on the new site-specific HCV treatment workflows. These workflows will be implemented by the seven diverse primary care clinics serving vulnerable, high-risk populations. Implementation and clinical outcomes will be measured using data collected through interviews with staff as well as through medical chart review. DISCUSSION: Our study provides a model of how to contextualize and implement site-specific HCV treatment workflows targeting vulnerable, high-risk populations in other geographic locations. This model can be adopted for future implementation research programs aiming to develop and implement site-specific treatment workflows for vulnerable, high-risk populations and in primary care clinical settings for other disease states beyond just HCV. TRIAL REGISTRATION: Registered on ClinicalTrials.gov on July, 14, 2022. Identifier: NCT05460130 .

Hepatocellular carcinoma in patients cured of chronic hepatitis C: Minimal steatosis.

BACKGROUND: Successful treatment of hepatitis C reduces liver inflammation and fibrosis; however, patients remain at risk of developing hepatocellular carcinoma (HCC). AIMS: To identify risk factors for new-onset HCC in patients cured of hepatitis C. METHODS: Imaging, histological, and clinical data on patients whose first HCC was diagnosed >12 months of post-SVR were analyzed. Histology of 20 nontumor tissues was analyzed in a blinded manner using the Knodel/Ishak/HAI system for necroinflammation and fibrosis/cirrhosis stage and the Brunt system for steatosis/steatohepatitis. Factors associated with post-SVR HCC were identified by comparison with HALT-C participants who did not develop post-SVR HCC. RESULTS: Hepatocellular carcinoma was diagnosed in 54 patients (45 M/9F), a median of 6 years of post-SVR [interquartile range (IQR) =1.4-10y] at a median age of 61 years (IQR, 59-67). Approximately one-third lacked cirrhosis, and only 11% had steatosis on imaging. The majority (60%) had no steatosis/steatohepatitis in histopathology. The median HAI score was 3 (1.25-4), indicating mild necroinflammation. In a multivariable logistic regression model, post-SVR HCC was positively associated with non-Caucasian race (p = 0.03), smoking (p = 0.03), age > 60 years at HCC diagnosis (p = 0.03), albumin<3.5 g/dL (p = 0.02), AST/ALT>1 (p = 0.05), and platelets <100 × 103 cells/µL (p < 0.001). Alpha fetoprotein ≥4.75 ng/mL had 90% specificity and 71% sensitivity for HCC occurrence. Noncirrhotic patients had larger tumors (p = 0.002) and a higher prevalence of vascular invasion (p = 0.016) than cirrhotic patients. CONCLUSIONS: One-third of patients with post-SVR HCC did not have liver cirrhosis; most had no steatosis/steatohepatitis. Hepatocellular carcinomas were more advanced in noncirrhotic patients. Results support AFP as a promising marker of post-SVR HCC risk.

Impact of Direct-Acting Antiviral Therapy on Liver Fibrosis Regression among People with Chronic HCV Infection: Results from a Real-Life Cohort in Patients Who Achieved Sustained Virological Response.

Background and Objectives: The global prevalence of chronic hepatitis C virus (HCV) infection is 0.8%, affecting around 58 million people worldwide. Treatment with DAAs reduces all-cause HCV mortality by 49-68%. This work aims to determine whether there is liver fibrosis regression (LFR) in patients who achieved Sustained Virological Response (SVR) after treatment with DAAs. Materials and Methods: An analytical, observational, single-center, and cohort study was carried out. The final sample consisted of 248 HCV-infected patients. All started treatment with DAAs between January 2015 and December 2017. Five measurements were performed to determine the fibrotic stage in patients (measured in kilopascals (kPa)) using transient elastography (FibroScan®, Echosens, The Netherlands). Results: Taking the baseline fibrotic stage as a reference, the distribution in subgroups was as follows: 77 F4 patients (31.0%); 55 F3 patients (22.2%); 53 F2 patients (21.4%); and 63 F0/F1 patients (25.4%). There were 40 patients (16.1%) with at least one HCV complication and 13 (5.2%) who developed hepatocellular carcinoma. The overall LFR rate was 77.8% (144 of 185 F2/F3/F4 patients, p = 0.01) at the end of the follow-up period. The highest mean FibroScan® values were observed in patients with: "male gender"; "metabolic syndrome"; "subtype 1a"; "NRP DAA"; "at least one HCV complication"; "death from HCV complications"; and "liver transplantation requirement". Conclusions: Treatment with DAAs achieved high rates of LFR and a decrease in mean FibroScan® values in all subgroups.