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) decrease in liver stiffness measurement (LSM) in cACLD as a decrease of ≥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 patients with cACLD (LSM ≥10 kPa) with paired liver stiffness measurement (LSM) before (BL) and after (FU) HCV cure by interferon-free therapies from 15 European centres. The cumulative incidence of hepatic decompensation was compared according to these criteria, considering hepatocellular carcinoma and non-liver-related death as competing risks. RESULTS: A total of 2,335 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: 1,002 [42.9%], ≥20 kPa: 465 [19.9%]) translating into a median LSM change of -5.3 (-8.8 to -2.4) kPa corresponding to -33.9 (-48.0 to -15.9) %. Patients achieving a clinically significant decrease (65.4%) had a significantly lower risk of hepatic decompensation (subdistribution hazard ratio: 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 (5-year 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 (5-year cumulative incidence: 1.7%), and importantly, the risk of hepatic decompensation did not differ between those with/without an LSM decrease of ≥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. IMPACT AND IMPLICATIONS: Liver stiffness measurement (LSM) is increasingly applied as a prognostic biomarker and commonly decreases in patients with compensated advanced chronic liver disease achieving HCV cure. Although Baveno VII proposed criteria for a clinically significant decrease, little is known about the prognostic utility of LSM dynamics (changes through antiviral therapy). Interestingly, in those with a post-treatment LSM of 10-19.9 kPa, LSM dynamics did not provide incremental information, arguing against the consideration of LSM dynamics as prognostic criteria. Thus, post-treatment LSM should guide the management of patients with compensated advanced chronic liver disease achieving HCV cure.

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.

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.

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.

Reverse inflammaging: Long-term effects of HCV cure on biological age.

BACKGROUND & AIMS: Chronic hepatitis C virus (HCV) infection can be cured with direct-acting antivirals (DAAs). However, not all sequelae of chronic hepatitis C appear to be completely reversible after sustained virologic response (SVR). Recently, chronic viral infections have been shown to be associated with biological age acceleration defined by the epigenetic clock. The aim of this study was to investigate whether chronic HCV infection is associated with epigenetic changes and biological age acceleration and whether this is reversible after SVR. METHODS: We included 54 well-characterized individuals with chronic hepatitis C who achieved SVR after DAA therapy at three time points: DAA treatment initiation, end of treatment, and long-term follow-up (median 96 weeks after end of treatment). Genome-wide DNA methylation status was determined in peripheral blood mononuclear cells (PBMCs) and used to calculate epigenetic age acceleration (EAA) using Horvath's clock. RESULTS: Individuals with HCV had an overall significant EAA of 3.12 years at baseline compared with -2.61 years in the age- and sex-matched reference group (p <0.00003). HCV elimination resulted in a significant long-term increase in DNA methylation dominated by hypermethylated CpGs in all patient groups. Accordingly, EAA decreased to 1.37 years at long-term follow-up. The decrease in EAA was significant only between the end of treatment and follow-up (p = 0.01). Interestingly, eight individuals who developed hepatocellular carcinoma after SVR had the highest EAA and showed no evidence of reversal after SVR. CONCLUSIONS: Our data contribute to the understanding of the biological impact of HCV elimination after DAA therapy and demonstrate that HCV elimination can lead to "reverse inflammaging". In addition, our data support the potential use of biological age as a biomarker for HCV sequelae after SVR. IMPACT AND IMPLICATIONS: Chronic hepatitis C virus infection is now curable with direct-acting antivirals, but it remains unclear whether hepatitis C sequelae are fully reversible after viral elimination. Our results suggest that epigenetic changes or acceleration of biological age are reversible in principle, but this requires time, while a lack of reversibility appears to be associated with the development of hepatocellular carcinoma. While most clinical risk scores now take chronological age into account, it may be worthwhile to explore how biological age might improve these scores in the future. Biological age may be a cornerstone for the individualized clinical assessment of patients in the future, as it better reflects patients' lifestyle and environmental exposures over decades.

A 3-Year Course Of Bulevirtide Monotherapy May Cure Hdv Infection In Cirrhotics.

Bulevirtide has been recently conditionally approved by the European Medicines Agency for the treatment of Chronic Hepatitis Delta, but the ideal duration of therapy is unknown. Here we describe the first case of cure of Hepatitis Delta following 3 years of Bulevirtide monotherapy in a patient with compensated cirrhosis and esophageal varices. During the 72-week off-Bulevirtide follow-up, virological and biochemical responses were maintained. In the off-therapy liver biopsy, intrahepatic HDV RNA and Hepatitis D antigen were undetectable, <1% hepatocytes were Hepatitis B surface antigen positive while hepatitis B core antigen was negative. Grading and staging improved compared to pre-treatment biopsy.

The role of serum sphingolipids as potential biomarkers of non-response to direct acting antiviral therapy in chronic hepatitis C virus infection.

Elimination strategies of chronic hepatitis C virus (HCV) infection aim to optimize the high antiviral potency of direct-acting antivirals (DAAs). Sphingolipids (SLs) constitute bioactive lipid compounds with a remarkable second messenger potential. SL levels associate with responsiveness to interferon treatment in HCV-patients, thus prompting the question whether failure to DAAs can be predicted by the serologic sphingolipidomic profile. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to retrospectively quantify various sphingolipid metabolites in baseline serum samples of 97 chronic HCV patients with DAA failure compared with an age-matched cohort of 95 HCV-patients with sustained virological response (SVR). Sphingosine, sphinganine, sphingosine-1-phosphate (S1P) and sphinganine-1-phosphate (SA1P) serum concentrations were significantly upregulated at baseline in patients with DAA failure compared to patients with SVR. Similarly, GluC24:1Cer baseline levels were significantly upregulated in patients with DAA failure compared to the patients with SVR. However, GluC18Cer serum levels showed decreased baseline levels for patients with DAA failure compared to patients with SVR. In multivariate analysis sphinganine (OR 0.08494, CI 0.07393-0.9759, p = .021223), SA1P (OR 0.9818, CI 0.9653-0.9987, p = .034801), GluCerC18 (OR 1.0683, CI 1.0297-1.1104, p = .000786) and GluCer24:1 (OR 0.9961, CI 0.994-0.998, p = .000294) constituted independent predictors of treatment response. In conclusion, serum sphingolipid concentrations, in particular sphingosine, sphinganine and their derivatives S1P and SA1P as well as glucosylceramides may identify at baseline the minority of HCV patients with DAA failure. Serum sphingolipids could constitute additional biomarkers for national treatment strategies aiming to eliminate HCV infection.

Comparison of acknowledged hepatocellular carcinoma risk scores in high-risk hepatitis C patients with sustained virological response.

Hepatitis C patients with advanced fibrosis or cirrhosis are at high risk of developing hepatocellular carcinoma (HCC) even after sustained virological response (SVR). Several HCC risk scores have been developed but which one is most suitable for this population is unclear. In this study, we compared the prediction ability of the aMAP model, THRI model, PAGE-B model and Models of HCV in a prospective hepatitis C cohort in order to propose better model(s) to clinical practice. Adult hepatitis C patients with baseline advanced fibrosis (141 cases), compensated cirrhosis (330 cases) and decompensated cirrhosis (80 cases) were included and followed up every 6 months for about 7 years or until HCC development. Demographic data, medical history and laboratory results were recorded. HCCs were diagnosed by radiography, AFP or liver histology. The median follow-up period was 69.93(60.99-74.93) months, during which 53 (9.62%) patients developed HCC. The areas under the receiver operating characteristic curve of aMAP, THRI, PAGE-B and Models of HCV scores were 0.74, 0.72, 0.70 and 0.63 respectively. The predictive power of the aMAP model score was comparable to that of THRI, PAGE-Band higher than that of Models of HCV (p < 0.05). Dividing patients into non-high-risk and high-risk groups, the cumulative incidence rates of HCC based on aMAP, THRI, PAGE-B and Models of HCV was 5.57% vs. 24.17%, 1.10% vs. 13.90%, 5.80% vs. 15.90% and 6.41% vs. 13.81% (all p < 0.05). The AUC of the four models were all below 0.7 in male while all were higher than 0.7 in female. The performance of all the models was not influenced by fibrosis stage. aMAP, THRI model and PAGE-B model were all performed well while THRI model and PAGE-B model were easier to calculate. There was no need to select score according to fibrosis stage but should be caution when explain the results in male patients.

Risk factors for liver-related and non-liver-related mortality following a sustained virological response after direct-acting antiviral treatment for hepatitis C virus infection in a real-world cohort.

A direct-acting antiviral (DAA)-induced sustained virological response (SVR) reduces the risk of mortality. However, the risk factors associated with liver-related and non-liver-related mortality following a SVR after DAA treatment are unclear. We assessed the incidence and risk factors of liver-related and non-liver-related mortality in 1180 patients who achieved a SVR after DAA treatment. During the follow-up period after DAA treatment (median duration, 1099 [range: 84-2345] days), 53 (4.5%) patients died: 15 due to liver-related mortality, 25 due to non-liver-related mortality and 13 due to unknown causes. The all-cause, liver-related and non-liver-related mortality rates were 14.9, 4.2 and 7.0/1000 person-years, respectively. In a multivariate analysis, the development of hepatocellular carcinoma (HCC) after DAA treatment (p = .009; hazard ratio [HR], 31.484), an estimated glomerular filtration rate (eGFR) at baseline ≤61.68 ml/min/1.73 m2 (p = .015; HR, 6.607), and an α-fetoprotein level post-treatment ≥7.6 ng/ml (p = .041; HR, 18.490) were significantly associated with liver-related mortality. Furthermore, eGFR ≤67.94 ml/min/1.73 m2 at baseline (p = .012; HR, 3.407) and albumin-bilirubin (ALBI) grade ≥ 2 at SVR (p = .024; HR, 3.449) were significantly associated with non-liver-related mortality. Early diagnosis and therapeutic interventions for HCC development after DAA treatment are important to reduce liver-related mortality. The ALBI grade, which reflects the hepatic functional reserve, is a useful predictor of non-liver-related mortality after a SVR induced by DAA treatment. Furthermore, the renal dysfunction caused by metabolic syndrome may affect prognosis even after eliminating hepatitis C virus.

Usefulness of dried blood spot samples for monitoring hepatitis C treatment outcome and reinfection among people who inject drugs in a test-and-treat program.

Dried blood spots (DBS) are a reliable tool to diagnose viremic hepatitis C virus (HCV) infection. We evaluated the clinical performance of a DBS-based molecular assay for the assessment of cure and reinfection after on-site treatment at a harm reduction center (HRC). Genotyping from DBS samples was also assessed to discriminate reinfection from treatment failure. People who inject drugs (PWID) from an ongoing test-and-treat pilot at the largest HRC in Barcelona were included in the study. HCV-RNA detection from DBS collected after treatment (with follow-up at 12, 36, and 60 weeks) was compared with a molecular point-of-care test using finger-stick blood (GeneXpert). Baseline and follow-up DBS samples were genotyped by NS5B sequencing or commercial real-time PCR. Among treated patients, 193 follow-up DBS samples were tested. The DBS-based assay showed 100% specificity (129/129), and sensitivity ranged from 84.4% to 96.1% according to different viral load cut-offs (from detectable to 3000 IU/mL). Sensitivity as test of cure (follow-up 12) ranged from 85.1% to 97.4%. Among the 64 patients with recurrent viremia, 10.9% had low viral loads (≤1000 IU/mL); HCV genotyping allowed us to classify 73.5% of viremic cases either as reinfection or as treatment failure. DBS samples are useful to assess cure and differentiate reinfection from relapse after HCV antiviral treatment in the real world, facilitating decentralization of treatment and posttreatment follow-up in PWID. However, a fraction of patients presented with low viral loads, limiting viremia detection and genotyping in DBS and, therefore, repeat testing is recommended.

Simple Predictive Markers and Clinicopathological Features of Primary Liver Cancer following HCV Clearance with Direct-Acting Antivirals.

INTRODUCTION: Simple predictive markers enabling even nonspecialized medical doctors and clinicopathological features of primary liver cancer (PLC) following HCV clearance with direct-acting antivirals (DAAs) are unclear. METHODS: The subjects of this retrospective study were 2,476 patients following HCV clearance with DAAs. All patients were confirmed to be PLC-free before and during DAAs. RESULTS: PLC was diagnosed in 73 patients during the follow-up, with an incidence rate per 1 000 person-years of 5.9. The annual rate of PLC during the first 6 years was 0.6%. Multivariate analysis identified gender, GGT, and FIB-4 index as the significant determinants of PLC. According to a combination of these risk factors, the cumulative PLC incidence rates were significantly different among the five subgroups based on the number of PLC risk scores. In 73 patients with PLC, the rates of abnormal AFP, PIVKAII, and serum TERT C228T positive were 37.0, 32.4, and 22.2%. PIVKAII levels in BCLC stage A and B were significantly higher than those in stage 0. In 41 patients, who underwent surgical resection for PLC, maximum tumor diameters of abnormal PIVKAII were significantly larger than those of normal PIVKAII. PLC of abnormal PIVKAII significantly indicated presence of vp more than that of normal PIVKAII, and did not contain well-differentiated HCC. CONCLUSIONS: Combination of simple markers, enabling even nonspecialized medical doctors, is useful for the evaluation of PLC risk following HCV clearance with DAAs. However, imaging studies are regularly recommended for the early detection of PLC.

Ledipasvir/Sofosbuvir Is Effective as Sole Treatment of Porphyria Cutanea Tarda with Chronic Hepatitis C.

BACKGROUND AND AIMS: Chronic hepatitis C [CHC] is a risk factor for porphyria cutanea tarda [PCT]. To assess whether ledipasvir/sofosbuvir is effective for treating both PCT and CHC, we treated patients with CHC + PCT solely with ledipasvir/sofosbuvir and followed them for at least 1 year to assess cure of CHC and remission of PCT. METHODS: Between September 2017 and May 2020, 15 of 23 screened PCT + CHC patients were eligible and enrolled. All were treated with ledipasvir/sofosbuvir at recommended doses and durations, according to their stage of liver disease. We measured plasma and urinary porphyrins at baseline and monthly for the first 12 months and at 16, 20, and 24 mos. We measured serum HCV RNA at baseline, 8-12, and 20-24 mos. Cure of HCV was defined as no detectable serum HCV RNA ≥ 12 weeks after the end of treatment (EOT). Remission of PCT was defined clinically as no new blisters or bullae and biochemically as urinary uro- plus hepta-carboxyl porphyrins ≤ 100 mcg/g creatinine. RESULTS: All 15 patients, 13 of whom were men, were infected with HCV genotype 1. 2/15 withdrew or were lost to follow-up. Of the remaining 13, 12 achieved cure of CHC; 1 had complete virological response, followed by relapse of HCV after ledipasvir/sofosbuvir but was subsequently cured by treatment with sofosbuvir/velpatasvir. Of the 12 cured of CHC, all achieved sustained clinical remission of PCT. CONCLUSIONS: Ledipasvir/sofosbuvir [and likely other direct-acting antivirals] is an effective treatment for HCV in the presence of PCT and leads to clinical remission of PCT without additional phlebotomy or low-dose hydroxychloroquine treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT03118674.

Impact of Interferon-Free Direct-Acting Antivirals on the Incidence of Extrahepatic Malignancies in Patients with Chronic Hepatitis C.

BACKGROUND: The incidence of extrahepatic malignancies (EHMs) after hepatitis C virus (HCV) eradication by interferon (IFN)-based and IFN-free direct-acting antivirals (DAAs) treatment remains unclear. AIMS: The aim was to evaluate the cumulative incidence of EHMs diagnosed for the first time after the antiviral treatments. METHODS: We analyzed a total 527 patients with chronic HCV infection and without prior history of any malignancies who achieved sustained virological response by antiviral treatments, including IFN-based (n = 242) or IFN-free DAAs (n = 285). The baseline predictors for EHM occurrence were analyzed using Cox regression analysis. RESULTS: Thirty-two patients were diagnosed with EHMs, 14 in IFN-based and 18 in IFN-free DAAs, respectively. The total duration of follow-up was 1,796 person-years in IFN-based and 823 person-years in IFN-free DAAs. The incidence of EHMs in IFN-based and IFN-free DAAs was 7.8 and 21.9 per 1,000 person-years, respectively. The cumulative incidence of EHMs was significantly higher in IFN-free DAAs than IFN-based (p = 0.002). IFN-free DAAs was a single independent predictor for incidence of EHMs (p = 0.012). As for gender, the incidence of EHMs was significantly higher in IFN-free DAAs only in the female cohort (p = 0.002). After propensity score matching, IFN-free DAAs was a single independent predictor for incidence of EHMs in the female patients (p = 0.045). CONCLUSIONS: The incidence of EHMs after HCV eradication is higher in IFN-free DAAs than IFN-based regimens, especially in female patients. We should carefully follow-up not only HCC but also EHMs after IFN-free DAAs regimens.

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.

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.

Population-level estimates of hepatitis C reinfection post scale-up of direct-acting antivirals among people who inject drugs.

BACKGROUND & AIMS: Scale-up of highly effective direct-acting antivirals (DAAs) for HCV among people who inject drugs (PWID) in Scotland has led to a reduction in the prevalence of viraemia in this population. However, the extent of reinfection among those treated with DAAs remains uncertain. We estimated HCV reinfection rates among PWID in Scotland by treatment setting, pre- and post-introduction of DAAs, and the potential number of undiagnosed reinfections resulting from incomplete follow-up testing. METHODS: Through linkage of national clinical and laboratory HCV data, a retrospective cohort of PWID who commenced treatment between 2000-2018 and achieved a sustained virological response (SVR) were followed up for reinfection to December 2019. Reinfection was defined as a positive HCV antigen or RNA test. RESULTS: Of 5,686 SVRs among 5,592 PWID, 4,126 (73%) had an HCV RNA or antigen test post-SVR. Of those retested, we identified 361 reinfections (3.9/100 person-years [PY]). The reinfection rate increased from 1.5/100 PY among PWID treated in 2000-2009 to 8.8/100 PY in 2017-2018. The highest reinfection rates were observed among those treated in prison (14.3/100 PY) and community settings (9.5/100 PY). Among those treated in the DAA era (2015-2018), 68% were tested within the first year post-SVR but only 30% in the second year; while 169 reinfections were diagnosed in follow-up, an estimated 200 reinfections (54% of the estimated total) had gone undetected. CONCLUSIONS: HCV reinfection rates among PWID in Scotland have risen alongside the scale-up of DAAs and broadened access to treatment for those at highest risk, through delivery in community drug services. Promotion of HCV testing post-SVR among PWID is essential to ensure those reinfected are identified and retreated promptly. LAY SUMMARY: Increased rates of hepatitis C reinfection in Scotland were observed following the rapid scale-up of highly effective direct-acting antiviral (DAA) treatments among people who inject drugs. This demonstrates that community-based treatment pathways are reaching high-risk groups, regarded vital in efforts to eliminate the virus. However, we estimate that less than half of reinfections have been detected in the DAA era because of inadequate levels of retesting beyond the first year following successful treatment. Sustained efforts that involve high coverage of harm reduction measures and high uptake of annual testing are required to ensure prompt diagnosis and treatment of those reinfected if the goals of elimination are to be met.

Sustainable and equivalent improvements in symptoms and functional well-being following viral cure from ledipasvir/sofosbuvir versus elbasvir/grazoprevir for chronic hepatitis C infection: Findings from the randomized PRIORITIZE trial.

The PRIORITIZE trial (clinicaltrials.gov: NCT02786537) was the first comparative effectiveness study to directly compare ledipasvir/sofosbuvir (LDV/SOF) and elbasvir/grazoprevir (EBR/GZR) for the treatment of chronic hepatitis C virus (HCV). A secondary aim of this study was to compare LDV/SOF and EBR/GZR on sustainable changes in several HCV-associated symptoms and functional well-being in patients who achieved sustained virological response (SVR). PRIORITIZE, a randomized controlled trial conducted between 2016 and 2020, evaluated change in six PROMIS® symptom scores (fatigue, sleep disturbance, cognitive disturbance, nausea, diarrhoea, abdominal pain) and functional well-being using the disease-specific HCV-PRO instrument. Survey assessments were administered at baseline, early post-treatment (median = 6 months) and late post-treatment (median = 21 months). Constrained longitudinal linear mixed-effects models were used to evaluate within-treatment change and between-treatment differences. Data from 793 participants (average 55 years old, 57% male, 44% black, 17% with cirrhosis) were analysed. From baseline to early post-treatment, 5 out of 6 symptoms and functional well-being significantly improved (all p's < .05). In the LDV/SOF arm, mean changes ranged from -3.73 for nausea to -6.41 for fatigue and in the EBR/GZR, mean changes ranged from -2.19 for cognitive impairment to -4.67 for fatigue. Change of >3 points was consider clinically meaningful. Improvements in most symptoms slightly favoured LDV/SOF, although the magnitude of differences between the regimens were small. Both regimens demonstrated significant improvements in symptoms and functional well-being that were sustained during the late post-treatment phase. EBR/GZR and LDV/SOF regimens had clinically equivalent and durable improvements in HCV symptoms and functional well-being up to two years after SVR.

Factors linked to hepatocellular carcinoma development beyond 10 years after viral eradication in patients with hepatitis C virus.

The risk factors for hepatocellular carcinoma (HCC) development in patients whose duration of sustained virological response (SVR) is over 10 years are not fully understood. We compared the incidence of HCC development within and beyond 10 years after SVR. A total of 1384 patients who achieved SVR (714, interferon-based therapy; 670, direct-acting antiviral therapy) were enrolled. Factors associated with HCC development were analysed within and beyond 10 years after SVR by Cox proportional hazards models. The annual incidence rates of HCC development were 0.568% within 10 years after SVR and 0.190% beyond 10 years, and there was a significant difference in the incidence of HCC development between the 2 periods (p = 0.0242, log-rank test). Male gender (adjusted hazard ratio [aHR] 2.930; 95% confidence interval [CI] 1.508-5.693, p = 0.0015), fibrosis-4 (FIB-4) score > 3.25 (aHR 4.364; 95%CI 2.206-8.633, p < 0.0001) and alpha-fetoprotein ≥5.0 ng/ml (aHR 2.381; 95%CI 1.325-4.280, p = 0.0037) were independently associated with HCC development within 10 years after SVR. Male gender (aHR 4.702; 95%CI 1.366-16.190, p = 0.0141), presence of diabetes mellitus (aHR 2.933; 95%CI 1.240-6.935, p = 0.0143) and gamma-glutamyl transpeptidase (GGT) ≥ 56 U/l (aHR 4.157; 95%CI 1.400-12.350, p = 0.0103) were independently associated with HCC development beyond 10 years after SVR. The incidence of HCC development beyond 10 years after SVR was very low, and the associated factors were mainly extrahepatic, including DM and elevated GGT. Annual routine check-ups with abdominal ultrasound may be sufficient for such patients. (242 words).

Impact of the PNPLA3 genotype on the risk of hepatocellular carcinoma after hepatitis C virus eradication.

Almost all chronic hepatitis C (CHC) patients can achieve sustained virological response (SVR) with direct-acting antivirals. However, the development of hepatocellular carcinoma (HCC), even after the achievement of SVR, continues to be a serious problem. The aim of this study was to assess the association between host genetic factors and de novo HCC after SVR. This single-center, retrospective study consisted of 442 consecutive CHC patients without a history of HCC who achieved SVR through interferon (IFN)-based and IFN-free therapy. Predictive factors associated with the development of HCC were determined by the Cox proportional hazards model. The single-nucleotide polymorphism (SNP) genotyping data of 223 patients were available for analysis. Of the seven SNPs analyzed in this study, only the patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 GG genotype was significantly, positively associated with the development of de novo HCC after adjusting for age, sex, and fibrosis status (adjusted hazard ratio [aHR] 5.66, p = 0.003). In multivariable analysis, age (aHR 1.05, p = 0.007), advanced fibrosis (aHR 2.69, p = 0.019), α-fetoprotein at post-12 weeks of treatment ≥7.0 ng/ml (aHR 3.85, p = 0.001), and PNPLA3 GG genotype (aHR 3.02, p = 0.004) were extracted as independent predictors of the development of de novo HCC. In conclusion, the PNPLA3 genotype was independently associated with the de novo HCC of CHC patients who achieved SVR. Such detailed knowledge of host genetic factors will be useful for HCC surveillance after HCV elimination.

The impact of genetic variations in sofosbuvir metabolizing enzymes and innate immunity mediators on treatment outcome in HCV-infected patients.

Hepatitis C virus (HCV) is the leading cause of liver diseases worldwide. At present, combinations of different classes of direct-acting antiviral agents (DAAs) are used as treatment options for HCV, in which sofosbuvir (SOF) is the common DAA among different therapeutic regimes. In Egypt, SOF plus daclatasvir (DCV) is the widely used anti-HCV treatment protocol. Herein, we aimed to assess the association between 3 single-nucleotide polymorphisms (SNPs) at the genes coding for 2 SOF metabolizing enzymes: histidine triad nucleotide-binding protein 1 (HINT1) rs4696/rs7728773 and nucleoside diphosphate kinase 1 (NME1) rs3760468, together with the most potent anti-HCV innate molecule, i.e., interferon lambda 3 (IFNL3) rs12979860 and the response to SOF/DCV in Egyptian patients chronically infected with genotype 4 (GT4). SNPs were genotyped using real-time PCR in DNA from patients who achieved sustained virological response (SVR) at 12 weeks post-SOF/DCV treatment (i.e., responders; n = 188), patients who failed to achieve SVR12 (i.e., non-responders; n = 109), and healthy controls (n = 62). Our results demonstrated that patients bearing HINT1 rs7728773 CT/TT (odds ratio 2.119, 95% CI 1.263-3.559, p = 0.005) and IFNL3 rs12979860 CC (odds ratio 3.995, 95% CI 2.126-7.740, p = 0.0001) were more likely to achieve SVR12. However, neither HINT1 rs4696 nor NME1 rs3760468 seems to contribute to the responsiveness to SOF/DCV. Binary regression analysis defined 5 predictor factors independently associated with SVR12: age, bilirubin, hemoglobin, early stages of fibrosis, and combined HINT1 rs7728773 and IFNL3 rs12979860 favorable and mixed genotypes (odds ratio 3.134, 95% CI 1.518-6.47, p = 0.002), and that was confirmed by the combined ROC curve for the 5 predictor factors (AUC = 0.91, 95% CI 0.869-0.95, P = 0.0001). In conclusion, these data suggest that the two SNPs have the potential in predicting the response rate to SOF/DCV treatment in patients infected with HCV GT4. This study is the first to investigate the pharmacogenetics of SOF metabolizing enzyme and introduce HINT1 rs7728773 as a novel SNP that predicts the treatment efficacy.