Chronic hepatitis C-related decompensated cirrhosis is associated with lower sustained virologic response (SVR)-12 rates and variable regression of disease severity after direct-acting antiviral agents. We assessed rates of SVR-12, recompensation (Baveno VII criteria), and survival in such patients.

Between July 2018 and July 2023, patients with decompensated chronic hepatitis C-related cirrhosis after direct-acting antiviral agents treatment were evaluated for SVR-12 and then had 6-monthly follow-up.

Of 6516 patients with cirrhosis, 1152 with decompensated cirrhosis (age 53.2 ± 11.5 years; 63% men; Model for End-stage Liver Disease-Sodium [MELD-Na]: 16.5 ± 4.6; 87% genotype 3) were enrolled. SVR-12 was 81.8% after 1 course; ultimately SVR was 90.8% after additional treatment. Decompensation events included ascites (1098; 95.3%), hepatic encephalopathy (191; 16.6%), and variceal bleeding (284; 24.7%). Ascites resolved in 86% (diuretic withdrawal achieved in 24% patients). Recompensation occurred in 284 (24.7%) at a median time of 16.5 (interquartile range, 14.5-20.5) months. On multivariable Cox proportional hazards analysis, low bilirubin (adjusted hazard ratio [aHR], 0.6; 95% confidence interval [CI], 0.5-0.8; P < 0.001), international normalized ratio (aHR, 0.2; 95% CI, 0.1-0.3; P < 0.001), absence of large esophageal varices (aHR, 0.4; 95% CI, 0.2-0.9; P = 0.048), or gastric varices (aHR, 0.5; 95% CI, 0.3-0.7; P = 0.022) predicted recompensation. Portal hypertension progressed in 158 (13.7%) patients, with rebleed in 4%. Prior decompensation with variceal bleeding (aHR, 1.6; 95% CI, 1.2-2.8; P = 0.042), and presence of large varices (aHR, 2.9; 95% CI, 1.3-6.5; P < 0.001) were associated with portal hypertension progression. Further decompensation was seen in 221 (19%); 145 patients died and 6 underwent liver transplantation. A decrease in MELDNa of ≥3 was seen in 409 (35.5%) and a final MELDNa score of <10 was seen in 335 (29%), but 2.9% developed hepatocellular carcinoma despite SVR-12.

SVR-12 in hepatitis C virus-related decompensated cirrhosis in a predominant genotype 3 population led to recompensation in 24.7% of patients over a follow-up of 4 years in a public health setting. Despite SVR-12, new hepatic decompensation evolved in 19% and hepatocellular carcinoma developed in 2.9% of patients. (ClinicalTrials.gov, Number: NCT03488485).

Background and Objectives: Sustained virologic responses (SVRs) lead to a decrease in portal hypertension, the regression of fibrosis, and the improvement in the hepatic synthesis of procoagulant and anticoagulant factors. We aimed to assess the influence of SVR on coagulation parameters in cirrhotic patients with HCV treated with DAAs. Methods: We performed a prospective study in the Institute of Gastroenterology and Hepatology Iasi, Romania, between January 2022 and February 2024. We included patients diagnosed with compensated and decompensated HCV-related liver cirrhosis, treated with direct antivirals (PrOD ± RBV or SOF/LED ± RBV) for 12/24 weeks. Blood samples for biochemical, immunological, and coagulation tests were collected at the baseline, end of treatment (EOT), and once sustained virological response had been achieved over a period of 12/24 weeks (SVR12/24). Results: We analyzed a group of 52 patients with HCV-related liver cirrhosis, predominantly female (68.0%), and the degree of severity of cirrhosis placed the patients mainly in Child-Pugh classes B (40%) and C (36%). All patients achieved SVRs. The MELD score decreased at EOT (13.48 ± 4.273; p = 0.001) and SVR (9.88 ± 2.774; p = 0.000), compared to the baseline (14.92 ± 4.707). The FibroScan values decreased at SVR (17.596 ± 3.7276; p = 0.000) compared to the baseline (26.068 ± 7.0954). For all common coagulation parameters (platelets, INR, PT, fibrinogen, aPTT), there was a trend towards improvement during treatment, including changes which were statistically significant for the majority of patients. Factor II was low at the baseline (75.40 ± 7.506) but increased at EOT (87.40 ± 9.587) and, later, at SVR (99.12 ± 11.695; p = 0.000). The FVIII values increased at the baseline (175.52 ± 16.414) and decreased at EOT (151.48 ± 13.703) and SVR (143.40 ± 13.937). The FvW values decreased during treatment (146.84 ± 9.428, at baseline; 141.32 ± 9.690, p = 0.000, at EOT; and 126.68 ± 17.960, at SVR). In regard to the anticoagulant factors (PC, PS, ATIII), a significant improvement was brought on by SVR. Advanced stages of liver disease showed the most diminished FII activity, while at the baseline and in Child-Pugh C patients we recorded the highest values of FVIII and FvW. Conclusions: Our study proved that the "reset" of coagulopathy might be due to the improvement in liver function due to viral eradication secondary to AAD therapy.

(1) Background: Little is known about the long-term impact of sustained virological response (SVR) on fibrosis progression and patient survival in liver transplantation (LT) recipients treated with direct-acting antivirals (DAAs). We investigated liver fibrosis evolution and patient survival in hepatitis C virus (HCV)-infected patients receiving DAAs after LT. (2) Methods: All consecutive HCV-infected patients treated with DAAs after LT between May 2014 and January 2019 were considered. The clinical and virological features were registered at the baseline and during the follow-up. The liver fibrosis was assessed by liver biopsy and/or transient elastography (TE) at the baseline and at least 1 year after the end of treatment (EoT). (3) Results: A total of 136 patients were included. The SVR12 was 78% after the first treatment and 96% after retreatment. After the SVR12, biochemical tests improved at the EoT and remained stable throughout the 3-year follow-up. Liver fibrosis improved after the SVR12 (p < 0.001); nearly half of the patients with advanced liver fibrosis experienced an improvement of an F ≤ 2. The factors associated with lower survival in SVR12 patients were the baseline platelet count (p = 0.04) and creatinine level (p = 0.04). (4) Conclusions: The long-term follow-up data demonstrated that SVR12 was associated with an improvement in hepatic function, liver fibrosis, and post-LT survival, regardless of the baseline liver fibrosis. The presence of portal hypertension before the DAAs has an impact on patient survival, even after SVR12.

Direct acting antiviral agents are emerging line of treatment to eradicate Hepatitis C virus. Recent controversy over whether direct acting antiviral agents increase rate of hepatocellular carcinoma in HCV patients or prevent it, has increased the need to elaborate underlying mechanisms on molecular basis. This work was aimed to investigate the effect of sofosbuvir on the expression of selected oncogenes from the Ras/Raf/MEK/ERK pathway in Huh7 cell line. Results found concrete molecular evidence that sofosbuvir has significantly altered the expression of selected genes when huh7 cell line was treated with sofosbuvir. Nine genes related to HCC were found to be affected by sofosbuvir in a mixed effect manner. The relative expression of growth factors (VEGF, PDGFRB and HGF) was increased in sofosbuvir treated cell lines. The kinase family genes H-RAS, B-RAF, MET except MAPK1 were downregulated. Similarly, DUSP1 was upregulated and SPRY2 was slightly downregulated; both were negative feedback inhibitors of ERK signalling cascade. Sofosbuvir upregulated the growth factors and MAPK1 which suggests it to be a carcinogen. The downregulation of kinases and upregulation of DUSP1 make it an anticancer drug. Hence, the results from this study are important to prove that sofosbuvir neither reduce nor induce hepatocellular carcinoma.

Introduction: The development of direct-acting antiviral (DAA) agents for the treatment of hepatitis C virus (HCV) infection has completely transformed the management of this disease. The advantages of using DAA therapies include high efficacy (sustained virological response (SVR) rate >95%) with minimal side effects, good tolerability, easy drug administration (once daily oral dosing), and short duration of treatment (8-12 weeks). This transformative nature of DAA therapy underpins the goal of the World Health Organization to eliminate HCV infection as a public health threat by 2030.Areas covered: This review seeks to address the current status of DAA therapies, including recent developments, current limitations, and future challenges.Expert opinion: The current DAA regimens, with their high effectiveness and safety profiles, have changed patient perception of HCV infection from a disease that requires complex evaluation and long-term monitoring to a disease that can be cured after one visit to the general practitioner. Despite the remarkably high success rate of DAAs, few patients (4-5%) fail to obtain SVR even after treatment. Five years ahead, the landscape of HCV treatment will undoubtedly continue to evolve, and more pan-genotypic treatment options will be available to all patients.

Chronic viral hepatitis is a significant health problem throughout the world, which already represents high annual mortality. By 2040, chronic viral hepatitis due to virus B and virus C and their complications cirrhosis and hepatocellular carcinoma will be more deadly than malaria, vitellogenesis-inhibiting hormone, and tuberculosis altogether. In this review, we analyze the global impact of chronic viral hepatitis with a focus on the most vulnerable groups, the goals set by the World Health Organization for the year 2030, and the key points to achieve them, such as timely access to antiviral treatment of direct-acting antiviral, which represents the key to achieving hepatitis C virus elimination. Likewise, we review the strategies to prevent transmission and achieve control of hepatitis B virus. Finally, we address the impact that the coronavirus disease 2019 pandemic has had on implementing elimination strategies and the advantages of implementing telemedicine programs.

Despite the availability of highly effective and well-tolerated direct-acting antivirals, not all patients with chronic hepatitis C virus infection receive treatment. This retrospective, multi-centre, noninterventional, case-control study identified patients with chronic hepatitis C virus infection initiating (control) or not initiating (case) treatment at 43 sites in Germany from September 2017 to June 2018. It aimed to compare characteristics of the two patient populations and to identify factors involved in patient/physician decision to initiate/not initiate chronic hepatitis C virus treatment, with a particular focus on historical barriers. Overall, 793 patients were identified: 573 (72%) who received treatment and 220 (28%) who did not. In 42% of patients, the reason for not initiating treatment was patient wish, particularly due to fear of treatment (17%) or adverse events (13%). Other frequently observed reasons for not initiating treatment were in accordance with known historical barriers for physicians to initiate therapy, including perceived or expected lack of compliance (14.5%), high patient age (10.9%), comorbidities (15.0%), alcohol abuse (9.1%), hard drug use (7.7%), and opioid substitution therapy (4.5%). Patient wish against therapy was also a frequently reported reason for not initiating treatment in the postponed (35.2%) and not planned (47.0%) subgroups; of note, known historical factors were also common reasons for postponing treatment. Real-world and clinical trial evidence is accumulating, which suggests that such historical barriers do not negatively impact treatment effectiveness. Improved education is key to facilitate progress towards the World Health Organization target of eliminating viral hepatitis as a major public health threat by 2030.

Hepatitis C virus (HCV) infection is the major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). The mechanisms of HCC initiation, growth, and metastasis appear to be highly complex due to the decade-long interactions between the virus, immune system, and overlapping bystander effects of host metabolic liver disease. The lack of a readily accessible animal model system for HCV is a significant obstacle to understand the mechanisms of viral carcinogenesis. Traditionally, the primary prevention strategy of HCC has been to eliminate infection by antiviral therapy. The success of virus elimination by antiviral treatment is determined by the SVR when the HCV is no longer detectable in serum. Interferon-alpha (IFN-α) and its analogs, pegylated IFN-α (PEG-IFN-α) alone with ribavirin (RBV), have been the primary antiviral treatment of HCV for many years with a low cure rate. The cloning and sequencing of HCV have allowed the development of cell culture models, which accelerated antiviral drug discovery. It resulted in the selection of highly effective direct-acting antiviral (DAA)-based combination therapy that now offers incredible success in curing HCV infection in more than 95% of all patients, including those with cirrhosis. However, several emerging recent publications claim that patients who have liver cirrhosis at the time of DAAs treatment face the risk of HCC occurrence and recurrence after viral cure. This remains a substantial challenge while addressing the long-term benefit of antiviral medicine. The host-related mechanisms that drive the risk of HCC in the absence of the virus are unknown. This review describes the multifaceted mechanisms that create a tumorigenic environment during chronic HCV infection. In addition to the potential oncogenic programming that drives HCC after viral clearance by DAAs, the current status of a biomarker development for early prediction of cirrhosis regression and HCC detection post viral treatment is discussed. Since DAAs treatment does not provide full protection against reinfection or viral transmission to other individuals, the recent studies for a vaccine development are also reviewed.

With the availability of direct acting antivirals (DAA) for hepatitis C virus (HCV) infection, alcoholic liver disease (ALD) has evolved as the leading indication for listing and receipt of liver transplantation (LT) followed by non-alcoholic steatohepatitis and HCV infection. However, data are limited on etiology specific trends on listings and need for LT for hepatocellular carcinoma (HCC).

We analyzed UNOS database to examine etiology specific listings and receipt of LT for patients with and without HCC. Listings and receipt of LT in the pre-DAA (2007-2012) era were compared to the DAA (2013-2018) era.

The analysis shows that among patients without HCV, there is a decreasing trend on the proportion of patients listed and transplanted for HCV, with simultaneous increase on listings and LT for NASH and ALD. Specifically for listings and transplants for HCC, the leading etiology remains HCV infection followed by NASH and ALD. The analysis also showed that LT for AH contributes to about 20% of increase in listings and receipt of LT for ALD.

Direct-acting antivirals (DAAs) are expected to improve outcomes for patients with hepatitis C virus (HCV) infection after liver transplantation (LT). We aim to evaluate trends in post-LT outcomes with availability of DAAs.

We retrospectively evaluated US adults transplanted from January 1, 2002, to March 31, 2018, using the United Network for Organ Sharing Registry, stratified by pre-DAA (January 1, 2002- to December 31, 2013) vs. post-DAA (January 1, 2014-, to March 31, 2018) eras. Adjusted multivariate Cox regression analyses and competing risk models evaluated likelihood of graft failure, death, and retransplantation (re-LT).

Among 97,147 patients, 30.2% had HCV infection and 19.4% had hepatocellular carcinoma (HCC). Of all patients, 31.9% experienced graft failure, 27.1% died after LT, and 4.7% underwent re-LT. The post-DAA era experienced lower likelihood of graft failure (hazard ratio [HR] = 0.69, p < 0.001). Although patients with HCV infection (HR = 1.18, p < 0.001) and HCC (HR = 1.11, p < 0.001) had higher likelihood of graft failure in the pre-DAA era, no differences were seen in the post-DAA era. Although patients with HCV infection (HR = 1.20, p < 0.001) and HCC (HR = 1.17, p < 0.001) had higher likelihood of death after LT in the pre-DAA era, no differences were seen in the post-DAA era. The post-DAA era had lower likelihood of post-LT death when stratified by non-HCC (HR = 0.70, p < 0.001) and HCC cohorts (HR = 0.67, p < 0.001) or by non-HCV (HR = 0.73, p < 0.001) and HCV (HR = 0.58, p < 0.001) cohorts.

Although patients with HCV infection and HCC had higher risk of post-LT graft failure and death in the pre-DAA era, the disparity disappeared in the post-DAA era independently of each other. This likely reflects impact of DAAs on improving post-LT outcomes among patients with HCV infection and improved selection of patients with HCC for LT after 2014.

Utilization of direct acting antiviral (DAA) therapy in candidates with well-compensated hepatitis C virus (HCV) cirrhosis and hepatocellular carcinoma (HCC) accruing end stage liver disease (MELD) exception points is highly variable among transplant centers based on center location, local organ procurement dynamics, HCV(+) organ availability, and patient preference. The association between DAA utilization prior to transplant and incidence of lymphovascular invasion on explant is unknown.

Retrospective evaluation from 2013-2017 of patients on a liver transplant (LT) waitlist with HCV-related cirrhosis, MELD-Na < 15, and HCC (within T2/Milan criteria). The cohort was divided into the pre-LT DAA treated group and untreated group with clinical/viral demographics collected. Tumor presenting characteristics, locoregional treatments, wait time to LT, dropout rates and explant pathology were compared.

DAAs were used in 44 patients prior to LT (SVR12 of 37/44 [84%]) and 19 left untreated with LT performed in 81% (51/63) of the waitlisted cohort. No significant differences were found between groups with regards to clinical/viral demographics, local-regional therapy (LRT) sessions, or frequency of lymphovascular invasion on explant. The untreated cohort had a higher rate of dropout (6.3% vs. 3.2%) (p = 0.041). On subgroup analysis of 51 subjects undergoing LT, AFP > 250 ng/ml (p = 0.003) and multifocal HCC (> 1 lesion) (p = 0.006) were associated with lymphovascular invasion on explant while DAA therapy was not (p = 0.578).

DAA therapy for waitlist active HCV candidates accruing MELD exception points has no deleterious effects on bridging LRT, nor is it associated with increased frequency of lymphovascular invasion on explant. The latter appears driven by tumor related characteristics (AFP and number of lesions) irrespective of DAA utilization prior to LT.