Hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC) accounting for around one-third of all HCC cases. Prolonged inflammation in chronic hepatitis C (CHC), maintained through a variety of pro- and anti-inflammatory mediators, is one of the aspects of carcinogenesis, followed by mitochondrial dysfunction and oxidative stress. Immune response dysfunction including the innate and adaptive immunity also plays a role in the development, as well as in the recurrence of HCC after treatment. Some of the tumor suppressor genes inhibited by the HCV proteins are p53, p73, and retinoblastoma 1. Mutations in the telomerase reverse transcriptase promoter and the oncogene catenin beta 1 are two more important carcinogenic signaling pathways in HCC associated with HCV. Furthermore, in HCV-related HCC, numerous tumor suppressor and seven oncogenic genes are dysregulated by epigenetic changes. Epigenetic regulation of gene expression is considered as a lasting “epigenetic memory”, suggesting that HCV-induced changes persist and are associated with liver carcinogenesis even after cure. Epigenetic changes and immune response dysfunction are recognized targets for potential therapy of HCC.

Background: Hepatocellular carcinoma (HCC) frequently develops in patients with chronic hepatitis B and C. Early detection is critical, but current methods, including ultrasound and AFP, have suboptimal accuracy. Objectives: This study aimed to evaluate the predictive performance of protein induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha-fetoprotein (AFP) testing, alone and in combination, for HCC development. Methods: A retrospective cohort study at a single university center included 242 CHB and 181 CHC patients. Data on demographics, clinical status, laboratory parameters, and imaging were collected, with fibrosis and steatosis assessed by FibroScan^®. Serum AFP and PIVKA-II were measured, but measurements of PIVKA-II in patients receiving vitamin K antagonists were excluded from the analysis. HCC diagnosis and staging followed clinical guidelines. Cox regression and ROC analyses identified independent predictors and evaluated biomarker accuracy for HCC detection. Results: HCC incidence was comparable between cohorts (5.0% in CHB vs. 5.5% in CHC). Both AFP and PIVKA-II independently predicted HCC development in multivariate models adjusted for age and sex. The combined biomarker score (AFP × PIVKA-II) showed superior predictive accuracy with hazard ratios of 1.38 (CHB) and 1.36 (CHC). ROC analyses demonstrated high discriminative ability for PIVKA-II (AUC ~0.81) and AFP (AUC ~0.83) in both cohorts. Additional independent predictors were chronic alcohol abuse, cirrhosis, and higher liver stiffness measurements. Specific viral factors such as HBeAg positivity and HCV subgenotype 1b were also associated with increased HCC risk. Conclusions: AFP and PIVKA-II are independent, valuable biomarkers for HCC risk in chronic hepatitis B and C. Combined use improves early detection, aiding timely treatment. These results support adding PIVKA-II to AFP in surveillance, but larger studies are needed to confirm the findings and refine cut-off values.

This study, conducted at two university-based infectious disease clinics, included 216 patients with chronic hepatitis C. The primary objective was to assess the positive and negative predictive values, sensitivity, and specificity of achieving a sustained virological response (SVR) at 4 weeks compared to 12 weeks post-therapy. The results demonstrated a maximum sensitivity of 100% for achieving SVR at 12 weeks after reaching SVR at 4 weeks for all analyzed genotypes, except for genotype 1b treated with EBR/GZR therapy, where the specificity was 75%. Additionally, younger age and less advanced liver fibrosis were identified as independent predictors of achieving a sustained virological response at both 4 and 12 weeks. The significant normalization of various biochemical parameters was observed after treatment, indicating an overall improvement in liver function. This study suggests that shortening the monitoring period to 4 weeks might be effective for younger patients without significant fibrosis, potentially reducing loss to follow-up, which is a critical issue in HCV treatment. These findings align with the “test and treat” approach. Further research is needed to confirm these findings and incorporate them into official guidelines, which could simplify and enhance the effectiveness of HCV treatment protocols, aiding global efforts to eliminate HCV as a public health issue by 2030.

People who inject drugs (PWIDs) experience high rates of hepatitis C virus (HCV) infection, primarily due to needle sharing and limited healthcare access, resulting in a disproportionate disease burden within this population. This prospective study evaluated treatment outcomes in 432 adult patients with chronic hepatitis C (CHC) treated with direct-acting antivirals (DAAs) at the University Clinical Center of Serbia. Patients were categorized into two groups based on a history of drug addiction: PWIDs (163, 37.7%) and non-PWIDs (269, 62.3%). The PWID group was further categorized into subpopulations of problematic PWIDs (39, 23.9%), ex-PWIDs (124, 76.1%), and PWIDs on OST (96, 58.9%). The PWID group demonstrated significantly lower treatment adherence, with an intention-to-treat (ITT) rate of 82.8%, compared to 96.3% in the control group (p < 0.001). In contrast, no significant differences were observed in per-protocol (PP) outcomes between the two groups. Additionally, PWIDs were significantly younger (p < 0.001) and had higher rates of psychiatric disorders (p < 0.001), alcohol abuse (p < 0.001), and HCV genotype 1a (p < 0.001). Advanced fibrosis was predictor of PP treatment failure among PWIDs, while mood disorders and alcohol use disorder were associated with interruptions before the scheduled completion time. For non-PWIDs, older age and advanced fibrosis emerged as key predictors of PP treatment failure. The loss to follow-up was most commonly observed in the problematic PWID subgroup (p = 0.001). These findings highlight the importance of addressing barriers in PWIDs through integrated care strategies that concurrently manage addiction and HCV.