Risk of Hepatocellular Carcinoma after HCV Clearance by Direct-Acting Antivirals Treatment Predictive Factors and Role of Epigenetics

Abstract

Direct-acting antivirals (DAAs) induce a rapid virologic response (SVR) in up to 99% of chronic hepatitis C patients. The role of SVR by DAAs on the incidence or recurrence of hepatocellular carcinoma (HCC) is still a matter of debate, although it is known that SVR does not eliminate the risk of HCC. In this review, we made an updated analysis of the literature data on the impact of SVR by DAAs on the risk of HCC as well as an assessment of risk factors and the role of epigenetics. Data showed that SVR has no impact on the occurrence of HCC in the short–medium term but reduces the risk of HCC in the medium–long term. A direct role of DAAs in the development of HCC has not been demonstrated, while the hypothesis of a reduction in immune surveillance in response to the rapid clearance of HCV and changes in the cytokine pattern influencing early carcinogenesis remains to be further elucidated. HCV induces epigenetic alterations such as modifications of the histone tail and DNA methylation, which are risk factors for HCC, and such changes are maintained after HCV clearance. Future epigenetic studies could lead to identify useful biomarkers and therapeutic targets. Cirrhosis has been identified as a risk factor for HCC, particularly if associated with high liver stiffness and α-fetoprotein values, diabetes and the male sex. Currently, considering the high number and health cost to follow subjects’ post-HCV clearance by DAAs, it is mandatory to identify those at high risk of HCC to optimize management.

Chitinase 3‐like‐1, Tolloid‐like protein 1, and intergenic gene polymorphisms are predictors for hepatocellular carcinoma development after hepatitis C virus eradication by direct‐acting antivirals

“…Studies on this SNP were performed only on coronary artery disease by Zain et al 15 and Cresci et al 24 The present study also reported a significant difference in the genotypes of rs1503298 in the male cohort. These results are matched with Rinaldi et al, 25 who showed that male sex is one of the significant predictors of the onset of HCC.…”

Incidence of Hepatocellular Carcinoma after Treatment with Sofosbuvir-Based or Sofosbuvir-Free Regimens in Patients with Chronic Hepatitis C

“…We chose to use the PSM FUZZY extension command in Python to balance the SOF-based and SOF-free groups. Variables used in the PSM model included sex, age, serum albumin, ALT, platelet count, AFP, eGFR, cirrhosis, and treatment experience, all of which are clinically important variables for predicting the development of HCC according to recent reports [4][5][6][7][8][11][12][13]16,17]. Caliper matching of the propensity scores was done, and pairs were matched to within a range of 0.2 standard deviations of the logit of the propensity scores [35].…”

“…Fortunately, with the advent of direct-acting antivirals (DAAs) in 2013, the rates of sustained viral response (SVR) now range from 85% to almost 100%, depending on the HCV genotype and the presence of cirrhosis or active HCC [1][2][3]. This has contributed to a reduction of the risk for HCC [4][5][6][7][8] and the number of patients requiring a liver transplant [9,10].…”

“…However, the development of HCC has not been well-controlled, even after HCV cure, especially for those with cirrhosis or in old age [4][5][6][7][8]11]. Some fibrosis-related biomarkers, such as FIB-4 index, aspartate aminotransferase to platelet ratio index, liver stiffness measurement, and α-fetoprotein (AFP) level, have been recognized as useful predictors for the development of HCC [4,5,[11][12][13].…”

Hepatocellular Carcinoma Risk According to Regimens for Eradication of Hepatitis C Virus; Interferon or Direct Acting Antivirals

“…In a similar context, another study reported that sofosbuvir (SOF) may activate epidermal growth factor receptor (EGFR)-dependent pathways, inducing liver-related pathological processes [ 14 ]. Nevertheless, subsequent studies have failed to reproduce such kinds of data systematically yet, indicating that there has been no difference in the risk of HCC occurrence or recurrence following SVR from DAA- vs. IFN-based therapy so far [ 15 , 16 , 17 , 18 ]. However, Ogawa et al [ 19 ] recently proposed a trend toward a higher short-term HCC incidence in a subgroup treated with a specific DAA, i.e., SOF.…”