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

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.

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Risk Factors Contributing to the Occurrence and Recurrence of Hepatocellular Carcinoma in Hepatitis C Virus Patients Treated with Direct-Acting Antivirals

Biomedicines ◽

10.3390/biomedicines8060175 ◽

2020 ◽

Vol 8 (6) ◽

pp. 175

Author(s):

Sara Kishta ◽

Ashraf Tabll ◽

Tea Omanovic Kolaric ◽

Robert Smolic ◽

Martina Smolic

Keyword(s):

Risk Factors ◽

Hepatocellular Carcinoma ◽

Hepatitis C ◽

Dna Ploidy ◽

Hcv Rna ◽

Direct Acting Antivirals ◽

Hepatic Cells ◽

Chronic Hcv ◽

Direct Acting

Although hepatitis C virus (HCV) RNA may be eliminated from blood circulation by direct-acting antivirals (DAA) therapy as assessed by real-time polymerase chain reaction (PCR), HCV RNA can still be present in liver tissue, and this is known as occult HCV. There has been a lot of controversy surrounding the recurrence of hepatocellular carcinoma (HCC) after DAA treatment of hepatic cells infected with chronic HCV. One of the main risk factors that leads to de novo HCC is the chronicity of HCV in hepatic cells. There are many studies regarding the progression of HCV-infected hepatic cells to HCC. However, there is a lack of research on the different molecular mechanisms that lead to the progression of chronic HCV infection to HCC, as well as on the effect of HCV on the alteration of DNA ploidy, which eventually leads to a recurrence of HCC after DAA treatment. In this review article, we will address some risk factors that could lead to the development/recurrence of HCC after treatment of HCV with DAA therapy, such as the role of liver cirrhosis, the alteration of DNA ploidy, the reactivation of hepatitis B virus (HBV), the role of cytokines and the alteration of the immune system, concomitant non- alcoholic fatty liver disease (NAFLD), obesity, alcohol consumption and also occult HCV infection/co-infection. Clinicians should be cautious considering that full eradication of hepatocarcinogenesis cannot be successfully accomplished by anti-HCV treatment alone.

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Long-term Kinetics of Alpha-fetoprotein in Chronic Hepatitis C Patients Treated with Direct-acting Antivirals and Possible Predictive Role of AFP Response to Treatment on Development of Hepatocellular Carcinoma

Viral Hepatitis Journal ◽

10.4274/vhd.galenos.2021.2021-5-3 ◽

2021 ◽

Vol 27 (2) ◽

pp. 49-52

Author(s):

Celal Ulaşoğlu ◽

Banu Erkalma Şenateş ◽

Suna Yapalı ◽

Betül Dumanoğlu ◽

Feruze Enc ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Chronic Hepatitis ◽

Response To Treatment ◽

Direct Acting Antivirals ◽

Predictive Role ◽

Direct Acting ◽

Kinetics Of ◽

Chronic Hepatitis C Patients

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HIV infection is associated with lower risk of hepatocellular carcinoma after sustained virological response to direct-acting antivirals in hepatitis C infected-patients with advanced fibrosis

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1111 ◽

2020 ◽

Cited By ~ 1

Author(s):

A Corma-Gómez ◽

J Macías ◽

J R Lacalle-Remigio ◽

F Téllez ◽

L Morano ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hiv Infection ◽

Sustained Virological Response ◽

Virological Response ◽

Lower Risk ◽

Multivariable Analysis ◽

Liver Stiffness ◽

Advanced Fibrosis ◽

Direct Acting ◽

The Impact

Abstract Background The aim of this study was to assess the impact of HIV infection on the risk of developing hepatocellular carcinoma (HCC) in HCV-infected patients who achieve sustained virological response (SVR) with direct-acting antiviral (DAA). Methods Multisite prospective cohort study, where HCV-monoinfected patients and HIV/HCV-coinfected individuals were included if they met: 1) SVR with DAA-based combination; 2) Liver stiffness (LS) ≥9.5 kPa previous to treatment; 3) LS measurement at the SVR time-point. The main endpoint was the occurrence of HCC. Propensity score (PS) was calculated to address potential confounders due to unbalanced distribution of baseline characteristics of HIV/HCV-coinfected and HCV-monoinfected patients. Results 1035 HCV-infected patients were included, 667 (64%) coinfected with HIV. After a median (Q1-Q3) follow-up time of 43 (31-49) months, 19 (1.8%) patients developed HCC [11 (3.0%) HCV-monoinfected, 8(1.2%) HIV/HCV-coinfected individuals; p=0.013]. In the multivariable analysis, HIV co-infection was associated with a lower adjusted risk of developing HCC [sHR=0.27, 95% IC (0.08-0.90); p=0.034]. Predictors of HCC emergence were: HCV genotype 3 [sHR=7.9 (2.5-24.9); p<0.001], MELD score at SVR>10 [sHR=1.37 (1.01-1.86); p=0.043] and LS value at SVR [sHR=1.03 (1.01-1.06) for 1 kPa increase; p=0.011]. Using inverse probability weighting method on the PS, HIV-infected patients had a lower risk of HCC [powered HR=0.33 (0.11-0.85)]. Conclusions Among HCV-infected patients with advanced fibrosis, who achieve SVR with DAA, HIV-coinfection seems to be associated with a lower risk of HCC occurrence. The underlying causes for this finding need to be investigated.

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Impact of liver‐stiffness measurement on hepatocellular carcinoma development in chronic hepatitis C patients treated with direct‐acting antivirals: A systematic review and time‐to‐event meta‐analysis

Journal of Gastroenterology and Hepatology ◽

10.1111/jgh.15243 ◽

2020 ◽

Author(s):

Myung‐Won You ◽

Kyung Won Kim ◽

Jae‐Jun Shim ◽

Junhee Pyo

Keyword(s):

Hepatocellular Carcinoma ◽

Systematic Review ◽

Meta Analysis ◽

Liver Stiffness ◽

Direct Acting Antivirals ◽

Time To Event ◽

Liver Stiffness Measurement ◽

Stiffness Measurement ◽

Direct Acting ◽

Chronic Hepatitis C Patients

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Lymphocyte Landscape after Chronic Hepatitis C Virus (HCV) Cure: The New Normal

International Journal of Molecular Sciences ◽

10.3390/ijms21207473 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7473

Author(s):

Alip Ghosh ◽

Sara Romani ◽

Shyam Kottilil ◽

Bhawna Poonia

Keyword(s):

Hepatocellular Carcinoma ◽

Immune System ◽

Virologic Response ◽

Viral Clearance ◽

Liver Pathology ◽

Direct Acting Antiviral ◽

Chronic Hcv ◽

Direct Acting ◽

Immune Defects ◽

The Impact

Chronic HCV (CHC) infection is the only chronic viral infection for which curative treatments have been discovered. These direct acting antiviral (DAA) agents target specific steps in the viral replication cycle with remarkable efficacy and result in sustained virologic response (SVR) or cure in high (>95%) proportions of patients. These treatments became available 6–7 years ago and it is estimated that their real impact on HCV related morbidity, including outcomes such as cirrhosis and hepatocellular carcinoma (HCC), will not be known for the next decade or so. The immune system of a chronically infected patient is severely dysregulated and questions remain regarding the immune system’s capacity in limiting liver pathology in a cured individual. Another important consequence of impaired immunity in patients cleared of HCV with DAA will be the inability to generate protective immunity against possible re-infection, necessitating retreatments or developing a prophylactic vaccine. Thus, the impact of viral clearance on restoring immune homeostasis is being investigated by many groups. Among the important questions that need to be answered are how much the immune system normalizes with cure, how long after viral clearance this recalibration occurs, what are the consequences of persisting immune defects for protection from re-infection in vulnerable populations, and does viral clearance reduce liver pathology and the risk of developing hepatocellular carcinoma in individuals cured with these agents. Here, we review the recent literature that describes the defects present in various lymphocyte populations in a CHC patient and their status after viral clearance using DAA treatments.

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