Direct-acting antivirals (DAAs) have dramatically changed the landscape of chronic hepatitis C virus (HCV) treatment and significantly reduced the risk of HCV-related hepatocellular carcinoma (HCC) after achieving sustained virologic response. However, the risk of HCC persists, particularly in patients with pre-treatment cirrhosis or fibrosis stage 3 (F3), even after DAA-induced viral eradication. While professional guidelines agree on the need for surveillance in cirrhotic patients, there is no consensus regarding surveillance for the pre-treatment F3 population following HCV eradication. The risk of HCC in the F3 population falls below the threshold for cost-effective surveillance. However, co-existing risk factors-such as diabetes, hepatic steatosis, alcohol use, advanced age, and elevated alpha-fetoprotein levels-may warrant reconsideration of HCC surveillance in this group. This underscores the need for an individualized, risk-based approach to HCC surveillance. This review provided a simplified algorithm to assist clinicians in managing patients with HCV after DAA-induced sustained virologic response.

Direct-acting antivirals (DAAs) are highly effective in treating hepatitis C virus (HCV) infection. The long-term hepatic and extrahepatic outcomes of DAAs in chronic hepatitis C (CHC) patients receiving curative antivirals are elusive.

CHC patients were retrieved from two phase III sofosbuvir-based clinical trials conducted from 2013-2014. Patients who achieved a sustained virological response have been followed prospectively for 5 years since 2016. A propensity score-matched interferon-based historical control with a 1:3 ratio was used for comparison. Quality of life (QoL) was measured by the SF-36, liver fibrosis was measured by electrography, and fibrosis-related markers were followed annually in the prospective cohort.

A total of 160 DAA- and 480 interferon-treated patients were enrolled. Twenty-eight patients developed hepatocellular carcinoma (HCC) over a follow-up period of 4424 person-years (annual incidence: 0.6%). The incidence of HCC did not differ significantly between the DAA cohort and interferon-treated patients (P = 0.07). Cox regression analysis revealed that FIB-4 was the only factor independently associated with HCC development (hazard ratio [HR]: 95% confidence interval [CI] 3.59/1.68-7.66, P = 0.001). The incidence of newly developed cardio-cerebrovascular disease was 13.8 per 1000 person-years and 0.9 per 1000 person-years in interferon-treated patients and the DAA cohort, respectively (P < 0.001). Interferon-based patients had a significantly greater incidence of cardio-cerebrovascular disease (HR/CI 3.39/1.28-8.96, P = 0.014). There was a substantial decrease in liver stiffness (Ptrend = 0.08) and M2BPGi (Ptrend = 0.05) and a significant reduction in LOXL2 (Ptrend = 0.02) over 5 years. A significant decrease in QoL was observed in role limitations due to physical health and emotional problems, whereas the other parameters were maintained consistently throughout the 5 years of follow-up.

HCV eradication by DAAs improved liver- and non-liver-related outcomes, constantly promoted liver fibrosis regression, and maintained quality of life after HCV cure.

NCT03042520.

The epidemiological landscape of hepatocellular carcinoma (HCC) in Europe is evolving. This study aims to provide an updated description of the current epidemiology of liver cancer in Spain.

This multicenter prospective study collected demographic and clinical data on primary liver cancer between October 2022 and January 2023. We conducted descriptive and comparative analyses with data collected in 2008 and 2014.

Of the 767 cases of primary liver cancer collected from 52 centers, 91% were diagnosed as HCC. The majority of patients were male (83.3%), average age 68 years, 80.7% had cirrhosis. The primary causes were alcohol (29.9% alone, 55% combined with other etiologies), liver disease related to metabolic syndrome (LDrMS, 23%) and hepatitis C (17.3%). Treatments included ablation (15.7%), systemic therapy (14.7%), and chemoembolization (14.6%). Data from 29 centers (n = 1,351) across three registries revealed a significant increase in LDrMS (from 4.9% to 24%) and HCC in non-cirrhotic livers (from 4.2% to 7.9%). Meanwhile, hepatitis C decreased sharply (from 43% to 17.5%). Alcohol-related cases remained stable. There was a slight increase in male patients and hypertension, diabetes, and obesity. Patients with cirrhosis diagnosed outside of screening programs presented with larger tumors and more advanced disease. This led to fewer evaluations for curative treatments.

Alcohol accounts for 30% of HCC cases and is the main etiology. The registry shows a decrease in hepatitis C-related HCC, an increase in LDrMS and HCC in non-cirrhotic livers. Surveillance was implemented in ∼80% of the recommended population. There is a need for improved screening and prevention strategies, particularly for alcohol abuse and LDrMS, to enhance HCC management.

Our study showcases the involvement of numerous reference centers across Spain and examines over 1,300 patients to track the changing epidemiology of hepatocellular carcinoma (HCC) over 14 years. In patients with known liver cirrhosis, more than 80% of HCC diagnoses were made through screening leading to early-stage identification and curative treatment opportunities. Notably, there has been a shift in HCC etiology within the registries from hepatitis C to liver disease related to metabolic syndrome, with an increase in cases without cirrhosis. Findings indicate a need for the prevention and early detection of HCC, particularly focusing on alcohol and liver disease related to metabolic syndrome, along with greater involvement of health authorities, to improve the participation of at-risk patients in screening programs.

Recent data suggest emerging rural-urban disparities in hepatocellular carcinoma (HCC) burden in the United States. We aimed to assess (i) trends in rural vs urban HCC-related mortality and (ii) differences in underlying chronic liver disease etiologies contributing to HCC-related deaths.

We used the National Vital Statistics System to examine crude and age-adjusted HCC death rates overall and by etiology for rural and urban residents from 2005 to 2023. Using the National Cancer Institute Joinpoint Trend Analysis Software, we identified statistically significant changes in annual percentage change (APC) in HCC mortality rates.

Examining mortality rates over time, average APC in HCC deaths was significantly higher in rural residents (crude average annual percentage change [AAPC] 4.64, 95% confidence interval [CI] 4.10, 5.34; age-adjusted AAPC 3.53, 95% CI 3.09, 4.07) compared with urban residents (crude AAPC 2.72, 95% CI 2.43, 3.01; age-adjusted AAPC 1.68, 95% CI 1.28, 2.13). Differences in HCC death rate changes were driven by a significantly greater recent decline in HCC cases from hepatitis C virus (HCV) in urban residents (crude APC -6.69, 95% CI -8.85, -5.30 from 2017 to 2023) compared with rural residents (crude APC -3.31, 95% CI -8.05, 0.73 from 2016 to 2023).

Annual increases in HCC deaths have been more pronounced in rural compared with urban populations. Deaths from HCV-related HCC have declined with a geographical disparity that favors urban populations, possibly driven by decreased access to HCV screening or availability of highly effective direct-acting antiviral therapies for rural residents. These findings underscore the need for targeted HCV screening and treatment strategies in rural populations in addition to ongoing strategies to combat alcohol use and metabolic diseases.

Approximately 95% of patients with chronic hepatitis C achieve viral eradication through direct-acting antiviral (DAA) treatment. Ensuing clinical benefits include halting liver fibrosis, thereby reducing the need for liver transplantation, and decreasing both liver-related and overall mortality. It is well established that, although ameliorated, the risk of developing hepatocellular carcinoma (HCC) persists, particularly among patients with pre-treatment advanced fibrosis/cirrhosis. Current guidelines recommend indefinite HCC surveillance in these patients. However, a recent Markov model evaluation shows that HCC surveillance is cost-effective only for patients with cirrhosis but not so for those with F3 fibrosis, a finding which points out the need to better define the risk of HCC in hepatitis C patients after cure and further characterize pre- and post-treatment factors that might affect the incidence of HCC in this setting. We reviewed the literature analyzing this aspect. Here we summarize the main findings: male gender and older age are independent predictors of increased risk of post-cure HCC development. Moreover, non-invasive tests for hepatic fibrosis, namely FIB4, APRI, and liver stiffness, measured before and after treatment and their post-therapy change, contribute to better stratifying the risk of HCC occurrence. Furthermore, low serum albumin, as well as an AFP above 7 ng/mL prior to and after DAA therapy, also constitute independent predictors of HCC development. Considering these findings, we propose to classify patients with HCV viral eradication and advanced fibrosis/cirrhosis into groups of low, medium, or high risk of HCC and to adopt adequate surveillance strategies for each group, including protocols for abbreviated magnetic resonance imaging (MRI) for those at the highest risk.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with chronic infections by hepatotropic viruses such as hepatitis B virus (HBV), and hepatitis C virus (HCV), being major risk factors. Chronic infections with these viruses are the leading cause of HCC worldwide, with HBV alone responsible for over 50% of cases. Despite advances in direct-acting antivirals (DAAs) for HCV and nucleos(t)ide analogues (NAs) for HBV, challenges remain in HCC prevention, early detection, and treatment. Recent research highlights the role of viral-induced metabolic alterations, such as the Warburg effect, mitochondrial dysfunction, and lipid dysregulation, in promoting HCC. Moreover, immune checkpoint inhibitors have emerged as effective treatments for advanced HCC, though responses vary between HBV- and HCV-related cancers. Additionally, novel therapeutic approaches and metabolic-targeted therapies offer promising avenues for virus-associated HCC treatment. Advancements in liquid biopsy biomarkers and artificial intelligence-driven diagnostics are improving HCC surveillance and risk stratification, potentially enabling earlier interventions. While HBV vaccination has significantly reduced HCC incidence, disparities in global vaccination coverage persist. Furthermore, antiviral therapies combined with structured surveillance programs have proven effective in reducing HCC incidence and mortality. This review highlights the complex connection between viral, genetic, and environmental factors in HCC development and underscores the importance of integrated prevention strategies to reduce its burden globally.

The risk of hepatocellular carcinoma (HCC) remains elevated in cirrhotic hepatitis C patients with sustained virological response (SVR) after DAA treatment. We assessed long-term HCC risk stratified by pretreatment liver stiffness measurement (LSM) and developed a risk score algorithm.

This register-based nationwide cohort study of 7,227 DAA-treated patients with SVR evaluated annual HCC incidence rates (IRs) and cumulative incidences stratified by pretreatment LSM. The association between LSM and HCC risk was analyzed using multivariate Cox regression. A risk score algorithm was developed and internally validated in 2,664 individuals with LSM >9.5 kPa, assigning each patient a score based on risk factors, proportionally weighted by the association with HCC risk.

During a median follow-up of 1.8 years (3.2 years for LSM ≥12.5 kPa), 92 patients (1.3%) developed HCC. The IRs for LSM 9.5-12.4, 12.5-19.9 and ≥20 kPa were 0.21, 0.99 and 2.20 HCC/100 PY, respectively, with no significant risk reduction during follow-up. The HRs (and 95% CI) for LSM 9.5-12.5, 12.5-19.9 and ≥20 kPa are 1.19 (0.43-3.28), 4.66 (2.17-10.01) and 10.53 (5.26-21.08), respectively. Risk score models including FIB-4, alcohol, diabetes, age and LSM effectively stratified patients with LSM >9.5 kPa into low-, intermediate- and high-risk groups, with a Harrell's C of 0.799. Notably, 48% with LSM ≥9.5 kPa and 27% ≥12.5 kPa were classified as low-risk.

Pretreatment LSM is associated with HCC risk, which remains stable during the initial five years post-SVR. The HCC risk score algorithm effectively identifies low-risk patients, who may not require HCC surveillance.

HCV genotype (GT) 3 is associated with rapid liver disease progression. However, the liver disease progression and its risk factors in patients with HCV GT 3 infection after sustained virological response (SVR) following direct-acting antivirals (DAAs) remain unclear. Therefore, we aimed to investigate the liver disease progression of patients with GT 3 after SVR.

This was a retrospective cohort study of patients with HCV infection who achieved SVR by DAAs. The clinical outcome was overall liver disease progression (OLDP), defined as newly diagnosed compensated liver cirrhosis, decompensated liver cirrhosis, or hepatocellular carcinoma. The incidence of OLDP was evaluated by Kaplan-Meier analysis. Cox regression analysis identified the risk factors for OLDP.

A total of 409 patients (46.9% GT3) were followed for 43.7 (32.9, 58.7) months. The incidence of OLDP was higher in patients with GT 3 (4.63/100PY) than non-GT 3 (0.60/100PY; P < 0.001). According to Cox multivariate analysis, GT 3 was significantly associated with OLDP (HR 6.41, 95% CI 1.82 - 22.56; P=0.004). The predictors of OLDP in patients with GT 3 were HCV recurrence (HR 12.15, 95% CI 3.18 - 46.46; P < 0.001) and FIB-4 > 3.25 (HR 16.40, 95% CI 1.03 - 39.81; P = 0.046) at baseline.

HCV GT 3-infected patients remain at a higher risk of OLDP even after achieving SVR by DAAs, especially patients with advanced liver fibrosis and at high risk for reinfection or virological late relapse.

Direct-acting antiviral (DAA) therapy is associated with a significant reduction in hepatocellular carcinoma (HCC) incidence among patients with cirrhosis, but data are conflicting about the risk of recurrence following DAA therapy. DAA-PASS was a prospective, pragmatic, observational study designed to estimate the risk of HCC recurrence associated with DAA therapy exposure during routine clinical care. Eligible patients were DAA treatment naive with Barcelona Clinic Liver Cancer (BCLC) stage A. Patients were followed at regular intervals for up to 24 months. To provide additional data, outcomes were compared to the Italian Liver Cancer Group (ITA.LI.CA) cohort. Of 42 patients enrolled, 24 were treated with DAA therapy. Ten HCC recurrence events were observed during the study, with 5 each in DAA-treated and DAA-untreated patients (cumulative incidences of 23 and 37 per 100 PY, respectively). The overall crude hazard ratio (HR) for HCC recurrence associated with DAA therapy was 0.6 (95% CI, 0.2-2.2). In the ITA.LI.CA cohort, HCC recurrence was observed in 193 patients during 24 months of follow-up, resulting in a cumulative incidence rate of 28 per 100 PY. Although limited by small sample size, this prospective study suggests DAA therapy is not associated with increased HCC recurrence risk among patients with a history of complete response to prior HCC therapy.

The research intended to present prospective data on the long-term prognosis of individuals with hepatitis C virus (HCV) infection who received direct-acting antiviral agent (DAA) treatment.

Patients who received DAA treatment at Tianjin Third Central Hospital and Tianjin Second People's Hospital were prospectively enrolled and subsequently underwent a longitudinal follow-up. This research monitored occurrences of virological relapse, hepatocellular carcinoma (HCC), mortality, and liver disease progression. The annualized incidence rates (AIRs), cumulative incidence rates of adverse events and risk factors were investigated. Changes in liver stiffness measurement (LSM), aspartate aminotransferase-to-platelet ratio index (APRI) score, fibrosis-4 (FIB-4) index, as well as the albumin-bilirubin (ALBI) scores were also documented.

A total of 862 individuals were followed up for 4.86 (P25, P75; 4.48, 5.48) years. The proportion of all participants with undetectable HCV-RNA exceeded 98% at all follow-up time points. Patients experienced virological relapse, HCC, death and disease progression with a cumulative AIRs of 1.03% (95% confidence interval [CI] 0.6-1.5), 1.76% (95% CI 1.2-2.3), 1.51% (95% CI 1.0-2.0), and 5.81% (95% CI 4.8-6.8), respectively. Cirrhotic patients were at a heightened risk of virological relapse (adjusted hazard ratio [aHR] 3.20, 95% CI 1.59-9.75; p = 0.016), HCC (aHR 6.57, 95% CI 2.66-16.28; p < 0.0001), and unfavorable prognosis (aHR 6.93, 95% CI 2.56-18.74; p < 0.0001). Additionally, patients with diabetes faced an elevated risk of HCC (aHR 2.33, 95% CI 1.05-5.15; p = 0.038) and poor prognosis (aHR 2.72, 95% CI 1.13-6.55; p = 0.026). Furthermore, liver stiffness measurement (LSM) exhibited a significant decrease compared to baseline. Additionally, patients in the cirrhosis group showed reductions in APRI score, FIB-4 index and ALBI score to different degrees.

Cirrhotic patients exhibited increased susceptibility to virological relapse, HCC, unfavorable prognosis, and liver disease progression following DAA treatment. Consequently, it is imperative to implement a rigorous monitoring protocol for all cirrhotic patients after DAA treatment.

Preventive interventions are expected to substantially improve the prognosis of patients with primary liver cancer, predominantly HCC and cholangiocarcinoma. HCC prevention is challenging in the face of the evolving etiological landscape, particularly the sharp increase in obesity-associated metabolic disorders, including metabolic dysfunction-associated steatotic liver disease. Next-generation anti-HCV and HBV drugs have substantially reduced, but not eliminated, the risk of HCC and have given way to new challenges in identifying at-risk patients. The recent development of new therapeutic agents and modalities has opened unprecedented opportunities to refine primary, secondary, and tertiary HCC prevention strategies. For primary prevention (before exposure to risk factors), public health policies, such as universal HBV vaccination, have had a substantial prognostic impact. Secondary prevention (after or during active exposure to risk factors) includes regular HCC screening and chemoprevention. Emerging biomarkers and imaging modalities for HCC risk stratification and detection may enable individual risk-based personalized and cost-effective HCC screening. Clinical studies have suggested the potential utility of lipid-lowering, antidiabetic/obesity, and anti-inflammatory agents for secondary prevention, and some of them are being evaluated in prospective clinical trials. Computational and experimental studies have identified potential chemopreventive strategies directed at diverse molecular, cellular, and systemic targets for etiology-specific and/or agnostic interventions. Tertiary prevention (in conjunction with curative-intent therapies for HCC) is an area of active research with the development of new immune-based neoadjuvant/adjuvant therapies. Cholangiocarcinoma prevention may advance with recent efforts to elucidate risk factors. These advances will collectively lead to substantial improvements in liver cancer mortality rates.

In regions with a high prevalence of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, coinfected patients face a heightened risk of developing hepatocellular carcinoma (HCC), termed HBV/HCV-related HCC (HBCV-HCC). We aimed to investigate the contribution of preexisting chronic hepatitis B (CHB) and subsequent chronic hepatitis C (CHC) to the development of HBCV-HCC.

We examined HBV's involvement in 93 HBCV-HCC cases by analyzing HBV DNA integration as an indicator of HCC originating from HBV-infected hepatocytes, compared with 164 HBV-HCCs and 56 HCV-HCCs as controls.

Next generation sequencing revealed that 55% of HBCV-HCCs exhibited clonal HBV integration, which falls between the rates observed in HBV-HCCs (88%) and HCV-HCCs (7%), with similar integration patterns to HBV-HCCs. Common HCC somatic mutation analysis indicated HCV superinfection in HBCV-HCCs correlated with increased mutation rates in the telomerase reverse transcriptase (TERT) promoter and beta-catenin genes. Transcriptome analysis showed a prevalence of replicating HCV over HBV in HBCV-HCCs, with preexisting HBV exerting a proliferative role. The comparison of clinical characteristics revealed similarities between HBCV-HCC and HCV-HCC patients, including later onset for HBCV-HCC, possibly due to HCV superinfection slowing carcinogenesis. Notably, HBCV-HCCs with the same driver mutation, HBV integration at the TERT promoter, tended to develop later and showed a better prognosis post-tumor resection than HBV-HCCs.

Our findings shed light on the interplay between preexisting CHB and subsequent CHC in elevating the risk of HBCV-HCC. These insights are crucial for understanding viral etiology-specific carcinogenesis and guiding surveillance policies for HBCV-HCC post-antiviral therapy.

Hepatitis C virus (HCV) infection is a significant risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). Traditionally, the primary prevention strategy for HCV-associated HCC has focused on removing infection through antiviral regimes. Currently, highly effective direct-acting antivirals (DAAs) offer extraordinary success across all patient categories, including cirrhotics. Despite these advancements, recent studies have reported that even after sustained virologic response (SVR), individuals with advanced liver disease/cirrhosis at the time of DAA treatment may still face risks of HCC occurrence or recurrence. Based on this premise, this review tries to shed light on the multiple mechanisms that establish a tumorigenic environment, first, during chronic HCV infection and then, after eventual viral eradication by DAAs. Furthermore, it reviews evidence reported by recent observational studies stating that the use of DAAs is not associated with an increased risk of HCC development but rather, with a significantly lower chance of liver cancer compared with DAA-untreated patients. In addition, it seeks to provide some practical guidance for clinicians, helping them to manage HCC surveillance of patients who have achieved SVR with DAAs.

Direct-acting antivirals (DAA) achieve high virological response rates with minimal side effects for many patients. Despite their significant impact on the progression and epidemiology of hepatitis C virus (HCV) associated liver disease, the global annual incidence of chronic infections is expected to remain relatively constant, averaging 1.42 million new cases each year until 2030. Furthermore, by 2030, there will be a 14-17% increase in end-stage liver disease outcomes such as liver-related deaths, hepatocellular carcinoma (HCC), and decompensated cirrhosis in adults aged 18 years and over. Although reductions in liver decompensation, HCC occurrence, and mortality have been shown in patients with advanced liver disease who achieved sustained virological response (SVR) with DAA, these benefits may be less significant in those with decompensated liver cirrhosis. This review aims to summarise the impact of the virological response to DAA on liver disease progression and outcomes in patients with advanced chronic liver disease, which appears to be crucial for defining patient-specific follow-up.

This study aimed to compare the determinants and impact of hepatocellular carcinoma (HCC) surveillance rates for people with metabolic dysfunction-associated steatotic liver disease (MASLD) versus other chronic liver diseases.

A dataset of HCC patients from a UK hospital (2007-2022) was analyzed. The Mann-Whitney U-test compared continuous variables. The χ2 and two-tailed Fisher exact tests compared categorical data. Regression modeling analyzed the impact of MASLD on the size and number of HCC nodules and curative treatment. The Cox proportional hazards model assessed the influence of MASLD on overall survival.

A total of 176 of 687 (25.6%) HCC patients had MASLD. Fewer people with MASLD HCC were enrolled in HCC surveillance compared to non-MASLD HCC (38 [21.6%] vs 215 [42.1%], P < 0.001). Patients with MASLD HCC were less likely to have been under secondary care (n = 57 [32.4%] vs 259 [50.7%], P < 0.001) and less likely to have cirrhosis (n = 113 [64.2%] vs 417 [81.6%], P < 0.001). MASLD was associated with a 12.3-mm (95% confidence interval [CI] 10.8-14.0 mm) greater tumor diameter compared to people without MASLD (P = 0.002). Patients with MASLD HCC had 0.62 reduced odds (95% CI 0.43-0.91) of receiving curative treatment compared to non-MASLD HCC (P = 0.014). Overall survival was similar for patients with MASLD HCC versus non-MASLD HCC (hazard ratio 1.03, 95% CI 0.85-1.25, P = 0.748).

Patients with MASLD are less likely to have been enrolled in HCC surveillance due to undiagnosed cirrhosis or presenting with non-cirrhotic HCC. Patients with MASLD HCC present with larger tumors and are less likely to receive curative treatment.

The advent of direct-acting antiviral (DAA) therapy has revolutionized hepatitis C virus (HCV) treatment, enabling most HCV-infected patients to achieve a sustained viral response (SVR) easily and safely in a short period. On the other hand, it is gradually being recognized that a significant proportion of patients are still at risk of developing de novo and recurrent hepatocellular carcinoma (HCC), even after HCV elimination, and therefore, elucidation of the risk of de novo and recurrent HCC, investigation of its molecular basis, and construction of accurate prediction models are emerging as new important clinical topics. In this review, we present recent advances regarding these issues.

This research was designed to determine the long-term outcomes in patients with liver cirrhosis who achieved sustained virological response (SVR) after direct-acting anti-viral drugs (DAAs) based regimens.

This study involved 193 patients with HCV-related cirrhosis who had previously completed DAAs regimens and accomplished SVR. Clinical, laboratory, and radiological features at the first and 3rd-year follow-up after the end of treatment were analyzed. Overall survival (OS) and incidence of liver decompensation or hepatocellular carcinoma (HCC) were determined at the 5-year follow-up.

About 68.4% of our patients with HCV-related cirrhosis were males and their mean age was 54.8 ± 7.7 years. Follow-up at the first and the 3rd-year showed significant improvements in albumin (P = 0.001), liver enzymes (P = 0.001), alpha-fetoprotein (AFP) (P < 0.001), platelet count (P = 0.001), the model for end-stage liver disease (MELD) score (P = 0.001 and 0.01), FIB4 and Aspartate Aminotransferase-to-Platelet Ratio Index (APRI) scores (p < 0.001). The liver stiffness (LS) also significantly improved (p = 0.001). At the 5th year, the mean OS was 58.3 months, with 14.5% and 17.6% of patients developing de-novo HCC and decompensation, respectively. The mean OS at the 5th-year follow-up was shorter in patients who developed HCC and those with liver decompensation (p = 0.001). Alfa-fetoprotein and LS are predictive factors for HCC development.

Despite achieving SVR, continuous surveillance for HCC and new-onset decompensation is mandatory in patients with liver cirrhosis.

Achieving a sustained virologic response (SVR) through direct-acting antivirals for hepatitis C virus (HCV) infection significantly reduces the long-term risk of hepatocellular carcinoma (HCC), particularly in patients with advanced fibrosis (F3) or cirrhosis (F4). However, despite this improvement, the risks associated with HCC and the optimal surveillance strategies for patients who have achieved SVR remain topics of debate. This controversy is compounded by challenges in reliably staging liver fibrosis non-invasively, especially at advanced fibrosis (F3), and the unclear cost-effectiveness, modality, frequency, and duration of HCC surveillance in individuals with SVR but without cirrhosis. These factors contribute to significant variations in surveillance guidelines recommended by different professional societies. Therefore, there is a pressing need for an optimal surveillance strategy that is both simplified and cost-effective to facilitate wider adoption by clinicians. This review article evaluates the existing data, addresses ongoing controversies, and aims to provide new perspectives on HCC surveillance strategies for patients who have achieved SVR from HCV.

Chronic hepatitis C virus (HCV) infection is associated with an increased risk of extrahepatic cancers, particularly non-Hodgkin lymphoma. The introduction of direct-acting antivirals (DAAs) has revolutionized HCV therapy, resulting in high cure rates. However, concerns have been raised about potential effects on cancer risk. This review summarizes the current evidence on extrahepatic cancer risk in HCV-infected patients treated with DAAs. We examined epidemiologic data on HCV-associated extrahepatic cancers and explored potential mechanisms linking HCV to carcinogenesis outside the liver. Studies evaluating cancer outcomes after DAA therapy were critically reviewed while considering methodological challenges. While some studies suggested a reduced risk of extrahepatic cancers after DAA therapy, others showed no significant change. Limitations included short follow-up periods and confounding variables. Immunological changes following rapid HCV clearance may have complex effects on cancer risk. Long-term prospective studies and mechanistic investigations are needed to fully elucidate the relationship between DAA therapy and extrahepatic cancer risk in HCV patients. Clinicians should remain vigilant for extrahepatic malignancies in this population.

Chronic hepatitis C (CHC) increases the risk of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). This nationwide cohort study assessed the effectiveness of viral eradication of CHC.

The Taiwanese chronic hepatitis C cohort and Taiwan hepatitis C virus (HCV) registry are nationwide HCV registry cohorts incorporating data from 23 and 53 hospitals in Taiwan, respectively. This study included 27,577 individuals from these cohorts that were given a diagnosis of CHC and with data linked to the Taiwan National Health Insurance Research Database. Patients received either pegylated interferon and ribavirin or direct-acting antiviral agent therapy for > 4 weeks for new-onset LC and liver-related events.

Among the 27,577 analyzed patients, 25,461 (92.3%) achieved sustained virologic response (SVR). The mean follow-up duration was 51.2 ± 48.4 months, totaling 118,567 person-years. In the multivariable Cox proportional hazard analysis, the hazard ratio (HR) for incident HCC was 1.39 (95% confidence interval [CI]: 1.00-1.95, p = 0.052) among noncirrhotic patients without SVR compared with those with SVR and 1.82 (95% CI 1.34-2.48) among cirrhotic patients without SVR. The HR for liver-related events, including HCC and decompensated LC, was 1.70 (95% CI 1.30-2.24) among cirrhotic patients without SVR. Patients with SVR had a lower 10-year cumulative incidence of new-onset HCC than those without SVR did (21.7 vs. 38.7% in patients with LC, p < 0.001; 6.0 vs. 18.4% in patients without LC, p < 0.001).

HCV eradication reduced the incidence of HCC in patients with and without LC and reduced the incidence of liver-related events in patients with LC.

Epigenetic changes are a common feature of human disease, including liver disease and its progression to liver cancer. The most frequent form of liver cancer, HCC, is unusual because most of its causes, or etiologic drivers, are known and are dominated by environmental exposures, including viral infection, alcohol abuse, and overnutrition/metabolic syndrome. The epigenome is a regulatory system overlayed on the genetic material that regulates when, where, and to what extent genes are expressed in developmental, cell type, and disease-associated contexts. Deregulation of the epigenome has emerged as a major player in the pathologic effects of liver disease driving exposures, particularly during their early phases when genetic changes are uncommon. Although it is inherent in the definition of an epigenetic process to be reversible, emerging evidence indicates that epigenetic changes persist after the removal of the exposure and contribute to long-term risk of disease progression. In other systems, environmental exposures lead to beneficial adaptive changes in expression that facilitate processes such as wound healing, and these too are driven by epigenetic changes. What remains unclear, however, is what drives the transition from a beneficial epigenetic memory to a maladaptive scar, the epigenetic processes involved in forming these memories, and whether this process can be modulated for therapeutic purposes. In this review, we discuss these concepts in relation to liver disease and more broadly using examples from other tissue types and diseases, and finally consider how epigenetic therapies could be used to reprogram maladaptive epigenetic memories to delay and/or prevent hepatocarcinogenesis.

Surveillance for hepatocellular carcinoma (HCC) has been proven to increase the proportion of tumors detected at early stages and the chance of receiving curative therapies, reducing mortality by about 30%.

Current recommendations consist of a semi-annual abdominal ultrasound with or without serum alpha-fetoprotein measurement in patients with cirrhosis and specific subgroups of populations with chronic viral hepatitis. Antiviral therapies, such as nucleot(s)ide analogs that efficiently suppress the replication of hepatitis B virus (HBV) and direct-acting antiviral drugs able to eliminate the hepatitis C virus (HCV) in >90% of patients, have radically changed the outcomes of viral liver disease and decreased, but not eliminated, the risk of HCC in both cirrhotic and non-cirrhotic patients. HCC risk is a key starting point for implementing a cost-effective surveillance and should also guide the decision-making process concerning its modality. As the global number of effectively treated viral patients continues to rise, there is a pressing need to identify those for whom the benefit-to-harm ratio of surveillance is favorable and to determine how to conduct cost-effective screening on such patients.

This article addresses this topic and attempts to determine which patients should continue HCC surveillance after HBV suppression or HCV eradication, based on cost-effectiveness principles and the fact that HCC risk declines over time. We also formulate a proposal for a surveillance algorithm that switches the use of surveillance for HCC from the "one-size-fits-all" approach to individualized programs based on oncologic risk (precision surveillance).

Hepatitis C virus (HCV) infection significantly contributes to global hepatocellular carcinoma (HCC) incidence. N-Acetylcysteine (NAC), known for its antioxidant properties, is a potential therapeutic agent. However, evidence on its efficacy in reducing HCC risk among HCV patients is limited. A retrospective cohort analysis using Taiwan's National Health Insurance Research Database (2008-2018) included ≥18-year-old HCV patients. NAC usage (≥28 cumulative defined daily doses [cDDDs]) was assessed for its association with HCC risk using Cox regression models and propensity score matching. The study comprised 269,647 HCV patients, with detailed NAC dosage characterization and hazard ratios (HRs) for HCC risk. Post-matching, NAC usage emerged as the significant predictor of reduced HCC risk (adjusted HR: 0.39, 95% CI: 0.37-0.41, P<0.0001). Dose-response analysis showed reduced HCC risk with increasing cDDDs of NAC (P<0.0001). Higher daily NAC dosage (≥1 DDD) was associated with significantly lower HCC risk (adjusted HR: 0.33, 95% CI: 0.31-0.36, P<0.0001). The study provides compelling evidence for NAC's potential in reducing HCC risk among HCV patients. Insights into dose-dependent effects and optimal daily intensity thresholds offer valuable directions for future therapeutic strategies and clinical trials targeting HCC burden in HCV-infected individuals.

Hepatitis C virus (HCV) infection is one of the major etiologies of hepatocellular carcinoma (HCC) with approximately 30% of HCC being due to HCV infection worldwide. HCV eradication by antivirals greatly reduces the risk of HCC; nevertheless, HCC remains to occur in chronic hepatitis C (CHC) patients who have achieved a sustained virological response (SVR). The proportion of post-SVR HCC among newly diagnosed HCC patients is increasing in the direct-acting antiviral (DAA) era and might be due to preexisting inflammatory and fibrotic liver backgrounds, immune dysregulation between host and virus interactions, as well as host epigenetic scars, genetic predispositions and alternations. By means of applying surrogate markers and adopting risk stratification, HCC surveillance should be consistently performed in high-risk populations. In this review, we discuss the possible molecular mechanism, risk factors, and HCC surveillance strategy for HCC development after HCV eradication in CHC patients.

Hepatitis C virus (HCV) infection is a significant global health burden, particularly among people who inject drugs. Rapid point-of-care HCV testing has emerged as a promising approach to improve HCV detection and linkage to care in harm reduction organizations such as needle and syringe programs. The objective of this study was to use an intersectionality lens to explore the barriers and enablers to point-of-care HCV testing in a needle and syringe program.

A qualitative study was conducted using semi-structured interviews with clients (people who inject drugs) and service providers in a large community organization focused on the prevention of sexually transmitted and blood borne infections and harm reduction in Montreal, Canada. An intersectionality lens was used alongside the Theoretical Domains Framework to guide the formulation of research questions as well as data collection, analysis, and interpretation.

We interviewed 27 participants (15 clients, 12 providers). For clients, four themes emerged: (1) understanding and perceptions of HCV testing, (2) the role of an accessible and inclusive environment, (3) the interplay of emotions and motivations in decision-making, and (4) the impact of intersectional stigma related to HCV, behaviors, and identities. For providers, five themes emerged: (1) knowledge, skills, and confidence for HCV testing, (2) professional roles and their intersection with identity and lived experience, (3) resources and integration of services, (4) social and emotional factors, and (5) behavioral regulation and incentives for HCV testing. Intersectional stigma amplified access, emotional and informational barriers to HCV care for clients. In contrast, identity and lived experience acted as powerful enablers for providers in the provision of HCV care.

The application of an intersectionality lens provides a nuanced understanding of multilevel barriers and enablers to point-of-care HCV testing. Findings underscore the need for tailored strategies that address stigma, improve provider roles and communication, and foster an inclusive environment for equitable HCV care. Using an intersectionality lens in implementation research can offer valuable insights, guiding the design of equity-focused implementation strategies.

Patients with chronic hepatitis C (CHC) can be cured with the new highly effective interferon-free combination treatments (DAA) that were approved in 2014. However, CHC is a largely silent disease, and many individuals are unaware of their infections until the late stages of the disease. The impact of wider access to effective treatments and improved awareness of the disease on the number of infections and the number of patients who remain undiagnosed is not known in Canada. Such evidence can guide the development of strategies and interventions to reduce the burden of CHC and meet World Health Organization's (WHO) 2030 elimination targets. The purpose of this study is to use a back-calculation framework informed by provincial population-level health administrative data to estimate the prevalence of CHC and the proportion of cases that remain undiagnosed in the three most populated provinces in Canada: British Columbia (BC), Ontario and Quebec.

We have conducted a population-based retrospective analysis of health administrative data for the three provinces to generate the annual incidence of newly diagnosed CHC cases, decompensated cirrhosis (DC), hepatocellular carcinoma (HCC) and HCV treatment initiations. For each province, the data were stratified in three birth cohorts: individuals born prior to 1945, individuals born between 1945 and 1965 and individuals born after 1965. We used a back-calculation modelling approach to estimate prevalence and the undiagnosed proportion of CHC. The historical prevalence of CHC was inferred through a calibration process based on a Bayesian Markov chain Monte Carlo (MCMC) algorithm. The algorithm constructs the historical prevalence of CHC for each cohort by comparing the model-generated outcomes of the annual incidence of the CHC-related health events against the data set of observed diagnosed cases generated in the retrospective analysis.

The results show a decreasing trend in both CHC prevalence and undiagnosed proportion in BC, Ontario and Quebec. In 2018, CHC prevalence was estimated to be 1.23% (95% CI: .96%-1.62%), .91% (95% CI: .82%-1.04%) and .57% (95% CI: .51%-.64%) in BC, Ontario and Quebec respectively. The CHC undiagnosed proportion was assessed to be 35.44% (95% CI: 27.07%-45.83%), 34.28% (95% CI: 26.74%-41.62%) and 46.32% (95% CI: 37.85%-52.80%) in BC, Ontario and Quebec, respectively, in 2018. Also, since the introduction of new DAA treatment in 2014, CHC prevalence decreased from 1.39% to 1.23%, .97% to .91% and .65% to .57% in BC, Ontario and Quebec respectively. Similarly, the CHC undiagnosed proportion decreased from 38.78% to 35.44%, 38.70% to 34.28% and 47.54% to 46.32% in BC, Ontario and Quebec, respectively, from 2014 to 2018.

We estimated that the CHC prevalence and undiagnosed proportion have declined for all three provinces since the new DAA treatment has been approved in 2014. Yet, our findings show that a significant proportion of HCV cases remain undiagnosed across all provinces highlighting the need to increase investment in screening. Our findings provide essential evidence to guide decisions about current and future HCV strategies and help achieve the WHO goal of eliminating hepatitis C in Canada by 2030.

Lysyl oxidase-like 2 (LOXL2) mediates the crosslinking of extracellular collagen, reflecting qualitative changes in liver fibrosis. This study aimed to validate the utility of serum LOXL2 levels as a predictive biomarker for the development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection who achieved a sustained virological response (SVR). This retrospective study included 137 patients with chronic HCV infection without history of HCC development and who achieved SVR via direct-acting antiviral therapy. Median LOXL2 levels decreased significantly after SVR achievement (pre-Tx, 2.33 ng/mL; post-Tx, 1.31 ng/mL, p < 0.001). Post-Tx LOXL2 levels, fibrosis-4 index, platelet counts, Wisteria floribunda agglutinin-positive human Mac-2 binding protein levels, and alpha-fetoprotein (AFP) levels were identified as independent predictive factors for post-SVR HCC development in the univariate analysis. The incidence of post-SVR HCC development was significantly higher in patients with post-Tx LOXL2 levels ≥ 2.08 ng/mL and AFP levels ≥ 5.0 ng/mL than in patients with elevated levels of either marker or with lower marker levels. Serum LOXL2 levels can serve as a predictive biomarker for HCC development after achieving SVR. The combination of serum LOXL2 and AFP levels provides robust risk stratification for HCC development after SVR, suggesting an enhanced surveillance strategy.

The current multiday diagnosis and treatment paradigm for hepatitis C virus (HCV) infection results in far fewer patients receiving treatment with direct-acting antiviral agents than those with diagnosed HCV infection. To achieve HCV elimination, a paradigm shift in access to HCV treatment is needed from multiday testing and treatment algorithms to same-day diagnosis and treatment. This shift will require new tools, such as point-of-care (POC) antigen tests or nucleic acid tests for HCV and hepatitis B virus (HBV) and nucleic acid tests for human immunodeficiency virus (HIV) that do not require venous blood. This shift will also require better use of existing resources, including expanded access to HCV treatment and available POC tests, novel monitoring approaches, and removal of barriers to approval. A same-day diagnosis and treatment paradigm will substantially contribute to HCV elimination by improving HCV treatment rates and expanding access to treatment in settings where patients have brief encounters with healthcare.