Long-term Risk Of Hepatocellular Carcinoma Research Articles

COMPARATIVE EFFECTIVENESS OF ENTECAVIR VERSUS TENOFOVIR FOR PREVENTING HEPATOCELLULAR CARCINOMA IN PATIENTS WITH CHRONIC HEPATITIS B: A COMPREHENSIVE SYSTEMATIC REVIEW

COMPARATIVE EFFECTIVENESS OF ENTECAVIR VERSUS TENOFOVIR FOR PREVENTING HEPATOCELLULAR CARCINOMA IN PATIENTS WITH CHRONIC HEPATITIS B: A COMPREHENSIVE SYSTEMATIC REVIEW

Repeated Measurement of FIB-4 to Predict Long-Term Risk of HCC Development Up to 10 Years After SVR.

It is unclear whether and how the long-term risk of hepatocellular carcinoma (HCC) will change in hepatitis C virus (HCV) infected patients who have reached sustained virologic response (SVR) with direct-acting antivirals (DAA). In this study, we assessed the long-term risk of HCC up to 10 years after SVR using fibrosis 4 score (FIB-4) and its dynamic changes. A total of 701 DAA-treated patients who achieved SVR between January 2012 to October 2020 were enrolled in the study. The FIB-4 score of each patient was measured at the date of SVR and each follow-up visit annually. Patients were followed until December 31, 2021, with the longest follow-up time being 9.82 years. Following SVR, 27 cases of HCC were observed. The annual incidence rate of HCC remained stable with no obvious downward trend. Patients with a FIB-4 >3.25 at baseline or anytime during follow-up were at a higher risk of developing HCC than those whose FIB-4 remained below 3.25. Patients with cirrhosis and patients with no cirrhosis but a FIB-4 >3.25 were at higher risk of developing HCC than patients with no cirrhosis and a FIB-4 ≦3.25. FIB-4 >3.25 measured at SVR or any time post-SVR was associated with HCC risks. The repeated measurement of FIB-4 revealed a better predictive ability of HCC risks than the simple measurement of FIB-4 at baseline. The additional stratification of patients by combining FIB-4 and cirrhosis leads to more accurately identifying high-risk patients. Surveillance of HCC is recommended for virologically cured patients with a FIB-4 >3.25 at SVR or anytime afterward and patients diagnosed with cirrhosis.

Long-term Risk of Hepatocellular Carcinoma Following Direct-Acting Antiviral Therapy in Compensated Liver Cirrhosis Induced by Hepatitis C Virus Infection

Background: Considering the excellent safety profile and the high efficacy rates, great benefits were expected with the availability of the new direct-acting antivirals (DAAs) in treating hepatitis C virus (HCV) infection. Following the publication of two articles in 2016 on the high incidence rates of hepatocelullar carcinoma (HCC) following DAAs, several papers revealed contradictory results, thereby casting shadows on the role of DAAs in hepatocarcinogenesis. Objectives: The present study aimed to assess the incidence and risk factors of HCC in patients with HCV genotype 1b infection and compensated cirrhosis with the sustained virological response (SVR) following DAAs. Methods: This multicentric prospective study encompassed 479 patients with HCV genotype 1b compensated cirrhosis treated with paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD) +/- ribavirin (RBV) for 12 weeks in two tertiary centers in Northeastern Romania. The patients were prospectively followed up in the Institute of Gastroenterology Iasi, Romania, from November 2015 to December 2020. Results: During the follow-up period (mean 60.11 ± 3.87 months), 23 patients (4.8%) developed HCC. The 1-, 3-, and 5-year cumulative incidence rates of HCC were 1.1, 1.9, and 2.6%, respectively. At the time of the diagnosis, 15 patients (65%) had a single tumor, 12 patients (52.2%) were within the Milan criteria, and nine persons (39%) had Barcelona liver cancer stage 0-A. In this regard, the mean AFP level was 35.3 ± 93.1 ng/mL. A multivariate analysis, age above 65 years, and a cutoff point of AFP ≥ 10 ng/mL at the end of treatment were independent factors associated with HCC. A majority of the patients (n = 11, 47.8%) received curative treatment by surgical resection. In this study, histopathological examination identified a moderately differentiated tumor (G2) in 5 patients, five patients had a poorly differentiated tumor (G3), and only one patient had a well-differentiated tumor (G1). Conclusions: Our study revealed no evidence of the high incidence rate of HCC after the long-term follow-up of patients with HCV-related liver cirrhosis and SVR following DAA treatment. However, the cumulative 5-year risk remained above the cutoff point, and this makes the HCC screening cost-effective. The HCC occurrence appears to be associated with aging and a moderately increased AFP level at EOT (≥ 10 ng/mL).

A blood-based prognostic liver secretome signature and long-term hepatocellular carcinoma risk in advanced liver fibrosis

Accurate non-invasive prediction of long-term hepatocellular carcinoma (HCC) risk in advanced liver fibrosis is urgently needed for cost-effective HCC screening; however, this currently remains an unmet need. A serum-protein-based prognostic liver secretome signature (PLSec) was bioinformatically derived from previously validated hepatic transcriptome signatures and optimized in 79 patients with advanced liver fibrosis. We independently validated PLSec for HCC risk in 331 cirrhosis patients with mixed etiologies (validation set 1 [V1]) and thereafter developed a score with clinical prognostic variables. The score was then validated in two independent cohorts: validation set 2 (V2): 164 patients with advanced liver fibrosis due to hepatitis C virus (HCV) infection cured after direct-acting antiviral therapy; validation set 3 (V3): 146 patients with advanced liver fibrosis with successfully-treated HCC and cured HCV infection. An 8-protein blood-based PLSec recapitulated transcriptome-based hepatic HCC risk status. In V1, PLSec was significantly associated with incident HCC risk (adjusted hazard ratio [aHR], 2.35; 95% confidence interval [CI], 1.30-4.23). A composite score with serum alpha-fetoprotein (PLSec-AFP) was defined in V1, and validated in V2 (adjusted odds ratio, 3.80 [95%CI, 1.66-8.66]) and V3 (aHR, 3.08 [95%CI, 1.78-5.31]; c-index, 0.74). PLSec-AFP outperformed AFP alone (Brier score, 0.165 vs. 0.186 in V2; 0.196 vs. 0.206 in V3, respectively). The blood-based PLSec-AFP can accurately stratify patients with advanced liver fibrosis for long-term HCC risk and thereby guide risk-based tailored HCC screening.

Long-term risk of primary liver cancers in entecavir versus tenofovir treatment for chronic hepatitis B

It remains controversial whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) is associated with different clinical outcomes for chronic hepatitis B (CHB). This study aimed to compare the long-term risk of ETV versus TDF on hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) in CHB patients from a large multi-institutional database in Taiwan. From 2011 to 2018, a total of 21,222 CHB patients receiving ETV or TDF were screened for eligibility. Patients with coinfection, preexisting cancer and less than 6 months of follow-up were excluded. Finally, 7248 patients (5348 and 1900 in the ETV and TDF groups, respectively) were linked to the National Cancer Registry database for the development of HCC or ICC. Propensity score matching (PSM) (2:1) analysis was used to adjust for baseline differences. The HCC incidence between two groups was not different in the entire population (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.66–1.02, p = 0.078) and in the PSM population (HR 0.83; 95% CI 0.65–1.06, p = 0.129). Among decompensated cirrhotic patients, a lower risk of HCC was observed in TDF group than in ETV group (HR 0.54; 95% CI 0.30–0.98, p = 0.043, PSM model). There were no differences between ETV and TDF groups in the ICC incidence (HR 1.84; 95% CI 0.54–6.29, p = 0.330 in the entire population and HR 1.04; 95% CI 0.31–3.52, p = 0.954 in the PSM population, respectively). In conclusion, treatment with ETV and TDF showed a comparable long-term risk of HCC and ICC in CHB patients.

Epidemiology of Virus Infection and Human Cancer.

Seven viruses including the Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), Kaposi's sarcoma herpes virus (KSHV), human immunodeficiency virus, type-1 (HIV-1), human T cell lymphotrophic virus, type-1 (HTLV-1), and human papillomavirus (HPV) have been classified as Group 1 human carcinogens by the International Agency for Research on Cancer (IARC). The conclusions are based on the findings of epidemiological and mechanistic studies. EBV, HPV, HTLV-1, and KSHV are direct carcinogens; HBV and HCV are indirect carcinogens through chronic inflammation; and HIV-1 is an indirect carcinogen through immune suppression. Some viruses may cause more than one cancer, while some cancers may be caused by more than one virus. However, only a proportion of persons infected by these oncogenic viruses will develop specific cancers. A series of studies have been carried out to assess the viral, host, and environmental cofactors of EBV-associated nasopharyngeal carcinoma, HBV/HCV-associated hepatocellular carcinoma, and HPV-associated cervical carcinoma. Persistent infection, high viral load, and viral genotype are important risk predictors of these virus-caused cancers. Risk calculators incorporating host and viral risk predictors have been developed for the prediction of long-term risk of hepatocellular carcinoma, nasopharyngeal carcinoma and cervical cancer. These risk calculators are useful for the triage and clinical management of infected patients. Both clinical trials and national programs of immunization, antiviral therapy and screening have demonstrated a significant reduction in the incidence of cancers caused by HBV, HCV, and HPV. Future research on gene-gene and gene-environment interactions of oncogenic viruses and the human host using large-scale longitudinal studies with serial measurements of biosignatures are in urgent need.

Cholecystitis and risk of pancreatic, liver, and biliary tract cancer in patients undergoing cholecystectomy

BackgroundCholecystitis before cholecystectomy may increase risk of cancers in the hepato-pancreato-biliary area. MethodsA population-based cohort study of all patients undergoing cholecystectomy in Denmark during 1996–2015, using nationwide healthcare registries. We retrieved information on cholecystitis within two years before the date of surgery and information on pancreatic cancer, hepatocellular carcinoma (HCC), and biliary tract cancer. We examined cancer risk using a Cox model to calculate the hazard ratios (HRs). We also computed cumulative incidence functions with 95% CIs, comparing patients with and without cholecystitis before cholecystectomy. ResultsWe included 132,794 patients, of which 73.0% were women. In the first five years of follow-up, we observed an increased risk of biliary tract cancer, but not pancreatic cancer or HCC, in patients with prior cholecystitis. After more than five years of follow-up, patients with prior cholecystitis had an increased risk of pancreatic cancer (adjusted HR: 1.26; 95% CI: 0.98–1.63) and possibly biliary tract cancer (adjusted HR: 1.33; 95% CI: 0.64–2.77). Long-term risk of HCC was decreased in patients with prior cholecystitis. For all cancers, the 20-year absolute risks were less than 1%. ConclusionIn patients undergoing cholecystectomy, prior cholecystitis was associated with increased risk of pancreatic and possibly biliary tract cancer.

Hepatocellular Carcinoma Risk Stratification by Genetic Profiling in Patients with Cirrhosis.

Prediction of future hepatocellular carcinoma (HCC) risk in the sizable chronic liver disease population is an urgent unmet need to enable regular HCC screening for early detection. Germline deoxyribonucleic acid polymorphisms likely represent etiology-specific host factors that determine HCC susceptibility, including single nucleotide polymorphisms in EGF, IFNL3, MICA, and TLL1 in hepatitis C with or without active viral infection, and PNPLA3, TM6SF2, and MBOAT7 in metabolic liver diseases. Transcriptome-based prognostic liver signature in diseased liver tissue has been associated with long-term HCC risk in viral and metabolic etiologies. Transcriptomic signatures of hepatic injury and specific cell type such as aggregated lymphocytes also predict HCC development. Circulating factors such as proteins and their chemical modification, nucleotides, and metabolites may serve for less-invasive assessment of short- or long-term HCC risk. These biomarkers will enable individual HCC risk-based personalized clinical management for cost-effective early HCC detection and improvement of patient survival.

Post-treatment alpha fetoprotein and platelets predict hepatocellular carcinoma development in dual-infected hepatitis B and C patients after eradication of hepatitis C.

We investigated the long-term risk of hepatocellular carcinoma (HCC) in dual-infected hepatitis B and C patients after eradication of hepatitis C virus (HCV). A total of 164 (62% male, median age, 50.5 years) hepatitis B and C dual-infected patients who achieved HCV sustained virological response were recruited. Half the patients were HCV genotype 1 with a median viral load of 5.5 log10 IU/mL, and 22.6%had an HBV DNA level ≥ 2000 IU/mL before therapy. HCC developed in 14 patients (8.5%), with an annual incidence of 1.38% per person-year. The 3-year, 5-year, 10-year, and 15-year cumulative probabilities were 2.5%, 5.1%, 12.6%, and 22.7%, respectively. Six months after treatment, a Cox regression hazard analysis revealed platelet level (HR: 0.98, 95% CI: 0.957–0.999, P = 0.038) and AFP level (HR: 1.20, 95% CI: 1.031–1.400, P = 0.019) to be independent factors in HCC. A higher 10-year cumulative risk of HCC was detected in patients with 6-month post-treatment AFP levels > 5.0 ng/mL and platelet levels < 130 x1000/µL (54.9%), compared to patients with neither (8.6%). Although the risk of HCC is low, surveillance of HCC is encouraged in dual-infected patients after eradication of HCV. Post-treatment AFP and platelet levels predict HCC development.

Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: Data from three ANRS cohorts

Sustained virological response following interferon-based antiviral treatment of chronic hepatitis C is associated with decreased long-term risk of hepatocellular carcinoma (HCC) in advanced liver fibrosis. An unexpected high rate of HCC recurrence following antiviral treatment using direct-acting antiviral (DAA) has recently been reported. We analyzed data individually from three French prospective multicentre ANRS cohorts including more than 6000 patients treated with DAA and we focused on HCC patients who underwent curative procedures before DAA treatment. The aim was to assess the rates of HCC recurrence in these patients according to antiviral treatment regimen. In the ANRS CO22 "Therapeutic options for hepatitis B and C: a French cohort" (HEPATHER) cohort, 267 patients with chronic hepatitis C who were previously treated for HCC were analyzed, among whom 189 received DAA and 78 did not. The rates of recurrence were 0.73/100 and 0.66/100 person-months, respectively. In the ANRS CO12 "Cirrhose Virale" (CirVir) cohort, 79 cirrhotic patients in whom HCC was diagnosed and treated, 13 received DAA and 66 did not. The rates of recurrence were 1.11/100 and 1.73/100 person-months, respectively. In the ANRS CO23 "Compassionate use of Protease Inhibitors in viral C Liver Transplantation" (CUPILT) Cohort, 314 liver transplant recipients for HCC who were subsequently treated with DAA were analyzed. Seven HCC recurrences were reported after a median time of 70.3months after liver transplantation. The rate of recurrence was 2.2%. In three distinct prospective cohorts, we did not observe an increased risk of HCC recurrence after DAA treatment, notably in patients who underwent curative HCC treatment including liver transplantation. Since an unexpected high rate of hepatocellular carcinoma (HCC) recurrence after direct-acting antiviral (DAA) treatment has been suggested in a retrospective study, we analyzed data from three French prospective multicentre ANRS cohorts of >6000 DAA-treated patients who underwent curative HCC therapies. We did not observe an increased risk of HCC recurrence after DAA treatment: the rates of recurrence were similar in treated and untreated patients (0.73/100 and 0.66/100 person-months in in the ANRS CO22 HEPATHER cohort including 189 DAA+ and 78 DAA- and 1.11/100 in 13 DAA+ and 1.73/100 person-months in 66 DAA- in the ANRS CO12 CirVir cohort), respectively. Finally, in the ANRS CO23 CUPILT Cohort, HCC recurred in only 7 among 314 (2.2%) liver transplant recipients for HCC subsequently treated after 70months after liver transplantation.

THU-108 - Long-Term Risk of Hepatocellular Carcinoma during Follow-Up of Patients with Chronic Hepatitis B with Normal Alanine Aminotransferase

THU-108 - Long-Term Risk of Hepatocellular Carcinoma during Follow-Up of Patients with Chronic Hepatitis B with Normal Alanine Aminotransferase

Achieving Sustained Virological Response in Hepatitis C Reduces the Long-Term Risk of Hepatocellular Carcinoma: An Updated Meta-Analysis Employing Relative and Absolute Outcome Measures.

We studied the effect of achieving sustained virological response (SVR) on the risk of developing hepatocellular carcinoma (HCC) in patients with hepatitis C receiving anti-hepatitis C virus treatment. Avoiding HCC is considered the main long-term benefit of successful antiviral treatment. Our literature search extended up to June 2015. We identified all studies that assessed the risk of HCC in patients achieving or not achieving SVR. Meta-analysis was based on a standard random-effect model. The end-point was occurrence of HCC compared between patients with and without SVR; this end-point was expressed as an odds ratio and percent reduction in risk and was also presented separately for patients with and without cirrhosis. All results estimates presented with 95% confidence intervals (CIs). The presence of any temporal trend in these indexes was investigated by standard meta-regression. Our search identified 25 observational studies (19,822 patients). The odds ratio of HCC for SVR versus no-SVR was 0.19 (95% CI 0.15-0.24) in the overall series of 25 studies. The difference in this index between patients with any stage of fibrosis/cirrhosis and those with cirrhosis was small. With regard to risk difference, the 25 studies indicated an overall reduction of 10% (95% CI 8.00-12.0); this effect was much less pronounced in the group with any stage of fibrosis/cirrhosis (risk difference 6.7%) than in the selected group with cirrhosis (risk difference 22%). Meta-regression showed no temporal trend. Our analysis was successful in providing an updated overview on this controversial topic. Some pharmacoeconomic assessments are also presented to interpret the clinical results of our analysis.

Spontaneous seroclearance of hepatitis B seromarkers and subsequent risk of hepatocellular carcinoma

Background and aimsThe associations between long-term risk of hepatocellular carcinoma (HCC) and spontaneous seroclearance of HBV e antigen (HBeAg), HBV DNA and HBV surface antigen (HBsAg) have never been examined...

Predictive value of alpha-fetoprotein in the long-term risk of developing hepatocellular carcinoma in patients with hepatitis B virus infection – Results from a clinic-based longitudinal cohort

BackgroundAlthough serum level of alpha-fetoprotein (AFP) has long been used to complement imaging tests in the screening and diagnosis of hepatocellular carcinoma (HCC), whether it can be used as a predictive marker of long-term risk for developing HCC in patients with hepatitis B virus (HBV) has not been extensively evaluated and thus remains controversial. MethodsWe retrospectively conducted a clinic-based longitudinal cohort study including 617 Korean American patients with HBV who had been followed for up to 22years (median follow-up time, 6.2years) to evaluate the association between baseline serum AFP level and the long-term risk of HCC. ResultsThe median baseline AFP value of these patients was 3.8 ng/ml. Compared to patients with lower-than-median AFP value, those with higher-than-median baseline serum AFP had a significantly increased risk of developing HCC with a hazard ratio (HR) of 2.73 (95% confidence interval [CI] 1.25–5.99), independent of other major HCC risk factors. In addition, we calculated the cumulative incidence of HCC during different years of follow-up time by baseline serum AFP, and found that the cumulative incidence of HCC was significantly higher in HBV patients with high baseline serum AFP compared to those with low baseline serum AFP in each of the five follow-up time periods examined. ConclusionsOur results indicated that AFP was a strong independent prospective predictor of long-term HCC risk in high-risk HBV patients. More targeted prevention and early detection of HCC may be considered for these patients.