Hepatocellular Carcinoma Development In Chronic Hepatitis B Patients Research Articles

Risk assessment of hepatitis B virus-related hepatocellular carcinoma development using vibration-controlled transient elastography: Systematic review and meta-analysis.

Liver stiffness measurement (LSM) using vibration-controlled transient elastography (VCTE) can assess fibrotic burden in chronic liver diseases. The systematic review and meta-analysis was conducted to determine whether LSM using VCTE can predict the risk of development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. A systematic literature search of the Ovid-Medline, EMBASE, Cochrane, and KoreaMed databases (from January 2010 to June 2023) was conducted. Of the 1,345 individual studies identified, 10 studies that used VCTE were finally registered. Hazard ratios (HRs) and the 95% confidence intervals (CIs) were considered summary estimates of treatment effect sizes of ≥11 kilopascal (kPa) standard for HCC development. Meta-analysis was performed using the restricted Maximum Likelihood random effects model. Among the ten studies, data for risk ratios for HCC development could be obtained from nine studies. When analyzed for the nine studies, the HR for HCC development was high at 3.33 (95% CI, 2.45-4.54) in CHB patients with a baseline LSM of ≥11 kPa compared to patients who did not. In ten studies included, LSM of ≥11 kPa showed the sensitivity and specificity for predicting HCC development were 61% (95% CI, 50-71%) and 78% (95% CI, 66-86%), respectively, and the diagnostic accuracy was 0.74 (95% CI, 0.70-0.77). The risk of HCC development was elevated in CHB patients with VCTE-determined LSM of ≥11 kPa. This finding suggests that VCTE-determined LSM values may aid the risk prediction of HCC development in CHB patients.

A machine learning model for predicting hepatocellular carcinoma risk in patients with chronic hepatitis B.

Machine learning (ML) algorithms can be used to overcome the prognostic performance limitations of conventional hepatocellular carcinoma (HCC) risk models. We established and validated an ML-based HCC predictive model optimized for patients with chronic hepatitis B (CHB) infections receiving antiviral therapy (AVT). Treatment-naïve CHB patients who were started entecavir (ETV) or tenofovir disoproxil fumarate (TDF) were enrolled. We used a training cohort (n = 960) to develop a novel ML model that predicted HCC development within 5 years and validated the model using an independent external cohort (n = 1937). ML algorithms consider all potential interactions and do not use predefined hypotheses. The mean age of the patients in the training cohort was 48 years, and most patients (68.9%) were men. During the median 59.3 (interquartile range 45.8-72.3) months of follow-up, 69 (7.2%) patients developed HCC. Our ML-based HCC risk prediction model had an area under the receiver-operating characteristic curve (AUC) of 0.900, which was better than the AUCs of CAMD (0.778) and REAL B (0.772) (both p < .05). The better performance of our model was maintained (AUC = 0.872 vs. 0.788 for CAMD and 0.801 for REAL B) in the validation cohort. Using cut-off probabilities of 0.3 and 0.5, the cumulative incidence of HCC development differed significantly among the three risk groups (p < .001). Our new ML model performed better than models in terms of predicting the risk of HCC development in CHB patients receiving AVT.

Association of Physical Activity with the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B.

Simple SummaryAlthough viral replication in patients with a chronic hepatitis B (CHB) infection is effectively suppressed by potent antiviral therapy such as entecavir or tenofovir, the risk of hepatocellular carcinoma (HCC) development in CHB patients cannot be totally eliminated. Thus, control of modifiable risk factors for HCC development such as lifestyle modification is important to minimize the HCC risk. In this study, we analyzed a nationwide population-based cohort to evaluate whether there is a significant association between physical activity and development of HCC in CHB patients treated with entecavir or tenofovir. Results in this study suggest that physical activity was significantly associated with a lower risk of HCC development in CHB patients treated with potent antiviral therapy. Increasing physical activity can have beneficial outcomes on HCC development in CHB patients treated with entecavir or tenofovir.Background and Aims: In the general population, previous studies reported that physical activity was associated with risk of hepatocellular carcinoma (HCC) development. However, it is unclear whether physical activity is associated with risk of HCC development in patients with chronic hepatitis B (CHB). We aimed to elucidate the association between physical activity and risk of HCC development in CHB patients. Methods: This nationwide cohort study involved treatment-naive patients with CHB (n = 9727) who started treatment with entecavir or tenofovir and answered self-reported questionnaires between January 2012 and December 2017, using data from the Korean National Health Insurance Service database. The primary endpoint was development of HCC. Multivariable Cox regression and competing risk analyses were used. Results: During a median follow-up of 3.1 years, cumulative HCC incidence rates were 8.3%. There was an inverse association between physical activity and the risk of HCC (p < 0.001). Patients with 1000–1500 metabolic equivalent task (MET)-min/week, compared to those without physical activity, showed a significantly lower risk of HCC in both patients without cirrhosis (adjusted hazard ratio [aHR] 0.66, p = 0.02) and patients with cirrhosis (aHR 0.61, p = 0.02). In patients who were younger (<60), male, without diabetes, and with high BMI, amounts of physical activity of 1000–1500 MET-min/week showed an inverse association with the risk of HCC (aHR 0.65, 0.63, 0.65, and 0.64, respectively, all p < 0.05). Conclusion: Physical activity was significantly associated with a low risk of HCC in CHB patients treated with entecavir or tenofovir.

Serum PreS1 and HBsAg ratio reflects liver fibrosis and predicts the development of hepatocellular carcinoma in chronic hepatitis B patients.

While the preS1 region of the large hepatitis B surface protein plays an essential role in hepatitis B virus (HBV) infection, the effect of preS1 on liver fibrosis and hepatocarcinogenesis in chronic hepatitis B (CHB) patients is not well known. In this study, we measured serum preS1levels by chemiluminescent immunoassay technology in 690 CHB patients and evaluated the correlation between serum preS1levels and HBV, liver function markers and liver inflammation, fibrosis assessed by histological findings. Predictive factors for hepatocellular carcinoma (HCC) development in patients who had no previous history of HCC at the time of preS1level measurement were also analysed. Median hepatitis B surface antigen (HBsAg) and preS1levels were 3.08log IU/mL and 98ng/mL, respectively. PreS1values were significantly correlated with serum HBsAg (p <0.001), hepatitis B core-related antigen (HBcrAg) (p <0.001) and HBV DNA levels (p <0.01). PreS1values were also significantly correlated with serum alanine aminotransferase levels (p <0.001) and were significantly higher in patients who had higher grading of liver inflammatory activity (p <0.05). HBsAg level was correlated, but preS1/HBsAg ratio reflected liver fibrosis staging more directly than HBsAg alone. Multivariate analysis identified age ≥53years (hazard ratio [HR], 18.360 for <53years; p = 0.021) and preS1/HBsAg ratio ≥0.12 (HR, 6.205 for <0.12; p = 0.040) as significant and independent factors for HCC development in CHB patients. The preS1/HBsAg ratio directly reflects liver fibrosis, and the ratio might be a predictive marker for HCC development in CHB patients.

Prediction models for development of hepatocellular carcinoma in chronic hepatitis B patients.

Chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) is a major health problem in Asian-Pacific regions. Antiviral therapy reduces, but does not completely prevent, HCC development. Thus, there is a need for accurate risk prediction to assist prognostication and decisions on the need for antiviral therapy and HCC surveillance. A few risk scores have been developed to predict the occurrence of HCC in CHB patients. Initially, the scores were derived from untreated CHB patients. With the development and extensive clinical application of nucleos(t)ide analog(s) (NA), the number of risk scores based on treated CHB patients has increased gradually. The components included in risk scores may be categorized into host factors and hepatitis B virus factors. Hepatitis activities, hepatitis B virus factors, and even liver fibrosis or cirrhosis are relatively controlled by antiviral therapy. Therefore, variables that are more dynamic during antiviral therapy have since been included in risk scores. However, host factors are more difficult to modify. Most existing scores derived from Asian populations have been confirmed to be accurate in predicting HCC development in CHB patients from Asia, while these scores have not offered excellent predictability in Caucasian patients. These findings support that more relevant variables should be considered to provide individualized predictions that are easily applied to CHB patients of different ethnicities. CHB patients should receive different intensities of HCC surveillance according to their risk category.

Role of hepatitis D virus infection in development of hepatocellular carcinoma among chronic hepatitis B patients treated with nucleotide/nucleoside analogues

Hepatitis D virus (HDV) infection increases the risk of hepatocellular carcinoma (HCC) in the natural course of chronic hepatitis B (CHB) patients. Its role in patients treated with nucleotide/nucleoside analogues (NAs) is unclear. We aimed to study the role of hepatitis D in the development of HCC in CHB patients treated with NAs. Altogether, 1349 CHB patients treated with NAs were tested for anti-HDV antibody and RNA. The incidence and risk factors of HCC development were analyzed. Rates of anti-HDV and HDV RNA positivity were 2.3% and 1.0%, respectively. The annual incidence of HCC was 1.4 per 100 person-years after a follow-up period of over 5409.5 person-years. The strongest factor association with HCC development was liver cirrhosis (hazard ratio [HR]/95% confidence interval [CI] 9.98/5.11–19.46, P < 0.001), followed by HDV RNA positivity (HR/ CI 5.73/1.35–24.29, P = 0.02), age > 50 years old (HR/CI 3.64/2.03–6.54, P < 0.001), male gender (HR/CI 2.69/1.29–5.60, P: 0.01), and body mass index (BMI, HR/CI 1.11/1.03–1.18, P = 0.004). The 5-year cumulative incidence of HCC was 7.3% for patients with HDV RNA negativity compared to that of 22.2% for patients with HDV RNA positivity (P = 0.01). In the subgroup of cirrhotic patients, the factors associated with HCC development were HDV RNA positivity (HR/CI 4.45/1.04–19.09, P = 0.04) and BMI (HR/CI 1.11/1.03–1.19, P = 0.01). HDV viremia played a crucial role in HCC development in CHB patients who underwent NA therapy.

Comparison of the on-treatment risks for hepatocellular carcinoma between entecavir and tenofovir: A propensity score matching analysis.

Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) may reduce the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB). However, it is not clear whether there is difference in the on-treatment HCC risks between ETV and TDF. In this retrospective cohort study, we compared the on-treatment HCC incidence of ETV and TDF in 1340 consecutive nucleos(t)ide analog-naïve CHB patients by propensity score (PS) matching analysis. PS was calculated by using age, sex, drinking history, diabetes, liver cirrhosis, hepatitis B e antigen positivity, hepatitis B virus DNA, hepatitis B s antigen titer, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alpha-fetoprotein, albumin, bilirubin, prothrombin time, platelet count, and calendar year of treatment initiation as covariates. The HCC risk was assessed by Cox regression with death and liver transplantation as competing risks in the 1:1 PS-matched cohorts (n=596). TDF had higher cumulative virologic response (P=0.027) whereas ETV showed higher AST and ALT normalization rates (P=0.005 and<0.001, respectively) in PS-matched cohorts. HCC risk was similar between ETV and TDF, either by PS-matching analysis (hazard ratio [HR] for TDF over ETV=2.06, 95% confidence interval [CI]=0.98-4.33, P=0.058) or inverse probability of treatment weighting analysis (HR=1.30, 95% CI=0.81-2.10; P=0.276). ETV and TDF treatment was associated with similar risk for HCC development in CHB patients.

Tenofovir Treatment Has Lower Risk of Hepatocellular Carcinoma than Entecavir Treatment in Patients with Chronic Hepatitis B: A Systematic Review and Meta-Analysis

Purpose: Tenofovir (TDF) and entecavir (ETV) are both equally recommended as first-line treatments for patients with chronic hepatitis B (CHB). They have comparable efficacy in virologic response, but their effect on the development of hepatocellular carcinoma (HCC) in CHB is controversial. Therefore, we aimed to compare TDF and ETV evaluating the risk of HCC development in CHB patients. Methods: A systematic literature search was conducted up to November 2019 in MEDLINE/PubMed, SCOPUS, and Web of Science databases without language and time restrictions. DerSimonian and Laird random-effects models were used to estimate combined hazard ratios (HRs) and 95% CIs. Results: Seven studies containing 35,785 participants were included in this systematic review and meta-analysis. The pooled HR (95% CI) of HCC in the patients who used TDF versus patients who used ETV was 0.75 (0.56–0.96). There was no significant heterogeneity detected among the included studies results (I² = 47.5%). There was no significant publication bias detected among the included studies (Begg’s p = 0.88 and Egger’s regression test p = 0.96). Conclusions: Evidence to date suggests that TDF treatment is associated with significantly fewer cases of HCC when compared to ETV.

Prevalence of hepatocarcinoma-related hepatitis B virus mutants in patients in grey zone of treatment.

BACKGROUNDAntiviral treatment of patients with chronic hepatitis B (CHB) in the grey zone of treatment comands risk management in order to optimize the health outcome. In this sense, the identification of HBV mutants related with an increased risk of hepatocellular carcinoma (HCC) could be useful to identify subpopulations with potential indication of antiviral treatment.AIMTo analyze the prevalence/persistence of hepatitis B virus (HBV) preS and basal core promoter (BCP)/precore/core variants associated to HCC development in CHB patients in the grey zone.METHODSWork was designed as a longitudinal retrospective study, including 106 plasma samples from 31 patients with CHB in the grey zone of treatment: Hepatitis B e antigen negative, HBV-DNA levels between 12-20000 IU/mL, normal or discordant transaminase levels during follow up and mild/moderate necro-inflammatory activity in liver biopsy or Fibroscan (up to 9.5 kPa). Serum HBV-DNA was tested using the Abbott Real Time HBV Assay and the BCP/precore/core and the hepatitis B surface antigen (HBsAg) coding regions were analyzed in positive samples by PCR/bulk-sequencing to identify the HCC-related HBV mutants.RESULTSHigh-risk HCC related mutants were detected in 24 (77%) patients: 19 (61%) in the BCP/precore/core, and 7 (23%) in the HBsAg coding region (2 preS1 and 5 preS2 deletions). The prevalence of preS deletions was genotype-dependent: 3/5 (60%) patients with preS2 deletions and 1/2 with preS1 deletions were infected with the HBV-E genotype. Since HBV-E was the most prevalent in sub-Saharan patients, a correlation between preS deletions and ethnicity was also found: 6/8 (75%) sub-Saharan vs 1/19 (5%) Caucasian patients had preS deletions (P = 0.00016). Remarkably, this correlation was maintained in those patients infected with HBV-A, a minor genotype in sub-Saharan patients: 2/2 patients infected with HBV-A from West Africa vs 0/6 of Caucasian origin had preS deletions. The HCC related variants were the major strains and persisted over time (up to 48 mo). Patients with preS deletions had a significant higher prevalence of F2 fibrosis stage than the negatives (57% vs 10%, P = 0.0078).CONCLUSIONHBV genetic analysis of selected populations, like sub-Saharans infected with HBV-E/A genotypes, will allow identification of subpopulations with risk of HCC development due to accumulation of high-risk HBV variants, thus commanding their increased clinical surveillance.

Coexistence of low levels of HBsAg and high levels of anti-HBs may increase risk of hepatocellular carcinoma in chronic hepatitis B patients with high HBV load

ObjectiveThe clinical significance of coexistence of HBsAg/anti-HBs in chronic hepatitis B (CHB) patients remains controversial. This study was aimed to assess the association of this serological pattern with hepatocellular carcinoma (HCC) in patients with CHB. MethodsIn this cross-section study, 206 CHB patients with coexistence of HBsAg/anti-HBs and 206 CHB patients with HBsAg alone were included to evaluate the risk of HCC development by logistic regression analysis. In addition, a retrospective cohort of 260 patients with CHB was recruited to estimate the cumulative incidence of HCC by Kaplan–Meier analysis. ResultsThe serological pattern of coexistence of HBsAg/anti-HBs, with high levels of (“High”) HBsAg/low levels of (“Low”) anti-HBs, were considered as independent risk factors for HCC. In particular, patients with “High” HBsAg/“High” anti-HBs [odds ratio (OR), 4.295; 95% confidence interval (CI), 1.104–16.699; p = 0.035] and “Low” HBsAg/ “High” anti-HBs (OR, 3.207; 95%CI, 1.299–7.919; p = 0.012) exhibited significantly higher risk for HCC development. However, only “Low” HBsAg /“High” anti-HBs might increase risk of HCC in CHB patients with high HBV load (logrank p < 0.001) in our cohort study. ConclusionThe coexistence of “Low” HBsAg /“High” anti-HBs might increase the risk of HCC development in CHB patients with high HBV load, which reflected that the long-term interaction between immune response and virus might lead to the development of HCC. The identification of the patients with poor prognosis will help clinicians to refine the therapeutic decisions and individualize follow-up strategies.

Interferon-based treatment is superior to nucleos(t)ide analog in reducing HBV-related hepatocellular carcinoma for chronic hepatitis B patients at high risk

ABSTRACTBackground: The effect of nucleos(t)ide analogs (NAs) versus interferon (IFN) on the occurrence of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) is controversial. We assessed whether antiviral strategy affected HCC development in CHB patients at different HCC risks.Methods: 1112 CHB patients with antiviral therapy were included in this retrospective study. Patients treated with NAs only were classified into NAs group (n = 682) while those received IFN treatment with or without NAs were defined as IFN group (n = 430). Propensity score matching (PSM) was applied to minimize baseline differences.Results: Totally, 31 patients developed HCC during follow-up (median 5.41 years). The cumulative HCC incidence at 10 years was significantly lower in the IFN group than NAs group (2.7% vs 8.0%, p < 0.001). Similar results were obtained in the PSM-cohort. Patients with IFN-based treatment were less likely to develop HCC than those with NAs (Hazard ratio = 0.15; 95% CI 0.04–0.66; p = 0.012). Subgroup analyses demonstrated that this superiority of IFN in reducing HCC development was obvious in patients at high- but not low-risk of HCC.Conclusions: Reduction of HCC development was more significant in CHB patients at higher HCC risk with IFN-based therapy than NAs treatment.

Comparison of anti-HBV regimen with or without adefovir on hepatocellular carcinoma development of Chronic hepatitis B patients with compensated cirrhosis: a retrospective cohort study

BackgroundThe impact of different anti-virus regimens on prognosis of Chronic hepatitis B (CHB) related cirrhosis remains to be explored. We aim to investigate whether CHB-related HCC patients receiving nucleoside analogue regimen or not have a different prognosis.Methods242 CHB-related compensated cirrhosis patients from 2008 June to 2011 December were included in our study and attributed into groups based on their anti-virus regimens containing adefovir (ADV) or not. The clinical parameters and virological response between ADV-containing regimen group and non-ADV containing regimen groups were reviewed and compared. The risk of hepatocellular carcinoma (HCC) development were analyzed and compared between two groups.Results127 patients received anti-virus regimen containing ADV and 115 patients received anti-virus regimen without ADV. The cumulative risk of HCC development among patients treated with ADV-contained therapy was significantly lower than that observed in patients with non-ADV-contained therapy (p<0.05). Multivariate analysis indicated that ADV-containing regimen treatment was significantly associated with lower probability of HCC development, (hazard ratio, 0.18; 95% confidence interval range, 0.07-0.45, p<0.05).ConclusionBoth anti-virus regimens were effective in reducing serum HBV DNA. Regimen containing ADV decreased the incidence of HCC development in CHB patients with compensated cirrhosis.

Gamma-glutamyl transpeptidase-to-platelet ratio is an independent predictor of hepatitis B virus-related liver cancer.

Gamma-glutamyl transpeptidase-to-platelet ratio (GPR) can evaluate the degree of liver fibrosis. We investigated whether GPR can predict the development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. We retrospectively evaluated 1109 CHB patients that were enrolled between 2006 and 2012, and all patients had available data for the assessment of GPR at enrollment. Three risk groups were defined according to tertile stratification: GPR<0.05, low-risk (n=370 [33.4%]); GPR 0.05-0.24, intermediate-risk (n=370 [33.4%]); and GPR>0.24, high-risk (n=369 [33.2%]). The predictive accuracy of GPR, fibrosis-4 (FIB-4), and aspartate transaminase-to-platelet ratio index (APRI) in predicting HCC development was tested. The median age of the study population (746 men and 363 women) was 50years. During the follow-up period (median, 32months; interquartile range, 19-57months), 69 (6.2%) patients developed HCC. Together with age, male gender, diabetes mellitus, antiviral therapy, serum albumin, and alpha-fetoprotein, the relative risk of HCC development significantly increased from low-risk to high-risk GPR groups (hazard ratio [HR], up to 29.5; adjusted HR, up to 10.6; all P<0.05). In addition, FIB-4 was calculated to be a significantly high relative risk of HCC development (HR, up to 20.1; adjusted HR, up to 7.3; all P<0.05), whereas APRI was not (P=0.168). The cumulative incidence of HCC development was significantly different among three risk groups (P<0.001, log-rank test). This study suggests that GPR can be used as a noninvasive marker to assess the risk of HCC development in CHB patients.

Chronic inflammation contributes to the development of hepatocellular carcinoma by decreasing miR-122 levels.

Persistent inflammation in chronic hepatitis plays a major role in the development of hepatocellular carcinoma (HCC). In this study, the major inflammatory cytokines expressed in chronic hepatitis, IL-6 and TNF-α, induced a marked decrease in microRNA-122 (miR-122) levels, and miR-122 expression was downregulated in the livers of chronic hepatitis B (CHB) patients. The decrease of miR-122 caused upregulation of the proinflammatory chemokine CCL2. IL-6 and TNF-α suppressed miR-122 both by directly downregulating the transcription factor C/EBPα and indirectly upregulating c-myc, which blocks C/EBPα-mediated miR-122 transcription. In addition, IL-6 and TNF-α levels were elevated and miR-122 levels were decreased in mouse and rat models of diethylnitrosamine (DEN)-induced HCC. Restoration of miR-122 levels through delivery of agomir-122 suppressed DEN-induced hepatocarcinogenesis in mice. Our results show that inflammation-induced miR-122 downregulation in hepatitis contributes to carcinogenesis and suggest that increasing miR-122 may be an effective strategy for preventing HCC development in CHB patients.

Disease Progression in Chronic Hepatitis B Patients under Long-Term Antiviral Therapy.

Background/AimsWe investigated factors associated with the disease progression and development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients during long-term oral nucleos(t)ide analog (NA) therapy.MethodsThis retrospective study included 524 naive CHB patients who received oral NA therapy for more than 48 weeks between January 2003 and December 2007. The primary outcome was 5-year cumulative probability of disease progression and HCC development. Disease progression was defined as cirrhosis development, cirrhotic complications, HCC or liver-related mortality.ResultsFor the 524 patients, the cumulative probabilities of disease progression and HCC development at 1, 2, 3, 4 and 5 years were 1.1%, 6.3%, 9.0%, 11.6%, and 16.2% and 0.2%, 1.8%, 3.6%, 5.8%, and 9.3%, respectively. In multivariate analysis, age >50 years (hazard ratio [HR], 1.05) and cirrhosis (HR, 2.95) were significant factors for disease progression. Similarly, age >50 years (HR, 1.05), family history of HCC (HR, 5.48), and cirrhosis (HR, 17.16) were significant factors for HCC development. Importantly, longer duration (>12 months) of maintained virological response (<20 IU/mL) reduced the risks of disease progression (HR, 0.19) and HCC development (HR, 0.09).ConclusionsLonger duration of maintained virological response significantly reduces the risk of disease progression or HCC development in CHB patients undergoing long-term oral NA therapy.

Do statins reduce the risk of hepatocellular carcinoma in patients with chronic hepatitis B?

In subjects with chronic hepatitis B (CHB), the lifetime risk of developing hepatocellular carcinoma (HCC) is estimated to be 25-37 times compared to non-infected subjects. The process of hepatocarcinogenesis is complex and involves well-documented host, viral, and environmental risk factors. The most important risks include host factors such as older age, male gender, the presence of cirrhosis, and viral factors such as the viral load, genotype, and the presence of basal core promoter mutations. To date, antiviral therapy is the only intervention demonstrated to significantly reduce the risk of HCC development in CHB patients. Although oxidative stress has been implicated in cancer development, there is no established benefit shown from treatment with antioxidizing agents such as silymarin, green tea, and vitamin E.

Effect of Response to Interferon-α Therapy on the Occurrence of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B

Objectives: The aim of this study was to examine whether interferon-α (IFN-α) therapy may reduce the occurrence of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) and to determine its effect based on responsiveness to IFN-α therapy. Methods: A total of 641 biopsy-proven CHB patients were treated with IFN-α2b. They were followed by biochemistry and/or imaging studies at 3- to 6-month intervals for a median period of 113 months (range 6–222). Results: HCC was detected in 22 patients and 5- and 10-year cumulative occurrence rates were 0.4 and 3.2%, respectively. In univariate analysis, age (p < 0.001), serum AFP levels (p < 0.001), and serum HBV-DNA levels (p = 0.002) at baseline were associated with HCC development. HCC occurred less frequently in biochemical responders at the end of treatment than in non-responders (p = 0.001). However, virologic response was not associated with HCC development. Multivariate analysis showed that poor biochemical response (p = 0.007) as well as older age (p = 0.018) and a higher serum AFP level (p < 0.001) remained independent predisposing factors of HCC development in CHB patients treated with IFN-α. Conclusion: The results suggest that the biochemical but not virologic response to IFN-α therapy reduces independently the occurrence of HCC in patients with CHB.

Relationship of HLA-DRB1 Alleles With Hepatocellular Carcinoma Development in Chronic Hepatitis B Patients

We intended to analyze the relationship between specific human leukocyte antigen (HLA)-DRB1 alleles and development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. A database of 468 consecutive CHB patients who received lamivudine for more than 12 months between July 1996 and February 2011 was retrospectively analyzed. Sera and buffy coats samples were obtained between April 2008 and April 2010. Six-digit HLA-DRB1 genotyping was performed with sequence-based typing. Serum α fetoprotein levels and ultrasonography or computed tomography image studies were assessed every 3 to 6 months for surveillance of HCC. At baseline, median age was 43 years (range, 16 to 71) [male: 359 (76.7%); HBeAg positivity: 385 (82.3%)]. Among the 27 HLA-DRB1 alleles identified, HLA-DRB1*090102, *080302, and *070101 were the most frequent (>10%). HCC was diagnosed in 36 (7.7%) patients during the median follow-up of 69 months. The frequency of the HLA-DRB1*140101 allele was 9.0% and significantly higher in patients of the HCC group than those of the non-HCC group (19.4 vs. 8.1%, P=0.014). The 2-year, 4-year, and 6-year cumulative rates of HCC development were markedly higher in patients with HLA-DRB1*140101 than those without HLA-DRB1*140101 (2.4, 8.2, and 25.1% vs. 1.9, 4.7, and 7.4%, respectively, P=0.011). No other HLA-DRB1 alleles were associated with HCC development. Baseline clinical characteristics did not differ between patients with and without HLA-DRB1*140101. The HLA-DRB1*140101 allele may be potentially associated with increased risk of HCC development in CHB patients, irrespective of the replicative activity of hepatitis B virus and antiviral responsiveness.