entecavir and Carcinoma--Hepatocellular

Entecavir (ETV) and Tenofovir disoproxil fumarate (TDF) are the first-line drugs for the treatment of chronic hepatitis B virus (HBV). However, the impact of these two antiviral agents on the outcome of HBV-related hepatocellular carcinoma (HCC) after curative therapy remains to be explored. The purpose of the present study was to compare the effect of ETV and TDF on recurrence and mortality after curative treatment for HBV-related HCC. A comprehensive literature search of multiple electronic databases was conducted from 2000 to January 2022 for studies comparing ETV and TDF for HBV-related HCC patients after curative therapy. The adjusted hazard ratios (aHR) were pooled using a random-effects model. A total of nine studies with 5298 patients were included in the final meta-analysis. TDF was associated with a lower risk of HCC recurrence [aHR 0.73, 95% confidence interval (CI) 0.65-0.81] compared to HCC. TDF reduced the risk of late recurrence compared to ETV (aHR 0.58, 95% CI 0.45-0.76) but not early recurrence (aHR 0.88, 95% CI 0.76-1.02). The mortality risk was also lower with TDF compared to ETV (aHR 0.62, 95% CI 0.50-0.77). TDF was associated with a lower risk of recurrence and mortality than ETV after resection or ablation of HBV-related HCC. Further prospective randomized controlled studies are warranted to validate these results.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir; Tertiary Prevention; Treatment Outcome

Currently, enough studies with aggregated study-level data have demonstrated that there was no clinically meaningful difference in the risk of hepatocellular carcinoma (HCC) between patients who received entecavir and patients who received tenofovir treatment for chronic hepatitis B virus (CHBV). However, many studies found many differences in prognosis of these HCC patients. This meta-analysis of high-quality propensity score-matched (PSM) studies was designed to provide robust estimates for comparative HCC prognosis between groups receiving tenofovir or entecavir.. PubMed, Embase, Cochrane Library, and Web of Science were searched from inception to July 10, 2022, for relevant studies that compare the different prognoses of HCC between tenofovir and entecavir treatment. The primary outcomes were the difference of overall death or liver transplantation between tenofovir and entecavir treatment. The secondary outcomes included risk factors of overall death or liver transplantation and different treatment responses between tenofovir and entecavir treatment for CHBV. All statistical analyses were performed using the standard statistical procedures provided in Review Manager 5.2.. A total of 15 PSM studies were identified, with 24,035 sample sizes in tenofovir group and 61,410 sample sizes in entecavir group, respectively. Pooled data indicated that, compared with entecavir, patients receiving tenofovir experienced significantly lower overall death or liver transplantation, with a pooled OR of 0.55 (95% CI: 0.45-0.68; p < 0.00001). Subgroup analysis by population also found similar results with pooled ORs of 0.52 (95% CI: 0.38-0.70; p < 0.0001) in entire cohort and 0.62 (95% CI: 0.50-0.77; p < 0.0001) in PSM cohort. Similarly, the subgroup analysis also found that HCC patients without cirrhosis receiving tenofovir experienced significantly lower overall death or liver transplantation than entecavir (OR: 0.56; 95% CI: 0.49-0.66), but no significant result was found in HCC patients with cirrhosis. In addition, both univariate (OR: 0.46; 95% CI: 0.31-0.69) and multivariable analyses (OR: 0.86; 95% CI: 0.82-0.91) also indicated significant reduction of overall death or liver transplantation in tenofovir group than entecavir group.. Our analysis indicated that there was clinically meaningful difference in prognosis of HCC between patients who received entecavir and patients who received tenofovir. Patients who received tenofovir experienced much lower overall death or liver transplantation than patients who received entecavir. Tenofovir treatment may be one of independent favorable factors of prognosis for HCC patients with CHBV.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis B virus; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Prognosis; Propensity Score; Retrospective Studies; Tenofovir; Treatment Outcome

The comparative risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving tenofovir disoproxil fumarate (TDF) vs. entecavir (ETV) remains controversial. In this individual patient data (IPD) meta-analysis, we aimed to compare HCC risk between the two drugs and identify subgroups who may benefit more from one treatment than the other.. Published meta-analyses, electronic databases and congress proceedings were searched to identify eligible studies through January 2021. We compared HCC risk between the two drugs using a multivariable Cox proportional hazards model with anonymised IPD from treatment-naïve patients with CHB receiving TDF or ETV for ≥1 year. Treatment effect consistency was explored in propensity score matching (PSM), weighting (PSW) and subgroup analyses for age, sex, hepatitis B e-antigen (HBeAg) positivity, cirrhosis and diabetes status.. We included 11 studies from Korea, Taiwan and Hong Kong involving 42,939 patients receiving TDF (n = 6,979) or ETV (n = 35,960) monotherapy. Patients receiving TDF had significantly lower HCC risk (adjusted hazard ratio [HR] 0.77; 95% CI 0.61-0.98; p = 0.03). Lower HCC risk with TDF was consistently observed in PSM (HR 0.73; 95% CI 0.59-0.88; p <0.01) and PSW (HR 0.83; 95% CI 0.67-1.03; p = 0.10) analyses and in all subgroups, with statistical significance in the ≥50 years of age (HR 0.76; 95% CI 0.58-1.00; p <0.05), male (HR 0.74; 95% CI 0.58-0.96; p = 0.02), HBeAg-positive (HR 0.69; 95% CI 0.49-0.97; p = 0.03) and non-diabetic (HR 0.79; 95% CI 0.63-1.00; p <0.05) subgroups.. TDF was associated with significantly lower HCC risk than ETV in patients with CHB, particularly those with HBeAg positivity. Longer follow-up may be needed to better define incidence differences between the treatments in various subgroups.. Previous aggregate data meta-analyses have reported inconsistent conclusions on the relative effectiveness of tenofovir disoproxil fumarate and entecavir in reducing hepatocellular carcinoma risk in patients with chronic hepatitis B (CHB). This individual patient data meta-analysis on 11 studies involving 42,939 patients from Korea, Taiwan and Hong Kong suggested that tenofovir disoproxil fumarate-treated patients have a significantly lower hepatocellular carcinoma risk than entecavir-treated patients, which was observed in all subgroups of clinical interest and by different analytical methodologies. These findings should be taken into account by healthcare providers when determining the optimal course of treatment for patients with CHB and may be considered in ensuring that treatment guidelines for CHB remain pertinent.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Female; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Tenofovir; Treatment Outcome

Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are equally recommended as first-line treatments for antiviral treatment-naïve (ART-naïve) chronic hepatitis B (CHB) patients by practice guidelines because of their similarly high antiviral efficacy and low resistance rate. However, whether one is superior to the other in terms of hepatocellular carcinoma (HCC) prevention is currently largely controversial. We aimed to identify and synthesize these existing studies regarding the HCC risk of these two highly potent antivirals in treatment-naïve CHB patients. PubMed, EMBASE, and Cochrane Library were searched for studies between January 1, 2012 and June 25, 2022. These studies used ETV monotherapy and/or TDF monotherapy to treat ART-naïve CHB patients and reported the incidence of HCC. The extracted data were analyzed using a DerSimonian-Laird random-effects models. The HCC incidence difference was expressed as hazard ratio (HR) and 95% confidence interval (95% CI). A total of 17 studies with 90,897 ART-naïve CHB patients (ETV = 60,980 vs TDF = 29,917) were included in this meta-analysis. Compared with ETV, TDF was associated with a significant lower cumulative incidence of HCC (HR 0.66; 95% CI 0.56-0.76). No significant heterogeneity or publication bias was found among the included studies (I

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis B, Chronic; Humans; Liver Neoplasms; Retrospective Studies; Tenofovir; Treatment Outcome

Tenofovir and Entecavir are recommended as the first-line medicine of treatment for chronic hepatitis B. The occurrence of hepatocellular carcinoma after the treatment of chronic hepatitis B is a major problem. For the time being it is still unclear whether there remains a difference in risk correlation of hepatocellular carcinoma after the treatment of Tenofovir and Entecavir for chronic hepatitis B. Since previous studies have raised different ideas, this article aims to come to a conclusion targeting such a topic through analyzing the latest data.. We searched some databases, such as PubMed, Web of Science, and Cochrane Library, for related studies on patients with chronic hepatitis B receiving the treatment of Tenofovir and Entecavir and then developing hepatocellular carcinoma. The search time was set to begin from the establishment time of the above-mentioned databases to May 2022. Two researchers were designated to screen the literature independently according to the inclusion and exclusion criteria set in this study; they then evaluated the quality of the literature included and extracted the data. Revman 5.3 software was used for meta-analysis.. After screening the literature, a total of 20 pieces of cohort study literature conformed to the inclusion criteria. Among which were 62,860 cases of patients receiving Entecavir, and 27,544 cases of patients receiving Tenofovir; there were 3669 cases with the occurrence of hepatocellular carcinoma in the Entecavir group and 1089 cases with the occurrence of hepatocellular carcinoma in Tenofovir group. The result of Meta analysis of these 20 pieces of literature shows that compared with the Tenofovir group, the Entecavir group has a lower occurrence rate of hepatocellular carcinoma, and the difference is statistically significant. The results are expressed as odd ratio (OR) and 95% confident interval (95%CI), (OR = 1.66, 95%CI: 1.35-2.05, P < .05). The result of Meta analysis of 10 studies related to Korea shows that the occurrence rate of hepatocellular carcinoma in the Tenofovir group is lower than that of the Entecavir group, and the difference is statistically significant (OR = 1.59, 95%CI: 1.29-1.95, P < .05). The result of meta-analysis of 5 studies related to China shows that the occurrence rate of hepatocellular carcinoma of Tenofovir group is lower than that of Entecavir group, and the difference is statistically significant (OR = 2.35, 95%CI: 1.15-4.81, P < .05).. The occurrence rate of hepatocellular carcinoma after the treatment of tenofovir for chronic hepatitis B is lower than that of the treatment of entecavir.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir; Treatment Outcome

Hepatitis B virus (HBV) is a life-threatening infectious virus associated with the risk of liver failure and hepatocellular carcinoma (HCC). Regarding HBV treatment, the recent development of nucleoside/nucleotide analogs (NUC), HBV reverse transcriptase inhibitors, enabled favorable viral control as well as improved prognosis in patients with chronic hepatitis B. However, NUC fails to clear HBV because the formation of covalently closed circular DNA or HBV surface antigen occurs upstream of the point of action of NUC. Recently, we found that acyclic nucleoside phosphonates (ANP) such as adefovir or tenofovir, but not lamivudine or entecavir, induced IFN-λ3 productions in the gastrointestinal tract and modulated lipopolysaccharide (LPS)-mediated cytokine profiles in peripheral blood mononuclear cells, such as interleukin (IL)-12p70 induction and IL-10 inhibition, which are immunologically favorable cytokine profiles for HBV elimination. Furthermore, IFN-α, in combination with ANP, showed additional and synergistic effects on IFN-λ3 and IL-12p70 production, respectively, while not affecting IL-10 levels. Mechanistic analyses of the cytokine modulation by ANP revealed that ANP blocked the mammalian target of the rapamycin (mTOR) pathway by inhibiting Akt translocation to the plasma membrane, thereby inhibiting Akt phosphorylation. As it has been reported that IFN-λ inhibits tumor growth directly or indirectly and the mTOR pathway is generally activated in most cancer cells, ANP might have potential anti-HCC effects. Our in vitro and ex vivo findings might stir the debate on whether types of NUC affect the risk of HBV-related HCC incidence.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interleukin-10; Leukocytes, Mononuclear; Liver Neoplasms; Nucleosides; Proto-Oncogene Proteins c-akt; Tenofovir; TOR Serine-Threonine Kinases; Treatment Outcome

Our study aimed to compare the predictive performance of different hepatocellular carcinoma (HCC) prediction models in chronic hepatitis B patients receiving entecavir or tenofovir, including discrimination, calibration, negative predictive value (NPV) in low-risk, and proportion of low-risk.. We conducted a systematic literature research in PubMed, EMbase, the Cochrane Library, and Web of Science before January 13, 2022. The predictive performance was assessed by area under receiver operating characteristic curve (AUROC), calibration index, negative predictive value, and the proportion in low-risk. Subgroup and meta-regression analyses of discrimination and calibration were conducted. Sensitivity analysis was conducted to validate the stability of the results.. We identified ten prediction models in 23 studies. The pooled 3-, 5-, and 10-year AUROC varied from 0.72 to 0.84, 0.74 to 0.83, and 0.76 to 0.86, respectively. REAL-B, AASL-HCC, and HCC-RESCUE achieved the best discrimination. HCC-RESCUE, PAGE-B, and mPAGE-B overestimated HCC development, whereas mREACH-B, AASL-HCC, REAL-B, CAMD, CAGE-B, SAGE-B, and aMAP underestimated it. All models were able to identify people with a low risk of HCC accurately. HCC-RESCUE and aMAP recognized over half of the population as low-risk. Subgroup analysis and sensitivity analysis showed similar results.. Considering the predictive performance of all four aspects, we suggest that HCC-RESCUE was the best model to utilize in clinical practice, especially in primary care and low-income areas. To confirm our findings, further validation studies with the above four components were required.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir

Previous smaller meta-analyses comparing the incidence of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients treated with tenofovir disoproxil fumarate (TDF) versus entecavir (ETV) provided controversial results. This updated meta-analysis aimed to reliably identify any difference in the HCC incidence between TDF-treated or ETV-treated CHB patients in general or in specific subgroups.. PubMed, EMBASE, Web of Science, and Cochrane Library were systematically searched for relevant studies with hazard ratios (HRs) for HCC between TDF-treated and ETV-treated CHB patients. Retrieved dates ranged from January 2009 to October 2021. HRs with or without adjustment were pooled with random-effects model.. Twenty-four comparative studies involving 37 771 CHB patients treated with TDF and 72 094 treated with ETV were included. TDF was associated with lower risk of HCC compared with ETV, with pooled unadjusted HR of 0.76 (95% confidence interval [CI]: 0.67-0.86) (24 studies) and adjusted HR of 0.81 (95% CI: 0.72-0.91) (21 studies). In propensity score matching cohorts, the TDF superiority was confirmed for unadjusted HR 0.83 (95% CI: 0.71-0.97) (14 studies) and was close to significance for adjusted HR (0.78, 95% CI: 0.58-1.04) (8 studies). Subgroup analyses showed that TDF was associated with lower HCC risk than ETV treatment in CHB patients who were from Asia (adjusted HR: 0.76, 95% CI: 0.66-0.87; 15 studies) or nucleos(t)ide naïve (adjusted HR:0.74, 95% CI: 0.65-0.84; 18 studies).. Current evidence from a sizable population suggests that TDF is associated with significantly lower HCC risk compared with ETV treatment in patients who are from Asia and/or nucleos(t)ide naïve.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Retrospective Studies; Tenofovir; Treatment Outcome

Long-term antiviral treatments are associated with a significantly lower hepatocellular carcinoma (HCC) incidence in chronic hepatitis B (CHB) patients by reducing HBV DNA concentrations. However, it is still controversial whether antiviral strategies affect HCC development in antiviral treatment-naïve CHB patients. This study aimed to estimate the incidence of HCC in antiviral treatment-naïve CHB patients who were treated with Entecavir (ETV) and Tenofovir Disoproxil Fumarate (TDF) and compare the efficacy of two treatment regimens in HCC reduction.. The PubMed, Embase, China National Knowledge Infrastructure, and Wanfang databases were systematically searched until June 24, 2021. The pooled incidence and 95% confidence interval of HCC were calculated by the Freeman-Tukey double arcsine transformation method. The efficacies of ETV and TDF treatments in HCC reduction were compared through a network meta-analysis.. A total of 27 studies were identified as eligible for this systematic review. The incidence densities in the ETV and TDF treatment groups were 2.78 (95% CI: 2.21-3.40) and 2.59 (95% CI: 1.51-3.96) per 100 persons-year among patients with preexisting cirrhosis and 0.49 (95% CI: 0.32-0.68) and 0.30 (95% CI: 0.06-0.70) per 100 persons-year among patients without preexisting cirrhosis. As the proportion of CHB patients with preexisting cirrhosis increased, the incidence density of HCC also increased gradually. Compared with other Nucleos(t)ide analogs (NAs) treatments, ETV and TDF treatments significantly lowered the risk of HCC, with hazard ratios (HRs) of 0.60 (95% CI: 0.40-0.90) and 0.56 (95% CI: 0.35-0.89), respectively. However, there was no difference in the incidence density of HCC between ETV and TDF treatments (HR = 0.92, 95% CI: 0.71-1.20) regardless of preexisting cirrhosis.. ETV and TDF treatments were associated with significantly lower risks of HCC than other NAs treatments. However, no difference was observed between ETV and TDF treatments in the risk of HCC development regardless of preexisting cirrhosis among treatment-naïve CHB patients.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Cirrhosis; Liver Neoplasms; Tenofovir; Treatment Outcome

Conventional meta-analyses with aggregated study-level data have yielded conflicting results for the comparative effectiveness of tenofovir disoproxil fumarate vs entecavir in reducing hepatocellular carcinoma (HCC) risk among patients with chronic hepatitis B virus. Within-study heterogeneity, between-study heterogeneity, and the inability of conventional meta-analyses to capture time-to-event data were associated with these results.. To perform a reconstructed individual patient data meta-analysis of high-quality propensity score-matched studies to provide robust estimates for comparative HCC risk between groups receiving tenofovir or entecavir.. Medline and Embase databases were searched from inception to October 6, 2021.. The initial search yielded 3435 articles. Fourteen studies that used propensity score matching to balance baseline characteristics were included in the final analysis.. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was followed. Individual patient data were reconstructed from Kaplan-Meier curves. Risk of HCC was evaluated using random-effects hazard ratios (HRs) via a shared-frailty model and a Cox proportional hazards model stratified by study group. Restricted mean survival time (RMST) analysis was conducted to account for varying estimated treatment effect across time.. The comparative risk of HCC with tenofovir vs entecavir treatment.. From analysis of 14 studes with 24 269 patients (10 534 receiving tenofovir and 13 735 receiving entecavir; mean age, 49.86 [95% CI, 48.35-51.36] years; 65.05% [95% CI, 58.60%-71.00%] men), tenofovir was associated with decreased HCC incidence compared with entecavir (stratified Cox HR, 0.85 [95% CI, 0.76-0.94] at 5 years; P = .002). However, there was no significant difference in subanalysis of clinical cohort studies (stratified Cox HR, 0.92 [95% CI, 0.80-1.06] at 5 years; P = .24). Among administrative database studies, proportionality was violated, and HRs could not be obtained via Cox proporational hazards-based models. The mean time to HCC development in RMST analysis was 2.8 (95% CI, 1.8-3.7) weeks longer (P < .001) for tenofovir vs entecavir at 5 years. The RMST analyses for other subgroups revealed either insignificant or minimal differences (<3 weeks) in the mean time to HCC at 5 years.. In this meta-analysis, there was no clinically meaningful difference in the risk of HCC between patients who received entecavir and patients who received tenofovir. There was no difference between tenofovir and entecavir among clinical cohort studies, whereas the mean time to HCC development was less than 3 weeks longer for patients who received tenofovir vs those who received entecavir at year 5 among administrative database studies. The choice between tenofovir or entecavir should be decided based on patient convenience and tolerability.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Middle Aged; Tenofovir

Chronic hepatitis B (CHB) can lead to hepatocellular carcinoma (HCC). While both tenofovir disoproxil (TDF) and entecavir (ETV) have been shown to reduce the risk of HCC, their comparative effectiveness is unclear. We estimated the comparative effectiveness of these two agents in reducing the risk of HCC in patients with CHB, through a systematic review and meta-analysis.. We searched multiple electronic databases from January 1, 1998, to October 31, 2019, for randomized controlled trials and observational comparative effectiveness studies in adults with CHB treated with ETV compared to TDF, reporting the incidence of HCC (minimum follow-up 12 months). Primary outcome was incidence of HCC, calculated as incidence rate ratio (IRR) with 95% confidence interval (CI, unadjusted analysis) and hazard ratio (HR) with 95% CI (adjusted analysis, where reported). Of 1,971 records identified, 14 studies (263,947 person-years) were included for quantitative analysis. On unadjusted meta-analysis of 14 studies, the risk of HCC was not statistically different between ETV and TDF (IRR, 1.28; 95% CI, 0.99-1.66). When using available adjusted data (multivariate or propensity-matched data), the risk of HCC among patients treated with ETV was 27% higher when compared to TDF (seven studies; 95% CI, 1.01-1.60, P = 0.04). Additional analysis of adjusted data when separately reported among patients with cirrhosis demonstrated an adjusted HR of 0.90 (95% CI, 0.66-1.23), suggesting no difference between ETV-treated and TDF-treated groups. The overall confidence in estimates was very low (observational studies, high heterogeneity).. TDF may be associated with lower risk of HCC when compared to ETV.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Cirrhosis; Liver Neoplasms; Observational Studies as Topic; Randomized Controlled Trials as Topic; Risk; Tenofovir

Tenofovir disoproxil fumarate (TDF) and entecavir are recommended as first-line treatments for chronic hepatitis B virus (HBV) infection. However, there is debate over the comparative effectiveness of these drugs in preventing hepatocellular carcinoma (HCC). We performed a systematic review and meta-analysis of the effectiveness of TDF vs entecavir in reducing the incidence of HCC among patients with chronic HBV infection.. We performed a systematic review of the MEDLINE, EMBASE, Web of Science, and Cochrane Library from 2010 through 2019 for full-text articles and conference abstracts on studies of effects of TDF vs entecavir in patients with HBV infection. Extracted data were analyzed with the random-effects model. Potential sources of heterogeneity were investigated using sensitivity, meta-regression, and subgroup analyses.. Our final analysis comprised 15 studies (61,787 patients; 16,101 patients given TDF and 45,686 given entecavir). TDF treatment was associated with a significantly lower risk of HCC than entecavir (hazard ratio, 0.80; 95% CI, 0.69-0.93; P = .003; I. In a meta-analysis of studies of patients with chronic HBV infection, we found that TDF treatment was associated with a significantly lower (20%) risk of HCC than entecavir treatment. Randomized trials are needed to support this finding.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir; Treatment Outcome

Both tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are accepted as first-line treatments for chronic hepatitis B (CHB). However, there are few randomized studies comparing their efficacy. The primary aim of this study was to compare the efficacy of TDF and ETV using a network meta-analysis of randomized trials. The secondary aim was to additionally include propensity-matched cohort studies in a conventional meta-analysis. We systematically searched PubMed, EMBASE, Cochrane Library and Web of Science for published English-language randomized and propensity-matched studies between 1/1/2000 and 4/2/2020. Outcomes included undetectable HBV DNA, ALT normalization and HBeAg seroconversion at 48 weeks. We excluded patients who had co-infection or significant prior treatment with antivirals. 13 517 participants from 16 studies (11 RCTs, n = 2675; five propensity-matched cohort studies, n = 10 842) were included. Virological response at 48 weeks was higher in patients receiving TDF compared to ETV using both the network meta-analytic approach (OR 1.69, P < .001) and the conventional meta-analysis including propensity-matched cohort studies (OR 1.40, P < .001). On subgroup analysis, this difference was only significant in HBeAg-positive patients (OR 1.81, P = .037). There was limited evidence to suggest a higher rate of ALT normalization with ETV (OR 0.74, P = .07). There was no difference in rates of HBeAg seroconversion between the two antivirals. TDF is more likely than ETV to induce virological response at 48 weeks in treatment-naïve CHB patients. Future studies should focus on elucidating associations between early and sustained virological response with adverse patient outcomes including development of HCC or cirrhosis.

Topics: Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Network Meta-Analysis; Tenofovir

Whether tenofovir disoproxil fumarate (TDF) is superior to entecavir in reducing hepatocellular carcinoma (HCC) risk among treatment-naïve chronic hepatitis B (CHB) patients remains controversial. We aimed to clarify this controversy. Several databases, including PubMed and Embase, were retrieved through November 2020. Cohort studies comparing the effectiveness of TDF and entecavir in reducing HCC incidence among treatment-naïve CHB patients were included if they reported multivariable-adjusted or propensity-score-matched risk estimates. A random-effects model was used to pool hazard ratios (HRs). Thirteen cohort studies, involving 4097 HCC cases and 80202 CHB patients, were included. Multivariable-adjusted meta-analysis revealed no significant difference in HCC incidence between TDF and entecavir groups (HR 0.86, 95% confidence interval 0.72-1.04), which was consistent with propensity-score-matched meta-analysis (HR 0.83, 95% confidence interval 0.66-1.03). Subgroup analysis showed that the observed similarity of TDF to entecavir for HCC prevention persisted in studies with follow-up length of ≥4 years but not in those with follow-up length of <4 years (

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Risk Factors; Tenofovir

This meta-analysis evaluated the comparative effectiveness of tenofovir disoproxil fumarate (TDF) versus entecavir (ETV) in reducing the risk of hepatocellular carcinoma (HCC).. It is unclear whether TDF or ETV is more effective in reducing the risk of HCC in chronic hepatitis B (CHB) patients with or without underlying cirrhosis.. We searched the MEDLINE database through April 13, 2020, for studies involving CHB treated with TDF and/or ETV. Primary and secondary outcomes were the incidence of HCC and overall survival, respectively, calculated as risk ratios (RRs). Adjusted results were further evaluated by pooling propensity score matched cohorts.. Of the 229 records identified, 17 studies were included in the quantitative analysis. TDF treatment was associated with a significantly lower risk of HCC development [RR, 0.63; 95% confidence interval (CI), 0.43-0.93; P=0.024] and mortality (RR, 0.69; 95% CI, 0.57-0.84; P=0.003) than ETV treatment. Moreover, TDF significantly lowered HCC risk in patients with cirrhosis (RR, 0.69; 95% CI, 0.56-0.84) and antiviral treatment-naive patients (RR, 0.59; 95% CI, 0.35-0.98) compared with ETV. Among treatment-naive patients, TDF significantly prolonged survival compared with ETV (RR, 0.69; 95% CI, 0.52-0.91).. TDF likely confers a lower risk of HCC development and longer survival in patients with CHB, especially among treatment-naive patients and those with underlying cirrhosis, than ETV.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Tenofovir; Treatment Outcome

Over the past several decades, entecavir (ETV) and tenofovir disoproxil fumarate (TDF) have remained the first-line antiviral agents in several international guidelines. These two antiviral agents have shown similar short to intermediateterm efficacy, including virologic, biochemical, serologic, and histologic responses. However, huge controversies regarding the antiviral efficacy of ETV and TDF in preventing the development of hepatocellular carcinoma (HCC) still exist. In this review, we summarized recent studies that compared the treatment efficacy of ETV and TDF in terms of HCC development.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir; Treatment Outcome

Controversy exists on whether tenofovir disoproxil fumarate (TDF) is superior to entecavir (ETV) in lowering the risk of hepatocellular carcinoma (HCC) development. This meta-analysis was performed to clarify this issue with critical clinical and methodological considerations.. PubMed, EMBASE, and Cochrane Library were searched from inception to Oct 28, 2019. Randomized control trials and observational studies reporting the impact of TDF and ETV on the risk of HCC in patients with chronic hepatitis B (CHB) were eligible. Risk ratios (RRs) calculated with cumulative incidence rate and/or annual incidence rate, or hazard ratio (HR) were pooled using random-effect models. Subgroup analyses were performed to assess the potential impact of between-study level and within-study level factors.. A total of 32 studies with 78,136 CHB patients were included. Overall cumulative incidence rate of HCC was lower in TDF group than ETV group (3.07% vs. 5.25%; RR 0.55; 95% CI 0.42-0.72). However, this difference was not statistically significant in pooled results of hazard ratio (HR 0.87; 95% CI 0.73-1.04) and RR calculated with annual incidence rate (RR 0.88; 95% CI 0.67-1.16). Potential confounding factors at between-study level included prior nucleos(t)ide usage, disease stage at baseline and region of study. More importantly, at within-study level, disparity in follow-up duration between TDF and ETV groups may impact the result, usually favoring a treatment with shorter follow-up duration.. Compared with ETV, TDF treatment tended to have a lower overall cumulative incidence rate of HCC. However, disparity in follow-up duration may be a key factor to influence the result.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir

Topics: Aminoisobutyric Acids; Antiviral Agents; Carbamates; Carcinoma, Hepatocellular; Cyclopropanes; Guanine; Hepatitis B, Chronic; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Lactams, Macrocyclic; Leucine; Liver Neoplasms; Liver Transplantation; Macrocyclic Compounds; Proline; Quinoxalines; Salvage Therapy; Sofosbuvir; Sulfonamides; Tenofovir; Transplants

Studies had shown that tenofovir (TDF) and entecavir (ETV) are widely used as the first-line therapy to inhibit hepatitis B virus replication, which can reduce the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients, but it was unclear which nucleos(t)ide analogue was most effective. Therefore, we performed a meta-analysis and a systematic review to compare the incidence of HCC in CHB patients who are either on TDF or ETV.. For this study, the following databases were searched for clinical trials published from its inception until November 2019: PubMed, Web of Science, MEDLINE, Embase, and Cochrane Library.. A total of 11 eligible studies were selected, including 70 864 patients. The meta-analysis showed that TDF was superior to ETV with regard to the incidence of HCC, the incidence of death or transplantation, and virologic response. There were no significant differences in terms of biochemical response and loss of seroconversion response among the entire cohort.. The conclusion was that CHB patients treated with TDF had a reduced incidence of HCC compared with patients treated with ETV.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Tenofovir

Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) have been shown to reduce incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This systematic review aims to evaluate the magnitude, change over time, and prediction of residual HCC risks in CHB patients treated with ETV/TDF therapy.. Available literature was systematically reviewed through searches of PubMed and EMBASE databases from January 1, 2006 to September 1, 2019, to identify cohort studies that reported HCC incidence in CHB patients during ETV/TDF therapy. Studies were screened by title and abstract and then evaluated for eligibility in terms of full text.. We identified 141 studies for full-text review, and 34 were eligible for analysis. From 19 studies with data separated by cirrhosis status, the 5-year cumulative incidence of HCC was 0.5-6.9% in patients without cirrhosis, 4.5-21.6% in compensated cirrhosis, and 36.3-46.5% in decompensated cirrhosis. All four studies that addressed temporal changes in HCC risks consistently found the incidence rate decreased over time in patients with cirrhosis, although the findings were inconsistent in patients without cirrhosis. Six predictive scores were developed and validated to predict incident HCC during ETV/TDF therapy in CHB patients. Common scoring variables included age, sex, cirrhosis (fibrosis grade), and hepatic function. Conflicting results were reported in seven individual studies and two meta-analyses that compared ETV versus TDF.. The residual risk of HCC remains during ETV/TDF treatment in CHB patients with cirrhosis but declines over time. Risk stratification is attainable by validated predictive scores.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Comorbidity; Female; Forecasting; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Risk; Tenofovir

Over 257 million individuals worldwide are chronically infected with the Hepatitis B Virus (HBV). Nucleos(t)ide analogues (NAs) are the first-line treatment option for most patients. Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are both potent, safe antiviral agents, have a high barrier to resistance, and are now off patent. They effectively suppress HBV replication to reduce the risk of cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Treatment is continued long-term in most patients, as NA therapy rarely induces HBsAg loss or functional cure. Two diverging paradigms in the treatment of chronic hepatitis B have recently emerged. First, the public health focussed "treat-all" strategy, advocating for early and lifelong antiviral therapy to minimise the risk of HCC as well as the risk of HBV transmission. In LMICs, this strategy may be cost saving compared to monitoring off treatment. Second, the concept of "stopping" NA therapy in patients with HBeAg-negative disease after long-term viral suppression, a personalised treatment strategy aiming for long-term immune control and even HBsAg loss off treatment. In this manuscript, we will briefly review the current standard of care approach to the management of hepatitis B, before discussing emerging evidence to support both the "treat-all" strategy, as well as the "stop" strategy, and how they may both have a role in the management of patients with chronic hepatitis B.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Duration of Therapy; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Public Health Practice; Tenofovir; Treatment Outcome; Viral Load; Withholding Treatment

It is unclear whether tenofovir disoproxil fumarate and entecavir differ in their association with risk of hepatocellular carcinoma in patients with chronic hepatitis B, and previous meta-analyses have shown conflicting conclusions with substantial heterogeneity. We aimed to analyse the updated data and elucidate the source of heterogeneity.. We searched PubMed, Embase, Web of Science, and the Cochrane library for relevant studies with time-to-event data for incident hepatocellular carcinoma occurring in patients with chronic hepatitis B who received tenofovir disoproxil fumarate or entecavir monotherapy with follow-up of at least 1 year. Studies published between Jan 1, 2006, and April 17, 2020, and abstracts from international conferences in 2018 and 2019 were included. We pooled covariate adjusted hazard ratios (HRs) for hepatocellular carcinoma using a random-effects model, assessed heterogeneity among included studies using the I. Our study found no significant difference between tenofovir disoproxil fumarate and entecavir in their association with incident hepatocellular carcinoma. We suggest that treatment should be guided by patient tolerability and affordability rather than whether one drug is more effective than the other.. Supported in part by E-DA Hospital (EDAHP 106008; EDAHP 103046).

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Tenofovir

Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are recommended as first-line therapies for chronic hepatitis B (CHB) infection. Although both drugs reduce hepatocellular carcinoma (HCC) risk, their comparative effectiveness remains controversial. We aimed to determine whether TDF is superior to ETV in preventing HCC.. PubMed, Embase, and Cochrane Library from inception until June 9, 2020, were searched according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Key terms included entecavir, tenofovir, and hepatocellular carcinoma. The adjusted hazard ratios (HRs) were pooled using a random effects model. Heterogeneity among studies was assessed by the Cochran Q test and I.. Thirteen observational studies (4 of which were conference abstracts) were included with 85,008 patients with CHB (ETV: 56,346; TDF: 28,662). TDF was associated with a lower HCC risk (adjusted HR [aHR]: 0.81; 95% confidence interval [CI]: 0.67-0.99). This beneficial effect was present in cirrhotic patients (aHR: 0.73; 95% CI: 0.62-0.85) and retrospective cohort studies using electronic data sets (aHR: 0.63; 95% CI: 0.51-0.78). However, this beneficial effect did not reach statistical significance for noncirrhotic patients (aHR: 0.83, 95% CI: 0.51-1.35) and retrospective/prospective cohort studies using clinical records (aHR: 0.97; 95% CI: 0.80-1.18).. TDF was associated with a lower HCC risk compared with ETV among patients with CHB, particularly cirrhotic patients. Further prospective large-scale studies with longer follow-up periods were required to identify specific subgroups that will benefit most from TDF.

Topics: Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Observational Studies as Topic; Risk Assessment; Tenofovir; Treatment Outcome

Studies have shown that nucleos(t)ide analogue (NA) treatment can reduce the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients, but it is unclear which NA is most effective. We performed a meta-analysis and systematic review comparing the efficacies of NAs in CHB patients.. We searched literature databases for randomized controlled trials (RCTs) and observational studies that analyzed the hepatic biochemical response, virological response, seroconversion rate, drug resistance rate, and HCC incidence rate in CHB patients treated with NAs. Meta-analyses were performed with RevMan and Stata/SE software.. Twelve cohort studies and one RCT were selected, in which entecavir (ETV), lamivudine (LAM), telbivudine (LdT), and/or tenofovir disoproxil fumarate (TDF) were evaluated in CHB patients. The meta-analysis showed that ETV was superior to LAM with regard to the HCC incidence (p<0.001), biochemical response (p=0.001), virological response (p=0.02), and drug resistance (p<0.001), and ETV was superior to LdT with regard to the virological response (p<0.001) and drug resistance (p<0.001). We found no significant difference between ETV and TDF with regard to the HCC incidence (p=0.08), biochemical response (p=0.39), virological response (p=0.31), serological conversion (p=0.38), or drug resistance (p=0.95). NA-treated patients with pre-existing cirrhosis had a 5.49 times greater incidence of HCC than those without cirrhosis (p<0.001).. ETV or TDF should be used for long-term first-line monotherapy in CHB patients according to the current guidelines. Standardized protocols are needed for future studies of ETV and TDF to facilitate conclusive comparisons. Patients with cirrhosis are at significantly elevated risk for HCC, despite the benefits of NA treatment.

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Nucleotides; Randomized Controlled Trials as Topic; Tenofovir; Treatment Outcome

To compare the efficacy of tenofovir and entecavir in nucleos(t)ide analogue-naive chronic hepatitis B.. The Web of Science, PubMed, Cochrane Library, EMBASE, Clinical Trials and China National Knowledge Infrastructure(CNKI) databases were electronically searched to collect randomized controlled trials (RCTs) regarding the comparison between tenofovir and entecavir in nucleos(t)ide analogue-naive chronic hepatitis B (CHB) since the date of database inception to July 2019. Two researchers independently screened and evaluated the obtained studies and extracted the outcome indexes. RevMan 5.3 software was used for the meta-analysis.. Early on, tenofovir had a greater ability to inhibit the hepatitis B virus, I2 = 0% [RR = 1.08, 95% CI (1.03, 1.13), P<0.01] (96 weeks). Entecavir can normalize the ALT levels earlier, I2 = 0% [RR = 0.87, 95% CI (0.77, 0.98), P = 0.02] (48 weeks). However, there was no statistically significant difference between TDF and ETV at 144 weeks. Tenofovir was as effective as entecavir in terms of HBeAg clearance and HBeAg seroconversion, I2 = 0% [RR = 1.05, 95% CI (0.68, 1.62), P = 0.82]; I2 = 69% [RR = 0.93, 95% CI (0.54, 1.61), P = 0.80]. The difference in the incidence of elevated creatine kinase levels was not statistically significant I2 = 0% [RR = 0.66, 95% CI (0.27, 1.60), P = 0.35].. Tenofovir and entecavir were equally effective in the treatment of patients with nucleos(t)ide analogue-naive chronic hepatitis B. In addition, TDF has an advantage in the incidence of hepatocellular carcinoma. Additional RCTs and a large-sample prospective cohort study should be performed.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Randomized Controlled Trials as Topic; Tenofovir; Treatment Outcome

Multiple studies have shown that oral antiviral therapies reduced the incidence of hepatocellular carcinoma (HCC) and improved the survival of patients with chronic hepatitis B when compared with that of untreated patients. In particular, entecavir and tenofovir share the qualities of high efficacy in reducing the HBV DNA levels, and they have excellent tolerability and safety. These drugs modified the natural history of liver fibrosis, improve liver function, decrease the incidence of HCC, decrease the need for liver transplantation, and improve survival. Many studies have suggested that long-term antiviral therapy reduces the risk of HCC and liver cirrhosis in patients with chronic hepatitis. The mechanism of these drugs in reducing the risk of HCC is not clear. This article reviews the mechanisms of carcinogenic HBV by conducting a review of the literature on the efficacy of therapy for reducing the risk of HCC. A few recent articles have suggested that tenofovir offers advantages over entecavir in terms of HCC prevention, but these articles have the inherent limitations of observational data. No other head-to-head randomized trials exist. Further randomized studies would help provide stronger evidence of the association between the type of antiviral agent and the HCC outcomes. Only achieving complete viral eradication from the liver will truly decrease the mortality and incidence of HCC.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Proportional Hazards Models; Tenofovir; Treatment Outcome

Nucleos(t)ide analogs (NAs) are effective, safe, and convenient antiviral therapy to suppress replication of hepatitis B virus, which can be translated into improved long-term outcome of chronic hepatitis B patients. The current recommended first-line NAs, namely, entecavir and tenofovir, are largely free from problems of drug resistance. Nonetheless, there are still a few challenges in the era of NA. First, the risk of hepatocellular carcinoma can only be reduced but not eliminated, particularly among cirrhotic patients. For cirrhotic patients who have persistent low-level viremia on NA, that is, partial responders, the risk of hepatocellular carcinoma is higher than those with complete viral suppression. The best strategy to manage partial responders to entecavir or tenofovir is uncertain. Second, immune-tolerant patients are very difficult to treat with NA. A significant proportion of immune-tolerant patients will have detectable viremia despite a few years of continuous NA treatment, and the rate of hepatitis B e-antigen seroconversion is very low. Third, most patients need long-term treatment as NA cannot eliminate covalently closed circular DNA in the hepatocytes. Some patients can consider stop NA according to treatment guidelines, but viral and clinical relapses often occur after treatment cessation. There is no concrete consensus on when one should stop NA in a hepatitis B e-antigen-negative patient among different treatment guidelines. New biomarkers such as hepatitis B surface antigen level can be used to select patients to stop NA, but the data are still preliminary.

Topics: Antiviral Agents; Biomarkers; Carcinoma, Hepatocellular; Guanine; Hepatitis B; Hepatitis B e Antigens; Humans; Immune Tolerance; Liver Neoplasms; Nucleotides; Tenofovir; Withholding Treatment

It has been proved that nucleos(t) ide analogues (NAs) therapy could improve underlying liver disease and reduce the incidence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, the difference of effectiveness in reducing HCC occurrence between tenofovir (TDF) and enticavir (ETV), two first-line NAs drugs, is still little known. This meta analysis aims to assess the efficacy in reducing incidence of HCC comparing tenofovir monotherapy with entecavir monotherapy among chronic hepatitis B (CHB) patients by analyzing their long-term clinical outcomes.. Databases including PubMed, Embase, Cochrane Central Register of Controlled Trial, and ISI Web of Science were fully investigated according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. For the included articles, two of the authors independently extracted and confirmed relevant data. Review Manager software (RevMan 5.3) was using for meta analysis.. Seven articles with 3698 patients were finally included in this research, 1574 in tenofovir group and 2124 in entecavir group. For meta analysis, the incidence of HCC was significantly lower among the tenofovir group than entecavir group [rate ratio (95% CI) of 0.66 (0.49, 0.89), P = 0.008], while there was no statistical significance in incidence of death or transplantation [rate ratio (95% CI) of 0.78 (0.55, 1.13), P = 0.19], encephalopathy [risk ratio (95% CI) of 0.72 (0.45, 1.13), P = 0.15] or variceal bleeding [risk ratio (95% CI) of 0.71 (0.34, 1.50), P = 0.37] between the two groups.. There is a better effect of tenofovir in reducing HCC incidence than entecavir, which indicates tenofovir should be used more widely while treating chronic hepatitis B patients. However before applying, randomized controlled trial and large prospective cohort study should be performed in the future.

Topics: Adult; Carcinoma, Hepatocellular; Controlled Clinical Trials as Topic; Female; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Retrospective Studies; Tenofovir

Dermatomyositis is an idiopathic inflammatory myopathy with specific cutaneous manifestations, which is closely associated with malignancy. However, the exact mechanism remains elusive. Even less is known about dermatomyositis with hepatocellular carcinoma (HCC).. We reported a case of dermatomyositis with hepatitis B virus (HBV) infection. He incidentally found his lower limbs little weakness accompanied with his wrist erythema. He was found HBsAg positive for forty years with slightly positive of α-fetal protein (AFP).. A dermapathology from his hand-wrist lesions demonstrated a scattered inflammatory infiltrate around the capillaries of the dermis. Abdominal enhanced computer tomography (CT) revealed infiltrative HCC affecting the whole liver, accompanied by liver metastasis and liver cirrhosis. Liver tumor needle biopsy pathology showed HCC with moderate differentiation. The left supraclavicular lymph node needle biopsy pathology confirmed metastasic HCC.. Prednisolone was gradually withdrawn with the introduction of Entecavir 0.5 mg daily. Radiofrequency ablation therapy for liver tumor was performed once in order to decrease the tumor load.. His muscle power improved to grade 4+/5 in the lower limb one month after anti-HBV treatment. However, this patient died finally from liver failure due to the development of liver tumor.. In the coming clinic work, we must pay more attention to the extrahepatic disorder induced by HBV. On treating experience, glucocorticoid administration is often contraindicated for HBV infected patients because of its potential promotion of HBV replication. Thus, it is necessary to administrate high-effective anti-HBV drug prior to glucocorticoid treatment in order to prevent liver failure.

Topics: alpha-Fetoproteins; Antiviral Agents; Carcinoma, Hepatocellular; Catheter Ablation; Dermatomyositis; Electromyography; Fatal Outcome; Glucocorticoids; Guanine; Hepatitis B; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver; Liver Neoplasms; Male; Middle Aged; Prednisolone; Tomography, X-Ray Computed

Topics: Adenine; Antiviral Agents; Arabinofuranosyluracil; Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver Neoplasms; Organophosphonates; Retrospective Studies; Survival Analysis; Telbivudine; Tenofovir; Thymidine

The goal of antiviral therapy is to improve the quality of life and survival of patients with chronic hepatitis B (CHB) by halting the progression to cirrhosis, end-stage liver disease or hepatocellular carcinoma (HCC), thus preventing anticipated liver-related death. Oral administration of potent and less resistance-prone nucleot(s)ide analogues (NUCs), such as entecavir (ETV) and tenofovir disoproxil fumarate (TDF) has become the most popular treatment strategy worldwide because of their excellent efficacy and safety profile as well as easy management confirmed in both registration trials and in clinical practice studies. Long-term administration of ETV or TDF suppresses HBV replication in >95% of patients, resulting in biochemical remission, histological improvement including the regression of cirrhosis and prevention or reversal of clinical decompensation but not the development of HCC, particularly in patients with cirrhosis. Moreover, NUCs can be administered to all patients including those with severe liver disease, the elderly and in those who do not respond, are unwilling to take or have contraindications to interferon. The need for long-term, perhaps indefinite, treatment is the main limitation of NUCs therapy with the associated costs, unknown long-term safety and the low rates of hepatitis B surface antigen (HBsAg) seroclearance, which is still the best stopping rule for NUCs-treated patients with cirrhosis.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Safety; Sustained Virologic Response; Tenofovir

The development of nucleos(t)ide analogues (NA) has influenced hepatitis B virus management. However, the annual incidence rate during NA treatment has been reported to be 0.3-1.2% in non-cirrhosis cases and 1.8-6.0% in cirrhosis cases, indicating that the suppressive effect of NA treatment on hepatocellular carcinoma (HCC) would be insufficient. Past studies, including one randomized control trial that compared lamivudine treatment with placebo, have revealed that NA treatment could suppress the incidence of HCC in patients with advanced fibrosis. However, it remains unknown whether NA treatment can suppress the incidence of HCC in chronic hepatitis patients without advanced fibrosis. The HCC incidence in patients treated with entecavir was similar to that of those treated with lamivudine, although entecavir exhibits a stronger viral suppression than lamivudine. The following risk factors related to the incidence of HCC during NA treatment have been identified: older age, male gender, pre-existing cirrhosis, a family clustering of hepatitis B virus, lower platelet counts, and higher hepatitis B core-related antigens as baseline factors and higher alpha fetoprotein levels as an on-treatment factor. Conversely, the loss of the hepatitis B surface antigen (HBsAg) by interferon or NA was correlated with a lower HCC incidence rate. Because interferon treatment has much more effects on reducing HBsAg levels compared with NA treatment, a combination treatment with NA and pegylated interferon can bring additional reduction of HBsAg levels compared with NA monotherapy. Further study is needed to clarify this.

Topics: Adult; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Guanine; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Incidence; Interferons; Lamivudine; Liver Neoplasms; Male; Middle Aged; Nucleosides; Nucleotides; Randomized Controlled Trials as Topic; Risk Factors

Entecavir is a nucleoside analogue of 2'-deoxyguanosine whose intracellular triphosphate form inhibits replication of the hepatitis B virus. Entecavir is recommended as a first-line monotherapy option for nucleos(t)ide-naïve patients with HBeAg-positive or -negative chronic hepatitis B infection. Entecavir has a three-step mechanism of action: It maintains viral suppression with a greater than 90% chance of undetectable hepatitis B virus DNA during continuous therapy, improves liver histology, and reduces the risk of liver failure or hepatocellular carcinoma development. The safety profile of long-term entecavir therapy is favorable; however, its optimal treatment duration is unknown. Entecavir monotherapy is not a rescue option for patients with lamivudine/adefovir resistance or baseline lamivudine-resistant mutants; rather, combination treatment is recommended for patients with lamivudine/adefovir resistance.

Topics: Animals; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Drug Administration Schedule; Drug Resistance, Multiple, Viral; Drug Substitution; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Treatment Outcome; Viral Load; Virus Replication

A number of studies have confirmed that antiviral therapy with nucleotide analogs (NAs) can improve the prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative therapy. However, what factors affected the prognosis of HBV-HCC after removal of the primary tumor and inhibition of HBV replication? A meta-regression analysis was conducted to explore the prognostic factor for this subgroup of patients.. MEDLINE, EMBASE, Web of Science, and Cochrane library were searched from January 1995 to February 2014 for clinical trials evaluating the effect of NAs on the prognosis of HBV-HCC after curative therapy. Data were extracted for host, viral, and intervention information. Single-arm meta-analysis was performed to assess overall survival (OS) rates and HCC recurrence. Meta-regression analysis was carried out to explore risk factors for 1-year OS rate and HCC recurrence for HBV-HCC patients after curative therapy and antiviral therapy.. Fourteen observational studies with 1284 patients met the inclusion criteria. Influential factors for prognosis of HCC were mainly baseline HBeAg positivity, cirrhotic stage, advanced Tumor-Node-Metastasis (TNM) stage, macrovascular invasion, and antiviral agent type. The 1-year OS rate decreased by more than four times (coefficient -4.45, P<0.001) and the 1-year HCC recurrence increased by more than one time (coefficient 1.20, P=0.003) when lamivudine was chosen for HCC after curative therapy, relative to entecavir for HCC.. HBV mutation may play a role in HCC recurrence. Entecavir or tenofovir, a high genetic barrier to resistance, should be recommended for HBV-HCC patients.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Combined Modality Therapy; Databases, Bibliographic; Female; Guanine; Hepatitis B; Hepatitis B virus; Humans; Liver Neoplasms; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Prognosis; Regression Analysis; Tenofovir

Hepatitis B is a major cause of hepatocellular carcinoma and liver cirrhosis. Interferon (IFN)-based therapies provide the highest likelihood of achieving off-treatment virological and serological control although their use is often avoided because of the side-effect profile. We review recent developments regarding the use of IFN in the treatment of chronic hepatitis B, including proposed strategies to enhance efficacy while limiting treatment exposure for patients who are unlikely to achieve acceptable treatment endpoints.. The utility of host genetics (human leukocyte antigen associations and interleukin 28B) is yet to be defined. In hepatitis B e antigen (HBeAg)-positive disease, add-on IFN therapy to patients on entecavir may allow curtailment of nucleos(t)ide analogue treatment. In HBeAg-negative disease, an on-treatment stopping rule that measures decline of hepatitis B surface antigen and hepatitis B virus DNA at 12 and 24 weeks may identify up to two-thirds of poor responders. Prolonging IFN therapy to 96 weeks in patients with HBeAg-negative disease may improve virological and serological response rates. The combination of telbivudine and IFN therapy is contraindicated because of high rates of peripheral neuropathy.. These findings need to be confirmed in larger trials before they can be instituted into routine clinical practice.

Topics: Adjuvants, Immunologic; Antiviral Agents; Carcinoma, Hepatocellular; Contraindications; Drug Administration Schedule; Drug Therapy, Combination; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-alpha; Liver Cirrhosis; Liver Neoplasms; Telbivudine; Thymidine

Chronic hepatitis B (CHB) is a global health problem, causing liver failure, cirrhosis and hepatocellular carcinoma. CHB treatment aims to prevent liver-related complication. The treatment of CHB infection includes monotherapy with either interferons (IFNs) or nucleos(t)ide (NUC) analogs. IFNs have moderate antiviral effects, and their use is limited by side effects. With the availability of NUCs, IFN-intolerant and decompensated cirrhotic patients began to be treated. Lamivudine and telbivudine, nucleoside analogs, have low genetic barrier to resistance. Adefovir, a nucleotide analog, has moderate potency and potential nephrotoxicity. Entecavir and tenofovir, with their high potency, high genetic barrier to resistance and favorable safety profile are the standard of care in CHB treatment. Long-term use of NUCs with maintained viral suppression results in a decrease in liver-related complications.

Topics: Adenine; Animals; Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Interferons; Lamivudine; Liver Neoplasms; Organophosphonates; Telbivudine; Thymidine; Treatment Outcome

Long-lasting HBV-DNA suppression is considered to be the best surrogate end-point of antiviral therapy in patients with hepatitis B virus (HBV) related chronic hepatitis or cirrhosis, and it is a prerequisite to prevent liver-related complications and improve survival. Treatment with oral antiviral drugs in patients with HBV cirrhosis is effective in restoring liver function and improving survival even in those with decompensated cirrhosis. These agents are generally well-tolerated for long-term treatment, and several evidences have demonstrated that they are able to reverse liver fibrosis and prevent the occurrence of HCC.

Topics: Adenine; Administration, Oral; Antiviral Agents; Carcinoma, Hepatocellular; Fibrosis; Guanine; Hepatitis B; Hepatitis B virus; Humans; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Nucleosides; Organophosphonates; Telbivudine; Tenofovir; Thymidine

Hepatocellular carcinoma (HCC) is a frequent, long term complication of chronic infection with hepatitis B virus (HBV) with an annual incidence ranging from 2 to 5%, often independent from the histological stage of underlying liver disease and serological status. Nevertheless, HCC is more often seen in older patients in whom HBV has been asserting its pro-oncogenic properties through both indirect and direct mechanisms. In Europe, HBV-related HCC is associated with cirrhosis in most patients, whereas this is not true in Asia and Africa where the tumour is also common among carriers with mild hepatic fibrosis, probably because of the coexistence of environmental co-carcinogens (aflatoxin) and long standing infection that is often acquired perinatally. Since hepatitis B-related carcinogenesis develops independently of the onset of cirrhosis, antiviral treatments such as nucleo(t)side analogues (NAs) that may result in the regression of fibrosis, prevent clinical decompensation and variceal bleeding, often fail to prevent HCC. Studies enrolling patients treated with lamivudine or rescued with adefovir, i.e. regimens characterized by limited potency and a low to moderate genetic barrier, have clearly been shown to help prevent HCC in patients with chronic hepatitis but not in those with cirrhosis, and in general not in patients that cannot achieve a sustained virological response. More potent anti-HBV drugs, such as entecavir and tenofovir, have been shown to improve the prevention of HCC in responders with cirrhosis, although HCC may still occur even in low risk patients. To attenuate HCC related outcomes, HBV replication must permanently be suppressed and HCC surveillance by abdominal ultrasound should be maintained even in responder patients.

Topics: Adenine; Antiviral Agents; Carcinoma, Hepatocellular; Drug Therapy, Combination; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-alpha; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Nucleosides; Organophosphonates; Tenofovir

Chronic hepatitis B (CHB) infection is a major cause of human mortality worldwide. The majority of people with CHB are infected early in life, and 20-40% of men and 15% of women with chronic infection will develop hepatocellular carcinoma (HCC). Antiviral therapy is recommended for patients with CHB who have cirrhosis or active disease with the aims of reducing disease progression to cirrhosis, liver failure and liver cancer, thereby preventing death. Evidence that treatment with interferon or with early nucleos(t)ide analogue therapy reduces HCC has been somewhat conflicting, however evidence is emerging to support a significant role in HCC prevention of the more effective antivirals, entecavir and tenofovir. Older patients, those with cirrhosis, and those undergoing curative treatments for HCC derive the greatest medium-term benefit in terms of HCC reduction, but HCC can still occur and long-term surveillance is recommended.

Topics: Adenine; Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir

Although a rather benign course of chronic hepatitis B virus (HBV) infection during childhood has been described, 3-5% and 0.01-0.03% of chronic carriers develop cirrhosis or hepatocellular carcinoma before adulthood. Considering the whole lifetime, the risk of hepatocellular carcinoma rises to 9-24% and the incidence of cirrhosis to 2-3% per year. The aim of this article is to review the current knowledge regarding the natural history and treatment of chronic hepatitis B in children and to focus on critical aspects and unresolved questions in the management of childhood HBV infection. A literature search was carried out on MEDLINE, EMBASE, and Web of Science for articles published in English in peer-reviewed journals from January 1980 to February 2013. The search terms used included "Hepatitis B virus infection," "children," "HBV," "interferon," "lamivudine," "adefovir," "entecavir," and "tenofovir." Articles resulting from these searches and relevant references cited in the articles retrieved were reviewed. The current goals of therapy are to suppress viral replication, reduce liver inflammation, and reverse liver fibrosis. Therapeutic options for children are currently limited, and the risk for viral resistance to current and future therapies is a particular concern. Based on the data available at this time, it is the consensus of the panel that it is not appropriate to treat children in the immune-tolerant phase or in the inactive carrier state. For children in the immune-active or reactivation phases, liver histology can help guide treatment decisions. Outside of clinical trials, interferon is the agent of choice in most cases; currently, available nucleoside analogs are secondary therapies.

Topics: Adenine; Antiviral Agents; Carcinoma, Hepatocellular; Carrier State; Child; Databases, Bibliographic; Guanine; Hepatitis B, Chronic; Humans; Immune Tolerance; Incidence; Interferons; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Nucleosides; Organophosphonates; Risk; Tenofovir

Five oral nucleos(t)ide analogues are available to treat chronic hepatitis B (CHB). With the availability of newer agents, their efficacy on incidence of hepatocellular carcinoma (HCC) is not well described.. To determine the efficacy of oral anti-viral agents in reducing HCC risk in relationship with other known factors.. Published studies of at least 20 CHB patients treated with an oral anti-viral agent and followed for >2 years were analysed for incidence of HCC per 100 person years follow-up.. Pooled homogeneous data from six studies showed lamivudine (LAM) treatment (n = 3306) to reduce HCC risk by 51% compared with no treatment (n = 3585) (3.3 vs. 9.7 per 100 person years, P < 0.0001). Pooled data from 49 studies (23 with LAM; 16 with adefovir; and 10 with entecavir, tenofovir or telbivudine) of 10 025 treated patients showed HCC incidence of 1.3 per 100 person years, independent of the agent used. Patient age >50 years and hepatitis B virus-DNA detectability at HCC diagnosis increased risk of HCC by twofold with a 10-fold higher risk among patients with cirrhosis compared with chronic hepatitis. Meta-regression showed patient age, study location (Eastern vs. Western) and type of study (randomised or not) contributed to heterogeneity.. Lamivudine treatment significantly reduces the incidence of HCC compared with no treatment. However, HCC still develops at a rate of 1.3 per 100 patient years in CHB patients receiving an oral anti-viral agent. This finding highlights the need for continued HCC surveillance, particularly in CHB patients with inadequate viral suppression, older age and cirrhosis.

Topics: Adenine; Administration, Oral; Age Factors; Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Organophosphonates; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Telbivudine; Tenofovir; Thymidine; Treatment Outcome

Of the estimated 400 million patients with chronic hepatitis B (CHB) globally, approximately 75% are Asians, representing a clinically important subgroup with a higher risk of cirrhosis and hepatocellular carcinoma than Caucasian patients. This review summarizes recent data from clinical long-term and real-life studies of entecavir and tenofovir, the recommended first-line oral therapies for treating CHB, in nucleoside/nucleotide-naive Asian CHB patients with compensated or decompensated liver disease. Long-term treatment with entecavir or tenofovir achieved profound and durable virological suppression, and led to improved liver histology and function. The data presented in this review will help physicians in making evidence-based decision choices regarding first-line antiviral therapy and long-term management in Asian CHB patients.

Topics: Adenine; Antiviral Agents; Asian People; Carcinoma, Hepatocellular; Disease Progression; Drug Resistance, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Organophosphonates; Tenofovir; Treatment Outcome

The main goal for treatment of chronic hepatitis B is to prevent complications such as liver cirrhosis or hepatocellular carcinoma. Knowledge from population studies of the long-term risk of chronic HBV infection, as well as the recent introduction of pegylated interferon and additional nucleoside analogues has changed the therapeutic situation. Recently, a Swedish expert panel convened to update the national recommendations for treatment. The panel recommends treatment for patients with active HBV infection causing protracted liver inflammation or significant liver fibrosis, verified by liver histology. In general, pegylated interferon alpha-2a is recommended as first-line treatment, in particular for HBeAg-positive patients with HBV genotypes A or B. Among nucleoside analogues, entecavir is the first choice and adefovir or tenofovir can be used as alternatives. Lamivudine monotherapy is not recommended due to the high risk of resistance development. Combinations of nucleoside analogues such as tenofovir and lamivudine or emtricitabine are alternatives for patients with non-response or infection with resistant variants, or as first choice for patients with advanced liver disease. Nucleoside analogue treatment should be monitored to detect primary non-response and virological breakthrough. Special recommendations are given for HBV/HIV coinfected patients, immunosuppressed patients, children, and for treatment before and after liver transplantation. The present guideline is translated from Swedish, where it is published on the MPA and RAV websites (www.mpa.se and www.rav.nu.se) including 7 separate papers based on thorough literature search. The complete reference list can be received from the Medical Products Agency upon request.

Topics: Adenine; Antiviral Agents; Carcinoma, Hepatocellular; Deoxycytidine; Drug Therapy, Combination; Emtricitabine; Guanine; Hepatitis B, Chronic; HIV Infections; Humans; Immunocompromised Host; Interferon alpha-2; Interferon-alpha; Lamivudine; Liver Cirrhosis; Liver Transplantation; Organophosphonates; Polyethylene Glycols; Recombinant Proteins; Sweden; Tenofovir

Studies in the past decades have shown that active hepatitis B virus (HBV) replication is the key driver of liver injury and disease progression, and thus sustained viral suppression is of paramount importance in the management of chronic HBV infection. The nucleos(t)ide analogues lamivudine, adefovir, entecavir, telbivudine and tenofovir are potent inhibitors of HBV polymerase/reverse transcriptase activity and are highly effective in the suppression of HBV replication, but rarely eliminate the virus. Long-term therapy is usually required to achieve sustained hepatitis B e antigen seroconversion, HBV DNA suppression, ALT normalization and fibrosis reversal. Maintained long-term therapy has been demonstrated to significantly lower the rate of hepatic decompensation and development of cirrhosis or hepatocellular carcinoma. However, drug resistance is a serious risk on prolonged nucleos(t)ide analogue therapy, and this poses a critical challenge. Prevention and proper management of drug resistance are crucial to ensure long-term success.

Topics: Adenine; Adenine Nucleotides; Alanine Transaminase; Carcinoma, Hepatocellular; DNA, Viral; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Nucleosides; Organophosphonates; Pyrimidinones; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Telbivudine; Thymidine; Treatment Outcome; Virus Replication

HBV cannot be fully eradicated from the body because of the persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. True cure is infrequent, but persistent suppression of HBV DNA slows liver disease progression and helps to prevent hepatocellular carcinoma. Treatment options for chronic hepatitis B include pegylated interferon and 4 licensed oral nucleosides/nucleotides (lamivudine, adefovir entecavir and tenofovir). Interferon is the only drug with a defined duration of treatment. It is effective in 30% to 40% of patients but is poorly tolerated. In contrast to interferon, nucleotide/nucleoside analogs have only minor adverse effects. However, a resurgence of the infection may occur when these drugs are withdrawn, implying that treatment may have to continue indefinitely. The onset of viral resistance to these agents also limits their long-term use but can be minimized by ensuring potent suppression of viral replication.

Topics: Adenine; Antiviral Agents; Carcinoma, Hepatocellular; Disease Progression; Guanine; Hepatitis B Vaccines; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Humans; Immunotherapy, Active; Interferon alpha-2; Interferon-alpha; Lamivudine; Liver Neoplasms; Organophosphonates; Polyethylene Glycols; Recombinant Proteins; Tenofovir; Treatment Outcome

The long-term goals of therapy for chronic hepatitis B are to reduce serum HBV DNA to low or undetectable levels and ultimately reduce or prevent the development of cirrhosis and hepatocellular carcinoma.. To review the current treatment of chronic hepatitis B, with a focus on diagnosis and management of resistance and active management of suboptimal responses.. A systematic review of the literature, with a focus on recent guidelines, was undertaken.. Among the six drugs licensed for the treatment of chronic hepatitis B in the US, the preferred agents in 2008 will include entecavir, peginterferon alfa-2a, possibly telbivudine, and tenofovir following licensure. When using an oral agent, a major focus of management is on the selection of a drug with high potency and low rate of resistance, and active on-treatment management to optimize therapy. Preventing the sequelae of antiviral drug resistance and appropriate management when resistance is initially detected are also the major focus of current management. The addition of an antiviral agent that is not cross-resistant is critical to restore suppression of viral replication.. Newer agents and modified treatment strategies, especially using combination therapy, hold promise to optimize the management of patients with chronic hepatitis B by achieving the high potency and the lowest rate of resistance.

Topics: Adenine; Antiviral Agents; Carcinoma, Hepatocellular; Deoxycytidine; Drug Resistance, Viral; Emtricitabine; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Liver Cirrhosis; Nucleosides; Organophosphonates; Polyethylene Glycols; Pyrimidinones; Recombinant Proteins; Reverse Transcriptase Inhibitors; Telbivudine; Tenofovir; Thymidine; Virus Replication

Topics: 2-Aminopurine; Adenine; Antiviral Agents; Arabinofuranosyluracil; Carcinoma, Hepatocellular; Contraindications; Deoxycytidine; Emtricitabine; Famciclovir; Guanine; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Liver Neoplasms; Organophosphonates; Organophosphorus Compounds; Polyethylene Glycols; Prodrugs; Prognosis; Recombinant Proteins; Tenofovir; Zalcitabine

Nucleotide analogs treatment can reverse liver fibrosis in chronic hepatitis B (CHB). However, it has limited effect on fibrosis resolution in patients with CHB, particularly in preventing progression to hepatocellular carcinoma (HCC). Ruangan granule (RG), a Chinese herbal formula, has proven to produce a therapeutic effect against liver fibrosis in animal experiment. Thus, we aimed to evaluate the effect of our Chinese herbal formula (RG) combined with entecavir (ETV) to reverse advanced liver fibrosis/early cirrhosis from CHB.. A total of 240 CHB patients with histologically confirmed advanced liver fibrosis/early cirrhosis from 12 centers were randomly and blindly allocated to consume either ETV (0.5 mg/day) plus RG (2 times/day) or control (ETV) for 48 weeks (wk) treatment. Changes in histopathology, serology and imageology were observed. Liver fibrosis reversion, defined as a reduction in the Knodell HAI score by ≥ 2 points and Ishak score by ≥ 1 grade, was assessed.. The rate of fibrosis regression and inflammation remission after 48 wk of treatment in histopathology was significantly higher in the ETV + RG group (38.73% vs. 23.94%, P = 0.031). The ultrasonic semiquantitative scores decreased by ≥ 2 points and were 41 (28.87%) and 15 (21.13%) in the ETV+RG and ETV groups, respectively (P = 0.026). The ETV+RG group had a significantly lower Fibrosis-4 score (FIB-4) index (P = 0.028). There was a significant difference between the ETV+RG and ETV groups in the liver function normalization rate (P < 0.01). Moreover, ETV plus RG combination treatment further reduced the risk of HCC in median 55-month follow-up (P < 0.01).. This study illustrates that the Chinese herbal formula RG with ETV can improve advanced liver fibrosis/early cirrhosis regression in patients with CHB, further reducing the risk of HCC.

Topics: Animals; Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis B virus; Hepatitis B, Chronic; Liver Cirrhosis; Liver Neoplasms; Treatment Outcome

Nucleot(s)ide analog treatment (entecavir (ETV) and tenofovir (TDF)) is reported to be associated with decreased tumor recurrence and death in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients, yet further work is needed to evaluate the different efficacies of these two agents on the prognosis of early-stage HBV-related HCC patients after curative liver resection.. From July 2017 to January 2019, 148 patients with HBV-related HCC who underwent curative liver resection were randomized to receive TDF ( n =74) or ETV ( n =74) therapy. The primary end point was tumor recurrence in the intention-to-treat population. Overall survival and tumor recurrence of patients were compared by multivariable-adjusted Cox regression and competing risk analyses.. During the follow-up with continued antiviral therapy, 37 (25.0%) patients developed tumor recurrence, and 16 (10.8%) patients died ( N =15) or received liver transplantation ( N =1). In the intention-to-treat cohort, the recurrence-free survival for the TDF group was significantly better than that for the ETV group ( P =0.026). In the multivariate analysis, the relative risks of recurrence and death/liver transplantation for ETV therapy were 3.056 (95% CI: 1.015-9.196; P =0.047) and 2.566 (95% CI: 1.264-5.228; P =0.009), respectively. Subgroup analysis of the PP population indicated a better overall survival and RFS of patients receiving TDF therapy ( P =0.048; hazard ratio (HR) =0.362; 95% CI: 0.132-0.993 and P =0.014; HR =0.458; 95% CI: 0.245-0.856). Additionally, TDF therapy was an independent protective factor against late tumor recurrence ( P =0.046; (HR)=0.432; 95% CI: 0.189-0.985) but not against early tumor recurrence ( P =0.109; HR =1.964; 95% CI: 0.858-4.494).. HBV-related HCC patients treated with consistent TDF therapy had a significantly lower risk of tumor recurrence than those treated with ETV after curative treatment.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis B; Hepatitis B, Chronic; Humans; Liver Neoplasms; Neoplasm Recurrence, Local; Prognosis; Tenofovir; Treatment Outcome

Antiviral therapy has been reported to be associated with lower recurrence rate of hepatocellular carcinoma (HCC) for patients with hepatitis B virus (HBV) infection. While entecavir (ETV) and tenofovir disoproxil fumarate (TDF) were both recommended as first-line therapies for HBV patients, recent retrospective studies proposed a lower incidence rate of HCC occurrence or recurrence in those receiving TDF compared ETV. However, the survival benefits of switching to TDF therapy after prolonged ETV treatment before surgery remain uncertain. We delineate the rationale and design of SWITE, a randomized, open-label, phase III trial contrasting TDF switch therapy versus ETV maintenance in HBV-related HCC patients.. This is a prospective, randomized, controlled, single-center study with two parallel groups of patients with HBV-related HCC who have received long-term ETV therapy before surgery. West China Hospital will enroll 238 patients, randomized in a 1:1 ratio to TDF switch therapy or ETV maintenance after surgery. The primary endpoint of this study is 3-year recurrence free survival (RFS), with the secondary endpoint being 3-year overall survival (OS) after curative surgery of HCC. Safety events will be diligently recorded.. The study protocol aligns with the ethical guidelines of the 1975 Declaration of Helsinki. It was approved by ethics committee of West China Hospital (approval number: 2022-074) and was registered with chictr.org.cn (chiCTR2200057867). Informed consent will be obtained from all participants. The results of this trial will be published in peer-reviewed journals and presentations at national and international conferences relevant to this topic.. chiCTR2200057867 . Date of registration is March 20 2022.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis B; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; Tenofovir; Treatment Outcome

Chronic hepatitis B (CHB) and liver fibrosis are associated with a high risk of hepatocellular carcinoma (HCC) development. We assessed whether entecavir (ETV) plus Biejia-Ruangan compound (BRC), an anti-fibrotic traditional Chinese medicine, can further reduce the risk of HCC in treatment-naïve Chinese patients with CHB and an Ishak fibrosis score of ≥3 points derived from our parent double-blind randomized placebo-controlled trial.. After a 72-week comparison between ETV+BRC and ETV+placebo treatment, participants were eligible to enter an open-label treatment phase and were followed up every 6 months. The primary [secondary] endpoints were the incidence of HCC [liver-related deaths, non-HCC events, and non-liver-related deaths]. Modified intention-to-treat (mITT), intention-to-treat (ITT), and per-protocol (PP) populations were defined for the time-to-event analysis.. A total of 1,000 patients were recruited; the median age was 42.0 years; 69.9% were male and 58.3% were HBeAg positive. In the mITT population, the 7-year cumulative incidence of HCC [liver-related deaths] was 4.7% [0.2%] for ETV+BRC, which was significantly lower than 9.3% [2.2%] for ETV monotherapy (p = 0.008 [p = 0.030]). Notably, ETV+BRC treatment yielded a lower incidence of HCC in those who did not achieve regression of fibrosis at week 72 than ETV monotherapy (p = 0.018). There were no differences in the other 2 secondary endpoints or safety profiles between the groups. Multivariable Cox proportional regression analysis, including the treatment allocation as a parameter, also demonstrated that ETV+BRC treatment was associated with a reduced incidence of HCC. The ITT and PP analyses showed consistent results.. ETV plus BRC combination treatment could further reduce the risk of HCC and liver-related deaths in patients with CHB and advanced fibrosis or cirrhosis, which may have important clinical implications for HCC prevention.. Patients with chronic hepatitis B virus infection are at an increased risk of developing liver cancer (specifically hepatocellular carcinoma [HCC]). While there are effective antiviral treatments that can suppress the virus in chronically infected patients, the risk of HCC remains. Herein, we show that adding a traditional Chinese medicine called Biejia-Ruangan compound to an antiviral reduced the risk of HCC in patients with chronic hepatitis B.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; China; Female; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Male

Antiviral therapy is effective in decreasing disease progression in HBV cirrhosis. However, the long-term effect of antiviral therapy on health-related quality of life (HRQoL) in patients with compensated HBV cirrhosis is unknown.. The patients with compensated HBV cirrhosis enrolled in a randomized controlled trial of entecavir-based therapy were recruited in the present study, if they had HRQoL score at 5-year follow-up or who developed liver-related events (LRE) during follow-up were included. HRQoL was measured with 36-Item Short-Form Health Survey (SF-36) and EuroQol-5D (EQ-5D) at baseline and yearly during follow-up. LRE was defined as the development of decompensation, HCC, or death.. A total of 161 patients were included in the present study, with a median age of 48.0 (41.0, 53.0) years, 77.6% being male and 37.2% being HBeAg-positive. During 5 years, 45 patients developed LRE. All eight dimensions of SF-36 were significantly improved after 5 years of antiviral therapy (all p < 0.001), with all dimensions improved more than five points except for physical functioning. Proportion of patients reporting no problems in all five dimensions in EQ-5D increased from 57.8 to 72.0%; visual analogue scale (VAS) and utility index (UI) increased significantly (VAS 79.8 ± 16.4 to 84.4 ± 13.2, UI 0.91 ± 0.13 to 0.95 ± 0.10, both p < 0.001). HRQoL improved or kept stable in the majority of patients who had LRE during follow-up, even stratified by Baveno VI criteria for clinically significant portal hypertension.. After 5 years of ETV treatment, HRQoL significantly improved in patients with compensated HBV cirrhosis. (NCT01943617, NCT02849132).

Topics: Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B virus; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Quality of Life; Surveys and Questionnaires

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.

Topics: Adult; Aged; Carcinoma, Hepatocellular; Female; Follow-Up Studies; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Risk Factors; Tenofovir; Time Factors

Chronic hepatitis B virus (HBV) infection results in a high risk of cirrhosis and its complications, cirrhosis decompensation (DC), hepatocellular carcinoma (HCC), liver transplantation (LT), death or any of these outcomes (composite endpoint [CE]). Nucleos(t)ide analogues (NUCs) such as tenofovir or entecavir are associated with a reduction in these complications.. To compare the impact of tenofovir and entecavir on these outcomes in patients treated for HBV infection and included in the prospective Hepather cohort.. All patients with HBV infection who had received tenofovir or entecavir for more than 6 months at or after entry in the ANRS CO22 cohort were selected. Patients with HDV and HCV co-infection or prior liver event were excluded. Incidence rates of events were compared using inverse probability of treatment weighting (IPW).. The cohort included 1800 patients (986 tenofovir and 814 entecavir). Median follow-up was 4.2 years. The incidences of HCC, DC, LT, ACD, LRD and CE were not different between tenofovir- (1.8 (0.9; 3.2), 0.6 (0.2; 1.6), 0.2 (0.0; 0.8), 1.7 (0.8; 3.0), 0.8 (0.2, 1.8) and 4.1 (3.0; 5.4) per 1000 person-years) and entecavir-treated patients (1.6 (0.7; 3.0), 0.7 (0.2; 1.8), 0.2 (0.0; 1.0), 3.0 (1.7, 4.8), 0.5 (0.1; 1.5) and 5.0 (3.3; 7.2)) per 1000 person-years, respectively.. The risk of liver-related events or death was not different between tenofovir- and entecavir-treated patients in this large prospective cohort of predominantly non-cirrhotic French patients.. NCT019553458.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Prospective Studies; Tenofovir; Treatment Outcome

Hepatitis B virus (HBV) suppression with nucleot(s)ide analogue therapy reduces the risk of hepatic decompensation and hepatocellular carcinoma (HCC) in patients with advanced liver disease.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Esophageal and Gastric Varices; Female; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Splenomegaly; Thrombocytopenia; Viral Load

ABSTRACT Background: Thymosin alpha-1 (Ta-1) suppresses HBV viral replication, while the evidence of combination effect with nucleoide is still limited. We aimed to investigate the efficacy and safety of combination therapy of Ta-1 with entecavir (ETV) in patients with compensated liver cirrhosis.. A total of 690 patients were randomized to receive Ta-1 plus ETV (n = 351) or ETV monotherapy (n = 339) for 52 weeks after 26 weeks of ETV treatment, followed by continued entecavir therapy. The primary endpoint was defined as liver decompensation, hepatocellular carcinoma (HCC) or death.. The median followed up was 38.2 months. The cumulative incidence of liver decompensation, HCC, or death were similar between two groups. During the Ta-1 combination treatment, the HCC incidence was 1.7% in combination group and 2.1% in ETV group, without new HCC cases developed during week 39 to week 77 in combination group. The virologic response, serologic response, biochemical response was similar between two groups at week 104. Both therapies were well-tolerated.. There was no significant difference between two groups in endpoint events, while combination therapy with Ta-1 has a tendency to inhibit the development of HCC.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Cirrhosis; Liver Failure; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Thymalfasin; Treatment Outcome

Hepatocellular carcinoma (HCC) risk-scores may predict HCC in Asian entecavir (ETV)-treated patients. We aimed to study risk factors and performance of risk scores during ETV treatment in an ethnically diverse Western population.. We studied all HBV monoinfected patients treated with ETV from 11 European referral centres within the VIRGIL Network.. A total of 744 patients were included; 42% Caucasian, 29% Asian, 19% other, 10% unknown. At baseline, 164 patients (22%) had cirrhosis. During a median follow-up of 167 (IQR 82-212) weeks, 14 patients developed HCC of whom nine (64%) had cirrhosis at baseline. The 5-year cumulative incidence rate of HCC was 2.1% for non-cirrhotic and 10.9% for cirrhotic patients (p<0.001). HCC incidence was higher in older patients (p<0.001) and patients with lower baseline platelet counts (p=0.02). Twelve patients who developed HCC achieved virologic response (HBV DNA <80 IU/mL) before HCC. At baseline, higher CU-HCC and GAG-HCC, but not REACH-B scores were associated with development of HCC. Discriminatory performance of HCC risk scores was low, with sensitivity ranging from 18% to 73%, and c-statistics from 0.71 to 0.85. Performance was further reduced in Caucasians with c-statistics from 0.54 to 0.74. Predicted risk of HCC based on risk-scores declined during ETV therapy (all p<0.001), but predictive performances after 1 year were comparable to those at baseline.. Cumulative incidence of HCC is low in patients treated with ETV, but ETV does not eliminate the risk of HCC. Discriminatory performance of HCC risk scores was limited, particularly in Caucasians, at baseline and during therapy.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Female; Follow-Up Studies; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Risk Assessment; Risk Factors; United Kingdom; White People

The aim of this study was to determine the long-term efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) on the natural course of disease in chronic hepatitis B patients (CHB) with/without cirrhosis in clinical practice. A total of 355 treatment-naïve CHB patients were enrolled into the study. The primary outcome measure was viral suppression as defined by serum HBV DNA level <20 IU/mL. A secondary outcome measure was to determine the development of Hepatocellular carcinoma (HCC). Virological and biochemical responses were similar between the two treatment groups over time. The presence of cirrhosis and hepatitis B e antigen (HBeAg) positivity did not appear to impact viral suppression. The cumulative probability of HBeAg loss was 41% at 4 years of therapy. Hepatitis B surface antigen (HBsAg) loss occurred in four patients. Model for End-Stage Liver Disease score was significantly improved from baseline to week 48 and 96 under antiviral therapy (P = 0.013, P = 0.01). HCC was diagnosed in 17 patients (4.8%). The cumulative probability of the development of HCC was 3.3% at 1 year and 7.3% at 4 years of therapy. The development of HCC was independently associated with older age (P = 0.031) and the presence of cirrhosis (P = 0.004). Serum creatinine levels and creatinine clearance remained stable over time. ETV and TDF effectively maintained virological and biochemical responses in long-term follow-up of CHB patients with/without cirrhosis. HCC may still develop, although at a lower rate, and is more likely to develop in patients with cirrhosis, especially in older patients.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Creatinine; DNA, Viral; Female; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Male; Metabolic Clearance Rate; Middle Aged; Prospective Studies; Retrospective Studies; Tenofovir; Treatment Outcome; Viral Load

To compare the efficacies ofentecavir and adefovir in patients with chronic hepatitis B (CHB) and cirrhosis when administered as monotherapies using a 240-week course.. Ninety patients diagnosed with CHB and cirrhosis (compensated or decompensated) were randomly divided into two treatment groups for administration of either entecavir (0.5 mg/day, oral; n =38) or adefovir (10 mg/day, oral; n =52) for 240 weeks. All participants underwent B-ultrasound and were tested for levels of HBV-DNA, alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen, creatinine, alpha-fetoprotein (AFP) and various serological markers of the hepatitis B virus at baseline and at treatment weeks 24, 48, 96, 144, 192, and 240. Instances of drug-related complications and adverse reactions were recorded. Patients who did not achieve complete virological response by treatment week 48 or who experienced virological breakthrough at any time during the study course were recorded and started on an appropriate combination therapy regimen. Statistical analyses were carried out using the t-test, chi-square test, and Cox regression modeling.. The dropout rate in the entecavir group was 2.6% and in the adefovir group was 13.5%. At treatment week 240, significantly more patients in the entecavir group had undetectable serum HBV-DNA (91.9% vs. adefovir group: 57.8%; x2=10.362, P=0.001), a negative conversion rate of hepatitis B e antigen (HBeAg) (46.2% vs. adefovir group: 24%; x2=5.055, P=0.025), and rate of HBeAg seroconversion (23.1% vs. adefovir group: 8%, P=0.047).The entecavir group and the adefovir group showed no significant differences upon per-protocol analysis and intention-to-treat analysis, nor in the rates of hepatocellular carcinoma development (entecavir group: 8.1% vs. adefovir group: 6.7%; x2=0.000, P=1.000) or mortality (entecavir group: 8.1% vs. adefovir group: 4.4%; x2=0.051, P=0.821). The possibility of achieving undetectable serum HBV-DNA was 2.761 times higher in the entecavir group than in the adefovir group (95.0% CI: 1.630 to 4.679). The possibility of HBeAg seroconversion was 0.192 times higher for males than for females (95.0% CI: 0.046 to 0.806).. Compared to adefovir, entecavir provides high efficiency and rapid viral suppression as a monotherapy for CHB patients when administered in a 240-week course.

Topics: Adenine; Aged; Alanine Transaminase; alpha-Fetoproteins; Antiviral Agents; Aspartate Aminotransferases; Biomarkers; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Organophosphonates; Time Factors

The comparative effectiveness of tenofovir (TDF) vs entecavir (ETV) in reducing the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) remains unclear. Data from a retrospective Korean cohort study published by Choi et al

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Retrospective Studies; Tenofovir; Treatment Outcome

We investigated whether baseline and on-treatment alanine aminotransferase (ALT) levels during entecavir (ETV) therapy are associated with achieving subcirrhotic liver stiffness (LS) and hepatocellular carcinoma (HCC) development in patients with hepatitis B virus (HBV)-related cirrhosis.. We analyzed data from 347 treatment-naïve patients with HBV-related cirrhosis, who started ETV between 2006 and 2011 and were followed up for >5 years without developing HCC. The study outcomes were achieving subcirrhotic LS at 5 years of ETV, and risk of HCC development beyond 5 years of ETV. Subcirrhotic LS was defined as <12 kPa by transient elastography.. After 5 years of ETV, 227 (65.4%) patients achieved subcirrhotic LS. During a median follow-up of 9.2 years, 49 (14.1%) patients developed HCC beyond 5 years of ETV. ALT levels at baseline, at 1 year of ETV therapy, and 5 years of ETV therapy were not associated with the probability of achieving subcirrhotic LS at 5 years of ETV therapy or risk of HCC development beyond 5 years of ETV therapy (all P > .05). Patients achieving subcirrhotic LS at 5 years of ETV therapy had significantly lower risk of HCC development than those who did not (adjusted hazard ratio, 0.33; 95% confidence interval, 0.17-0.64; P = .001).. Baseline and on-treatment ALT levels were not associated with achieving subcirrhotic LS at 5 years of ETV therapy or with risk of HCC development beyond 5 years of ETV therapy in patients with HBV-related cirrhosis. Achieving subcirrhotic LS at 5 years of ETV therapy was independently associated with lower risk of HCC development beyond 5 years of ETV therapy.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Retrospective Studies; Treatment Outcome

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir; Treatment Outcome; Viral Load

There is still controversy about whether tenofovir disoproxil fumarate (TDF) and entecavir (ETV) have different effects on the outcomes of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).. The aim of this study was to compare the prognoses between ETV and TDF treatment among patients with HBV-related HCC after hepatectomy.. An analysis was done on data from the Taiwan Cancer Registry, which was linked to Taiwan National Health Insurance Research Database, for the years 2011-2016. We identified 7107 patients with HBV-related HCC after curative hepatectomy, and 25.3% of them used ETV or TDF after surgery. After propensity score overlap weighting, 1797 patients treated with ETV (n = 1365) or TDF (n = 432) were included for analyses. Cox proportional hazards models were used to compare the efficacy of ETV and TDF for recurrence and overall survival (OS).. After hepatectomy, the recurrence rate per 100 person-years was 14.87 for the ETV group and 9.25 for the TDF group. The risk of recurrence was similar in the TDF group and the ETV group (HR [95% CI]: 0.91 [0.69-1.19; p = 0.479]), as was the risk of all-cause mortality (HR [95% CI]: 0.67 [0.42-1.07]; p = 0.091). When considering early recurrence (<2 years) and late recurrence (≧2 years), the TDF and ETV groups showed no significant differences. Subgroup analyses and sensitivity analyses demonstrated consistent results.. Both TDF and ETV showed similar health benefits in terms of recurrence and OS in patients with HBV-related HCC patients after hepatectomy.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatectomy; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Prognosis; Tenofovir; Treatment Outcome

At present, there are a variety of antiviral drugs for HBV in clinical practice, but there is no standard scheme for transcatheter arterial chemoembolization(TACE) combined with antiviral drugs. The aim of this study was to investigate whether TACE must be combined with antiviral therapy in patients of HBV-related hepatocellular carcinoma(HCC). Meanwhile, the efficacy and safety of TACE combined with entecavir and TACE combined with tenofovir in the treatment of HBV-related HCC were compared.. This study included 536 patients with HBV-related HCC who underwent TACE in Union Hospital from March 2017 to March 2020, and they met the criteria. They were divided into three groups: control group (N = 212): TACE alone; Entecavir group (N = 220): TACE combined with entecavir; and Tenofovir group (N = 228): TACE combined with tenofovir. We conducted a retrospective study to analyze the efficacy and safety of the three groups of patients.. Objective response rate(ORR): 29.2% in control group, 54.1% in entecavir group, and 63.2% in tenofovir group (P < 0.05). Disease control rate(DCR): 63.7% in control group, 80.9% in entecavir group, and 88.1% in tenofovir group (P < 0.05). Median overall survival(mOS): control group, 12.2 months; entecavir group, 17.3 months; tenofovir group, 22.5 months (p < 0.05). Median progression-free survival (mPFS): control group, 9.3 months; entecavir group, 15.5 months; tenofovir group, 16.6 months (p < 0.05). At 6 months, there was an increase in creatinine(Cr) and a decrease in glomeruar filtration rate(GFR) in tenofovir group, which were statistically different from control and entecavir groups (p < 0.05).. TACE combined with entecavir and TACE combined with tenofovir had higher ORR and DCR, longer OS and PFS than TACE alone. The OS of TACE combined with tenofovir was higher than that of TACE combined with entecavir. TACE combined with tenofovir is a safe strategy, but we cannot completely ignore the impact of tenofovir on renal function.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Hepatitis B virus; Humans; Liver Neoplasms; Retrospective Studies; Tenofovir; Treatment Outcome

Long-term administration of TDF/ETV in patients with HBV-related compensated cirrhosis reduces HCC and decompensation events but the effect of this regimen on development/regression of oesophageal varices (EV) is currently unknown.. To assess the risk of EV development/progression in this population.. A total of 186 Caucasian HBV-monoinfected compensated cirrhotics were enrolled in a long-term cohort study from TDF/ETV introduction. Upper GI endoscopies were performed according to Baveno recommendations. Primary endpoint was development/progression of oesophageal/gastric varices over time.. At TDF/ETV start, median age was 61 years, 80% males, 60% HBV-DNA undetectable, 63% NUCs previously exposed, 73% normal ALT, 40% platelets <150,000/mmc and 25 (13%) with low-risk varices (LRV). During 11 years of antiviral therapy and 666 endoscopies performed, 9 patients either developed or had a progression of oesophageal or gastric varices with an 11-year cumulative probability of 5.1% (95% CI 3-10%); no patient bled. Out of 161 patients without EV at baseline, the 11-year probably was 4.5% with all varices developing within the first six years of treatment. In 25 patients with LRV at baseline, the 11-year probability of progression or regression was 9.3% and 58%, respectively. Only baseline platelet count (HR 0.96, p = 0.028) was associated with LRV development at multivariate analysis: platelet ≤90,000/mmc (AUROC 0.70) had 98.1% specificity, 42.9% sensitivity, 50% PPV for LRV onset.. In compensated cirrhotic patients under long-term effective TDF/ETV treatment, the 11-year risk of developing/progressing EV is negligible, thus challenging the current endoscopic surveillance recommendations in patients without EV at baseline.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Esophageal and Gastric Varices; Female; Hepatitis B virus; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Tenofovir; Treatment Outcome; Varicose Veins

The PAGE-B model consists of variables at the initiation of antiviral therapy (AVT), whereas the SAGE-B and CAGE-B models consist of variables after 5 years of AVT. We aimed to compare the predictive accuracy of three risk prediction models for hepatocellular carcinoma (HCC) development after 5 years of AVT in patients with chronic hepatitis B (CHB).. A total of 1335 patients who initiated entecavir (ETV) treatment between 2006 and 2011 and were followed up for more than 5 years were enrolled in the study.. At ETV initiation, the median age was 49 years and the median score of the PAGE-B model was 14. After 5 years of ETV treatment, the median SAGE-B and CAGE-B scores were 6 and 6. During the study period, 93 (7.0%) patients developed HCC after 5-year treatment. In multivariate analysis, PAGE-B (hazard ratio [HR] 1.151, 95% confidence interval [CI] 1.087-1.219), SAGE-B (HR 1.340, 95% CI 1.228-1.463), and CAGE-B (HR 1.327, 95% CI 1.223-1.440) models independently predicted HCC development after 5 years of treatment (all P < 0.001). The high-risk groups of the three risk prediction models showed a significantly higher risk of HCC development compared to the medium- and low-risk groups (both P < 0.05). The AUROC of the SAGE-B (0.772-0.844) and CAGE-B (0.785-0.838) models was significantly higher than those of the PAGE-B model (0.696-0.745) in predicting HCC development after 5 years of treatment (both P < 0.05).. The SAGE-B and CAGE-B models might be better than the PAGE-B model in predicting HCC development after 5 years of ETV treatment.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Middle Aged; Retrospective Studies

The clinical significance of persistent positive in Hepatitis B Virus (HBV) DNA level in patients receiving antiviral therapy is not well known. We investigated factors associated with persistent viremia (PV) in patients with chronic hepatitis B (CHB) given 78-week entecavir.. A total of 394 treatment-naïve CHB patients who had undergone liver biopsy at baseline and week 78 of treatment were analyzed in this prospective multicentre study. We identified patients with PV (above the lower limit of quantification, 20 IU/ml) after 78 weeks of entecavir therapy. Stepwise, forward, multivariate regression analyses of specified baseline parameters were apllied to identify factors associated with PV. Futhermore, we assessed the incidence of hepatocellular carcinoma (HCC) in all patients using models of the risk of HCC development.. Of the 394 patients, 90 (22.8%) still with PV after 78-week antiviral treatment. Factors associated significantly with PV (vs complete virological response, CVR) were HBV DNA level ≥8 log10 IU/mL (OR, 3.727; 95% CI, 1.851-7.505; P < 0.001), Anti-HBc level < 3 log10 IU/mL (OR, 2.384; 95% CI, 1.223-4.645; P=0.011), and HBeAg seropositivity (OR, 2.871; 95% CI, 1.563-5.272; P < 0.001). Patients with PV were less likely to have fibrosis progression and HCC development than those with the CVR. Of the 11 HBeAg-positive patients with HBV DNA level ≥8 log10 IU/mL and Anti-HBc level < 3 log10 IU/mL at baseline, 9 (81.8%) had persistent positivity in HBV DNA level and 0 had fibrosis progression at week 78 of treatment.. In conclusion, HBV DNA level ≥8 log10 IU/mL, Anti-HBc level < 3 log10 IU/mL and HBeAg seropositivity at baseline contribute to PV in patients with CHB receiving 78-week antiviral treatment. In addition, the rate of fibrosis progression and the risk of HCC development in patients with PV were kept low. The complete protocol for the clinical trial has been registered at clinicaltrials.gov (NCT01962155 and NCT03568578).

Topics: Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Fibrosis; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Prospective Studies; Treatment Outcome

Considerable controversy exists regarding the superiority of tenofovir disoproxil fumarate (TDF) over entecavir (ETV) for reducing the risk of HCC. This study aimed to compare outcomes of ETV versus TDF after liver transplantation (LT) in patients with HBV-related HCC. We performed a multicenter observational study using data from the Korean Organ Transplantation Registry. A total of 845 patients who underwent LT for HBV-related HCC were divided into 2 groups according to oral nucleos(t)ide analogue used for HBV prophylaxis post-LT: ETV group (n = 393) and TDF group (n = 452). HCC recurrence and overall death were compared in naïve and propensity score (PS)-weighted populations, and the likelihood of these outcomes according to the use of ETV or TDF were analyzed with various Cox models. At 1, 3, and 5 years, the ETV and TDF groups had similar HCC recurrence-free survival (90.7%, 85.6%, and 84.1% vs. 90.9%, 84.6%, and 84.2%, respectively, p = 0.98) and overall survival (98.4%, 94.7%, and 93.5% vs. 99.3%, 95.8%, and 94.9%, respectively, p = 0.48). The propensity score-weighted population showed similar results. In Cox models involving covariates adjustment, propensity score-weighting, competing risk regression, and time-dependent covariates adjustment, both groups showed a similar risk of HCC recurrence and overall death. In subgroup analyses stratified according to HCC burden (Milan criteria, Up-to-7 criteria, French alpha-fetoprotein risk score), pretransplantation locoregional therapy, and salvage LT, neither ETV nor TDF was superior. In conclusion, ETV and TDF showed mutual noninferiority for HCC outcomes when used for HBV prophylaxis after LT.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis B; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Liver Transplantation; Tenofovir; Treatment Outcome

Considering the lower risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients receiving long-term potent antiviral therapy, models predicting HCC after 5 years of therapy are needed. We conducted a multicenter retrospective cohort study to construct and validate a model predicting HCC after 5 years of entecavir (ETV) or tenofovir (TFV) therapy for CHB. The endpoint was HCC after 5 years of ETV/TFV therapy. Information on age, sex, liver cirrhosis (assessed by diagnosis code and confirmed by clinical findings) and type of antiviral agent was obtained at baseline (initiation of ETV/TFV). Laboratory values were collected at baseline and 5 years. Risk factors for HCC were identified in the training set and the final prediction model was validated using the test set. Among 7542 patients, 345 (4.6%) developed HCC after 5 years of ETV/TFV therapy. HCC risk after 5 years of ETV/TFV therapy was increased by 4-fold in patients with liver cirrhosis than in those without cirrhosis at baseline. Furthermore, Platelet counts and Prothrombin time at 5 years, Age at baseline and Sex were associated with risk of HCC and were incorporated into a prediction model, PPACS. PPACS showed a good performance with a time-dependent area under the curve of 0.80 (95% confidence interval, 0.75-0.85) at 8-year of ETV/TFV therapy, a Brier score of 0.031 and an integrated Brier score of 0.006 in the test set. In conclusion, the PPACS model provides a reliable assessment of HCC risk after 5 years of ETV/TFV therapy (https://ppacs.shinyapps.io/shiny_app_up/).

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Retrospective Studies; Risk Factors; Tenofovir; Treatment Outcome

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatectomy; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lipoproteins; Liver Neoplasms; Tenofovir; Treatment Outcome

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatectomy; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lipoproteins; Liver Neoplasms; Tenofovir; Treatment Outcome

Tenofovir disoproxil and entecavir are both commonly used first-line antiviral treatments, but their comparative recurrence and overall survival (OS) benefits remain unclear.. To explore differences of tenofovir disoproxil vs entecavir in recurrence-free survival (RFS) and OS after liver resection with curative intent in patients with hepatocellular cancer (HCC) related to hepatitis B virus (HBV).. This retrospective cohort study was conducted at Eastern Hepatobiliary Surgery Hospital, a tertiary referral hospital in Shanghai, China, between January 4, 2015, and April 1, 2023. Participants included patients with HBV-related HCC who underwent liver resection with curative intent from January 2015 to December 2018. Patients who received tenofovir disoproxil were matched with patients who received entecavir in a 1:1 ratio using propensity score matching. Data were analyzed from April 3 to May 31, 2023.. Receiving tenofovir disoproxil or entecavir as antiviral treatment for HBV.. Primary end points were RFS and OS rates.. Among 4451 patients (mean [SD] age, 58.1 [10.0] years; 3764 male [84.6%]; median [range] follow-up, of 51 [3 to 91] months), 989 patients in each of the groups were selected in propensity score matching. Baseline characteristics were comparable. In propensity score-matched groups, OS rates were 92.2% at 1 year, 70.9% at 3 years, and 54.2% at 5 years in the entecavir group, compared with 90.9% at 1 year, 75.2% at 3 years, and 64.0% at 5 years in the tenofovir disoproxil group. RFS rates were 83.9% at 1 year, 50.0% at 3 years, and 43.3% at 5 years in the entecavir group, compared with 85.3% at 1 year, 55.6% at 3 years, and 51.4% at 5 years in the tenofovir disoproxil group. Patients in the tenofovir disoproxil group had better OS (hazard ratio, 0.82; 95% CI, 0.72 to 0.94; P = .004) and RFS rates (hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = .001) compared with the entecavir group. Restricted mean survival time differences of entecavir vs tenofovir disoproxil groups were -0.05 (95% CI, -0.18 to 0.08) months at 1 year (P = .45), 0.20 (95% CI, -0.62 to 1.03) months at 3 years (P = .63), and 1.82 (95% CI, 0.14 to 3.51) months at 5 years (P = .03).. These findings suggest that in patients undergoing curative liver resection for HBV-related HCC, tenofovir disoproxil was associated with better long-term OS and RFS rates compared with entecavir, providing insights for antiviral treatment.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; China; Hepatitis B virus; Humans; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Tenofovir; Tertiary Care Centers

Serum hepatitis B core-related antigen (HBcrAg) and surface antigen (HBsAg) are surrogate markers of intrahepatic covalently closed circular DNA. The measurement range of the current HBcrAg assay is relatively narrow. Thus, we examined the potential of HBcrAg and HBsAg measured by ultrasensitive assays for predicting hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B treated with entecavir (ETV). We conducted a retrospective cohort study of 180 patients who received ETV for >1 year. All patients had hepatitis B e-antigen negativity at baseline. Serum HBcrAg and HBsAg levels at baseline and year 1 were measured in all patients by ultrasensitive assays using immunoassay for total antigen including complex by pretreatment (iTACT) technology. During the median follow-up of 11.0 years, 22 patients developed HCC (11.8/1,000 person-years). Baseline HBsAg levels were not associated with HCC development during ETV treatment. However, high HBcrAg levels at baseline and at year 1 were significantly associated with HCC development (log-rank test; P < 0.001). In 110 patients (61.1%) with ≥4.0 log U/mL at baseline (high HBcrAg cohort), HBcrAg declined to ≤2.9 log U/mL at year 1 in 25 patients (22.7%). The adjusted hazard ratio for HCC incidence was significantly lower in patients with HBcrAg ≤2.9 log U/mL at year 1 than in those in the high HBcrAg cohort. Conclusion: Measurement of HBcrAg by ultrasensitive assay has better potential for predicting HCC during antiviral treatment than the current HBcrAg assay.

Topics: Antiviral Agents; Biomarkers, Tumor; Carcinoma, Hepatocellular; DNA, Circular; Female; Guanine; Hepatitis B Core Antigens; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Immunoassay; Liver Neoplasms; Male; Middle Aged; Retrospective Studies

Several models have recently been developed to predict risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Our aims were to develop and validate an artificial intelligence-assisted prediction model of HCC risk.. Using a gradient-boosting machine (GBM) algorithm, a model was developed using 6,051 patients with CHB who received entecavir or tenofovir therapy from 4 hospitals in Korea. Two external validation cohorts were independently established: Korean (5,817 patients from 14 Korean centers) and Caucasian (1,640 from 11 Western centers) PAGE-B cohorts. The primary outcome was HCC development.. In the derivation cohort and the 2 validation cohorts, cirrhosis was present in 26.9%-50.2% of patients at baseline. A model using 10 parameters at baseline was derived and showed good predictive performance (c-index 0.79). This model showed significantly better discrimination than previous models (PAGE-B, modified PAGE-B, REACH-B, and CU-HCC) in both the Korean (c-index 0.79 vs. 0.64-0.74; all p <0.001) and Caucasian validation cohorts (c-index 0.81 vs. 0.57-0.79; all p <0.05 except modified PAGE-B, p = 0.42). A calibration plot showed a satisfactory calibration function. When the patients were grouped into 4 risk groups, the minimal-risk group (11.2% of the Korean cohort and 8.8% of the Caucasian cohort) had a less than 0.5% risk of HCC during 8 years of follow-up.. This GBM-based model provides the best predictive power for HCC risk in Korean and Caucasian patients with CHB treated with entecavir or tenofovir.. Risk scores have been developed to predict the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. We developed and validated a new risk prediction model using machine learning algorithms in 13,508 antiviral-treated patients with chronic hepatitis B. Our new model, based on 10 common baseline characteristics, demonstrated superior performance in risk stratification compared with previous risk scores. This model also identified a group of patients at minimal risk of developing HCC, who could be indicated for less intensive HCC surveillance.

Topics: Adult; Antiviral Agents; Artificial Intelligence; Asian People; Carcinoma, Hepatocellular; Cohort Studies; Computer Simulation; Female; Follow-Up Studies; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Middle Aged; Republic of Korea; Tenofovir; White People

The objective of this study was to assess whether entecavir (ETV) in combination with interferon-α (IFN-α) could reduce hepatocellular cancer (HCC) and extrahepatic cancers (EHCs) in patients with chronic hepatitis B (CHB).. The cohort consisted of 4194 patients with CHB treated with ETV combined with IFN-α or ETV monotherapy at a tertiary hospital in Beijing, China, from January 2009 to December 2017. The risks, hazard ratios (HRs), and 95% confidence intervals (CIs) of HCC and EHCs were compared in the 2 groups.. In a multivariate Cox regression analysis, a significantly lower risk of HCC (HR, 0.6; 95% CI, 0.3-0.9; P = .0310) and a marginally significantly lower risk of EHCs (HR, 0.2; 95% CI, 0.02-1.3; P = .0854) were observed in the group receiving ETV combined with IFN-α in comparison with the ETV monotherapy group. The annual virological response rates were significantly higher in the combination therapy group versus the monotherapy group (33.8% vs 21.2%; P < .0001), but the hepatitis B surface antigen (HBsAg) seroclearance rates were not (1.2% vs 0.9%; P = .8537). The HRs were consistent with propensity score-based matching, inverse probability weighting adjustments, and adjustments for virological response and HBsAg seroclearance.. ETV combined with IFN-α therapy is superior to ETV monotherapy in reducing the risk of HCC and EHCs for patients with CHB. People who can tolerate and benefit from IFN-α therapy could consider combination therapy.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-alpha; Liver Neoplasms; Treatment Outcome

Chronic hepatitis B (CHB) is a major cause of chronic liver diseases and tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and entecavir (ETV) are recommended as primary treatments. This study aimed to evaluate the efficacy and safety of ETV, TDF, and TAF in a real-world clinical setting.. In this retrospective cohort study, a total of 363 CHB patients who were treated with ETV (n = 163), TDF (n = 154), or TAF (n = 46) from July 2007 to September 2019 were enrolled.. Median patient age was 51 years and 66.4% of patients were male. Median duration of treatment with ETV, TDF, or TAF was 49.0 months (interquartile range, 27.0-74.0 months). In terms of safety, cholesterol was mildly increased in the ETV and TAF groups and significantly lowered in the TDF group than baseline (p < 0.001). There was no significant difference in liver cirrhosis-related complications among the 3 groups at 48 weeks (p = 0.235). Hepatitis B e antigen seroconversion, complete virological response, and alanine aminotransferase normalization at 48 weeks as measures of treatment efficacy were not significantly different among the 3 groups (p = 0.142, 0.538, and 0.520, respectively). There was also no significant difference in cumulative incidence rate of hepatocellular carcinoma (HCC) between the ETV and TDF groups (p = 0.894).. ETV, TDF, and TAF were safe antiviral agents and showed similar antiviral effect for CHB at 48 weeks. Cirrhosis-related complications and annual HCC incidence rates did not differ significantly between the ETV and TDF groups over the 48 week follow-up period.

Topics: Alanine; Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Tenofovir; Treatment Outcome

Soluble immune checkpoint molecules are emerging novel mediators of immune regulation. However, it is unclear whether soluble immune checkpoint proteins affect the development of hepatocellular carcinoma (HCC) during nucleos(t)ide analogue (NA) treatment in patients with chronic hepatitis B virus infection. This study included 122 NA-naïve patients who received NA therapy. We assessed the associations of clinical factors, including soluble immune checkpoint proteins, with HCC development during NA treatment. The baseline serum concentrations of 16 soluble immune checkpoint proteins were measured using multiplexed fluorescent bead-based immunoassay. In total, 13 patients developed HCC during the follow-up period (median duration, 4.3 years). Of the 16 proteins, soluble inducible T-cell co-stimulator (≥ 164.71 pg/mL; p = 0.014), soluble programmed cell death-1 (sPD-1) (≤ 447.27 pg/mL; p = 0.031), soluble CD40 (≤ 493.68 pg/mL; p = 0.032), and soluble herpes virus entry mediator (≤ 2470.83 pg/mL; p = 0.038) were significantly associated with HCC development (log-rank test). In multivariate analysis, an sPD-1 level ≤ 447.27 pg/mL (p = 0.014; hazard ratio [HR], 4.537) and α-fetoprotein level ≥ 6.4 ng/mL (p = 0.040; HR, 5.524) were independently and significantly associated with HCC development. Pre-treatment sPD-1 is a novel predictive biomarker for HCC development during NA treatment.

Topics: Adult; Aged; Antiviral Agents; Biomarkers; Carcinoma, Hepatocellular; Female; Fluoroimmunoassay; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Middle Aged; Nucleosides; Predictive Value of Tests; Programmed Cell Death 1 Receptor; Time Factors; Treatment Outcome; Young Adult

Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are the first-line treatment agents for chronic hepatitis B virus (HBV). Recently, whether the degree to which the risk of hepatocellular carcinoma (HCC) may be reduced by ETV vs TDF has been debated. We compared the incidence of HCC among treatment-naïve patients receiving TDF vs ETV in the United States.. From a large administrative medical claims database of commercially insured patients, we identified 166,933 adults with a diagnosis of chronic hepatitis B and a minimum of 12 months of prior enrolment, of whom 3934 and 6127 initiated ETV and TDF respectively. Fine-Gray hazard regression models incorporating treatment propensity scores (PS) were used to estimate the risk of HCC incidence associated with TDF vs ETV; variables considered for adjustment included demographic characteristics, concomitant medication use and baseline comorbidities, as well as competing events including liver transplantation and medication changes.. After PS weighting, the TDF and ETV groups were well-matched. During the follow-up, 90 patients developed HCC, including 50 receiving ETV and 40 receiving TDF, giving rise to crude incidence rates of 0.62 per 100 person-years (PY) and 0.30 per 100 PY respectively. In PS-weighted, multivariable analysis, TDF was associated with a subdistribution hazard ratio for HCC of 0.58 (95% confidence interval [CI]: 0.38-0.89) compared to ETV. Results were similar when patients ≥40 years and men and women were analysed separately.. Among commercially insured, treatment-naïve patients with chronic hepatitis B in the United States, treatment with TDF was associated with significantly lower risk of HCC than ETV.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Retrospective Studies; Tenofovir; Treatment Outcome; United States

Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are recommended as first-line choices regarding the treatment of chronic hepatits B. The impact of the two antiviral agents on prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative liver resection remains to be explored. We aimed to assess the effect of antiviral therapy with ETV or TDF after curative resection on the prognosis of patients with HBV-related HCC.. A total of 1173 consecutive patients who were treated with ETV or TDF after curative liver resection for HCC were enrolled in the study. HCC recurrence, overall survival, postoperative liver function reserve, and early virologic (VR) and biochemical responses (BR) of patients were compared between the ETV and TDF groups by propensity score matching (PSM) from the date of liver resection for HCC.. No difference was observed with recurrence-free survival between TDF and ETV in the PSM cohort (hazard ratio [HR], 0.91; 95% confidence interval [CI] 0.70-1.17; P = 0.45). No difference was observed with early VR and BR between TDF and ETV in the PSM cohort. Compared with ETV, TDF therapy was associated with significantly better protection of liver function and higher overall survival rates in the PSM cohort (HR, 0.37; 95% CI 0.20-0.71; P = 0.002). After PSM, 69 (40.8%) patients in the ETV group and 63 (57.3%) patients in the TDF group had single tumor recurrence, while the TDF group had significantly more patients with single tumor recurrence in the PSM cohort (P = 0.007).. For patients who underwent curative resection for HBV-related HCC, TDF treatment had a significantly better overall survival and better protection of liver function, but no difference in the incidences of HCC recurrence than ETV treatment.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Prognosis; Retrospective Studies; Tenofovir; Treatment Outcome

For patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) treated with curative radiofrequency ablation (RFA), the effect of entecavir (ETV) vs. tenofovir disoproxil fumarate (TDF) on recurrence-free survival (RFS) and overall survival (OS) remains unclear. We aimed to compare the outcomes of patients receiving ETV or TDF after RFA. This study consecutively collected patients who were treated with ETV (n = 202) or TDF (n = 102) for chronic hepatitis B (CHB) after curative RFA of HCC from December 2015 to January 2021 at Sun Yat-sen University Cancer Center. There were 130 patients in the ETV group and 77 patients in the TDF group after we performed 1-to-n propensity score matching. Kaplan−Meier and Cox regression analyses were performed to validate possible risk factors for RFS and OS. In addition, we estimated the curative effect of ETV and TDF for HBV-related hepatitis by recording the change in serum HBV DNA and ALBI grade after RFA. During the study period (median 34.1 (interquartile range: 19.6−47.4 months) months), 123 (40.5%) patients suffered HCC recurrence, and 15 (4.9%) died. In the full cohort, the probability of HCC recurrence (41.6% vs. 37.3%, p = 0.49) and overall survival (95% vs. 95.1%, p = 0.39) at 5 years were similar between the ETV and TDF groups. In the matched cohort, HCC recurrence (40.8% vs. 40.3%, p = 0.35) and overall survival (96.9% vs. 93.5%, p = 0.12) at 5 years were similar between the ETV and TDF groups. Furthermore, the early RFS (<2 years) did not differ significantly between the two groups in the full and matched cohorts (p = 0.26, p = 0.13). Compared with the ALBI grade before RFA, the ALBI grade of 80 patients (41%) remained stable or improved in the ETV group and 64 patients (64%) in the TDF group (p < 0.001). The mean time of serum HBV DNA reduction to 0 was 9.13 (95% CI: 5.92−12.33) and 2.75 (95% CI: 2.01−3.49) months in the ETV and TDF groups, respectively (p = 0.015). The RFS and OS of patients after curative RFA for HCC were not significantly different between the ETV and TDF groups. TDF therapy was associated with a better effect of protecting liver function and reducing the load of HBV. Further validation studies are needed.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Radiofrequency Ablation; Retrospective Studies; Tenofovir; Treatment Outcome

Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are both recommended as first-line treatments for patients with chronic hepatitis B virus (CHB) infection according to international HBV treatment guidelines. However, recent studies reported conflicting results regarding the preferred antiviral in the prevention of hepatocellular carcinoma (HCC). This cohort study aimed to investigate this issue by using Taiwan's National Health Insurance Research Database, wherein a "finite" but not life-long treatment policy was applied.. From January 2008 to December 2013, a total of 12,388 consecutive adult patients with CHB who received a finite course of TDF treatment (n = 1250) or ETV treatment (n = 11,138) were analyzed through screening for study eligibility followed by the 1:4 propensity score matching method.. In the entire cohort, the annual incidence and survival between the ETV and TDF groups were not significantly different regarding HCC occurrence (2.05 vs 2.74 per 100 patient-years [PY]; P = 0.055; hazard ratio [HR], 0.975; log-rank, P = 0.966), cirrhosis-related complications (1.9 vs 2.4 per 100 PY; P = 0.149; HR, 0.869; log-rank, P = 0.388), or all-cause mortality (2.16 vs 1.6 per 100 PY; P = 0.119; HR, 0.831; log-rank, P = 0.342), respectively. Propensity score matching analyses yielded similar results regarding HCC occurrence, cirrhosis-related complications, and all-cause mortality. In addition, these findings were consistently reproduced in the subgroups of patients with chronic hepatitis and cirrhosis that developed before antiviral treatment.. ETV and TDF did not significantly differ in prevention of HCC occurrence or reduction of cirrhosis-related complications and all-cause mortality in patients with CHB receiving a finite period of treatment.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Guanine; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Prognosis; Taiwan; Tenofovir; Treatment Outcome

Topics: Carcinoma, Hepatocellular; Guanine; Humans; Liver Neoplasms; Tenofovir

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Humans; Liver Neoplasms; Tenofovir

Viral integration profiles attract increased interest in the study of HBV-related hepatocellular carcinoma (HCC), but their features in the early stage of infection and changes due to antiviral treatments remain largely unknown.. Liver biopsies and paired blood samples were obtained from HBeAg-positive patients before and after 48 weeks of entecavir treatment, and a probe-based capture strategy was applied for analyzing the HBV integrations in these samples. Serum HBV markers, including viral DNA, pgRNA, and HBsAg, were longitudinally assessed.. Entecavir treatment successfully reduced the levels of ALT, AST, and HBV serological markers (HBeAg, HBV pgRNA, and HBV DNA) in all patients (<40 years old). As expected, HBV integrations contributed to HBsAg production, with the total number of integrations positively correlated with serum HBsAg level (r = 0.47, P = 0.04). Along with repressed HBV replication, the number of viral integrations in liver biopsies decreased by about 1.94-fold after ETV treatment, with viral breakpoints significantly enriched within nt 1600-1900 of the HBV genome. No recurrent events were observed both at baseline and after treatment for the same individual, and only one same integration was found in two patients. Unlike in tumors, integrations in CHB biopsies seemed to have no chromosomal preference. Moreover, CHB integrations demonstrated lower enrichment scores for open active states than tumors, such as DNase, TssA, and ZNF/Rpts, and the scores reduced after ETV treatment. The antiviral therapy led to the disappearance of the enrichment tendency of integrations in both open chromatin and heterochromatin regions.. Reduced HBV replications by the nucleoside analogue may lead to decreased viral integrations in the liver, and those contributing to the HBsAg production may consistently occur. The pattern of HBV integration after ETV treatment is more random and irregular, which may contribute to a reduced risk of liver cancer due to antiviral treatment.

Topics: Adult; Antiviral Agents; Biopsy; Carcinoma, Hepatocellular; DNA, Viral; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Prognosis; Tenofovir; Treatment Outcome

Nucleos(t)ide analogues (NAs) suppress hepatitis B virus (HBV) replication, but the risk of hepatocellular carcinoma still remains. The presence of detectable HBV DNA in the serum during NA therapies for chronic hepatitis B patients has been reported to be associated with the risk of hepatocellular carcinoma. In this study, we investigated the antiviral effect of switching from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) in chronic hepatitis B patients who had detectable HBV DNA in the serum at least once within a year. Among a total of 77 cases in 7 hospitals that switched NAs from ETV to TAF, 23 patients with detectable HBV DNA in a year before switching were analyzed. When the detection frequencies of HBV DNA in the 1st and 2nd years after switching to TAF were analyzed, they were significantly lower than those in the year before switching (68.8% vs. 34.1% for the 1st year and 21.3% for the 2nd year, P < 0.001 for both). The HBsAg decline tended to be larger after switching than before (-2.5% vs. -3.0% for 1st year and -3.1% for 2nd year), but the difference was not significant. One patient died of a cardiovascular event 11 months after the treatment switch, but no adverse effects due to TAF including renal function were observed. In conclusion, it was suggested that switching from ETV to TAF might be effective to suppress the HBV DNA level further in patients whose HBV DNA is detectable, even if at a very low level.

Topics: Adenine; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Fumarates; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir; Treatment Outcome

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Humans; Liver Neoplasms; Tenofovir

Cirrhosis and age (CAGE-B) and stiffness and age (SAGE-B) models assess the risk of hepatocellular carcinoma (HCC) development in white patients with chronic hepatitis B (CHB) undergoing sustained antiviral therapy (AVT). Herein, we checked the predictive performance of these models in Asian patients with CHB.. We reviewed 734 treatment-naive patients with CHB who started entecavir between 2006 and 2011 and were followed up for more than 5 years without HCC development during AVT. The predictive performance of CAGE-B and SAGE-B models was calculated using area under the receiver operating characteristic curves (AUROCs).. Median liver stiffness assessed using transient elastography after 5 years of AVT was 6.8 kPa. Median CAGE-B and SAGE-B models after 5 years of AVT were 7.0 and 6.0, respectively. More than 5 years after AVT initiation, 66 patients (9.0%) developed HCC. The AUROCs of the CAGE-B and SAGE-B models were 0.764 and 0.785 after 7 years and 0.799 and 0.802 after 10 years of AVT, respectively. The cumulative incidence of HCC was significantly higher in the high-risk groups according to CAGE-B and SAGE-B risk stratification than in the medium- and low-risk groups (P < .05 in all cases). The SAGE-B model showed a higher likelihood ratio (χ. Both SAGE-B and CAGE-B showed acceptable performance in predicting HCC after 5 years of AVT in Asian patients with CHB.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms

The treatment evidence for entecavir-treated chronic hepatitis B (CHB) patients without maintaining of virologic response (MVR, defined as persistent HBV DNA <20 IU/mL during therapy) remains uncertain. We aimed to determine the relationship between non-MVR and hepatocellular carcinoma (HCC) risk in entecavir-treated CHB patients.. A cohort of 1447 entecavir-treated CHB patients were enrolled. Multivariate and propensity score-based inverse probability weighting (IPW) model was performed to estimate the effect of MVR on HCC.. During a median follow-up of 5 years, 214 (14.8%) patients occurred with non-MVR. Non-MVR patients had a higher risk of HCC [the IPW model: hazard ratio (HR) = 3.59, 95% confidence interval (CI): 2.23-5.75] than MVR patients, especially in those with cirrhosis (HR = 4.60, 95% CI: 2.81-7.56) and the high HCC score by the Chinese University of Hong Kong (HR = 4.35, 95% CI: 2.58-7.32). MVR patients with transient (HR = 4.72, 95% CI: 1.98-11.24) or persistent (HR = 12.16, 95% CI: 3.58-41.31) abnormal ALT after virologic response had higher HCC hazard.. Our study indicated an elevated HCC probability for entecavir-treated CHB patients with Non-MVR, especially for those with cirrhosis or a high predicted score at baseline. For MVR patients, the trajectories of ALT after virologic response suggested different HCC risks.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; China; Female; Follow-Up Studies; Guanine; Hepatitis B, Chronic; Humans; Liver Function Tests; Liver Neoplasms; Male; Middle Aged; Propensity Score

This study evaluated the clinical implications of hepatitis B surface antigen quantification (qHBs Ag) in chronic hepatitis B (CHB) patients treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF) and identified the association between qHBs Ag and the risk of hepatocellular carcinoma (HCC) in these patients.Between January 2007 and December 2018, the qHBs Ag and clinical data of 183 CHB patients who initially received ETV (n = 45, 24.6%) or TDF (n = 138, 75.4%) were analyzed.The mean follow-up period of the 183 CHB patients was 45.3 months, of which 59 (32.2%) patients showed a reduction in qHBs Ag by >50% after 1 year of antiviral treatment (ETV or TDF). The HCC development (P = .179) or qHBs Ag reduction (P = .524) were similar in the ETV and TDF groups. Patients with a ≥50% decrease in qHBs Ag had a significantly lower incidence of HCC or decompensated cirrhosis complications (P = .005). Multivariate analysis showed that a >50% reduction of qHBs Ag (hazard ratio 0.085, P = .018) and the presence of cirrhosis (hazard ratio 3.32, P = .016) were independent factors predicting the development of HCC.Patients whose qHBs Ag value decreased >50% at 1 year after antiviral treatment for CHB showed a significant decrease in HCC or decompensated cirrhosis events. A reduction in qHBs Ag could be used as a predictive factor of HCC development or critical complications in CHB patients treated with TDF or ETV.

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Middle Aged; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Tenofovir

Antiviral therapy should reduce the recurrence of hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC) after surgical resection. However, there is little research on whether various antiviral drugs have different prognostic effects in patients with HBV-related HCC after curative liver resection. The present study compared the effects of nucleotide analog (NtA) and nucleoside analog (NsA) antiviral therapies after surgical resection on the prognosis of HBV-related HCC.. A total of 1303 patients with HBV-related HCC who received curative hepatectomy at five institutes between April 2014 and April 2019 were retrospectively enrolled and analyzed. Propensity matching analysis was used to compare the outcomes of HCC patients given NsA versus NtA therapy. Subgroup analysis of patients treated with entecavir (ETV) and tenofovir disoproxil fumarate (TDF) was also performed.. Among 1303 patients, 759 (58.2%) patients developed recurrence, and 460 (35.3%) patients died. Multivariable analyses revealed that NtA therapy significantly decreased the risk of HCC recurrence (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.51-0.80; p < 0.001) and HCC-related death (HR, 0.52; 95% CI, 0.36-0.76; p = 0.001) compared to that with NsA therapy. Subgroup analysis showed that TDF treatment was associated with significantly lower rates of HCC recurrence (HR, 0.64; 95% CI, 0.49-0.83; p = 0.001) and death (HR, 0.32; 95% CI, 0.20-0.50; p < 0.001) than ETV treatment.. Nucleotide analog treatment, but not NsA treatment, significantly reduced the risk of HCC recurrence in patients with HBV-related HCC and improved overall survival after curative hepatic resection.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatectomy; Hepatitis B virus; Humans; Liver Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Nucleosides; Nucleotides; Prognosis; Retrospective Studies; Survival Analysis; Tenofovir

Antiviral agents for chronic hepatitis B (CHB) reduced the risk of hepatocellular carcinoma (HCC) development. The outcomes of entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) were compared in patients with CHB.. Between 2017 and 2019, treatment-naïve patients with CHB treated with ETV, TDF, and TAF were recruited from three Korean tertiary institutes. The cumulative incidences of HCC and orthotopic liver transplantation (OLT) or mortality were calculated and compared using Kaplan-Meier analysis before and after trimatch.. Among recruited 2082 patients, 43 patients developed HCC, whereas 66 developed OLT or mortality. Before trimatch, the cumulative incidence of HCC was statistically similar among patients treated with three antiviral agents (p = 0.340). However, the cumulative probability of OLT or mortality development in patients treated with ETV or TDF was significantly higher than that of patients with TAF before trimatch (all p < 0.05). On multivariate analysis, male sex [hazard ratio (HR) 2.990] and older age (HR 1.044) were independently associated with an increased risk of HCC development, whereas higher platelet count (HR 0.993) was independently associated with a decreased risk (all p < 0.05). The type of antiviral agents did not significantly influence the risk of HCC and OLT or mortality development (all p > 0.05). After trimatch, no significant difference in the cumulative probability for HCC and OLT or mortality according to antiviral agents was found (all p > 0.05).. The outcomes of ETV, TDF, and TAF on the risk of HCC and OLT or mortality were statistically similar in treatment-naïve patients with CHB.

Topics: Aged; Alanine; Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Tenofovir; Treatment Outcome

Hepatectomy for hepatocellular carcinoma (HCC) beyond the Milan criteria is shown to be beneficial. However, a high rate of post-operative HCC recurrence hinders the long-term survival of the patients. This study aimed to investigate and compare the impacts of tenofovir (TDF) and entecavir (ETV) on the recurrence of hepatitis B viral (HBV)-related HCC beyond the Milan criteria.. Data pertaining to 1532 patients who underwent hepatectomy and received antiviral therapy between January 2014 and January 2019 were collected from five centers. Recurrence-free survival (RFS) analysis was performed using the Kaplan-Meier method. Cox proportional hazards regression analysis was performed to determine prognostic factors for HCC recurrence.. The analysis incorporates 595 HBV-related HCC patients. The overall 5-year RFS was 21.3%. Among them, 533 and 62 patients received ETV and TDF treatment, respectively. The 1-, 3-, and 5-year RFS rates were 46.3%, 27.4%, and 19.6%, respectively, in the ETV group compared with 65.1%, 41.8%, and 37.2%, respectively, in the TDF group (P < 0.001). Multivariate analysis showed that TDF treatment (hazard ratio [HR]: 0.604, P = 0.005), cirrhosis (HR: 1.557, P = 0.004), tumor size (HR: 1.037, P = 0.008), microvascular invasion (MVI) (HR: 1.403, P = 0.002), portal vein tumor thrombus (PVTT) (HR: 1.358, P = 0.012), capsular invasion (HR: 1.228, P = 0.040), and creatinine levels (CREA) (HR: 0.993, P = 0.031) were statistically significant prognostic factors associated with RFS.. Patients with HCC beyond the Milan criteria exhibited a high rate of HCC recurrence after hepatectomy. Compared to the ETV therapy, TDF administration significantly lowered the risk of HCC recurrence.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatectomy; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Retrospective Studies; Tenofovir

Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are first-line agents for the treatment of chronic hepatitis B (CHB). Recent studies have challenged the assumption that these agents are equally effective at preventing hepatocellular carcinoma (HCC). We aimed to determine whether the risk of HCC and mortality differ in patients with CHB treated with ETV and TDF.. We performed a retrospective cohort study of Veterans Affairs patients with CHB in the USA who initiated treatment with ETV or TDF between the dates of Food and Drug Administration approval of these medications and 1 January 2017. Multivariable Cox proportional hazards regression was used to determine the association between antiviral therapy and HCC risk as well as the risk of death or liver transplantation. Propensity score adjustment and competing risks analysis were performed.. We identified 2193 ETV-treated and 1094 TDF-treated patients who were followed for a mean of 5.4 years. We found no difference in the risk of HCC in ETV-treated versus TDF-treated patients (adjusted HR (aHR) 1.00, 95% CI 0.76 to 1.32). Results were similar in propensity score adjusted and competing risks analysis, and in multiple sensitivity analyses. We also found no difference in the risk of death or liver transplantation (aHR 1.16, 95% CI 0.98 to 1.39).. We found no difference in the risk of HCC between patients with CHB treated with ETV versus TDF. Our results support current guideline recommendations that both agents are appropriate first-line options for the treatment of CHB.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Middle Aged; Propensity Score; Proportional Hazards Models; Retrospective Studies; Risk Factors; Tenofovir

Studies have suggested that tenofovir disoproxil fumarate (TDF) treatment is associated with a significantly lower risk of hepatocellular carcinoma (HCC) occurrence when compared with entecavir (ETV) therapy in patients with chronic hepatitis B. We aimed to compare HCC recurrence and survival of patients treated with TDF or ETV after surgical resection for hepatitis B virus (HBV)-related HCC.. This historical cohort study included 1,695 consecutive patients treated with ETV (n = 813) or TDF (n = 882) after curative-intent hepatectomy for HBV-related HCC of Barcelona Clinic Liver Cancer stage 0 or A in Korea between 2010 and 2018. HCC recurrence and overall survival of patients were compared between ETV and TDF groups by propensity score-matched and multivariable-adjusted Cox regression analyses from the date of hepatectomy for HCC. The mean age of the study patients was 54.8 years, and 1,294 patients (76.3%) were male. During the median follow-up duration of 37.6 months with continued ETV or TDF therapy, 561 (33.1%) patients developed HCC recurrence, 144 (8.4%) died, and 22 (1.3%) received liver transplant. Compared with ETV, TDF therapy was associated with significantly higher recurrence-free (P = 0.02) and overall survival (P = 0.03) rates by propensity score-matched analysis. By multivariable-adjusted analysis, the TDF group was associated with significantly lower rates of HCC recurrence (hazard ratio [HR], 0.82; 95% confidence interval, 0.68-0.98; P = 0.03), and death or transplantation (HR, 0.62; 95% confidence interval, 0.44-0.88; P = 0.01). TDF therapy was an independent protective factor for both early (<2 years; HR, 0.79; P = 0.03) and late (≥2 years; HR, 0.68; P = 0.03) postoperative HCC recurrence.. Among patients who underwent curative hepatectomy for HBV-related HCC, TDF therapy was associated with a significantly lower risk of HCC recurrence and better overall patient survival compared with ETV therapy.

Topics: Aged; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Disease-Free Survival; Follow-Up Studies; Guanine; Hepatectomy; Hepatitis B, Chronic; Humans; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Retrospective Studies; Tenofovir

Adherence to medication and maintained virologic response (MVR) are related to the risk of adverse clinical outcomes. This study aimed to compare the efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) in relation to the adverse clinical outcomes among chronic hepatitis B (CHB) patients stratified according to adherence to medication and MVR.. A total of 1794 treatment-naive CHB patients treated with ETV (n = 894) or TDF (n = 900) for > 1 year were identified.. Adherence rates were significantly higher in the TDF than in the ETV (93.4% vs. 89.1%, respectively; P < 0.001). The MVR of ETV and TDF were 64.5% and 71.7%, respectively (P = 0.001). The MVR of ETV and TDF in the good adherence group were 72.1% and 76.4%, respectively (P = 0.083); in the poor adherence group, the MVR of ETV and TDF were 63.0% and 54.0%, respectively (P = 0.384) Multivariate analysis showed that the risk of HCC and death or transplantation was similar between groups (HR 0.826, 95% CI 0.522-1.306; P = 0.413 and HR 0.636, 95% CI 0.258-1.569; P = 0.325, respectively) after adjusting for adherence to medication and MVR. In the 589 propensity-matched pairs of patients, risk of HCC and death or transplantation was similar between treatment groups after stratification according to adherence rates and MVR.. After adjustment for adherence and MVR, ETV, and TDF did not differ in terms of the risk of HCC and death or transplantation in all patients and propensity score-matched cohorts.

Topics: Adenine; Adult; Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Liver Transplantation; Male; Medication Adherence; Middle Aged; Phosphorous Acids; Retrospective Studies; Risk Assessment; Risk Factors; Sustained Virologic Response; Time Factors; Treatment Outcome

Topics: Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Humans; Liver Neoplasms; Neoplasm Recurrence, Local; Tenofovir

Topics: Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Neoplasm Recurrence, Local; Tenofovir

Topics: Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Humans; Liver Neoplasms; Neoplasm Recurrence, Local; Tenofovir

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir

Topics: Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Neoplasm Recurrence, Local; Tenofovir

Several prediction scores for the early detection of hepatocellular carcinoma (HCC) are available. We validated the predictive accuracy of age, albumin, sex, liver cirrhosis (AASL), RESCUE-B, PAGE-B and modified PAGE-B (mPAGE-B) scores in chronic hepatitis B (CHB) patients treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF). Between 2007 and 2014, 3171 patients were recruited (1645, ETV; 1517, TDF). The predictive accuracy of each prediction score was assessed. The mean age of the study population (1977 men; 1194 women) was 48.8 years. Liver cirrhosis was present in 1040 (32.8%) patients. During follow-up (median, 58.2 months), 280 (8.8%) patients developed HCC; these patients were significantly older; more likely to be male; had significantly higher proportions of liver cirrhosis, hypertension and diabetes; and had significantly higher values for the four risk scores than those who did not develop HCC (all P < .05). Older age (hazard ratio [HR] = 1.048), male sex (HR = 2.142), liver cirrhosis (HR = 3.144) and prolonged prothrombin time (HR = 2.589) were independently associated with an increased risk of HCC (all P < .05), whereas a higher platelet count (HR = 0.996) was independently associated with a decreased risk of HCC (P < .05). The predictive accuracy of AASL score was the highest for 3- and 5-year HCC predictions (areas under the curve [AUCs] = 0.818 and 0.816, respectively), followed by RESCUE-B, PAGE-B and mPAGE-B scores (AUC = 0.780-0.815 and 0.769-0.814, respectively). In conclusion, four HCC prediction scores were assessed in Korean CHB patients treated with ETV or TDF. The AASL score showed the highest predictive accuracy.

Topics: Aged; Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B, Chronic; Humans; Infant, Newborn; Liver Neoplasms; Male; Retrospective Studies; Tenofovir

It is unclear whether suboptimal adherence contributes to adverse clinical outcomes in patients with chronic hepatitis B (CHB). Moreover, there is no consensus regarding the optimal level of drug adherence. This was a population-based historical cohort study including 51 975 adult CHB patients treated with entecavir (0.5 mg/d orally). Data were obtained from the Korean national health insurance service claims database, which covers >99% of the entire population, between 2007 and 2015. Medication adherence was categorized as high (proportion of days covered [PDC], ≥90%; n = 32 089), intermediate (PDC, 80%-89%; n = 10 197) and low (PDC, <80%; n = 9689). During a median 4.5 years (maximal 9 years) of follow-up in 51 975 CHB patients treated with entecavir, multivariable analyses revealed that the risk of mortality/transplantation was significantly greater in the low-adherers (adjusted hazard ratio [HR], 1.38; P < .001) and intermediate-adherers (adjusted HR, 1.44; P < .001) than the high-adherers (P for trend < 0.001). The risk of renal failure in the low- and intermediate-adherence groups was also significantly higher than the high-adherence group (P for trend < 0.001). By contrast, the risk of hepatocellular carcinoma (HCC) was not significantly different between groups (P for trend = 0.70). The higher risk of mortality/transplantation and renal failure but similar risk of HCC for low- and intermediate-adherers compared with high-adherers was consistent in inverse probability treatment weighting analysis of the entire cohort and subcohorts with or without cirrhosis. In conclusion, high medication adherence (≥90%) is required to significantly lower risk of mortality and renal failure in patients with CHB during long-term treatment with entecavir.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Medication Adherence

: The clinical significance of partial virological response (PVR) in patients undergoing antiviral therapy is not well known. This study investigated whether PVR after 2 years of entecavir (ETV) therapy is associated with hepatocellular carcinoma (HCC) development in cirrhotic patients.. A total of 472 naïve patients with hepatitis B virus (HBV)-associated cirrhosis who were treated with ETV for at least 2 years were retrospectively enrolled. Clinical characteristics, laboratory data, PVR, and noninvasive fibrosis markers (aspartate aminotransferase to platelet ratio and FIB-4 index) at 2 years after ETV commencement were analyzed for HCC risk.. After excluding those who developed HCC within 2 years of ETV therapy, 359 patients (mean age, 51±10 years; male 64.3%) were examined. During a median follow-up of 82 months, 80 patients developed HCC. In the univariate analysis, older age (hazard ratio [HR], 1.056; p<0.001), PVR (HR, 2.536; p=0.002), higher aspartate aminotransferase (HR, 1.018; p=0.005), lower albumin level (HR, 0.463; p<0.001), lower platelet count (HR, 0.993; p=0.01), and higher FIB-4 index (HR, 1.141; p<0.001) at 2 years after ETV commencement were risk factors for HCC. In the multivariate analysis, older age (HR, 1.046; 95% confidence interval [CI], 1.022 to 1.072; p<0.001), PVR (HR, 2.358; 95% CI, 1.310 to 4.245; p=0.004), and higher FIB-4 index (HR, 1.103; 95% CI, 1.035 to 1.177; p=0.003) were independent risk factors.. PVR and higher FIB-4 index after 2 years of ETV therapy were independent risk factors for HCC. Therefore, efforts to accomplish a complete virological response and reduce the FIB-4 index should be made.

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Treatment Outcome

Topics: Carcinoma, Hepatocellular; Guanine; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir

Topics: Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Tenofovir

Topics: Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Tenofovir

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Europe; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Europe; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir

The HCC-RESCUE score was developed to predict hepatocellular carcinoma (HCC) risk in Korean chronic hepatitis B (CHB) patients under entecavir therapy. We aimed to validate the HCC-RESCUE score to predict HCC risk in Caucasian CHB patients under entecavir or tenofovir therapy and to compare the predictive performance of the HCC-RESCUE score with those of the CAMD, PAGE-B and modified PAGE-B (mPAGE-B) scores. The study included 647 nucleos(t)ide analogue-naive noncirrhotic and compensated/decompensated cirrhotic patients who had received entecavir or tenofovir for ≥6 months and did not develop HCC during the first 6 months of therapy. Patients with HCC-RESCUE scores ≤64, 65-84 and ≥85 points were classified into low-, intermediate- and high-risk groups, respectively. The AUROCs of the HCC-RESCUE, CAMD, PAGE-B and mPAGE-B scores to predict HCC risk at 5 years were 0.875, 0.870, 0.866 and 0.880, and those at 10 years were 0.862, 0.845, 0.841 and 0.862, respectively (both p > .05). Cumulative HCC incidences at 5 years were 0.0%, 10.5% and 15.8%, and those at 10 years were 1.4%, 15.5% and 24.9%, respectively, in the low-, intermediate- and high-risk groups based on the HCC-RESCUE score (both log rank p < .001). In the entecavir versus tenofovir cohorts, the AUROCs of the HCC-RESCUE score to predict HCC risk at 5 and 10 years were 0.831 versus 0.898 and 0.803 versus 0.910, respectively (both p > .05). The HCC-RESCUE score accurately predicted HCC risk in Caucasian CHB patients under entecavir or tenofovir therapy. A substantial proportion of patients can be dropped from HCC surveillance by using the HCC-RESCUE score.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir

To evaluate the impact of chronic hepatitis B virus infection (CHB) treatment on risk of cirrhosis, liver-related outcomes, and death among a diverse CHB cohort with a large proportion of African Americans.. Adults with noncirrhotic CHB without human immunodeficiency virus from 2010 to 2018 were retrospectively evaluated across 4 US safety-net health systems. CHB was identified with International Classification of Diseases, Ninth Revision/Tenth Revision diagnosis coding and confirmatory laboratory data. Propensity-score matching, Kaplan-Meier methods, and adjusted Cox proportional hazards models were used to evaluate impact of CHB treatment on risk of cirrhosis, hepatocellular carcinoma (HCC), death, and composite of cirrhosis, HCC, or death.. Among 4,064 CHB patients (51.9% female, 42.0% age <45 years, 31.6% African American, 26.6% Asian, 26.7% Hispanic), 23.2% received CHB antiviral therapy and 76.8% did not. Among the propensity score-matched cohort (428 treated and 428 untreated), CHB treatment was associated with lower risk of cirrhosis (hazards ratio 0.65, 95% confidence interval 0.46-0.92, P = 0.015) and composite of cirrhosis, HCC, or death (hazards ratio 0.67, 95% confidence interval 0.49-0.94, P = 0.023). Females vs males and African Americans vs non-Hispanic whites had significantly lower risk of cirrhosis. When treatment effects were stratified by age, sex, and ethnicity, the benefits of antiviral therapies in reducing risk of cirrhosis were seen primarily in CHB patients who were females, age <45 years, and of Asian ethnicity.. Our propensity score-matched cohort of noncirrhotic CHB patients demonstrated significant reductions in risk of cirrhosis due to CHB treatment.

Topics: Adult; Aged; Alanine; Antiviral Agents; Asian; Black or African American; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B, Chronic; Humans; Kaplan-Meier Estimate; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Mortality; Propensity Score; Proportional Hazards Models; Retrospective Studies; Safety-net Providers; Tenofovir; United States; Urban Population; White People

Aspirin may reduce the risk of chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) in patients receiving antiviral treatment. We aimed to investigate the impact of aspirin on reducing HCC risk in patients treated with first-line oral nucleos(t)ide analogs (NAs; entecavir and/or tenofovir disoproxil fumarate).. We conducted a territorywide, retrospective cohort study in NA-treated CHB patients between 2000 and 2018 from the electronic healthcare data repository in Hong Kong. Subjects were classified into aspirin users for at least 90 days during NA treatment (aspirin group) or no aspirin or any other antiplatelet use during follow-up period (no aspirin group). Incidence rates of HCC and gastrointestinal bleeding (GIB) in 2 groups with propensity score matching with 1:3 ratio.. Of 35,111 NA-treated CHB patients of mean age of 53.0 years and 61.6% men, sixty-nine (4.0%) and 1,488 (4.5%) developed HCC at a median (interquartile range) of 2.7 (1.4-4.8) years and 3.2 (1.8-6.0) years in the aspirin group and no aspirin group, respectively. A duration-dependent association between aspirin and the risk of HCC was observed (subhazard ratio [sHR] 3 months-2 years: 0.65; 95% confidence interval [CI] 0.47-0.92; sHR 2-5 years: 0.63; 95% CI 0.43-0.94; sHR from ≥5 years: 0.41; 95% CI 0.18-0.91). Patients who took aspirin for ≤2 years had significantly higher risk of GIB (sHR: 1.73, 95% CI 1.07-2.79) than those not receiving aspirin. The risk of GIB started declining with the longer use of aspirin and becoming insignificant for ≥5 years' use (sHR: 0.79, 95% CI 0.19-3.21).. Long-term aspirin use is associated with a lower risk of HCC in a duration-dependent manner in NA-treated CHB patients without a significant increase in the risk of gastrointestinal adverse effects.

Topics: Adult; Aged; Alanine; Antiviral Agents; Aspirin; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Follow-Up Studies; Gastrointestinal Hemorrhage; Guanine; Hepatitis B, Chronic; Hong Kong; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Tenofovir

Whether entecavir (ETV) or tenofovir disoproxil fumarate (TDF) affords the better prognosis after curative treatment of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains unclear. We compared recurrence and death rates between patients taking ETV and those taking TDF.. Between 2013 and 2017, patients with HBV-related HCC who had undergone hepatic resection (n=421) or radiofrequency ablation (n=305) as first-line anti-HCC treatment in three institutes were consecutively enrolled. All patients received ETV or TDF as a first-line antiviral. The cumulative probabilities of recurrence and death were assessed. We adjusted for viral factors, including the HBV-DNA load, and tumor and demographic factors.. During the study period (median 46.6 [interquartile range 25.3-58.9] months), 227 patients experienced recurrence and 53 died. In the ETV (n=405) and TDF (n=321) groups, the annual incidences of recurrence (10.61 and 11.21 per 100 person-years, respectively; P=727) and death (2.28 and 1.79 per 100 person-years, respectively; P=277) were similar, with adjusted hazard ratios (aHRs) of 0.932 (P=0.622) and 0.667 (P=0.193), respectively. When stratified by treatment modality and the timing of antiviral therapy commencement, the values were similar (all P>0.05). Inverse probability of treatment weighting (IPTW) analyses yielded results that were similar in the two groups in terms of recurrence (aHR=1.038, P=0.963) and death (aHR=0.799, P=0.431). Furthermore, the early (<2 years) and late (≥2 years) recurrence risks were not statistically different in the two groups (both P=0.400), as confirmed by IPTW analysis (P=0.502 and P=0.377, respectively).. The prognoses in terms of recurrence and death after curative treatment of HBV-related HCC were not statistically different between the ETV and TDF groups. Further validation studies are needed.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Neoplasm Recurrence, Local; Prognosis; Retrospective Studies; Tenofovir; Treatment Outcome

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir

Topics: Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Taiwan; Tenofovir

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir

Topics: Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Taiwan; Tenofovir

The occurrence of hepatocellular carcinoma (HCC) is a major concern during antiviral therapy for chronic hepatitis B. There are conflicting opinions regarding the effects of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) on HCC prevention. We assessed these two antiviral medications for preventing HCC in treatment-naïve patients with chronic hepatitis B.. We conducted a retrospective cohort study using nationwide claims data from the Korea Health Insurance Review and Assessment Service. We included 55,473 treatment-naïve adult cases where ETV or TDF treatment was started between 2013 and 2017 (cohort 1). The ETV and TDF groups were matched 1:2 based on age, sex, comorbidities, hospital type, and index date year. Patients were followed up until December 2018. The outcome was the development of HCC. Subgroup analyses were conducted according to sex, age, hospital type and the presence of cirrhosis. We also compared the outcomes of patients who had started antiviral therapy during the 2012-2014 period (cohort 2).. The matched participants (18,491 in the ETV and 36,982 in the TDF groups) were a part of the study for, on average, 41.2 months. The incidence of HCC did not differ significantly between the ETV (1.46 per 100 patient-years) and the TDF (1.36 per 100 patient-years) treatments (hazard ratio, 0.93; 95% confidence interval, 0.86-1.01;. In patients with chronic hepatitis B, the ETV treatment did not result in a higher rate of HCC than the TDF treatment.

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Databases, Factual; Female; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Proportional Hazards Models; Republic of Korea; Retrospective Studies; Tenofovir; Young Adult

Antiviral therapy with or without hepatitis B immune globulin (HBIG) is a common strategy for the prevention of hepatitis B virus (HBV) reinfection. But there is no consensus on management protocols, and long-term data are relatively rare on recurrence of HBV infection after liver transplantation using a nucleoside analogue and HBIG prophylaxis.. We performed 56 liver transplants since June 2006. Among them, 32 liver recipients had liver cirrhosis associated with HBV, 9 with hepatocellular carcinoma (HCC), and 23 without HCC. Three operative mortalities, 3 deaths within 1 year related to infection, and 1 follow-up loss less than 1 year were excluded from analysis. We analyzed 25 liver transplants retrospectively. We prevented HBV reinfection with entecavir or tenofovir lifelong with 7 days of daily intravenous HBIG, 10,000 units, including operative day, and then once a week for the next 3 weeks, and then once a month for 1 year. Afterward, 4000 or 6000 units every 2 or 3 months were given to maintain patients' serum hepatitis B antibody titer >200 mIU/mL.. Mean follow-up period for HBV reinfection was 120.3 months. No patients have had reinfection.. Lifelong HBIG and nucleoside is an excellent prevention strategy for HBV reinfection after liver transplant.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Drug Administration Schedule; Female; Guanine; Hepatitis B; Hepatitis B Antibodies; Hepatitis B virus; Humans; Immunoglobulins; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Recurrence; Retrospective Studies; Tenofovir

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir

Limited data are available on the use of oral antiviral therapy, particularly the long-term use of entecavir monotherapy in patients with hepatitis B virus (HBV)-related diseases after liver transplant (LT).. The clinical data on consecutive patients who underwent LT for HBV-related diseases from 2011 to 2019 were prospectively collected and retrospectively analyzed. All patients received entecavir monotherapy alone during the follow-up period; viral serology/load and liver biochemical tests were performed regularly.. Among the total of 89 patients were patients with decompensated cirrhosis (n = 27 [30%]), acute-on-chronic HBV (n = 21 [24%]), and hepatocellular carcinoma (HCC) (n = 41 [46%]). The median age of the patients was 50 years (range, 42-58 years), and the median follow-up was 37 months (range, 1-96 months). Before LT, 45 (51%) patients did not receive, whereas 44 (49%) were currently receiving, oral antiviral therapy. At the time of LT, serum level of HBV DNA of 34 (38%) patients was >20 IU/mL, with the median level being 270,000 IU/mL (range, 4270-2,020,000), and 53 patients (59%) had undetectable levels of HBV DNA (≤20 IU/mL). The cumulative rate of hepatitis B surface antigen loss was 79.8%, 100%, and 100% after 1 month, 1 year, and 5 years, respectively. Hepatitis B surface antigen positivity returned after seroclearance in 1 patient, who died of HCC recurrence with an undetectable level of HBV DNA. The overall survival rates at 1, 3, and 5 years after LT were 94.51%, 86.84%, and 85.27%, respectively. During the follow-up period, no entecavir adverse reactions or dose reductions were observed.. Long-term entecavir monotherapy was highly effective in preventing HBV reactivation and HBV-related diseases.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Female; Follow-Up Studies; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Recurrence, Local; Recurrence; Retrospective Studies; Survival Rate; Treatment Outcome

Hepatocellular carcinoma (HCC) is the most common liver cancer. The efficacy of the present treatment is disappointing, and the prognosis is poor. Donafenib, a novel multikinase inhibitor, is a new deuterated derivative of sorafenib. It can improve overall survival in patients with advanced HCC, with a favorable safety and tolerability profile over sorafenib.. Here, we report the case of a 51-year-old male patient who presented with experienced epigastric discomfort for the prior several days. He had a history of untreated chronic hepatitis B virus infection for >29 years and no other underlying diseases. Based on further investigations, he was diagnosed with advanced HCC and refused surgery.. Based on the patient's performance status, tumor status assessed by computed tomography, liver function, and percutaneous liver biopsy, he was diagnosed with advanced HCC Barcelona Clinic Liver Cancer Stage C.. The patient was administered a 200-mg oral dose of donafenib twice-daily.. The patient was followed-up from the time of diagnosis. He received donafenib for 31 months, and the progression-free survival time was 31 months (from May 2017 to December 2019); the overall survival time was not reached. The patient reported little abdominal distension with no other obvious discomfort while taking the medication.. Donafenib showed good efficacy for the treatment of advanced HCC, with mild side effects. Deuterium-containing drugs seem to be a promising avenue for medical innovation.

Topics: Biopsy; Carcinoma, Hepatocellular; Disease Progression; Drug Therapy, Combination; Guanine; Hepatectomy; Hepatitis B, Chronic; Humans; Liver; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Pyridines; Tomography, X-Ray Computed; Treatment Outcome

It is controversial whether entecavir or tenofovir differs in reducing hepatocellular carcinoma (HCC) risk. We aimed to compare the efficacy of entecavir and tenofovir in reducing HCC risk in chronic hepatitis B (CHB) patients.. This retrospective study included 607 nucleos(t)ide naive CHB patients who had received entecavir or tenofovir. Patients who developed HCC during the first 12 months of therapy were excluded. Cumulative HCC incidences at years 2, 3, 4, 5 and 10 were compared between entecavir and tenofovir groups. Factors associated with HCC were determined by univariate and multivariate analyses.. Nineteen (3.1%) patients developed HCC, 12 (4.8%) in entecavir group and 7 (1.9%) in tenofovir group (P = .045). In the entire cohort, cumulative HCC incidences at years 2, 3, 4, 5 and 10 were 1.8%, 2.9%, 4.4%, 5.2% and 9.9% in entecavir group, and 0.6%, 2.4%, 2.4%, 2.4% and 3.7% in tenofovir group, respectively (log-rank P = .130). In multivariate analysis, age ≥50 years, cirrhosis, decompensated cirrhosis, high GGT and low platelet levels were associated with HCC in the entire cohort. In advanced fibrosis/cirrhosis cohort, cumulative HCC incidences at years 2, 3, 4, 5 and 10 were 4.6%, 7.1%, 8.6%, 12.1% and 15.5% in entecavir group, and 1.8%, 5.6%, 5.6%, 5.6% and 8.5% in tenofovir group, respectively (log-rank P = .267). In multivariate analysis, age ≥50 years, decompensated cirrhosis, high GGT and low platelet levels were associated with HCC in the advanced fibrosis/cirrhosis cohort.. Entecavir and tenofovir are similarly effective in reducing HCC risk in CHB patients.

Topics: Aged; Aged, 80 and over; Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Risk Factors; Tenofovir; Turkey

Several studies suggested that efficacy of tenofovir in reducing the risk of the development of hepatocellular carcinoma (HCC) might be better than that of entecavir. It remains unknown whether a change in therapy can further reduce the risk of HCC in patients receiving entecavir therapy and achieved goal of antiviral therapy, a maintained undetectable hepatitis B virus (HBV) DNA level in the serum.. A total of 1336 treatment-naïve chronic HBV mono-infected adult patients, who started entecavir or tenofovir treatment and achieved a maintained virologic response during follow-up were analysed.. During a median 4.4 years of follow-up (range, 1.0-7.4 years) after achieving virologic response, 99 patients developed HCC. The 5-year cumulative HCC incidence rate was 7.3% and 6.3% for the entecavir and tenofovir groups, respectively, with similar risk of HCC between the two groups (adjusted HR, 0.82; 95% CI, 0.52-1.29; p = 0.3). The risk of HCC was similar in the propensity score-matched cohort (HR, 1.02; 95% CI, 0.68-1.52; p = 0.94) and inverse probability treatment weighting analysis (HR, 1.11; 95% CI, 0.74-1.66; p = 0.62). In the subgroup analysis, HCC risk was similar between the two drugs in both patients with and without cirrhosis.. In patients showing maintained virologic response, no difference in the risk of HCC between entecavir and tenofovir was observed. This indicates entecavir might be as effective as tenofovir in the prevention of HCC among those patients and suggest that a change in therapy in anticipation of further reducing the risk of HCC might not be necessary for patients receiving entecavir and showing virologic response.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Pharmaceutical Preparations; Retrospective Studies; Tenofovir; Treatment Outcome

Whether entecavir (ETV) or tenofovir alafenamide (TAF) is better at preventing hepatocellular carcinoma (HCC) development among patients with chronic hepatitis B (CHB) remains unclear. The present study was conducted to explore the ability of these two antivirals to prevent HCC.. From 2012 to 2019, treatment-naïve CHB patients undergoing ETV or TAF therapy were recruited at three academic teaching hospitals. The TAF group comprised patients starting TAF as first-line antiviral and those switching antivirals from tenofovir disoproxil fumarate to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded from the analysis. Cumulative probabilities of HCC were assessed using the Kaplan-Meier method.. In total, 1810 patients (1525 and 285 in ETV and TAF groups, respectively) were recruited. The annual HCC incidence was statistically not different between the ETV and TAF groups (1.67 vs. 1.19 per 100 person-years, respectively) with an adjusted hazard ratio (HR) of 0.681 (p = 0.255), as determined by multivariate analysis. Male, hypertension, liver cirrhosis, FIB-4 index, and albumin were independent prognostic factors for HCC development. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results, with non-statistically different HCC incidence between the ETV and TAF groups (1.07 vs. 1.19 per 100 person-years (HR = 0.973; p = 0.953) and 1.67 vs. 1.89 per 100 person-years, respectively (HR = 0.949; p = 0.743).. These findings suggest that ETV- and TAF-treated CHB patients have similar risk of developing HCC. Further studies with the larger sample size and longer follow-up are needed to validate these results.

Topics: Alanine; Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Retrospective Studies; Tenofovir; Treatment Outcome

As a continuation of earlier works, a series of novel quinazolinone derivatives (5a-s) were synthesized and evaluated for their in vitro anti-HBV and anti-hepatocellular carcinoma cell (HCC) activities. Among them, compounds 5j and 5k exhibited most potent inhibitory effect on HBV DNA replication in both drug sensitive and resistant (lamivudine and entecavir) HBV strains. Interestingly, besides the anti-HBV effect, compound 5k could significantly inhibit the proliferation of HepG2, HUH7 and SK- cells, with IC

Topics: Antineoplastic Agents; Antiviral Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Design; Drug Resistance, Viral; Hepatitis B virus; Humans; Liver Neoplasms; Quinazolinones; Virus Replication

There have been conflicting results from studies comparing the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection treated with tenofovir disoproxil fumarate (TDF) vs those treated with entecavir. We compared the effects of TDF vs entecavir on HCC risk in a large cohort of patients with chronic HBV infection in China.. We performed a retrospective study of consecutive adults with chronic HBV infection who initially received treatment with entecavir or TDF, for at least 6 months, from January 2008 through June 2018. Patients who had cancers or liver transplantation before or within the first 6 months of treatment were excluded. Propensity score weighting and 1:5 matching were used to balance the clinical characteristics between the 2 groups. Fine-Gray model was used to adjust for competing risk of death and liver transplantation.. We analyzed data from 29,350 patients (mean age, 52.9 ± 13.2 years; 18,685 men [63.7%]); 1309 were first treated with TDF (4.5%) and 28,041 were first treated with entecavir (95.5%). TDF-treated patients were younger (mean age, 43.2 years vs 53.4 years) and a lower proportion had cirrhosis (38 patients [2.9%] vs 3822 patients treated with entecavir [13.6%]). At a median follow-up time of 3.6 years after treatment began (interquartile range, 1.7-5.0 years), 8 TDF-treated patients (0.6%) and 1386 entecavir-treated patients (4.9%) developed HCC. Patients' clinical characteristics were comparable after propensity score weighting. TDF treatment was associated with a lower risk of HCC than entecavir treatment after propensity score weighting (weighted subdistribution hazard ratio, 0.36; 95% confidence interval 0.16-0.80; P = .013) and 1:5 matching (weighted subdistribution hazard ratio, 0.39; 95% confidence interval 0.18-0.84; P = .016).. In a retrospective analysis of 29,350 patients with chronic HBV infection in China, treatment with TDF was associated with a lower risk of HCC than treatment with entecavir, over a median follow-up time of 3.6 years.

Topics: Adult; Aftercare; Antiviral Agents; Carcinoma, Hepatocellular; China; Disease Progression; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Incidence; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Tenofovir; Treatment Outcome

It is unclear whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) differ in their effectiveness for preventing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB).. This retrospective cohort study analyzed an international consortium that encompassed 19 centers from 6 countries or regions composed of previously untreated CHB patients then treated with either ETV or TDF monotherapy. Those who developed HCC before antiviral treatment or within 1 year of therapy were excluded. The association between antiviral regimen and HCC risk was evaluated using competing-risk survival regression. We also applied propensity score matching (PSM) to 1:1 balance the 2 treatment cohorts. A total of 5,537 patients were eligible (n = 4,837 received ETV and n = 700 received TDF) and observed for HCC occurrence until December 23, 2018. Before PSM, the TDF cohort was significantly younger and had generally less advanced diseases.. In the unadjusted analysis, TDF was associated with a lower risk of HCC (subdistribution hazard ratio [SHR], 0.45; 95% confidence interval [CI], 0.26-0.79; P = 0.005). The multivariable analysis, however, found that the association between TDF and HCC no longer existed (SHR, 0.81; 95% CI, 0.42-1.56; P = 0.52) after adjustment for age, sex, country, albumin, platelet, α-fetoprotein, cirrhosis, and diabetes mellitus. Furthermore, the PSM analysis (n = 1,040) found no between-cohort differences in HCC incidences (P = 0.51) and no association between regimens (TDF or ETV) and HCC risk in the multivariable-adjusted analysis (adjusted SHR, 0.89; 95% CI, 0.41-1.92; P = 0.77).. TDF and ETV did not significantly differ in the prevention of HCC in patients with CHB.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; China; Cohort Studies; Disease Progression; Female; Guanine; Hepatitis B, Chronic; Hong Kong; Humans; International Cooperation; Japan; Liver Neoplasms; Male; Middle Aged; Proportional Hazards Models; Republic of Korea; Retrospective Studies; Taiwan; Tenofovir; Treatment Outcome; United States

The use of tenofovir (TDF) and entecavir (ETV) in patients with chronic hepatitis B (CHB) has led to a decrease in the incidence of hepatocellular carcinoma (HCC) and liver-related events. However, whether there is a difference between the two agents in the extent of improving such outcomes has not been clarified thus far. Therefore, we aimed to compare TDF and ETV on the risk of HCC and mortality.. A total of 7015 consecutive patients with CHB who were treated with TDF or ETV between February 2007 and January 2018 at the liver units of the Catholic University of Korea were screened for study eligibility and 3022 patients were finally analysed. Study end points were HCC and all-cause mortality or liver transplantation (LT) within 5 years after the initiation of antiviral therapy. Propensity score matching (PSM) and inverse probability of treatment weighting methods were used.. No difference was observed between TDF and ETV in the incidence rates of HCC in the entire cohort (HR 1.030; 95% CI 0.703 to 1.509, PSM model, p=0.880) and subgroups of patients with chronic hepatitis and cirrhosis. Also, no difference was observed between TDF and ETV in the incidence rates of all-cause mortality or LT in the entire cohort (HR 1.090; 95% CI 0.622 to 1.911, PSM model, p=0.763), and patients with chronic hepatitis and cirrhosis.. This study has demonstrated the clinical outcomes in patients with CHB who received TDF or ETV treatment. There was no difference in the intermediate-term risk of HCC and mortality or LT between the two drugs.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Cause of Death; Female; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Propensity Score; Republic of Korea; Risk; Tenofovir

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Drug Administration Schedule; Drug Therapy, Combination; Female; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-alpha; Liver Neoplasms; Male; Polyethylene Glycols; Recombinant Proteins; Treatment Outcome; Young Adult

Topics: Antiviral Agents; Carcinoma, Hepatocellular; China; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir

Real-world studies examining reduction in risk of hepatocellular carcinoma (HCC) in patients receiving antivirals are limited by the small size of the studies, or by data insufficiency and heterogeneity with short follow-up duration. We aimed to examine the real-world long-term outcome of patients receiving entecavir treatment on HCC incidence and HBsAg seroclearance. The incidence of HCC in 1225 entecavir-treated patients between 2002 and 2015 was compared with the HCC incidence estimated using the REACH-B, GAG-HCC and CU-HCC scores. Standardized incidence ratios (SIR) were calculated. The impact of entecavir treatment on HBsAg seroclearance was also explored. The median follow-up of the cohort was 6.6 years, with 66 cases of HCC development. Using the REACH-B model, the reduction of HCC risk was significant from year 6 onwards with SIR of 0.68 (95% CI 0.535-0.866) at year 10. In subgroup patients without cirrhosis, consistent risk reduction was observed from the fifth year and the SIR reached 0.51 (95% CI 0.271-0.704) by year 10. Benefit in cirrhotic patients was demonstrated when using the GAG-HCC and CU-HCC score, with the SIR at year 10 being 0.38 (95% CI 0.259-0.544) and 0.46 (95% CI 0.314-0.659), respectively. The cumulative rate of HBsAg seroclearance was 5.2%. HBsAg level at third year of treatment and baseline-to-3-year percentage reduction was predictive of subsequent HBsAg seroclearance. In conclusion, long-term entecavir therapy was associated with significant reduction in the risk of HCC in the real world. However, HBsAg seroclearance rate remained low. Additional therapy may be considered in patients with adverse predictive factors for subsequent HBsAg seroclearance.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; DNA, Viral; Guanine; Hepatitis B; Hepatitis B Surface Antigens; Humans; Liver Neoplasms

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Propensity Score; Republic of Korea; Tenofovir

Topics: Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Tenofovir

PAGE-B and modified PAGE-B (mPAGE-B) scores were developed to predict the risk of hepatocellular carcinoma (HCC) in patients on nucleos(t)ide analogue therapy. However, how and when to use these risk scores in clinical practice is uncertain.. Consecutive adult patients with chronic hepatitis B who had received entecavir or tenofovir for at least 6 months between January 2005 and June 2018 were identified from a territory-wide database in Hong Kong. The performance of PAGE-B and mPAGE-B scores for HCC prediction at 5 years was assessed by area under the time-dependent receiver operating characteristic curve (AUROC), and different cut-off values of these 2 scores were evaluated by survival analysis.. Of 32,150 identified patients with chronic hepatitis B, 20,868 (64.9%) were male. Their mean age was 53.0 ± 13.2 years. At a median (IQR) follow-up of 3.9 (1.8-5.0) years, 1,532 (4.8%) patients developed HCC. The AUROCs (95% CI) for the prediction of HCC at 5 years were 0.77 (0.76-0.78) and 0.80 (0.79-0.81), with PAGE-B and mPAGE-B scores, respectively (p <0.001). A total of 9,417 (29.3%) patients were classified as having a low HCC risk by either PAGE-B or mPAGE-B scores; their 5-year cumulative incidence of HCC was 0.6% (0.4%-0.8%). This classification achieved a negative predictive value of 99.5% (99.4%-99.7%) to exclude patients without HCC development at 5 years. The AUROCs for the prediction of HCC with PAGE-B and mPAGE-B scores were similar at baseline and after 2 years on treatment.. PAGE-B and mPAGE-B scores can be applied to identify patients on antiviral therapy who are at low risk of developing HCC. These patients could be exempted from HCC surveillance due to their very low HCC risk.. Risk scores have been developed to predict the likelihood of patients with chronic hepatitis B developing hepatocellular carcinoma (HCC). We investigated the role of 2 such scores, PAGE-B and modified PAGE-B, in predicting the risk of HCC in 32,150 nucleos(t)ide analogue-treated patients with chronic hepatitis B. These scores identified a group of patients at very low risk of developing HCC who could therefore be exempted from HCC surveillance.

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Female; Follow-Up Studies; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Hong Kong; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Prognosis; Research Design; Retrospective Studies; Risk Assessment; Risk Factors; Serologic Tests; Tenofovir

Topics: Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Hepatitis D; Humans; Liver Cirrhosis; Liver Neoplasms; Tenofovir; Virus Replication

Topics: Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Hepatitis D; Humans; Liver Cirrhosis; Liver Neoplasms; Tenofovir; Virus Replication

It was suggested that normalization of serum alanine aminotransferase (ALT) levels at 1 year of antiviral treatment is associated with a lower risk of hepatic events in patients with chronic hepatitis B (CHB). However, it remains unclear whether earlier ALT normalization is associated with lower hepatocellular carcinoma (HCC) risk, independent of fatty liver or cirrhosis and on-treatment virological response (VR), in patients with CHB.. We analyzed 4,639 patients with CHB who initiated treatment with entecavir or tenofovir using landmark analysis and time-dependent Cox analysis. We defined normal ALT as ≤35 U/L (men) and ≤25 U/L (women) and VR as serum hepatitis B virus DNA <15 IU/mL.. During a median 5.6 years of treatment, 509 (11.0%) patients developed HCC. ALT normalization occurred in 65.6% at 1 year and 81.9% at 2 years and was associated with a significantly lower HCC risk in landmark (P < 0.001) and time-dependent Cox analyses (adjusted hazard ratio [AHR] 0.57; P < 0.001). Compared with ALT normalization within 6 months, delayed ALT normalization at 6-12, 12-24, and >24 months was associated with incrementally increasing HCC risk (AHR 1.40, 1.74, and 2.45, respectively; P < 0.001), regardless of fatty liver or cirrhosis at baseline and VR during treatment. By contrast, neither earlier VR (AHR 0.93; P = 0.53) nor earlier hepatitis B e antigen seroclearance (AHR 0.91; P = 0.31) was associated with a significantly lower HCC risk.. In patients with CHB treated with entecavir or tenofovir, earlier ALT normalization was independently associated with proportionally lower HCC risk, regardless of fatty liver or cirrhosis at baseline and on-treatment VR.

Topics: Adult; Alanine Transaminase; Antiviral Agents; Biomarkers; Carcinoma, Hepatocellular; Female; Follow-Up Studies; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Risk; Tenofovir; Treatment Outcome

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Telomerase; Tenofovir

The prediction of hepatocellular carcinoma (HCC) development during nucleotide/nucleoside analog (NA) therapy is clinically important in patients with chronic hepatitis B. Although several useful models for HCC prediction have been previously reported, their usefulness in the Japanese population is unclear. Therefore, this study examines the applicability of these models in Japanese patients.. Four hundred forty-three patients with no history of HCC who were treated with entecavir, tenofovir alafenamide, or tenofovir disoproxil fumarate were enrolled. PAGE-B, modified-PAGE-B, and REACH-B scores were calculated, and subsequent HCC development was investigated.. The mean follow-up duration was 5.1 years, and a total of 33 patients (7.4%) developed HCC during the follow-up period. Multivariate analysis revealed that old age (hazard ratio [HR] 1.05, 95% confidence interval [CI] 1.01-1.09, P = 0.011), male gender (HR 2.62, 95% CI 1.06-6.49, P = 0.037), and low platelet count (HR 0.83, 95% CI 0.77-0.91, P < 0.001) were independent predictors of HCC development. These factors are the same as the factors identified in the PAGE-B model. Time-dependent area under the receiver operating characteristic (AUROC) curve revealed that the AUROCs for 3 and 7 years of PAGE-B (AUROC: 0.786 and 0.744 at 3 and 7 years, respectively) were continuously higher than those of REACH-B (0.658 and 0.543) and modified PAGE-B AUROC (0.772 and 0.731).. PAGE-B, which can easily identify high-risk cases, can be useful for predicting HCC development in Japanese patients treated with NA therapy.

Topics: Adenine; Adult; Alanine; Antiviral Agents; Asian People; Carcinoma, Hepatocellular; Cohort Studies; Female; Guanine; Hepatitis B, Chronic; Humans; Japan; Liver Neoplasms; Male; Middle Aged; Nucleotides; Platelet Count; Research Design; Risk; Tenofovir; Time Factors

Hepatocellular carcinoma (HCC) may develop in patients with chronic hepatitis (CHB) even after 5 years of oral therapy and cannot be easily predicted. We assessed predictors of HCC development and the need for HCC surveillance in this setting.. Of 1,951 adult Caucasians with CHB included in the PAGE-B cohort, 1,427 (73%) had completed >5 years of follow-up under therapy without developing HCC by year 5. Median follow-up was 8.4 years from treatment onset. Points-based risk scores were developed to predict HCC risk after year 5.. In years 5-12, HCC was diagnosed in 33/1,427 (2.3%) patients with cumulative incidences of 2.4%, 3.2% and 3.8% at 8, 10 and 12 years, respectively. Older age or age >50 years, baseline cirrhosis and liver stiffness (LSM) ≥12 kPa at year 5 were independently associated with increased HCC risk. The HCC incidence was lower in non-cirrhotics than cirrhotics at baseline with year-5 LSM <12; among cirrhotics at baseline, it was lower in those with year-5 LSM <12 than ≥12 kPa. CAGE-B score was based on age at year 5 and baseline cirrhosis in relation to LSM at year 5 and SAGE-B score was based only on age and LSM at year 5 (c-index = 0.809-0.814, 0.805-0.806 after bootstrap validation). Both scores offered 100% negative predictive values for HCC development in their low risk groups.. In Caucasians with CHB, the HCC risk after the first 5 years of antiviral therapy depends on age, baseline cirrhosis status and LSM at year 5. CAGE-B and particularly SAGE-B represent simple and reliable risk scores for HCC prediction and surveillance beyond year 5 of therapy.. In Caucasians with chronic hepatitis B, the risk of hepatocellular carcinoma after the first 5 years of entecavir or tenofovir therapy depends on age, baseline cirrhosis status and liver stiffness at year 5, which can provide simple and reliable risk scores for hepatocellular carcinoma prediction and surveillance beyond year 5. In patients with cirrhosis at baseline, liver stiffness <12 kPa at year 5 is associated with lower HCC risk, but surveillance may be still required.

Topics: Administration, Oral; Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Female; Follow-Up Studies; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Incidence; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Risk Factors; Tenofovir; Treatment Outcome; White People; Young Adult

Long-term antiviral therapy (AVT) for chronic hepatitis B (CHB) reduces the risk of hepatocellular carcinoma (HCC). We assessed the temporal trends in the incidence of HCC over time during long-term AVT among Asian patients with CHB.. Patients with CHB receiving entecavir/tenofovir (ETV/TDF) as a first-line antiviral were recruited from four academic hospitals in the Republic of Korea. We compared the incidence of HCC during and after the first 5 years of ETV/TDF treatment.. Among 3,156 patients, the median age was 49.6 years and males predominated (62.4%). During the follow-up, 9.0% developed HCC. The annual incidence of HCC per 100 person-years during the first 5 years (. Despite long-term AVT, the risk of HCC steadily persists over time among patients with CHB in the Republic of Korea, in whom HBV genotype C2 predominates.. Careful HCC surveillance is still essential.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Drug Therapy, Combination; Female; Follow-Up Studies; Genotype; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Incidence; Liver; Liver Neoplasms; Male; Middle Aged; Molecular Typing; Republic of Korea; Risk Adjustment; Risk Factors; Tenofovir; Time Factors

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Propensity Score; Republic of Korea; Tenofovir

Studies to evaluate risks of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection treated with the nucelos(t)ide analogues entecavir or tenofovir have produced contradictory results. These differences are likely to be the result of censored data, insufficient observation periods, and different observation periods for patients treated with different drugs. We aimed to compare the incidence of HCC development between patients treated with oral entecavir or tenofovir and followed up for the same time periods.. We performed a retrospective study, collecting data from 1560 treatment-naive patients with chronic HBV infection who were first treated with entecavir (n = 753) or tenofovir (n = 807) from 2011 through 2015 at 9 academic hospitals in Korea. Clinical outcomes were recorded over a mean time period of 4.7 ± 1.0 years, from 92.4% of patients treated with tenofovir and 92.7% of patients treated with entecavir.. Thirty-four patients in the entecavir group (4.5%) and 45 patients in the tenofovir group (5.6%) developed HCC during the follow-up period. The incidence of HCC did not differ significantly between groups, even in a 516-pair propensity score-matched population.. In a retrospective study of 1560 treatment-naive patients with chronic HBV infection, the incidence of HCC did not differ significantly between patients treated with entecavir vs tenofovir over the same observation period.. KCT0003487.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Retrospective Studies; Tenofovir; Treatment Outcome

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.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Female; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Middle Aged; Propensity Score; Retrospective Studies; Risk; Tenofovir

Topics: Antiviral Agents; Carcinoma, Hepatocellular; China; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir

Topics: Antiviral Agents; Carcinoma, Hepatocellular; China; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir

Direct comparison of the clinical outcomes between nucleos(t)ide analogue (NA) discontinuation versus NA continuation has not been performed in patients with chronic hepatitis B who achieved HBsAg-seroclearance. Whether NA discontinuation was as safe as NA continuation after NA-induced surface antigen of HBV (HBsAg) seroclearance was investigated in the present study.. This multicentre study included 276 patients from 16 hospitals in Korea who achieved NA-induced HBsAg seroclearance: 131 (47.5%) discontinued NA treatment within 6 months after HBsAg seroclearance (NA discontinuation group) and 145 (52.5%) continued NA treatment (NA continuation group). Primary endpoint was HBsAg reversion and secondary endpoints included serum HBV DNA redetection and development of hepatocellular carcinoma (HCC).. During follow-up (median=26.9 months, IQR=12.2-49.2 months), 10 patients (3.6%) experienced HBsAg reversion, 6 (2.2%) showed HBV DNA redetection and 8 (2.9%) developed HCC. Compared with NA continuation, NA discontinuation was not associated with HBsAg reversion in both univariable (HR=0.45, 95% CI=0.12 to 1.76, log-rank p=0.24) and multivariable analyses (adjusted HR=0.65, 95% CI=0.16 to 2.59, p=0.54). The cumulative probabilities of HBsAg reversion at 1, 3 and 5 years were 0.8%, 2.3% and 5.0% in the NA discontinuation group, and 1.5%, 6.3% and 8.4% in the NA continuation group, respectively. NA discontinuation was not associated with higher risk of either HBV redetection (HR=0.83, 95% CI=0.16 to 4.16, log-rank p=0.82) or HCC development (HR=0.53, 95% CI=0.12 to 2.23, log-rank p=0.38).. The discontinuation of NA was not associated with a higher risk of either HBsAg reversion, serum HBV DNA redetection or HCC development compared with NA continuation among patients who achieved HBsAg seroclearance with NA.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Female; Follow-Up Studies; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver Neoplasms; Male; Middle Aged; Sustained Virologic Response; Tenofovir

Topics: Carcinoma, Hepatocellular; China; Guanine; Hepatitis B virus; Humans; Liver Neoplasms; Tenofovir

Hepatitis B e antigen (HBeAg) seroclearance has been considered as the treatment endpoint in HBeAg-positive patients with chronic hepatitis B (CHB). Although HBeAg seroclearance has been accomplished, some aspects are yet unclear. We investigated the cumulative incidence of hepatocellular carcinoma (HCC) and evaluated hepatitis B surface antigen (HBsAg) seroclearance in patients undergoing nucleos(t) ide analogue (NA)-induced HBeAg seroclearance.. In this retrospective cohort study, 203 patients with CHB were HBsAg and HBeAg seropositive before NA (entecavir or tenofovir) treatment. All patient who experienced NA -induced HBeAg seroclearance were recruited. Patients with documented HBeAg seroclearance were followed-up every 6 months. Baseline characteristics and laboratory results were recorded.. The mean age at HBeAg seroclearance was 40 years (range, 20-84), and the mean follow-up duration was 5 years (range, 2-11). The cumulative incidence of HCC was 1.5 to 11.5% at 1 to 8 years after HBeAg seroclearance. Cirrhosis was the only significant factor for HCC development (hazard ratio [HR], 24.651; confidence interval [CI], 3.018 to 201.365; P = 0.003). The cumulative incidence of HBsAg seroclearance was 3.5 to 18.7% after 1 to 8 years from HBeAg seroclearance.. A significant proportion of patients developed HCC after NA-induced HBeAg seroclearance. The presence of liver cirrhosis at the time of HBeAg seroclearance serves as an independent factor for HCC development. Some patients with NA-induced HBeAg seroclearance achieved HBsAg seroclearance.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Carcinoma, Hepatocellular; Female; Follow-Up Studies; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Tenofovir; Young Adult

PURPOSE: The study compared the incidence and predictors of hepatocellular carcinoma (HCC) within and beyond year 5 of entecavir (ETV) therapy.. The study enrolled 1397 CHB patients who were naïve to nucleos(t)ide analogue (NA) treatment and had received ETV monotherapy for more than 12 months.. The cumulative incidences of HCC at 3, 5, and 10 years of ETV treatment were 4%, 9.1%, and 15.8%, respectively. In the entire cohort, the annual incidence rates of HCC were 2.28% within the first 5 years and 1.34% within 5-10 years of therapy. The incidences of HCC did not differ significantly within and beyond 5 years of ETV therapy (p = 0.53), including patients with cirrhosis (p = 0.85) and without cirrhosis (p = 0.47). At year 5 of treatment, the multivariate analysis showed that the fibrosis-4 (FIB-4) index and alpha-fetoprotein (AFP) levels were independent risk factors for HCC development beyond year 5. The 10-year cumulative incidences of HCC beyond year 5 in the high-risk group (FIB-4 > 2.20 and AFP > 3.21 ng/mL) and low-risk group (FIB-4 ≤ 2.20 and AFP ≤ 3.21 ng/mL) were 48.7% and 0%, respectively. APA-B score at 12 months and year 5 had a higher C-index for the prediction of HCC beyond year 5 than the PAGE-B at baseline and year 5 (p = 0.003 and p = 0.039, respectively) CONCLUSIONS: The HCC incidence tended to decrease but did not change significantly within and beyond 5 years of ETV therapy. The FIB-4 index and AFP levels at year 5 were predictive of HCC development beyond year 5 of ETV therapy.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Female; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Risk Factors; Taiwan; Ultrasonography

The use of tenofovir disoproxil fumarate (TDF) is associated with a risk of renal dysfunction. We investigated whether TDF is associated with the deterioration of renal function in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) requiring frequent computed tomography (CT) evaluations and transarterial chemoembolization (TACE) sessions, when compared to entecavir (ETV). Between 2007 and 2017, 493 patients with HBV-related HCC were enrolled. The number of CT evaluations and TACE sessions were collected through 3 years of follow-up. The median age of the study population (373 men and 120 women; 325 with ETV and 168 with TDF) was 56.5 years. TDF was significantly associated with a serum creatinine increase (≥25% from the baseline; unadjusted hazard ratio [uHR] = 1.620) and an estimated glomerular filtration rate (eGFR) reduction (<20% from the baseline) (uHR = 1.950) (all P < .05), when compared to ETV. In addition, CT evaluations ≥4 times/year were significantly associated with a serum creatinine increase (uHR = 2.709), eGFR reduction (uHR = 3.274) and chronic kidney disease (CKD) progression (≥1 CKD stage from the baseline) (uHR = 1.980) (all P < .05). In contrast, TACE was not associated with all renal dysfunction parameters (all P > .05). After adjustment, TDF use was independently associated with the increased risk of eGFR reduction (adjusted HR [aHR] = 1.945; P = .023), whereas CT evaluation ≥4 times/year was independently associated with the increased risk of serum creatinine increase (aHR = 2.898), eGFR reduction (aHR = 3.484) and CKD progression (aHR = 1.984) (all P < .01). In conclusion, patients with HBV-related HCC treated with TDF and frequent CT evaluations should be closely monitored for the detection of associated renal dysfunction.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Creatinine; Female; Glomerular Filtration Rate; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Kidney; Kidney Function Tests; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Tenofovir; Treatment Outcome

The risk of developing hepatocellular carcinoma (HCC) after hepatitis B e antigen seroclearance (ESC) remains unclear. We established and validated a new risk prediction model for HCC development after ESC in patients with chronic hepatitis B (CHB) receiving antiviral therapy (AVT). Between 2006 and 2016, 769 patients (training cohort) and 1,061 patients (validation cohort) with CHB who experienced ESC during AVT using entecavir (ETV) or tenofovir disoproxil fumarate (TDF) were recruited. In the multivariate analysis, male sex (hazard ratio [HR] = 2.092; 95% confidence interval [CI] = 1.152-3.800), cirrhosis (HR = 5.141; 95% CI = 2.367-11.167) and fibrosis-4 index (FIB-4) of >3.25 (HR = 2.070; 95% CI = 1.184-3.620) were the independent risk factors for HCC development (all P < .05). Accordingly, a novel HCC-ESC

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Tenofovir

Serum hepatitis B core-related antigen (HBcrAg) was shown to predict the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients undergoing treatment. We investigated the longitudinal profile of HBcrAg in entecavir (ETV)-treated CHB patients with subsequent HCC development. We identified HCC cases diagnosed at ≥1 year after ETV initiation. CHB patients without HCC (matched for age, sex, cirrhosis status, baseline hepatitis B virus [HBV] DNA level, and ETV treatment duration) were identified as controls at an HCC:non-HCC ratio of 1:2. Serum samples were retrieved at baseline (ETV initiation) and at 3 and 5 years of ETV therapy for HBcrAg measurement (log IU/mL). In total, 180 patients (60 HCC patients matched with 120 CHB patients without HCC; median age, 56.5 years; 80.6% male; baseline HBV DNA, 5.9 log IU/mL; median follow-up, 6.8 years) were recruited. The median time from ETV initiation to HCC development was 3.2 years. HBcrAg levels were higher in HCC cases than in controls at all three time points: 5.69 log IU/ mL versus 5.02 log IU/mL (p=0.025), 4.23 log IU/mL versus 3.36 log IU/mL (p=0.007), and 3.86 log IU/mL versus 3.36 log IU/mL (p=0.009), respectively. ETV led to similar rates of decline in HBcrAg from baseline to 3 years in both groups (0.34 log IU/mL/year vs 0.39 log IU/mL/year, p=0.774), although the decline from 3 to 5 years was slower in the non- HCC group (0.05 log IU/mL/year) than in the HCC group (0.09 log IU/mL/year, p=0.055). ETV time-dependently reduced HBcrAg in HCC and non-HCC patients. HBcrAg interpretation should consider the antiviral treatment duration.

Topics: Antiviral Agents; Biomarkers; Carcinoma, Hepatocellular; DNA, Viral; Female; Guanine; Hepatitis B Core Antigens; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Middle Aged; Treatment Outcome

Low-level viremia (LLV) after nucleos(t)ide analog treatment was presented as a possible cause of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). However, detailed information on patients' adherence in the real world was lacking. This study aimed to evaluate the effects of LLV on HCC development, mortality, and cirrhotic complications among patients according to their adherence to entecavir (ETV) treatment.. We performed a retrospective observational analysis of data from 894 consecutive adult patients with treatment-naïve CHB undergoing ETV treatment. LLV was defined according to either persistent or intermittent episodes of <2,000 IU/mL detectable hepatitis B virus DNA during the follow-up period. Good adherence to medication was defined as a cumulative adherence ≥90% per study period.. Without considering adherence in the entire cohort (n=894), multivariate analysis of the HCC incidence showed that LLV was an independent prognostic factor in addition to other traditional risk factors in the entire cohort (P=0.031). Good adherence group comprised 617 patients (69.0%). No significant difference was found between maintained virologic response and LLV groups in terms of the incidence of liver-related death or transplantation, HCC, and hepatic decompensation in good adherence group, according to multivariate analyses.. In patients with treatment-naïve CHB and good adherence to ETV treatment in the real world, LLV during treatment is not a predictive factor for HCC and cirrhotic complications. It may be unnecessary to adjust their antiviral agent for patients with good adherence who experience LLV during ETV treatment.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Longitudinal Studies; Male; Medication Adherence; Middle Aged; Multivariate Analysis; Risk Factors; Sustained Virologic Response; Viral Load

A recent study in Asian patients with chronic hepatitis B (CHB) reported that the incidence of hepatocellular carcinoma (HCC) was lower in patients treated with tenofovir disoproxil fumarate (TDF) than entecavir (ETV), but this finding remains controversial. We aimed to identify any differences in HCC incidence, or other patient outcomes, between patients receiving TDF or ETV in the well monitored, multicenter European PAGE-B cohort.. We included 1,935 Caucasians with CHB, with or without compensated cirrhosis, treated with ETV (n = 772) or TDF (n = 1,163) monotherapy. Mean follow-up was 7.1 ± 3.0 years from ETV/TDF onset.. The 5-year cumulative HCC incidence was 5.4% in ETV- and 6.0% in TDF-treated patients (log-rank, p = 0.321), with no significant difference in any patient subgroup (with or without cirrhosis, naïve or experienced to oral antiviral(s) [total, with or without cirrhosis]). In multivariable Cox regression analyses, the hazard of HCC was similar between ETV- and TDF-treated patients after adjustment for several HCC risk factors. ETV- and TDF-treated patients had similar rates of on-therapy biochemical and virological remission, HBsAg loss, liver transplantation and/or death. Elastographic reversion of cirrhosis at year 5 (liver stiffness <12 kPa) was observed in 245/347 (70.6%) patients with pretreatment cirrhosis, being more frequent in TDF- than ETV- treated patients (73.8% vs. 61.5%, p = 0.038).. In Caucasian patients with CHB, with or without cirrhosis, long-term ETV or TDF monotherapy is associated with similar HCC risk, rates of biochemical/virological remission, HBsAg loss and liver transplantation or death, but elastographic reversion of cirrhosis at year 5 was more frequent with TDF.. In a large cohort of Caucasians with chronic hepatitis B treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF) monotherapy, cumulative rates of hepatocellular carcinoma did not differ (up to 12 years). Nor did rates of biochemical/virological remission, HBsAg loss and liver transplantation or death. However, elastographic reversion of cirrhosis at year 5 was more frequent in TDF- than ETV-treated patients with pretreatment cirrhosis.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Elasticity Imaging Techniques; Female; Follow-Up Studies; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Incidence; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Risk Assessment; Tenofovir; White People

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Viremia

Conflicting results have been reported regarding which of entecavir (ETV) or tenofovir disoproxil fumarate (TDF) is associated with better outcomes. Chronic hepatitis B patients who started ETV or TDF between 2010 and 2015 were analysed. The primary outcomes were hepatocellular carcinoma and death and transplantation. The impact of the treatment on the primary outcomes was analysed using Cox proportional hazards models in the entire and propensity score-matched cohorts. A total of 404 patients (180 and 224 in the ETV and TDF groups, respectively) were analysed. The median duration of follow-up was significantly longer in the ETV group (64.0 vs. 49.1 months; P < 0.001). Virological response (79.4% vs. 68.4%; P = 0.018) and sustained virological suppression (59.7% vs. 45.2%; P = 0.005) were significantly higher in the TDF group. TDF was associated with lower hepatocellular carcinoma [hazard ratio (HR) 0.31, 95% confidence interval (95% CI), 0.12‒0.79; P = 0.014]; however, statistical significance was not reached after adjusting sustained virological suppression using propensity score matching (HR 0.36, 95% CI 0.12‒1.14; P = 0.08). Death and transplantation was comparable. In conclusion, the impact of TDF on the lower hepatocellular carcinoma was blunted after adjusting sustained virological suppression. Further comparison in a larger number of patients who show sustained virological suppression over a longer period of time is needed.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Female; Follow-Up Studies; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Survival Rate; Tenofovir; Treatment Outcome; Viral Load; Young Adult

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Humans; Liver Neoplasms; Tenofovir

The risk of developing hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is reduced by antiviral therapy. Here, we evaluated the chronological trends in HCC development risk starting in 2007, when entecavir reimbursement was first initiated in South Korea. Treatment-naïve patients with chronic hepatitis B (CHB) receiving entecavir 0.5 mg/d were stratified into three groups according to entecavir start time: early (2007-2010), middle (2011-2012) and late (2013-2014) cohorts Among 2442 patients, cumulative probabilities of developing HCC after 1, 3 and 5 years were, respectively, 1.7%, 5.1%, and 8.2% (early cohort; n = 672); 1.5%, 5.1% and 8.9% (middle cohort; n = 757); and 1.2%, 5.3% and 10.6% (late cohort; n = 1013; P > .05 between each pair). Older age, male, positive hepatitis B e antigen, liver cirrhosis, Child-Pugh class B (vs A) and lower platelet count significantly predicted HCC development in univariate analysis (P < .001), whereas entecavir start time (early vs middle vs late cohorts) did not affect the risk of HCC development (P = .457). A multivariate analysis revealed that older age (adjusted hazard ratio [aHR]=1.041), male gender (aHR = 2.069), liver cirrhosis (aHR = 3.771) and Child-Pugh class B (vs A, aHR = 1.548) were independently associated with an increased risk of HCC development, whereas higher platelet count was independently associated with a reduced risk of HCC development (aHR = 0.993; all P < .05). In conclusion, the risk of developing HCC among patients receiving entecavir in South Korea has been stable since 2007. To establish more effective HCC surveillance programs, further studies regarding the carcinogenic roles of nonviral factors are required.

Topics: Aged; Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Retrospective Studies; Treatment Outcome

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Tenofovir

Topics: Adenine; Administration, Oral; Alanine; Carcinoma, Hepatocellular; DNA, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Nucleotides; Tenofovir

Comparative long-term efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) for prevention of disease progression to hepatocellular carcinoma (HCC) among high-risk patients with chronic hepatitis B (CHB)-related compensated cirrhosis is controversial.. To compare the long-term efficacy of ETV and TDF in HCC prevention in patients with CHB-related cirrhosis, and to evaluate predictive risk factors for HCC development.. From January 2008 to March 2018, 894 treatment-naïve patients with CHB-related compensated cirrhosis on ETV or TDF were enrolled based on the longitudinal cohort study. Data were originally collected for 7.3 years of follow-up or after the launch of TDF in 2011. Only the 5-year cumulative incidence and risk factors of HCC were assessed.. Total 678 and 216 patients received ETV and TDF, respectively. The cumulative risk of HCC at 1, 3 and 5 years of follow-up was 1.6%, 11.3% and 18.7%, respectively, in the ETV group; and 0.9%, 6.7% and 10.7%, respectively, in the TDF group (P = 0.0305). Univariate and adjusted-multivariable models revealed that platelet count, alpha-fetoprotein (AFP) levels and upper gastrointestinal (UGI) varices were independent risk factors for HCC development. TDF resulted in risk of HCC development compared to ETV with adjusted hazard ratios (aHRs) of 0.66 (95% confidence interval [CI]:0.40, 1.08; P = 0.0971), 0.69 (95% CI: 0.42, 1.14; P = 0.1488) and 0.66 (95% CI: 0.38, 1.14; P = 0.1407) under stepwise selection, propensity score adjustment, and propensity score matching multivariable models, respectively.. For treatment-naïve patients with CHB-related compensated cirrhosis with 5-year follow-up, after variable adjustments, propensity score approaches and subgroup analyses, TDF showed a lower rate of HCC development that did not reach statistical significance, compared to the ETV.

Topics: Adult; Aged; alpha-Fetoproteins; Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Female; Guanine; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Longitudinal Studies; Male; Middle Aged; Retrospective Studies; Taiwan; Tenofovir

To evaluate virological breakthrough (VBT) and the risk of hepatocellular carcinoma (HCC) in HBeAg-positive chronic hepatitis B (CHB) patients receiving entecavir (ETV) treatment.. A retrospective cohort study was conducted in a tertiary referral hospital and a total of 228 HBeAg-positive CHB patients treated with ETV for more than 48 weeks were enrolled. Clinical outcome measures included HBeAg seroclearance, maintained virological response and the development of HCC.. During a median follow-up period of 197 weeks, VBT developed in 26 (11.4%) patients (VBT group), and the other 202 patients without VBT (non-VBT group). The overall cumulative rate of HBeAg seroclearance in the VBT group and non-VBT group were 23.1% and 23.8%, 27.1% and 37.9%, 27.1% and 55.1%, 27.1% and 74.1%, 27.1% and 76.7% from week 48 to 240, respectively(p = 0.013). The cumulative probability of maintained virological responses from week 48 to 240 were 7.69% and 21.78%, 7.69% in the VBT groups and 36.85%, 7.69% and 51.68%, 7.69% and 64.97%, 7.69% and 72.1% in the non-VBT groups, respectively (p<0.001). In the multivariate analysis, age (p<0.001) and virological response at week 24 (p = 0.005) were independently associated with VBT. Cox regression analysis showed that cirrhosis had carried the highest risk for HCC (HR = 4.99, CI = 1.14-21.81, p = 0.033). Subgroup survival analysis by Kaplan-Meier method showed that patients with VBT had higher incidence of developing HCC than without VBT in cirrhotic patients (50% (95%CI = 1-99%) vs 9% (95% CI = 1-9%); p = 0.048).. VBT was associated with adverse clinical outcomes, including a low probability of HBeAg seroclearance, failure to achieve maintained virological responses, and a risk of developing HCC. Patients, particularly with cirrhosis, who had experienced VBT during ETV treatment, more likely developed HCC.

Topics: Adult; Antiviral Agents; Biomarkers; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Function Tests; Male; Middle Aged; Prognosis; Retrospective Studies; Treatment Outcome; Viral Load

Noninvasive fibrosis indices can predict the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Modified FIB-4 (mFIB-4) is a promising noninvasive index for predicting liver fibrosis. To investigate the predictive accuracy of several extant noninvasive fibrosis indices, including mFIB-4, for HCC incidence in CHB patients receiving long-term entecavir therapy.. We enrolled 1325 nucleos(t)ide analogue-naïve CHB patients (noncirrhotic 844; cirrhotic 481) treated with entecavir. Baseline clinical features and fibrosis indices were collected and evaluated for predicting HCC risk through univariate and multivariate Cox regression analyses.. Of the 1325 patients, 105 (7.9%) developed HCC during a median follow-up period of 4.1 years. Age (hazard ratio [HR], 1.039; 95% confidence interval [CI], 1.020-1.059; P < 0.0001), diabetes mellitus (DM) (HR, 1.902; 95% CI, 1.185-3.052; P = 0.0077), and mFIB-4 (HR, 4.619; 95% CI, 1.810-11.789; P = 0.0014) were independent predictors of HCC in all patients (mFIB-4 ≥ 1.5 for the noncirrhotic cohort; DM and mFIB-4 ≥ 2.0 for the cirrhotic cohort). A combination of mFIB-4 and the DM status stratified the cumulative risk of HCC into three subgroups in all patients (high: mFIB-4 ≥ 1.5/DM; intermediate: mFIB-4 ≥ 1.5/non-DM; and low: mFIB-4 < 1.5, P < 0.0001) and in the cirrhotic cohort (high: mFIB-4 ≥ 2.0/DM; intermediate: mFIB-4 ≥ 2.0/non-DM; and low: mFIB-4 < 2.0, P = 0.0007). An mFIB-4 cutoff value of 1.5 stratified the cumulative risk of HCC in the noncirrhotic cohort (P = 0.015).. The mFIB-4 index alone or in combination with DM is the optimal noninvasive predictor of HCC risk in CHB patients receiving entecavir therapy.

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Diabetes Mellitus; Female; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Predictive Value of Tests; Retrospective Studies; Risk Assessment; Risk Factors; Taiwan; Time Factors; Treatment Outcome

We determined the antiviral potency and viral breakthrough rate after 10 years of continuous entecavir treatment in patients with chronic hepatitis B (CHB) infection.. The cumulative rates of undetectable hepatitis B virus DNA (HBV-DNA, < 2.1 log copies/mL), alanine aminotransferase (ALT) normalization, hepatitis B e antigen (HBeAg) seroclearance, hepatitis B surface antigen (HBsAg) seroclearance, and viral breakthrough of 1094 nucleos(t)ide analogue-naïve CHB patients (HBeAg-positive: 47%) who were on continuous entecavir treatment for 10 years were calculated.. The median age was 50 years and follow-up period was 5.5 years, with 999, 804, 591, 390, 182 and 87 patients followed up for at least 1, 3, 5, 7, 9 and 10 years, respectively. Incremental increases were noted in the rates of undetectable HBV-DNA, ALT normalization, HBeAg seroclearance, and HBsAg seroclearance, reaching 96, 79, 38 and 3.7%, respectively, by the tenth year. The mean decline in HBsAg level from baseline was - 0.08 log IU/mL/year. Multivariate analysis identified HBsAg level and genotype (A) as independent predictors of HBsAg seroclearance. Sixteen patients experienced viral breakthrough. The cumulative percentages of patients with viral breakthrough analyzed by the Kaplan-Meier test were 1.5 and 2.5% at years 5 and 10, respectively. There were no serious adverse events during treatment.. Long-term entecavir treatment of nucleos(t)ide analogue-naïve CHB patients was associated with an excellent viral response and a low rate of entecavir-resistant mutations at 10 years. Baseline HBsAg levels and genotype were predictors of HBsAg seroclearance during entecavir treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alanine Transaminase; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Drug Resistance, Viral; Female; Follow-Up Studies; Genotype; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Japan; Liver Neoplasms; Male; Middle Aged; Survival Rate; Time Factors; Treatment Outcome; Young Adult

It remains unclear whether there is an association between single-nucleotide polymorphisms (SNPs) and development of hepatocellular carcinoma (HCC) during entecavir (ETV) treatment in nucleos(t)ide analog-naïve patients with chronic hepatitis B virus infection. We investigated the risk factors for HCC, especially host factors, during ETV treatment.. A total of 127 Japanese patients undergoing ETV treatment were enrolled in this study. Univariate and multivariate analyses for clinical factors, hepatic fibrosis markers, and SNPs associated with HCC development were analyzed.. Our findings suggested that patients with AA genotype in the HLA-DQA1/DRB1 gene or cirrhosis should be carefully followed up as a population potentially at higher risk of HCC during ETV treatment.

Topics: Adult; Aged; Carcinoma, Hepatocellular; Female; Fibrosis; Genome-Wide Association Study; Genotype; Guanine; Hepatitis B, Chronic; HLA-DQ alpha-Chains; HLA-DRB1 Chains; Humans; Liver; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Polymorphism, Single Nucleotide; Risk Factors; Young Adult

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Republic of Korea; Tenofovir

Entecavir and tenofovir disoproxil fumarate have comparable efficacy in achieving surrogate end points, including virologic response, and are equally recommended as first-line treatments for patients with chronic hepatitis B (CHB). However, it is unclear whether treatment with these drugs is associated with equivalent clinical outcomes, especially development of hepatocellular carcinoma (HCC).. To compare entecavir and tenofovir in terms of the risk of HCC and death or liver transplant in patients with CHB infection.. A nationwide historical population cohort study involving treatment-naive adult patients with CHB who started treatment with entecavir (n = 11 464) or tenofovir disoproxil fumarate (n = 12 692) between January 1, 2012, and December 31, 2014, using data from the Korean National Health Insurance Service database. As validation, a hospital cohort of patients with CHB treated with entecavir (n = 1560) or tenofovir (n = 1141) in a tertiary referral center between January 1, 2010, and December 31, 2016, were analyzed. Nationwide cohort data were retrieved from January 1, 2010, to December 31, 2016, and hospital cohort data from January 1, 2010, to October 31, 2017.. Cumulative incidence rates of HCC and death and transplant rates.. Among the population cohort of 24 156, the mean (SD) age was 48.9 (9.8) years, and 15 120 patients (62.6%) were male. Among the hospital cohort of 2701, the mean (SD) age was 48.8 (10.5) years and 1657 patients (61.3%) were male. In the population cohort, the annual incidence rate of HCC was significantly lower in the tenofovir group (0.64 per 100 person-years [PY]) than in the entecavir group (1.06 per 100 PY). By multivariable-adjusted analysis, tenofovir therapy was associated with a significantly lower risk of HCC (hazard ratio [HR], 0.61; 95% CI, 0.54-0.70) and all-cause mortality or transplant (HR, 0.77; 95% CI, 0.65-0.92) compared with entecavir. The tenofovir group also showed a significantly lower risk of HCC in the 10 923-pair propensity score-matched population cohort (HR, 0.62; 95% CI, 0.54-0.70) and 869-pair propensity score-matched hospital cohort (HR, 0.68; 95% CI, 0.46-0.99) compared with the entecavir group.. This study suggests that tenofovir treatment was associated with a significantly lower risk of HCC compared with entecavir treatment in a population-based cohort of adults with CHB; these findings were validated in a hospital cohort. Given the poor prognosis of patients with HCC, these findings may have considerable clinical implications in prevention of this cancer in patients with CHB infection.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Cause of Death; Databases, Factual; Female; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Protective Factors; Republic of Korea; Risk Factors; Tenofovir; Time Factors; Treatment Outcome

In treated patients with chronic hepatitis B (CHB) who have achieved complete viral suppression, it is unclear if functional cure as indicated by hepatitis B surface antigen (HBsAg) seroclearance confers additional clinical benefit. We compared the risk of hepatocellular carcinoma (HCC) and hepatic events in nucleos(t)ide analogue (NA)-treated patients with and without HBsAg seroclearance.. We performed a territory-wide retrospective cohort study on all patients with CHB who had received entecavir and/or tenofovir disoproxil fumarate (TDF) for at least 6 months between 2005 and 2016 from Hospital Authority, Hong Kong. Patients' demographics, comorbidities, and laboratory parameters were analyzed. The primary outcome was HCC. The secondary outcomes were hepatic events including cirrhotic complications, liver transplantation, and liver-related mortality.. A total of 20,263 entecavir/TDF-treated patients with CHB were identified; 17,499 (86.4%) patients had complete viral suppression; 376 (2.1%) achieved HBsAg seroclearance. At a median (interquartile range) follow-up of 4.8 (2.8-7.0) years, 603 (3.5%) and 121 (4.4%) patients with and without complete viral suppression developed HCC; 2 (0.5%) patients with HBsAg seroclearance developed HCC. Compared to complete viral suppression, lack of complete viral suppression was associated with a higher risk of HCC (7.8% vs. 5.6% at 8 years, Gray's test, p <0.001) (adjusted hazard ratio [aHR] 1.69; 95% CI 1.36-2.09; p <0.001); patients who achieved functional cure had a lower risk of HCC (0.6% vs. 5.6% at 8 years, Gray's test, p <0.001) (aHR 0.24; 95% CI 0.06-0.97; p = 0.045) but not hepatic events (aHR 0.99; 95% CI 0.30-3.26; p = 0.991).. Patients who achieved HBsAg seroclearance on top of complete viral suppression with entecavir/TDF treatment may have a lower risk of HCC but not hepatic events.. We investigated 20,263 nucleos(t)ide analogue (NA)-treated patients with chronic hepatitis B. Patients with NA-induced hepatitis B surface antigen seroclearance on top of complete viral suppression have a lower risk of hepatocellular carcinoma but not hepatic events than those only achieving complete viral suppression under prolonged NA treatment.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Female; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hong Kong; Humans; Liver Neoplasms; Male; Middle Aged; Outcome and Process Assessment, Health Care; Retrospective Studies; Risk Assessment; Seroepidemiologic Studies; Sustained Virologic Response; Tenofovir

The experts of Taiwan Association for the Study of Liver (TASL) have actively participated and led the guidelines on hepatitis B virus (HBV) management by Asian Pacific Association for the Study of Liver (APASL) which is the first international association for the study of liver to publish the statement on HBV management before. However, there are more and more new data on the natural history and treatment of HBV infection in the past decade. These include new application of an old biomarker (quantitative HBsAg), clinical significance of HBV genotype and naturally occurring mutations, the role of non-invasive examination in evaluating severity of hepatic fibrosis, clinical significance of outcome calculators, new drug or new combination strategies towards more effective therapy and organ transplantation including liver and non-liver transplantation. It is time to publish the guidelines on HBV management of Taiwan. Hence, TASL have conducted an expert meeting to review, to discuss and to debate the relevant literatures, followed by draft the manuscript of HBV management guidelines and recommendations. The guidelines include general management, indications for fibrosis assessment, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patient receiving immune suppression or chemotherapy and patients in the setting of liver transplantation and hepatocellular carcinoma, are also included.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Consensus; Disease Management; Disease Progression; Female; Guanine; Hepatitis B Surface Antigens; Hepatitis B Vaccines; Hepatitis B virus; Hepatitis B, Chronic; HIV Infections; Humans; Immunization Programs; Interferon-alpha; Liver Cirrhosis; Liver Neoplasms; Male; Pregnancy; Societies, Medical; Taiwan; Viral Load

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B; Hepatitis B virus; Humans; Liver Neoplasms; Male; Middle Aged; Mutation; Trans-Activators; Viral Regulatory and Accessory Proteins

Nucleos(t)ide analogs are used for preventing liver cirrhosis in chronic hepatitis B patients, but the risk factors of hepatocellular carcinoma (HCC) in these patients remain unclear. We designed this retrospective cohort study, the aim is to determine the risk factors for HCC development and its image presentation under nucleos(t)ide analogs treatment.In this study, patients were treated with lamivudine (LAM), entecavir 0.5 mg (ETV), or telbivudine (LdT), and followed-up for at least 2 years to detect HCC and its presentation. Assessment of the risk factors for HCC included age, sex, HBeAg, viral load, liver cirrhosis, current and previous medications, and liver function tests.Totally, 396 patients were recruited, and 18 patients developed HCC. The mean time from the treatment to HCC development was 28.5 ± 16.7 months. The clinical characteristics in HCC and no-HCC groups showed significant differences among age (52.8 ± 6.1 vs 47.1 ± 12.6 years, P <.01), baseline alanine transaminase (ALT) levels (161.4 ± 177.3 vs 361.7 ± 496.3, P <.01), and baseline liver cirrhosis (72.2% vs 29.9%, P <.01). In patients aged ≥45 years, the hazard ratio of HCC was 10.2 and liver cirrhosis was 4.1. Majority of HCCs developed in the right liver (14/18), were single numbered (13/18), had tumor size about 1.9 ± 0.7 cm, were classified as T1 (14/18, TNM staging), and the atypical image occupied 88% of the HCC cases.The patients aged ≧45 years on long-term nucleos(t)ide analog therapy, and with baseline liver cirrhosis were at a high risk of HCC. Regular alpha-fetoprotein (AFP) assessment and image study of these patients are the gold standards for early HCC detection in patients with high percentage atypical HCC appearances.

Topics: Adult; alpha-Fetoproteins; Antiviral Agents; Carcinoma, Hepatocellular; Early Detection of Cancer; Female; Follow-Up Studies; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Nucleosides; Retrospective Studies; Risk Factors; Telbivudine

We compared rates of hepatitis B surface antigen (HBsAg) loss and hepatocellular carcinoma (HCC) development in hepatitis B e antigen (HBeAg)-negative patients without cirrhosis who continued or discontinued entecavir.. Patients who discontinued entecavir treatment for at least 12 months (discontinued group; n = 234) and patients who continued entecavir treatment for at least 4 years (continued group; n = 226) were recruited.. In the discontinued group, the 5-year cumulative incidences of virological relapse (VR), clinical relapse (CR), and HBsAg loss were 71.9%, 58.9%, and 13%, respectively. Patients with sustained response, VR but no CR, and CR without retreatment were 49-, 13-, and 18-fold more likely to develop HBsAg loss than those with retreatment. Patients who discontinued entecavir therapy had a higher rate of HBsAg loss than those who continued entecavir therapy, in all and 360 propensity score (PS)-matched patients. Cox regression analysis revealed that the discontinued group was an independent predictor for HBsAg loss. There was no significant difference in HCC development between the 2 groups in all and PS-matched patients.. HBeAg-negative patients without cirrhosis who discontinued entecavir treatment exhibited a higher HBsAg loss rate without an increased risk of HCC compared to those who continued entecavir treatment.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Recurrence; Taiwan; Treatment Outcome

Accurate assessment of hepatocellular carcinoma (HCC) risk in chronic hepatitis B (CHB) patients receiving entecavir (ETV)/tenofovir disoproxil fumarate (TDF) is likely to play a pivotal role in post-treatment follow-up strategy. We aimed to develop a simple and reliable predictive model for HCC risk in these patients.. A database of 1242 consecutive treatment-naive CHB patients who initially underwent ETV/TDF between February 2007 and January 2017 at four referral hospitals in South Korea was analyzed. The HCC risk model was constructed on the basis of a multivariable Cox proportional hazards model in the derivation dataset (n=944) and was validated using Harrell's C-statistic in a validation dataset (n=298).. The 3/5-year cumulative incidence rates of HCC were 3.9/6.5 and 4.2/11.6% in the derivation and the validation dataset, respectively (P=0.08). In the derivation dataset, we identified four factors associated with HCC, namely, age, albumin, sex, and liver cirrhosis. The AASL (age, albumin, sex, liver cirrhosis)-HCC scoring system was developed on the basis of these factors, and simplified to an integer scoring system. AASL-HCC scores were found to have high discriminating performance for the prediction of HCC development at 5 years in the derivation (C-statistics=0.802, 95% confidence interval: 0.716-0.888) and validation dataset (C-statistics=0.805, 95% confidence interval: 0.671-0.939). When AASL-HCC scores were classified as 5 or less, 6-19, and at least 20 (low-risk, intermediate-risk, and high-risk groups, respectively), the 5-year cumulative incidence rates of HCC were 0, 4.2, and 17.6%, respectively, in the derivation dataset.. The AASL-HCC model was simple and reliable for HCC risk prediction in treatment-naive CHB patients receiving ETV/TDF, and is easily applicable in the clinical setting.

Topics: Adult; Age Factors; Antiviral Agents; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Guanine; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Proportional Hazards Models; Reproducibility of Results; Risk Assessment; Serum Albumin; Sex Factors; Tenofovir

Hepatocellular carcinoma (HCC) can still develop in chronic hepatitis B (CHB) patients receiving antiviral treatment. Serum Mac-2-binding protein glycosylation isomer (M2BPGi) is a novel marker for liver fibrosis. We investigated its role on incidence of HCC in entecavir (ETV)-treated CHB patients.. We identified HCC cases diagnosed at ≥ 1 year of ETV treatment. CHB patients without HCC (matched for age, gender, baseline hepatitis B virus-DNA, and duration of ETV treatment) were identified in approximately 1:2 ratio (HCC: non-HCC) for comparison. Serum samples were retrieved at baseline (initiation of ETV), 3, and 5 years of ETV for serum M2BPGi measurement (expressed in cut-off index [COI]).. One hundred HCC cases were matched with 185 CHB patients without HCC (median age 56.7 years, 78.9% male, baseline hepatitis B virus-DNA 5.6 logIU/mL, and median follow-up 7.1 years). Median time from ETV initiation to incident HCC was 3.9 years. Serum M2BPGi levels were significantly higher in HCC cases compared with controls at baseline and year 3 (1.25 vs 0.98 [P = 0.004], 0.89 vs 0.74 [P = 0.018] COI, respectively). Multivariate analysis showed that baseline M2BPGi was the only independent factor associated with incident HCC (odds ratio 1.241, 95% confidence interval 1.039-1.482, P = 0.017). Using a cut-off value of 1.15 COI, the sensitivity, specificity, positive predictive value, and negative predictive value of baseline serum M2BPGi in cirrhotic patients to predict incident HCC were 90%, 53.8%, 69.6%, and 82.1%, respectively.. Baseline and 3-year serum M2BPGi may be useful to identify high risk patients on antiviral treatment for subsequent HCC development.

Topics: Antigens, Neoplasm; Antiviral Agents; Biomarkers; Biomarkers, Tumor; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B, Chronic; Hong Kong; Humans; Incidence; Liver Neoplasms; Male; Membrane Glycoproteins; Middle Aged; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Suppression of hepatitis B virus (HBV) replication with nucelos(t)ide analogues should be considered for patients with chronic hepatitis D virus (HDV) infection and ongoing HBV replication.. To verify the clinical outcome after long-term entecavir or tenofovir treatment in patients with advanced fibrosis/cirrhosis, ineligible to peg-interferon therapy.. Patients were prospectively followed-up at 3-6 month intervals; measured outcomes were decompensation, hepatocellular carcinoma (HCC), liver transplant and liver related death. HBV monoinfected patients receiving the same treatment served as reference after 1:1 matching by age, gender, platelet count, albumin level, bilirubin and INR.. 56 HDV patients (48 with cirrhosis; median follow-up 50 months) were enrolled; all achieved HBV DNA suppression. Death or liver transplant occurred in 19 patients, with a rate (n/1000 patient-months) of 2.92 in HDV patients vs 0.38 in HBV monoinfected patients (P < 0.001); similarly, decompensation occurred at a rate of 1.53 vs 0.13 (P = 0.015), respectively, and the rate of HCC was almost thrice in HDV cohort (3.12 vs 1.12; P = 0.02) Platelet count, Child-Pugh score and marginally HDV infection were associated with HCC development.. Patients with HDV infection and advanced liver disease maintain an increased risk of severe clinical events as compared with HBV monoinfected patients, during prolonged HBV DNA suppression with potent NA.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Female; Follow-Up Studies; Guanine; Hepatitis B; Hepatitis B virus; Hepatitis D, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Prospective Studies; Tenofovir; Treatment Outcome

To compare the reduction of hepatocellular carcinoma (HCC) risk between long-term treatment of entecavir and low genetic barrier antiviral agents in hepatitis B virus (HBV)-related cirrhotic patients.. An observational study.. Department of Infectious Diseases and Hepatology, the Second Hospital of Shandong University, Jinan, China, from October 2008 to October 2016.. HBV-related cirrhotic patients with antiviral treatment for at least 12 months were consecutively included. Propensity score matching analysis was performed to improve comparability of the data from both entecavir group and the control group. Log-rank test was used to compare influence of various nucleos(t)ide analogs (NAs) for incidence of HCC. Independent risk factors were estimated by multivariable Cox proportional hazards models.. The total cohort included 207 HBV-related cirrhotic patients, of which 83 patients were treated with entecavir initially. The present study found no statistical difference for the incidence of HCC between entecavir group and the control group in the total cohort (p=0.525). However, the difference became statistically significant (p=0.014) after propensity score matching. Number needed to treat (NNT) were 8 patients, 6 patients and 3 patients at years 2, 3 and 4, respectively. Multivariable Cox regression in propensity score matching cohort revealed older age (HR: 1.066, p=0.041), NAs of low generic barrier (HR: 6.944, p=0.016), NAs resistance (HR: 3.648, p=0.041), and lower platelet counts (<80x10 ⁹/L) (HR: 6.718, p=0.009) as independent risk factors for HCC incidence.. Entecavir is more efficient in reducing the incident HCC risk for HBV-related cirrhotic patients in comparison to low genetic barrier NAs.

Topics: Adenine; Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; China; Female; Guanine; Hepatitis B; Hepatitis B virus; Humans; Incidence; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Organophosphonates; Retrospective Studies; Risk Factors; Telbivudine

It is currently unclear which antiviral agent, entecavir (ETV) or tenofovir disoproxil fumarate (TDF), is superior for improving prognosis in patients with chronic hepatitis B (CHB). Here, we assessed the ability of these 2 antivirals to prevent liver-disease progression in treatment-naïve patients with CHB.. From 2012 to 2014, treatment-naïve patients with CHB who received ETV or TDF as a first-line antiviral agent were recruited from 4 academic teaching hospitals. Patients with decompensated cirrhosis or hepatocellular carcinoma (HCC) at enrollment were excluded. Cumulative probabilities of HCC and death or orthotopic liver transplant (OLT) were assessed.. In total, 2,897 patients (1,484 and 1,413 in the ETV and TDF groups, respectively) were recruited. The annual HCC incidence was not statistically different between the ETV and TDF groups (1.92 vs. 1.69 per 100 person-years [PY], respectively; adjusted hazard ratio [HR] 0.975 [p = 0.852] by multivariate analysis). Propensity score (PS)-matched and inverse probability of treatment weighting (ITPW) analyses yielded similar patterns of results (HR 1.021 [p = 0.884] and 0.998 [p = 0.988], respectively). The annual incidence of death or OLT was not statistically different between the ETV and TDF groups (0.52 vs. 0.53 per 100 PY, respectively; adjusted HR 1.202 [p = 0.451]). PS-matched and ITPW analyses yielded similar patterns of results (HR 1.248 [p = 0.385] and 1.239 [p = 0.360], respectively). These findings were consistently reproduced in patients with compensated cirrhosis (all p >0.05).. The overall prognosis in terms of HCC and death or OLT was not statistically different between the ETV and TDF groups. Further studies are needed to validate our results.. It is currently unclear which antiviral agent, entecavir or tenofovir disoproxil fumarate, is superior for improving prognosis in patients with chronic hepatitis B virus infection. In this analysis we found that there was no difference in terms of overall prognosis, including risk of hepatocellular carcinoma, death, or the need for a liver transplant, in patients receiving either antiviral.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Disease Progression; Female; Genotype; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Prognosis; Propensity Score; Republic of Korea; Retrospective Studies; Tenofovir; Treatment Outcome

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Republic of Korea; Tenofovir

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Republic of Korea; Tenofovir

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Republic of Korea; Tenofovir

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Republic of Korea; Tenofovir

Even during nucleos(t)ide analogue therapy, development of hepatocellular carcinoma (HCC) has been observed in patients with chronic hepatitis B virus (HBV) infection. We simulated the long-term prognosis of liver disease in patients with chronic HBV who received nucleos(t)ide analogue therapy.. A total of 254 patients with chronic HBV receiving nucleos(t)ide analogue therapy were enrolled. Yearly transition probabilities between liver disease states [chronic hepatitis, cirrhosis, HCC, and hepatitis B surface antigen (HBsAg)-negative status] were calculated using a Markov chain model.. In the analysis of 1-year liver disease state transition probabilities, the development of HCC occurred in men with chronic hepatitis in their 50s (1.8%) and at least 70 years (2.8%) and in patients with cirrhosis in all age groups (40-49, 50-59, 60-69, and ≥ 70 years). HBsAg-negative status was present in patients with chronic hepatitis in their 50s (1.8%) and 60s (2.6%), and in patients with cirrhosis in their 60s (0.6%). In female patients, the development of HCC occurred in patients with cirrhosis during their 50s (0.8%), 60s (0.8%), and older (4.5%). HBsAg-negative status was simulated in patients with cirrhosis in their 50s (0.8%) and 60s (0.8%). Assuming a chronic hepatitis state at age 40 as the starting condition for simulation over the next 40 years, the probability of developing HCC increased gradually with age in male patients and in female patients after the age of 70 years.. There is a risk of development of HCC in middle-aged men with chronic hepatitis or cirrhosis and older women with cirrhosis even while receiving nucleos(t)ide analogue therapy.

Topics: Adenine; Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Male; Markov Chains; Middle Aged; Nucleosides; Organophosphonates; Prognosis

Topics: Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Prognosis; Republic of Korea; Tenofovir

In Caucasian patients with compensated cirrhosis caused by hepatitis B virus (HBV), the risk of hepatocellular carcinoma (HCC) developing persist despite long-term nucleos(t)ide analogs (NUC) treatment. In the surveillance of this population with persistently normal transaminases because of NUCs, the added value of serum alpha-foetoprotein (AFP) monitoring is poorly defined.. Two hundred and fifty-eight Caucasian HCC-free patients with HBV-compensated cirrhosis who started tenofovir or entecavir while having normal serum AFP levels (≤7 ng/mL) at baseline or within the first year of treatment underwent HCC surveillance by semiannual ultrasound evaluation and serum AFP determination.. During 96 (18-120) months of antiviral therapy, 3947 AFP values were collected, median AFP level was 2 ng/mL. Thirty-five patients developed an HCC at an overall 8-year crude cumulative incidence of 14% (annual incidence of 2%). HCC incidence increased in parallel with increasing AFP thresholds: 24%, 36%, 64% and 92% for AFP levels after exceeding 2, 4, 6 and 7 ng/mL for the first-time. Of the 12 patients who experienced an AFP rise > 7 ng/mL, 11 developed an HCC and one had liver metastases of lung cancer. Overall, an AFP > 7 ng/mL had 99.6% specificity, 31.4% sensitivity, 91.7% PPV, 90.2% NPV, LR+ 70.1 and LR- 0.69 for HCC; this excellent specificity was maintained up to 18 months before HCC detection.. In Caucasian patients with HBV-compensated cirrhosis on long-term NUC, an increase in AFP over 7 ng/mL shows excellent specificity, heralding HCC development within 1 year.

Topics: Adult; Aged; Aged, 80 and over; alpha-Fetoproteins; Antiviral Agents; Biomarkers; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B, Chronic; Humans; Italy; Liver Cirrhosis; Liver Neoplasms; Longitudinal Studies; Male; Middle Aged; Tenofovir; Young Adult

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Prognosis; Republic of Korea; Tenofovir

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Prognosis; Republic of Korea; Tenofovir

It is unclear whether liver stiffness measurement (LSM) dynamic changes after anti-HBV treatment could predict the risk of liver-related events (LREs), particularly in patients with HBV-related compensated cirrhosis.. Treatment-naïve patients with HBV-related compensated cirrhosis were enrolled. All patients were under entecavir-based antiviral therapy, and followed up every 26 weeks for 2 years. The association between LSM and LREs was analysed by Cox proportional hazard model and Harrell C-index analysis.. A total of 438 patients were included in the study. At the follow-up of 104 weeks, LREs developed in 33/438 (7.8%) patients, including 16 episodes of decompensation, 18 HCC and 3 deaths. The median LSM remained high from 20.9, 18.6, 20.4 to 20.3 Kpa at week 0, 26, 52 and 78 among patients with LREs, whereas the LSM decreased from 17.8, 12.3, 10.6 to 10.2 Kpa in patients without LREs respectively. Percentage changes of LSM at 26 weeks from baseline were significantly associated with LREs (excluding 11 cases occurred within the first 26 weeks), with a crude hazard ratio of 2.94 (95% CI: 1.73-5.00) and an albumin-adjusted hazard ratio of 2.47 (95% CI: 1.49-4.11). The Harrell C-index of these 2 models for predicting 2-year LREs were 0.68 (95% CI: 0.56-0.80) and 0.75 (95% CI: 0.65-0.85) respectively. Nomograms were developed to identify individuals at high risk for point-of-care application.. Dynamic changes of LSM alone, or combined with baseline albumin, could predict LREs in patients with HBV-related compensated cirrhosis during antiviral therapy.

Topics: Adult; Aged; Albumins; Antiviral Agents; Carcinoma, Hepatocellular; China; Elasticity Imaging Techniques; Female; Guanine; Hepatitis B; Humans; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Nomograms; Proportional Hazards Models; Randomized Controlled Trials as Topic; Treatment Outcome; Young Adult

This study aimed to elucidate the temporal change and determinants for the risk of HCC in patients with chronic hepatitis B continuously receiving NUC. Through analysis of the national healthcare database in Taiwan, we screened a total of 65 426 infected patients receiving entecavir or tenofovir for at least 3 months and excluded those with lamivudine, adefovir or telbivudine exposure, malignancy, end-stage renal failure or a diagnosis of HCC within 3 months of starting treatment. Eligible patients (N = 27 820) were followed until HCC occurrence, completion of the allowed 3-year regimen or 31 December 2013. During a median follow-up of 25.1 (12.1-35.6) months, 802 patients developed HCC, with 1-, 2- and 3-year cumulative incidence of 1.82% (95% CI, 1.66-1.99%), 3.05% (95% CI, 2.82-3.28%) and 4.06% (95% CI, 3.77-4.36%), respectively. HCC annual incidence decreased with an adjusted IRR of 0.73 (95% CI, 0.66-0.80) per yearly interval and was associated with cirrhosis (IRR, 10.07; 95% CI, 6.00-16.90 in age <40 years; 4.69; 95% CI, 3.94-5.59 in age ≧40 years), age (IRR, 3.38; 95% CI, 2.10-5.47 for 40-50 years; 6.92; 95% CI, 4.27-11.21 for 50-60 years; 12.50; 95% CI, 7.71-20.25 for ≧60 years; <40 years as reference), male sex (IRR, 1.71; 95% CI, 1.44-2.04), HCV coinfection (IRR, 1.27; 95% CI, 1.02-1.58) and diabetes (IRR, 1.24; 95% CI, 1.05-1.45). In conclusion, the risk of HCC in patients with chronic hepatitis B receiving entecavir or tenofovir declines over time and is determined by cirrhosis, age, male sex, HCV coinfection and diabetes.

Topics: Adult; Age Factors; Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Comorbidity; Female; Follow-Up Studies; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Risk Assessment; Sex Factors; Taiwan; Tenofovir

Nucleot(s)ide analogues (NA) can reduce the risk of hepatocellular carcinoma (HCC), but not completely prevent its development.. Two hundred and thirty-four chronic hepatitis B patients virologically well controlled with entecavir or tenofovir disoproxil fumarate for more than 1 year were enrolled in this study. Over the median observation period of 51 (12-142) months, 24 of 234 patients developed HCC. We quantified HBV markers, alpha-fetoprotein (AFP) and Mac-2-binding protein glycosylation isomer (M2BPGi) at baseline and 48 weeks after therapy.. Serum AFP and M2BPGi tended to decline from baseline to 48 weeks after treatment both in patients who did and those who did not develop HCC. Univariate Cox regression analysis indicated that serum M2BPGi levels ≥ 1.215 COI at 48 weeks were associated with HCC development [hazard ratio (HR) 5.73; p ≤ 0.001]. Multivariate analysis showed that male sex (HR 5.6; p = 0.01), AFP ≥ 9.65 ng/ml (HR 22.01; p ≤ 0.001), M2BPGi ≥ 1.215 (HR 5.07; p = 0.004) at 48 weeks were significant independent predictive factors for HCC development. Based on a scoring system consisting of three factors above described, Kaplan-Meier analysis for four groups (score 0, 1, 2, ≥ 3), revealed significant differences in cumulative HCC occurrence for each group within 2 years. The rate of incidence of HCC was 0, 5.4, 23.4, and 75% in each group, respectively.. In patients receiving NA therapy, higher M2BPGi at 48 weeks, as well as male sex and higher AFP at 48 weeks were independent risk factors for HCC development.

Topics: Adult; alpha-Fetoproteins; Antigens, Neoplasm; Antiviral Agents; Biomarkers, Tumor; Carcinoma, Hepatocellular; Carrier Proteins; Female; Follow-Up Studies; Glycoproteins; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Incidence; Japan; Kaplan-Meier Estimate; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Research Design; Retrospective Studies; Sex Factors; Tenofovir

Nucleos(t)ide analogues (NAs) have been shown to decrease the risk of hepatocellular carcinoma (HCC) recurrence. This study evaluated whether high-potency NAs (entecavir and tenofovir disoproxil fumarate [TDF]) reduce the risk of tumour recurrence more potently than low-potency NAs after curative treatment of hepatitis B virus (HBV)-related HCC. This study included 607 consecutive HBV-related HCC patients treated with surgical resection or radiofrequency ablation. The patients were categorized into three groups according to antiviral treatment: group A (no antiviral; n = 261), group B (low-potency NA; n = 90) and group C (high-potency NA; n = 256). The primary end-point was recurrence-free survival (RFS). During the duration of follow-up, the median RFS was 29.4, 25.1, and 88.2 months in groups A, B and C, respectively (P < .001, log-rank test). The multivariate Cox analysis indicated that group C had a significantly longer RFS than both group A (adjusted hazard ratio [HR] = 0.39, P < .001) and group B (adjusted HR = 0.47, P < .001). When baseline characteristics were balanced using inverse probability weighting, group C still had a significantly longer RFS than group A (adjusted HR = 0.46, P < .001) and group B (adjusted HR = 0.59, P = .007). Group C had significantly lower risk of viral breakthrough than group B (HR = 0.19, P < .001). Viral breakthrough was an independent risk factor for shorter RFS among groups B and C (adjusted HR = 2.03, P = .007, time-dependent Cox analysis). Antiviral agents with high genetic barrier to resistance (entecavir and TDF) reduced the risk of HCC recurrence compared with other antivirals and no antiviral treatment, especially in patients with high baseline viral load.

Topics: Aged; Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Female; Guanine; Hepatitis B, Chronic; Humans; Male; Middle Aged; Secondary Prevention; Tenofovir; Treatment Outcome

The effects of long-term antiviral therapy on survival have not been adequately assessed in chronic hepatitis B (CHB). In this 10-centre, ongoing cohort study, we evaluated the probability of survival and factors affecting survival in Caucasian CHB patients who received long-term entecavir/tenofovir therapy.. We included 1,951 adult Caucasians with CHB, with or without compensated cirrhosis and without hepatocellular carcinoma (HCC) at baseline, who received entecavir/tenofovir for ≥12 months (median, six years). Kaplan-Meier estimates of cumulative survival over time were obtained. Standardized mortality ratios (SMRs) were calculated by comparing death rates with those in the Human Mortality Database.. The one-, five-, and eight-year cumulative probabilities were 99.7, 95.9, and 94.1% for overall survival, 99.9, 98.3, and 97.4% for liver-related survival, and 99.9, 97.8, and 95.8% for transplantation-free liver-related survival, respectively. Overall mortality was independently associated with older age and HCC development, liver-related mortality was associated with HCC development only, and transplantation-free liver-related mortality was independently associated with HCC development and lower platelet levels at baseline. Baseline cirrhosis was not independently associated with any type of mortality. Compared with the general population, in all CHB patients mortality was not significantly different (SMR 0.82), whereas it was lower in patients without HCC regardless of baseline cirrhosis (SMR 0.58) and was higher in patients who developed HCC (SMR 3.09).. Caucasian patients with CHB and compensated liver disease who receive long-term entecavir/tenofovir therapy have excellent overall and liver-related eight-year survival, which is similar to that of the general population. HCC is the main factor affecting their overall mortality, and is the only factor affecting their liver-related mortality.. Caucasian patients with chronic hepatitis B with or without compensated cirrhosis who receive long-term entecavir or tenofovir therapy have excellent overall eight-year survival, which is similar to that of the general population. Hepatocellular carcinoma is the main factor affecting their overall mortality, and is the only factor affecting liver-related mortality in this setting.

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Female; Follow-Up Studies; Guanine; Hepatitis B, Chronic; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Male; Middle Aged; Tenofovir

Chronic hepatitis B virus (HBV) infection is currently a major public health burden. Therefore, there is an urgent need for the development of novel antiviral inhibitors. The stable HBV-producing cell lines of genotype D are widely used to investigate the HBV life cycle and to evaluate antiviral agents. However, stable HBV-producing cell lines of different genotypes do not exist. To construct more convenient and efficient novel cell systems, stable cell lines of genotypes A, B, and C were established using a full-length HBV genome sequence isolated from chronic HBV patients in human hepatoma HepG2 cells. Novel HBV clones were identified and stable HBV-producing cell lines derived from these clones were constructed. HBV replication activities demonstrated time-dependent expression, and the novel cell lines were susceptible to several antiviral inhibitors with no cytotoxicity. Furthermore, infectious viruses were produced from these cell lines. In conclusion, we have established novel stable HBV-producing cell line systems of genotypes A, B, and C. These systems can provide valuable tools for screening antiviral agents and analyzing viral phenotypes in vitro.

Topics: Adult; Antiviral Agents; Base Sequence; Carcinoma, Hepatocellular; Clone Cells; DNA, Viral; Drug Evaluation, Preclinical; Female; Gene Expression Regulation, Viral; Guanine; Hep G2 Cells; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Phylogeny; Virus Replication; Young Adult

The risk of hepatocellular carcinoma (HCC) during antiviral therapy in patients with chronic hepatitis B (CHB) is inadequately predicted by the scores built from untreated patients. We aimed at developing and validating a risk score to predict HCC in patients with CHB on entecavir or tenofovir treatment.. This study analysed population-wide data from the healthcare databases in Taiwan and Hong Kong to identify patients with CHB continuously receiving entecavir or tenofovir. The development cohort included 23,851 patients from Taiwan; 596 (2.50%) of them developed HCC with a three-year cumulative incidence of 3.56% (95% CI 3.26-3.86%). The multivariable Cox proportional hazards model found that cirrhosis, age (cirrhosis and age interacted with each other), male sex, and diabetes mellitus were the risk determinants. These variables were weighted to develop the cirrhosis, age, male sex, and diabetes mellitus (CAMD) score ranging from 0 to 19 points. The score was externally validated in 19,321 patients from Hong Kong.. The c indices for HCC in the development cohort were 0.83 (95% CI 0.81-0.84), 0.82 (95% CI 0.81-0.84), and 0.82 (95% CI 0.80-0.83) at the first, second, and third years of therapy, respectively. In the validation cohort, the c indices were 0.74 (95% CI 0.71-0.77), 0.75 (95% CI 0.73-0.78), and 0.75 (95% CI 0.72-0.77) during the first three years, and 0.76 (95% CI 0.74-0.78) and 0.76 (95% CI 0.74-0.77) in the extrapolated fourth and fifth years, respectively. The predicted and observed probabilities of HCC were calibrated in both cohorts. A score <8 and >13 points identified patients at distinctly low and high risks.. The easily calculable CAMD score can predict HCC and may inform surveillance policy in patients with CHB during oral antiviral therapy.. This study analyses population-wide data from the healthcare systems in Taiwan and Hong Kong to develop and validate a risk score that predicts hepatocellular carcinoma during oral antiviral therapy in patients with chronic hepatitis B. The easily calculable CAMD score requires only simple information (i.e. cirrhosis, age, male sex, and diabetes mellitus) at the baseline of treatment initiation. With a scoring range from 0 to 19 points, the CAMD score discriminates the risk of hepatocellular carcinoma with a concordance rate of around 75-80% during the first three years on therapy. The risk prediction can be extrapolated to five years on treatment with similar accuracy. Patients with a score <8 and >13 points were exposed to distinctly lower and higher risks, respectively.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Data Accuracy; Female; Guanine; Hepatitis B, Chronic; Hong Kong; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Research Design; Risk Assessment; Risk Factors; Taiwan; Tenofovir

This study investigates the long-term incidences and predictors of developing hepatocellular carcinoma (HCC), cirrhotic events and mortality in cirrhotic patients receiving entecavir (ETV) therapy.. We enrolled 481 nucleos(t)ide analogue-naïve chronic hepatitis B (CHB) patients who had compensated cirrhosis upon entry and had received ETV monotherapy for >12 months.. The 8-year cumulative incidences of developing HCC, cirrhotic events and liver-related mortality were 26.5%, 8.62% and 10.03% respectively. Multivariate analysis revealed that diabetic mellitus (DM), higher fibrosis-4 (FIB-4) and alpha-foetoprotein (AFP) levels at 12 months of treatment, and FIB-4 increase from baseline to 12 months were independent factors of HCC. FIB-4 and AFP levels at 12 months of treatment were also independent factors of cirrhotic events and mortality. FIB-4 cut-off values of 3, 3 and 5 as well as AFP cut-offs of 5, 5, and 9 ng/mL at 12 months of treatment were optimal for predicting HCC, cirrhotic events and mortality during therapy respectively. The FIB-4 and AFP levels at 12 months of treatment were assessed for the combined risk of developing clinical outcomes. The 8-year incidences of HCC, cirrhotic events and liver-related mortality in the subgroups with low FIB-4 and AFP levels were only 5.95%, 1.03% and 2.43% respectively. DM was an independent predictor of HCC and mortality.. The combination of FIB-4 and AFP levels at 12 months of treatment is a useful marker for predicting the development of HCC, cirrhotic events and mortality in compensated cirrhotic patients with CHB who are receiving ETV therapy.

Topics: Adult; Aged; Alanine Transaminase; alpha-Fetoproteins; Antiviral Agents; Aspartate Aminotransferases; Biomarkers; Carcinoma, Hepatocellular; China; Female; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Platelet Count; Proportional Hazards Models; Retrospective Studies; Taiwan

The aim of this study was to investigate the reactivation of the hepatitis B virus (HBV) following transarterial chemoembolization (TACE) in primary hepatocellular carcinoma (HCC) patients with HBV-DNA negative and to evaluate the effects of TACE combined with antiviral therapy.. This prospective study involved 98 patients with HBV-related and HBV-DNA negative HCC (HBV DNA < 10 copies/mL) underwent TACE procedures with serial HBV DNA tests. Patients were divided into the antiviral treatment group and the no-antiviral group. The antiviral group received entecavir antiviral therapy, and the other group received no antiviral therapy. Two groups of patients were compared in rate of HBV reactivation and liver function before and after only 1 session of TACE in average 1-month follow-up after operation. P < .05 indicated differences with a statistical significance.. HBV reactivation occurred in 11 patients in the nonantiviral group (11/47, 23.4%) but only 3 patients in the antiviral group (3/51, 5.9%, P < .05). On multivariate analysis, HBeAg-positive status, number of tumors more than 3, and absence of antiviral therapy were the independent risk predictor of HBV reactivation. Liver function indicators did not differ significantly between the antiviral group and the nonantiviral group in 5 days after TACE. However, the level of alanine aminotransferase and bilirubin were raised and albumin was reduced at the HBV reactivation group compared with no HBV reactivation group (P < .05). At 1 month after TACE, liver function indicators did not differ significantly between the HBV reactivation group and without HBV reactivation group.. HCC patients with HBV DNA negative still remain associated with risk of HBV reactivation after TACE. HBeAg-positive, number of tumors more than 3, and absence of antiviral therapy in HCC patients after TACE have a higher risk of HBV reactivation. Antiviral therapy can reduce the risk of reactivation, helping improve liver function after TACE.

Topics: Aged; Antiviral Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Combined Modality Therapy; DNA, Viral; Female; Guanine; Hepatitis B; Hepatitis B virus; Humans; Liver; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Risk Factors; Treatment Outcome; Virus Activation

Optimal adherence to nucleoside analogue treatment is necessary to achieve undetectable levels of hepatitis B virus (HBV) DNA in patients with chronic hepatitis B (CHB), and to prevent cirrhotic complications. However, any large long-term follow-up study has not been investigated the effect of adherence to entecavir (ETV) treatment on specific liver-related events (LREs), namely, hepatocellular carcinoma (HCC), cirrhotic complications, and mortality.. This was a 10-year longitudinal observational study of treatment-naïve patients with CHB who received ETV treatment. The primary outcome was the cumulative probability of LREs. The cumulative level of adherence to medication was categorized as good (≥90%) or poor (<90%).. Data from 894 treatment-naïve CHB patients who received ETV were analyzed. Overall mean adherence rates were 89.1%. Patients with poor adherence had a higher risk of virologic breakthrough (VBT) (HR, 22.42; 95% CI, 19.57-52.52; P < 0.001) than those with good adherence. Multivariate analyses showed a higher risk of liver-related (HR, 14.29; 95% CI, 3.49-58.47; P < 0.001) or all-cause (HR, 4.96; 95% CI, 2.19-11.27; P < 0.001) mortality, HCC (HR, 2.86; 95% CI, 1.76-4.64; P < 0.001), and cirrhotic complications (HR, 2.86; 95% CI, 1.93-4.25; P < 0.001) with poor adherence. Medication adherence was further stratified into three groups according to adherence rates of <70%, ≥70 to <90%, and ≥90%. The dose-response analyses of adherence rates showed that the risk of LREs increased progressively as medication adherence declined. In particular, the unfavorable effects of nonadherence were more pronounced in patients with cirrhosis.. Poor adherence to medication was associated with a higher mortality and greater risk of HCC and cirrhotic complications, particularly among patients with liver cirrhosis.

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Cirrhosis; Liver Neoplasms; Longitudinal Studies; Male; Medical Records; Middle Aged; Patient Compliance; Republic of Korea

Few studies have directly compared the long-term clinical outcomes of entecavir (ETV) and tenofovir disoproxil fumarate (TDF). This study aimed to compare the risk of mortality, liver transplantation and hepatic complications including hepatocellular carcinoma (HCC) and hepatic decompensation between these drugs in treatment-naïve chronic hepatitis B (CHB). We performed a longitudinal observational analysis of data from 1325 consecutive adult CHB patients with a cumulative adherence of ≥80% to treatment with ETV (n = 721) or TDF (n = 604) at a tertiary referral hospital in Ulsan, Korea, from 1 January 2007 through 31 April 2017. Among the patients, 708 were analysed using propensity score matching with a ratio of 1:1. In the follow-up period of up to 5 years, five patients (0.4%) died, three patients (0.2%) underwent liver transplantation (LT) and 54 patients (4.1%) developed HCC. Hepatic decompensation occurred in 24 (1.8%) patients. ETV therapy did not significantly differ from TDF therapy regarding the risk of liver-related death or LT (HR 0.96; 95% CI, 0.23-4.07; log-rank P = 0.955), HCC (HR, 1.36; 95% CI, 0.72-2.56; log-rank P = 0.340) and hepatic decompensation (HR, 1.64; 95% CI, 0.67-4.00; log-rank P = 0.276). In the 708 propensity-matched pairs, ETV and TDF were also not significantly different with respect to the risk of mortality, LT and hepatic complications. In this longitudinal observational study of 1325 patients with CHB, ETV and TDF therapies were not significantly different regarding the risk of mortality, HCC, LT and hepatic decompensation.

Topics: Adolescent; Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B, Chronic; Humans; Korea; Liver Failure; Liver Transplantation; Longitudinal Studies; Male; Middle Aged; Survival Analysis; Tenofovir; Treatment Outcome; Young Adult

Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). Nucleos(t)ide analogue (NA) therapy effectively reduces the incidence of HCC, but it does not completely prevent the disease. Here, we show that dysregulation of microRNAs (miRNAs) is involved in post-NA HCC development. We divided chronic hepatitis B (CHB) patients who received NA therapy into two groups: 1) those who did not develop HCC during the follow-up period after NA therapy (no-HCC group) and 2) those who did (HCC group). miRNA expression profiles were significantly altered in CHB tissues as compared to normal liver, and the HCC group showed greater alteration than the no-HCC group. NA treatment restored the miRNA expression profiles to near-normal in the no-HCC group, but it was less effective in the HCC group. A number of miRNAs implicated in HCC, including miR-101, miR-140, miR-152, miR-199a-3p, and let-7g, were downregulated in CHB. Moreover, we identified CDK7 and TACC2 as novel target genes of miR-199a-3p. Our results suggest that altered miRNA expression in CHB contributes to HCC development, and that improvement of miRNA expression after NA treatment is associated with reduced HCC risk.

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Carrier Proteins; Cell Line, Tumor; Cyclin-Dependent Kinase-Activating Kinase; Cyclin-Dependent Kinases; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Guanine; Hep G2 Cells; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; MicroRNAs; Middle Aged; Tumor Suppressor Proteins

The development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) has decreased due to potent antiviral agents. However, it remains uncertain whether the risk of HCC will diminish after long-term antiviral therapy in Asia, where CHB is endemic and vertical transmission is common. This study aimed to compare the incidence of HCC within and beyond the first 5 years of entecavir (ETV) in treatment-naïve Korean patients with CHB.. We performed a retrospective observational analysis of data from 894 consecutive, adult patients with CHB undergoing ETV treatment at a tertiary referral hospital in Ulsan, Korea from January 1, 2007 through April 31, 2017. We compared the HCC incidence rates per 100 person-years within and beyond the first 5 years. Univariate and multivariate analyses for factors predictive of HCC were performed.. The incidence rate of HCC in patients with CHB did not differ statistically when we compared within and beyond the first 5 years of ETV therapy (2.29% vs 1.66% per person-year, P = 0.217). Failure to achieve maintained virological response (MVR) was a major independent risk factor for HCC in patients at a follow-up of <5 years. In contrast, in patients with a follow-up of ≥5 years, achieving MVR was not significantly associated with HCC development.. The incidence rate of HCC may not change significantly before and after 5 years of ETV therapy in Korean CHB patients. The risk of HCC in Asian CHB patients may remain in the long-term.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Incidence; Liver Cirrhosis; Liver Neoplasms; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Republic of Korea; Retrospective Studies; Risk Factors; Sustained Virologic Response; Treatment Failure; Viral Load

The clinical significance of polymorphisms in the interleukin-28B gene encoding interferon (IFN)-λ3, which has antiviral effects, is known in chronic HCV but not in HBV infection. Thus, we measured IFN-λ3 levels in patients with HBV and investigated its clinical significance and association with nucleos(t)ide (NUC) analogue administration.. Serum IFN-λ3 level was measured in 254 patients with HBV with varying clinical conditions using our own high sensitivity method. The resulting values were compared with various clinical variables. In addition, cell lines originating from various organs were cultured with NUCs, and the production of IFN-λ3 was evaluated.. Higher serum IFN-λ3 levels were detected in the patients treated with nucleotide analogues (adefovir or tenofovir) compared with those treated with nucleoside analogues (lamivudine or entecavir). There were no other differences in the clinical background between the two groups. A rise in the serum IFN-λ3 levels was observed during additional administration of the nucleotide analogues. In vitro experiments showed that the nucleotide analogues directly and dose-dependently induced IFN-λ3 production only in colon cancer cells. Furthermore, the supernatant from cultured adefovir-treated colon cancer cells significantly induced IFN-stimulated genes (ISGs) and inhibited hepatitis B surface antigen (HBsAg) production in hepatoma cells, as compared with the supernatant from entecavir-treated cells.. We discovered that the nucleotide analogues show an additional pharmacological effect by inducing IFN-λ3 production, which further induces ISGs and results in a reduction of HBsAg production. These findings provide novel insights for HBV treatment and suggest IFN-λ3 induction as a possible target.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antiviral Agents; Asymptomatic Infections; Carcinoma, Hepatocellular; Culture Media, Conditioned; DNA, Viral; Female; Gene Expression; Genotype; Guanine; Hep G2 Cells; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; HT29 Cells; Humans; Interferons; Interleukins; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Organophosphonates; Polymorphism, Genetic; Recombinant Proteins; Tenofovir; Up-Regulation; Young Adult

Long-term antiviral prophylaxis is required to prevent hepatitis B recurrence for patients with chronic hepatitis B after liver transplantation. We determined the long-term outcome of 265 consecutive chronic hepatitis B liver transplant recipients treated with entecavir monotherapy without hepatitis B immune globulin. Viral serology, viral load, and liver biochemistry were performed at regular intervals during follow-up. The median duration of follow-up was 59 months. The cumulative rates of hepatitis B surface antigen (HBsAg) seroclearance were 90% and 95% at 1 and 5 years, respectively. At 1, 3, 5, and 8 years, 85%, 88%, 87.0%, and 92% were negative for HBsAg, respectively, and 95%, 99%, 100%, and 100% had undetectable hepatitis B virus (HBV) DNA, respectively. Fourteen patients remained persistently positive for HBsAg, all of whom had undetectable HBV DNA. There was no significant difference in liver stiffness for those who remained HBsAg-positive compared to those who achieved HBsAg seroclearance (5.5 versus 5.2 kPa, respectively; P = 0.52). The overall 9-year survival was 85%. There were 37 deaths during the follow-up period, of which none were due to hepatitis B recurrence.. Long-term entecavir monotherapy is highly effective at preventing HBV reactivation after liver transplantation for chronic hepatitis B, with a durable HBsAg seroclearance rate of 92%, an undetectable HBV DNA rate of 100% at 8 years, and excellent long-term survival of 85% at 9 years. (Hepatology 2017;66:1036-1044).

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Hong Kong; Humans; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Recurrence, Local; Postoperative Complications; Recurrence; Retrospective Studies; Treatment Outcome; Viral Load; Young Adult

Performing repeated liver biopsies to assess the improvement of liver fibrosis is impractical. The purpose of this prospective cohort study was to assess the improvement of liver fibrosis during antiviral treatment by serial liver stiffness (LS) measurement using Fibroscan in chronic hepatitis B (CHB) patients with advanced fibrosis.. Nucleos(t)ide analog-naive CHB patients with advanced fibrosis in histological findings (stage ≥F3), high viral load (hepatitis B virus DNA ≥2,000 IU/ml), and normal liver enzyme levels (<2 × upper normal limit) before starting antiviral treatment were included in this study. LS measurement was performed at baseline and annually for 5 years during antiviral treatment. Five-year fibrosis improvement was defined as LS value <7.2 kPa (

Topics: Adult; Antiviral Agents; Aspartate Aminotransferases; Carcinoma, Hepatocellular; DNA, Viral; Elasticity Imaging Techniques; Female; Follow-Up Studies; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Platelet Count; Predictive Value of Tests; Prospective Studies; Severity of Illness Index

A new hepatocellular carcinoma risk prediction model, PAGE-B, which includes age, gender and platelet count as constituent variables, has recently been proposed in Caucasian chronic hepatitis B patients. We validated PAGE-B model and compared its accuracy with that of conventional risk prediction models in Asian chronic hepatitis B patients.. Chronic hepatitis B patients treated with entecavir or tenofovir were consecutively recruited. The performance of PAGE-B and three conventional risk prediction models (CU-HCC, GAG-HCC and REACH-B) were analysed.. A total of 1092 chronic hepatitis B patients (668 men, 61.2%) were selected between August 2006 and January 2015. The mean age was 48 years. During the follow-up period (median, 43.6 months), 36 (3.3%) patients developed hepatocellular carcinoma. Older age (hazard ratio [HR]=1.077), male gender (HR=3.676) and lower platelet count (HR=0.984) were independent predictors of hepatocellular carcinoma development. The PAGE-B showed similar area under receiver operating characteristic curves (AUROCs) to GAG-HCC and CU-HCC at 3 years (0.777 vs 0.793 and 0.743, respectively; all P>.05) and 5 years (0.799 vs 0.803 and 0.744, respectively; all P>.05), whereas the AUROCs of PAGE-B were significantly higher than those of the REACH-B (0.602 at 3 years and 0.572 at 5 years, P<.05).. Our study demonstrated that PAGE-B is applicable to Asian chronic hepatitis B patients receiving ETV or TDF therapy. The PAGE-B showed similar predictive performance to GAG-HCC and CU-HCC.

Topics: Adult; Antiviral Agents; Asian People; Carcinoma, Hepatocellular; Cohort Studies; Female; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Middle Aged; Models, Theoretical; Risk Assessment; Tenofovir

This study aimed to develop and validate a risk prediction model for the development of hepatocellular carcinoma (HCC) in treatment-naïve patients receiving oral antiviral treatment for chronic hepatitis B (CHB).. We investigated 2,061 Korean treatment-naïve patients with CHB treated with entecavir as an initial therapy. A risk score model for HCC development was developed based on multivariable Cox regression model in a single center (n=990) and was validated using the time-dependent area under the receiver operating characteristic curve (AUROC) in three other centers (n=1,071). The difference of HCC development among risk groups (low, intermediate, and high) categorized by risk score was also investigated.. The cumulative incidence rates of HCC at 5 years were 11.2% and 8.9% in the testing and validation cohorts, respectively. HCC-Risk Estimating Score in CHB patients Under Entecavir (HCC-RESCUE) is formulated as (age+15×gender [female=0 / male=1]+23×cirrhosis [absence=0 / presence=1]). The AUROCs at 1 year, 3 years, and 5 years were 0.82, 0.81, and 0.81, respectively, in the validation cohort. A significant difference of HCC development in each risk group was determined by the 5-year HCC risk score in the validation cohort (low risk group, 2.1%; intermediate risk group, 9.3%; high risk group, 41.2%,. The study presents a new risk score model with a good ability to predict HCC development and determine high risk patients for HCC development consisting of readily available clinical factors in treatment-naïve CHB patients receiving entecavir.

Topics: Administration, Oral; Adult; Antiviral Agents; Area Under Curve; Carcinoma, Hepatocellular; DNA, Viral; Female; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Proportional Hazards Models; Retrospective Studies; Risk Factors; ROC Curve

Whether there is a change of hepatocellular carcinoma (HCC) incidence in chronic hepatitis B patients under long-term therapy with potent nucleos(t)ide analogues is currently unclear. We therefore assessed the HCC incidence beyond year 5 of entecavir/tenofovir (ETV/TDF) therapy and tried to determine possible factors associated with late HCC occurrence. This European, 10-center, cohort study included 1,951 adult Caucasian chronic hepatitis B patients without HCC at baseline who received ETV/TDF for ≥1 year. Of them, 1,205 (62%) patients without HCC within the first 5 years of therapy have been followed for 5-10 (median, 6.8) years. HCCs have been diagnosed in 101/1,951 (5.2%) patients within the first 5 years and 17/1,205 (1.4%) patients within 5-10 years. The yearly HCC incidence rate was 1.22% within and 0.73% after the first 5 years (P = 0.050). The yearly HCC incidence rate did not differ within and after the first 5 years in patients without cirrhosis (0.49% versus 0.47%, P = 0.931), but it significantly declined in patients with cirrhosis (3.22% versus 1.57%, P = 0.039). All HCCs beyond year 5 developed in patients older than 50 years at ETV/TDF onset. Older age, lower platelets at baseline and year 5, and liver stiffness ≥12 kPa at year 5 were independently associated with more frequent HCC development beyond year 5 in multivariable analysis. No patient with low Platelets, Age, Gender-Hepatitis B score at baseline or year 5 developed HCC.. The HCC risk decreases beyond year 5 of ETV/TDF therapy in Caucasian chronic hepatitis B patients, particularly in those with compensated cirrhosis; older age (especially ≥50 years), lower platelets, and liver stiffness ≥12 kPa at year 5 represent the main risk factors for late HCC development. (Hepatology 2017;66:1444-1453).

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Europe; Female; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Risk Factors; Tenofovir; White People

Topics: Antiviral Agents; Carcinoma, Hepatocellular; DNA; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms

Nucleos(t)ide analogue (NA) therapy has been reported to reduce the risk of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B (CHB). However, even during NA therapy, development of HCC has been observed in patients with CHB. Therefore, we clarified the predictive power of clinical factors for HCC incidence using receiver operating characteristic (ROC) analysis that takes time dependence into account.. A total of 539 patients with CHB treated with NAs were enrolled. Univariate, multivariate, and time-dependent ROC curves for clinical factors associated with the development of HCC were analyzed.. Eighty-one patients developed HCC during the follow-up period (median duration, 5.9 years). α-fetoprotein (AFP) and FIB-4 index at 24 weeks from the initiation of treatment and sex were significantly associated with HCC incidence according to the log-rank test. Cox proportional hazards models including the covariates of sex, hepatitis B genotype, basal core promoter mutations, AFP at 24 weeks, and FIB-4 index at 24 weeks showed that FIB-4 index >2.65 (HR, 5.03; 95% CI, 3.06-8.26; P < 0.001) and male sex were independently associated with HCC incidence. In addition, time-dependent ROC analysis showed that compared with AFP at 24 weeks, FIB-4 index at 24 weeks had higher predictive power for HCC incidence throughout the follow-up period.. Elevated FIB-4 index at 24 weeks in patients with CHB receiving NA therapy is a risk factor for developing HCC. The FIB-4 index is an excellent predictor of HCC development.

Topics: Adenine; Alanine Transaminase; Antiviral Agents; Aspartate Aminotransferases; Biomarkers; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Follow-Up Studies; Guanine; Hepatitis B, Chronic; Humans; Incidence; Lamivudine; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Organophosphonates; Phosphorous Acids; Platelet Count; Proportional Hazards Models; Risk Factors; ROC Curve; Time Factors

This study aimed to evaluate the outcomes of chronic hepatitis B patients with cirrhosis who received long-term nucleos(t)ide analog therapy.. A total of 546 consecutive cirrhotic patients treated with entecavir (n = 359), telbivudine (n = 104), or tenofovir (n = 83) for chronic hepatitis B were enrolled. The incidence of hepatocellular carcinoma (HCC) and overall survival were evaluated.. Long-term nucleos(t)ide analog therapy does not guarantee against the HCC development and mortality in chronic hepatitis B-related cirrhotic patients. Careful HCC surveillance is necessary in patients with old age, statin use, low platelet count, and variceal bleeding history.

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Proportional Hazards Models; Renal Insufficiency, Chronic; Telbivudine; Tenofovir; Thymidine; Treatment Outcome

Topics: Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms

The long-term clinical impact of low-level viremia (LLV; <2,000 IU/mL) is not well understood. As a result, it is unclear whether the development of LLV during entecavir monotherapy requires a change in therapy. A retrospective cohort of 875 treatment-naive chronic hepatitis B virus (HBV) monoinfected patients (mean age 47.7 years, male = 564 [65.5%], cirrhosis = 443 [50.6%]) who received entecavir monotherapy were analyzed for the development of hepatocellular carcinoma (HCC). The HCC risk was compared between patients who maintained virological response (MVR), defined by persistently undetectable HBV DNA (<12 IU/mL), and patients who experienced LLV, defined by either persistent or intermittent episodes of <2,000 IU/mL detectable HBV DNA. During a median 4.5 years of follow-up (range 1.0-8.7 years), HCC was diagnosed in 85 patients (9.7%). HCC developed more frequently in patients who experienced LLV than MVR (14.3% versus 7.5% at 5 years, P = 0.015). The hazard ratio comparing those with LLV to MVR was 1.98 (95% confidence interval = 1.28-3.06, P = 0.002, adjusted for age, sex, hepatitis B e antigen, baseline HBV DNA levels, and cirrhosis). Among patients with cirrhosis, those with LLV exhibited a significantly higher HCC risk than those with MVR (HCC incidence rate at 5 years 23.4% versus 10.3%, adjusted hazard ratio = 2.20, 95% confidence interval 1.34-3.60; P = 0.002). However, for patients without cirrhosis, there was no significant difference in the HCC risk between LLV and MVR.. LLV observed during entecavir monotherapy was associated with a higher risk of HCC, especially for those with cirrhosis, indicating that LLV during potent antiviral therapy is consequential. (Hepatology 2017;66:335-343).

Topics: Adult; Age Factors; Analysis of Variance; Antiviral Agents; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Cohort Studies; DNA, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Prognosis; Proportional Hazards Models; Republic of Korea; Retrospective Studies; Risk Assessment; Severity of Illness Index; Sex Factors; Viral Load; Viremia

Sustained abnormal serum alanine aminotransferase (ALT) levels can increase the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B.. This study is aimed to confirm the impact of rapid ALT normalization (≤30 IU/L) on HCC risk in patients with hepatitis B virus (HBV)-associated cirrhosis after entecavir (ETV) commencement.. A total of 578 treatment-naïve patients with HBV-associated cirrhosis (mean age 51 ± 9 years, male sex 63.3%) were treated with ETV for more than 1 year. Serum ALT and HBV DNA levels were measured at three time points (baseline, 6, and 12 months after ETV commencement) and subjected to risk factor analysis.. Median follow-up after ETV commencement was 43 (12-98) months. Cumulative incidences of HCC at 1, 3, 5, and 7 years were 0.3, 8.5, 19.5, and 30.6%, respectively. Univariate Cox regression analysis showed that older age, abnormal ALT at 6 months or 12 months, and lower platelet count were significant risk factors for HCC. However, gender, HBeAg positivity, abnormal ALT levels or HBV DNA levels at baseline, and detectable HBV DNA at 6 or 12 months were not risk factors. Multivariate analysis showed that older age (P < 0.001), abnormal ALT at 12 months (P = 0.006), and lower platelet count (P = 0.034) were the risk factors for HCC.. Abnormal serum ALT levels after ETV commencement are significant risk factor for HCC. Therefore, ALT should be rapidly normalized to minimize the risk of HCC development in patients with HBV-associated cirrhosis.

Topics: Adult; Age Factors; Alanine Transaminase; Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Platelet Count; Prognosis; Republic of Korea; Risk Assessment

Topics: Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms

Long-term antiviral therapy has resulted in viral suppression and biochemical response in chronic hepatitis B, although the risk of hepatocellular carcinoma has not been abolished. The Page-B score could be useful to estimate the probability of HCC.. To analyze the effectiveness and safety of entecavir or tenofovir for more than 4 years and the usefulness of Page-B score in the real-world setting.. Analysis of Caucasian chronic hepatitis B subjects treated with entecavir or tenofovir from the prospective, multicenter database CIBERHEP.. A total of 611 patients were enrolled: 187 received entecavir and 424 tenofovir. Most were men, mean age 50 years, 32% cirrhotic and 16.5% HBeAg-positive. Mean follow-up was 55 (entecavir) and 49 (tenofovir) months. >90% achieved HBV DNA <69 IU/mL and biochemical normalization by months 12 and 36, respectively. Cumulative HBeAg loss and anti-HBe seroconversion were achieved by 33.7 and 23.8%. Four patients lost HBsAg; three HBeAg-positive. Renal function remained stable on long-term follow-up. Fourteen (2.29%) developed HCC during follow-up all of them with baseline Page-B ≥10. Nine were diagnosed within the first 5 years of therapy. This contrasts with the 27 estimated by Page-B, a difference that highlights the importance of regular HCC surveillance even in patients with virological suppression.. Entecavir and tenofovir achieved high biochemical and virological response. Renal function remained stable with both drugs. A Page-B cut-off ≥10 selected all patients at risk of HCC development.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Female; Follow-Up Studies; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Middle Aged; Prognosis; Research Design; Risk Assessment; Spain; Tenofovir; Treatment Outcome

We investigated the incidence and predictors of post-treatment hepatitis B virus (HBV) relapse and hepatitis B surface antigen (HBsAg) loss. After cessation of nucleoside analogue (NA) treatment in hepatitis B e antigen (HBeAg)-negative patients with cirrhosis. The rates of HBsAg loss and hepatocellular carcinoma (HCC) development in HBeAg-negative patients with cirrhosis who continued NA treatment were compared with those who discontinued treatment. Patients with compensated cirrhosis who had discontinued NA treatment for at least 12 months (discontinuing group; n=73) and patients who continued entecavir treatment for at least 4 years (continuing group; n=158) were recruited. Serum HBsAg levels were analysed at the end of treatment (discontinuing group) or at 2.5-3 years of treatment (continuing group). In the discontinuing group, the 6-year cumulative incidence of post-treatment virological relapse and HBsAg loss were 56.3% and 46.7%, respectively. The end-of-treatment HBsAg level of 300 IU/mL was a cut-off value for subsequent post-treatment HBsAg loss and sustained response. In the continuing group, HBsAg loss occurred in five of 158 patients. Cox regression analysis showed that HBsAg levels in the discontinuing group were independent predictors for HBsAg loss in all patients and 104 propensity score (PS)-matched patients. There was no significant difference in HCC development between the groups in all patients and 104 PS-matched patients. Two patients experienced post-treatment alanine aminotransferase flare with hepatic decompensation, and neither of them died after retreatment. In conclusion, HBeAg-negative patients with cirrhosis who discontinued NA treatment might have a higher rate of HBsAg loss and their risk of developing HCC did not increase compared with those who continued entecavir treatment.

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Recurrence; Retrospective Studies; Treatment Outcome

Chronic infection of hepatitis B virus (HBV) is closely associated with the development of hepatocellular carcinoma (HCC). Meta-analyses show that adjuvant anti-HBV therapy is effective for HBV-related HCC patients in clinical. However, the significance that anti-HBV drugs depress HCC is poorly understood. Here, we investigated the effects of telbivudine (LdT), entecavir (ETV) and interferon-α2b (IFN-α2b) on HBV-related HCC. Our data showed that the treatment with the drugs significantly suppressed the growth of HBV-expressing hepatoma cells in vitro and in vivo, but failed to work in HBV-free liver cells. We present the hypothesis that HBx may be involved in the event. As expected, we observed that the expression of HBx was down-regulated by the agents. Meanwhile, the expression of HBx downstream factors was significantly down-regulated. Interestingly, LdT, ETV and IFN-α2b lost the anti-proliferation effects on HBV-related hepatoma cells when the cells were treated with HBx siRNA. Moreover, combination of those drugs enhanced the anti-proliferation effects. In conclusion, LdT, ETV and IFN-α2b suppress the growth of HBV-related HCC through down-regulation of HBx. Our finding provides new insights into the mechanisms of anti-HBV drugs in HCC therapy.

Topics: Animals; Antiviral Agents; Carcinoma, Hepatocellular; Cell Proliferation; DNA Replication; DNA, Viral; Dose-Response Relationship, Drug; Down-Regulation; Drug Therapy, Combination; Guanine; Hep G2 Cells; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Liver Neoplasms; Male; Mice, Inbred BALB C; Mice, Nude; Mice, Transgenic; Recombinant Proteins; RNA Interference; Telbivudine; Thymidine; Time Factors; Trans-Activators; Transfection; Tumor Burden; Viral Regulatory and Accessory Proteins; Virus Replication; Xenograft Model Antitumor Assays

Entecavir is one of the most-used nucleoside analogues for the treatment of patients with chronic hepatitis B virus (HBV) infection. The aim of this study was to clarify the effects of long-term entecavir treatment on the incidence of hepatocellular carcinoma (HCC).. The participants were 249 patients with chronic HBV infection who had been treated by entecavir for more than 2 years. Hepatic functional reserve and incidence of HCC were evaluated, and the factors that might contribute to the development of HCC were analyzed.. Prothrombin activity was significantly elevated at 60 months after starting entecavir (from 85.9 ± 17.4 to 97.0 ± 16.9%, p < 0.001). The albumin level was also significantly elevated at 60 months after starting entecavir (from 4.0 ± 0.5 to 4.3 ± 0.3 mg/dL, p < 0.001). The annual incidence of HCC decreased over time, and the incidence of HCC was only 1.8% at 5 years after starting entecavir. On multivariate analysis for HCC incidence, older age and low platelet count were significant, independent contributing factors.. Long-term treatment with entecavir improved hepatic functional reserve and decreased the incidence of HCC over time after 3 years. To decrease the incidence of HCC, careful induction of long-term entecavir treatment in younger patients with chronic HBV infection and better hepatic functional reserve would be important.

Topics: Adult; Aged; Albumins; Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Female; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Prothrombin; Retrospective Studies; Risk Factors; Treatment Outcome

Little is known about the prognosis and complications of chronic hepatitis B in countries with low disease prevalence including Germany.. This retrospective/prospective study analyzes the course of 608 HBsAg-positive patients between 2002 and 2012 in Germany. The follow-up duration was 5.2±2.9 years (mean±SD) and the age of the patients was 40.4±13.8 years. Of the total cohort, 59.9% were men; 34.9% had been born in Germany, 30.4% in Turkey, and 34.7% in other countries.. In 78.3% of women, diagnosis was made during pregnancy screening, which is the only reinforced screening procedure in Germany. During follow-up, 21 patients died, five had a LTX, and 20 developed a hepatocellular carcinoma. Of the total cohort, 15% developed at least one severe liver-associated complication. By multivariate analysis, prognosis was associated with high age and cirrhosis, but not with sex, HBV-DNA, alanine aminotransferase, and ethnic origin. Of the 608 patients, 211 (34.7%) had at least one antiviral therapy. Of the 178 patients who were treated with nucleot(s)ides at the last visit 88.8% had an HBV-DNA less than 20 IU/ml.. Today, in Germany, hepatitis B is a disease of migrants. The present data show that mandatory screening is effective and needs to include more high-risk groups. Mortality and complications including hepatocellular carcinoma are associated primarily with cirrhosis and age, but not with HBeAg status or viral load probably because modern therapies considerably reduce viral replication in almost all patients. The prognosis is exclusively determined by the risk for hepatocellular carcinoma.

Topics: Adenine; Adult; Age Factors; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Drug Therapy, Combination; Female; Follow-Up Studies; Germany; Guanine; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Mass Screening; Middle Aged; Organophosphonates; Prognosis; Prospective Studies; Retrospective Studies; Telbivudine; Tenofovir; Thymidine; Time Factors; Turkey

Risk scores for hepatocellular carcinoma (HCC) developed in Asians offer poor-moderate predictability in Caucasian patients with chronic hepatitis B (CHB). This nine center cohort study aimed to develop and validate an accurate HCC risk score in Caucasian CHB patients treated with the current oral antivirals, entecavir/tenofovir.. We included 1815 adult Caucasians with CHB and no HCC at baseline who received entecavir/tenofovir for ⩾12 months. Using data from eight centers (derivation dataset, n=1325), a HCC risk score was developed based on multivariable Cox models and points system for simplification. Harrell's c-index was used as discrimination, bootstrap for internal validation and the data from the 9(th) and largest center (validation dataset, n=490) for external validation.. The 5-year cumulative HCC incidence rates were 5.7% and 8.4% in the derivation and validation dataset, respectively. In the derivation dataset, age, gender, platelets and cirrhosis were independently associated with HCC. The PAGE-B score was developed based on age, gender and platelets (c-index=0.82, 0.81 after bootstrap validation). The addition of cirrhosis did not substantially improve the discrimination (c-index=0.84). The predictability of PAGE-B score was similar (c-index=0.82) in the validation dataset. Patients with PAGE-B ⩽9, 10-17, ⩾18 had 5-year cumulative HCC incidence rates of 0%, 3%, 17% in the derivation and 0%, 4%, 16% in the validation dataset.. PAGE-B, which is based only on baseline patients' age, gender and platelets, represents a simple and reliable score for prediction of the 5-year HCC risk in Caucasian CHB patients under entecavir/tenofovir.

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Female; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Middle Aged; Proportional Hazards Models; Risk; Tenofovir

Off-treatment durability of nucleoside analogue (NA) therapy in patients with chronic hepatitis B has not been well investigated. In this study we monitored antiviral effect of NA therapy and evaluated off-treatment durability after NA cessation in patients with chronic hepatitis B.. A total of 94 consecutive patients (39 HBeAg-negative and 55 HBeAg-positive patients) who received NA therapy were followed up for approximately 9 years. We discontinued NA according to the following criteria; undetectable serum HBV-DNA by polymerase chain reaction (PCR) on three separate occasions at least 6 months apart in HBeAg-negative patients (APASL stopping recommendation), and seroconversion from HBeAg-positive to HBeAb-positive and undetectable serum HBV-DNA by PCR for at least 12 months in HBeAg-positive patients.. The cumulative rate of relapse after NA cessation was 48 % and 40 % in HBeAg-negative and -positive patients, respectively. Higher baseline serum alanine aminotransferase level was the only significant predictor for maintaining remission. No patients experienced decompensation after relapse. HBsAg loss occurred at an annual rate of 1.4 % and 0.4 % in HBeAg-negative and -positive patients, respectively. Hepatocellular carcinoma developed at an annual rate of 0.6 % in both HBeAg-negative and -positive patients.. Almost half of the patients did not relapse after cessation of NA therapy in both HBeAg-negative and -positive patients. Therefore, NA therapy could be discontinued with close monitoring if the APASL stopping recommendation is satisfied even in HBeAg-negative patients.

Topics: Adult; Alanine Transaminase; Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Disease Progression; DNA, Viral; Female; Follow-Up Studies; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Liver Neoplasms; Male; Middle Aged; Polymerase Chain Reaction; Recurrence; Remission Induction; Retrospective Studies; Reverse Transcriptase Inhibitors; Viral Load

Ground glass hepatocytes (GGHs) have been shown to predict the development of hepatocellular carcinoma (HCC). Type I GGH and type II GGH harbor hepatitis B virus (HBV) pre-S1 and pre-S2 deletion mutants, respectively. Whether anti-HBV therapy can inhibit the expression of GGHs and potentially reduce HCC development is explored in this study. Two sets of liver specimens were included: the first contained 31 paired biopsy specimens obtained from chronic HBV patients receiving oral nucleos(t)ide analogue (NA) treatment; the second contained 186 resected liver tissues obtained from HBV-related HCC patients receiving surgery: 82 received NA before surgery and 104 did not. Compared with the baseline biopsy specimens, type I (P=0.527) and type II GGH (P=0.077) were not significantly decreased after 48 weeks of NA treatment in the first set of patients. In the second set, despite suppression of viral load (P<0.001) and periportal necrosis (P=0.006) in treated patients, GGH (P=0.594), cccDNA (P=0.172) and serum pre-S mutants (p=0.401) were not significantly suppressed. A significant decrease of type I (P=0.049) and type II GGH (P=0.029) could only be observed in patients after long duration of treatment (median duration: 4.3 years). In the treated patients, the persisted type II GGH remained an independent variable associated with decreased local recurrence-free survival of HCC (P=0.019) as in non-treated patients (P=0.001). In conclusion, the persistence of GGHs could explain the residual risk of HCC development under anti-HBV treatment. Therefore, intrahepatic GGHs and pre-S mutant are potential additional targets for HCC prevention in patients already receiving anti-HBV treatment.

Topics: Adenine; Administration, Oral; Adolescent; Adult; Amino Acid Sequence; Antiviral Agents; Biopsy; Carcinoma, Hepatocellular; DNA, Circular; Drug Resistance, Viral; Fatty Liver; Female; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Humans; Lamivudine; Liver; Liver Neoplasms; Male; Middle Aged; Necrosis; Organophosphonates; Protein Precursors; Sequence Deletion; Viral Load; Young Adult

This study evaluated the clinical significance of subclinical ascites in patients with hepatitis B virus-related cirrhosis treated with lamivudine (LMV) or entecavir (ETV).. This multicenter retrospective study involved 8 hospitals. Patients were classified by degree of ascites: (1) no ascites (no ascites on imaging, no diuretics), (2) subclinical ascites (small amount of ascites on imaging, no diuretics), and (3) clinical ascites (moderate to severe ascites or diuretics).. Out of 501 patients, 336 (68%), 51 (10%), and 114 (23%) patients were classified as no-ascites, subclinical ascites, and clinical ascites, respectively. In all, 100 (20%) and 401 (80%) were treated with LMV and ETV, respectively. Over 58±24 months of follow-up, 105 patients (21%) developed hepatocellular carcinoma. The cumulative incidence of hepatocellular carcinoma did not differ between LMV-treated and ETV-treated patients (P=0.61); it was higher in the clinical-ascites group than the no-ascites (P=0.054) and subclinical-ascites (P=0.03) groups, but it was comparable between the latter 2 (P=0.225). Forty-five patients (9%) died during follow-up. Survival was significantly shorter in the clinical-ascites group than the other 2 (both P<0.005), but it was comparable between no-ascites and subclinical-ascites groups (P=0.444). Multivariate analysis showed that mortality was significantly associated with prothrombin time [hazard ratio (HR)=2.42; 95% confidence interval (CI), 1.59-3.70], serum albumin (HR=0.54; 95% CI, 0.29-0.99), and presence of clinical ascites (HR=3.58; 95% CI, 1.54-8.30).. Subclinical ascites did not affect prognosis in patients with hepatitis B virus-related cirrhosis receiving antiviral treatment.

Topics: Adult; Antiviral Agents; Ascites; Carcinoma, Hepatocellular; Female; Follow-Up Studies; Guanine; Hepatitis B, Chronic; Humans; Incidence; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Prognosis; Prothrombin Time; Retrospective Studies; Serum Albumin

Alpha-fetoprotein is produced by a variety of tumors such as hepatocellular carcinoma, hepatoblastoma, and germ cell tumors of the ovary and testes. However, we present a case of significantly elevated serum alpha-fetoprotein without evidence of malignant disease in a patient who is a carrier of chronic hepatitis B.. A 60-year-old Korean man presented with markedly increased alpha-fetoprotein (2350 ng/mL; normal <5 ng/mL). Various diagnostic evaluations, including computed tomography of the abdomen and thorax and ultrasonography of the abdomen and testes, showed liver cirrhosis and mild splenomegaly; however, no mass was detected in the liver, testes, or other organs scanned. The laboratory findings showed elevated liver function, positivity for hepatitis B e antigen, and a marked increase in hepatitis B virus deoxyribonucleic acid copy number (>7 × 105 IU/mL). Our patient was diagnosed with acute exacerbation of chronic hepatitis B, and we presumed that this condition might be related to extremely elevated alpha-fetoprotein. When our patient was treated with entecavir, the serum alpha-fetoprotein level immediately decreased, in parallel with the hepatitis B virus deoxyribonucleic acid copy number.. We report a rare case of extremely elevated alpha-fetoprotein due to acute exacerbation of chronic hepatitis B without any malignancy, and a decrease in this tumor marker simultaneous with a decrease in hepatitis B virus deoxyribonucleic acid copy number on entecavir treatment. This case report is important due to the rarity of the case; furthermore, it provides details of a diagnostic process for a variety of benign diseases and malignant tumors that should be considered in patients with elevated alpha-fetoprotein. Thus, we present a case report, along with a review, that will be helpful for diagnosis and treatment of patients with elevated alpha-fetoprotein.

Topics: alpha-Fetoproteins; Antiviral Agents; Carcinoma, Hepatocellular; Diagnosis, Differential; Disease Progression; DNA, Viral; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Middle Aged; Testicular Neoplasms; Viral Load

Antiviral therapy is a key component in the management of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients. However, whether the potent drug entecavir is more effective than a less potent drug, such as lamivudine, in HBV-related HCC is not clear.. A retrospective cohort of 451 newly diagnosed, HBV-related HCC patients without antiviral therapy at diagnosis, who started antiviral therapy with either entecavir (n=249) or lamivudine (n=202), were enrolled.. The median survival was longer for the entecavir group than for the lamivudine group, and lamivudine use (vs entecavir) was an independent factor for mortality (hazard ratio [HR], 1.49; p=0.002). Lamivudine use (vs entecavir) was an independent risk factor for new-onset hepatic decompensation (HR, 1.67; p=0.010) in 318 patients without previous hepatic decompensation, and it was also an independent risk factor for recurrence after curative therapy (HR, 1.84; p=0.002) in 117 patients who received curative therapy. The findings were similar in a propensity score-matched cohort.. Overall survival, decompensation-free survival, and recurrence-free survival were better in the entecavir-treated patients than in the lamivudine treated-patients, indicating that the potent antiviral drug should be the preferred choice in HBV-related HCC patients.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Propensity Score; Retrospective Studies; Risk Factors; Treatment Outcome

We performed a propensity-score matched analysis to investigate whether entecavir, compared with lamivudine, can reduce risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B after adjusting for level of fibrosis.. We performed a retrospective study of 1079 patients with chronic hepatitis B who received first-line therapy with lamivudine (n = 435) or entecavir (n = 644) from 2006 through 2013. Only patients with available liver stiffness value measured by transient elastography were recruited. Liver cirrhosis was diagnosed by ultrasonography. To adjust for the imbalance of patients treated with lamivudine versus entecavir, we performed propensity-score matching (PSM), at a ratio of 1:1, using 7 factors (age, sex, hepatitis B e antigen, alanine aminotransferase, serum albumin, platelet count, and liver stiffness; PSM1) or 8 factors (variables of PSM1 plus ultrasonography measurements of cirrhosis; PSM2). Patients with virologic breakthrough or resistance mutations received rescue therapy.. Over the 7-year period, 91 patients developed HCC and 104 had liver-related events in the entire cohort. In multivariate analyses, level of fibrosis, but not antiviral regimen, was independently associated with risk of HCC (P < .05). The PSM1 group included 342 pairs of patients and the PSM2 group included 338 pairs. Similar proportions of patients given lamivudine versus entecavir developed HCC in each model (10.5% given lamivudine vs 9.9% given entecavir in PSM1 and 11.9% vs 12.6% in PSM2; all P > .05). When PSM was applied to patients with liver stiffness value ≤13 kPa or >13 kPa, patients given lamivudine versus entecavir still had similar cumulative rates of HCC development (all P > .05).. In a PSM analysis, we associated level of fibrosis, rather than antiviral regimen, with risk of HCC, when patients received appropriate rescue therapy in case of virologic breakthrough or resistance mutations.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Elasticity Imaging Techniques; Female; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Propensity Score; Retrospective Studies; Treatment Outcome

Data from the United States are lacking regarding the impact of entecavir (ETV) on the risk of hepatocellular carcinoma (HCC). Our aim is to determine whether treatment with ETV is associated with a reduced HCC risk by calculating the expected HCC incidence based on the Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B (REACH-B) model and comparing it with the observed HCC incidence.. The incidence of HCC in US patients treated with ETV between 2005 and 2013 in a retrospective cohort was obtained. The predicted HCC incidence was calculated using the REACH-B model. The standardized incidence ratios (SIRs) were calculated as a ratio of observed over predicted HCC cases.. Of 841 patients, 646 (65% male, 84% Asian, median age 47 years, 36% hepatitis B e antigen positive, 9.4% with cirrhosis) met the inclusion criteria. Over a median follow-up of 4 years, 17 (2.6%) cases of HCC were diagnosed, including 8 out of 61 (13.1%) patients with cirrhosis and 9 out of 585 (1.5%) without cirrhosis. Compared with those without HCC, the 17 patients with HCC were older at 53 years vs. 47 years and more likely to have cirrhosis at 47.1% vs. 8.4%. Among patients without cirrhosis, the observed HCC incidence was significantly lower than predicted by the fourth year (SIR, 0.37; 95% confidence interval: 0.166-0.82). A sensitivity analysis that comprised all patients, including those with cirrhosis, showed that at the maximum follow-up time of 8.2 years, a significantly lower than predicted HCC incidence was noted with an SIR of 0.56 (95% confidence interval: 0.35-0.905).. Based on the REACH-B model, long-term ETV therapy was associated with a lower than predicted HCC incidence. However, the risk of HCC persisted, and careful HCC surveillance remains warranted despite the anti-viral treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Female; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Incidence; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; United States; Young Adult

Entecavir (ETV) is a potent nucleoside analogue with high genetic barrier to resistance. In this study, real-life clinical experiences in the long-term use of ETV and the durability of its off-treatment effectiveness were analyzed.. This study was based on a large real-life cohort of 2240 chronic hepatitis B patients treated with ETV between January 2006 and December 2012 using a centralized electronic data repository.. Among 2240 patients, 804 patients were treatment naive and underwent ETV monotherapy. Their mean treatment duration was 712±493 days, with a cumulative proportion of patients achieving HBV DNA less than 300 copies/ml in 85.8, 95.7, and 97.6% at years 1, 2, and 3, respectively. Predictors for earlier virologic response were female sex, lower HBV DNA, higher alanine transaminase, lower platelet count, and HBeAg negativity at baseline. In patients who achieved virologic response and HBeAg loss, the cumulative relapse rate was 91.3% in 2 years after the cessation of treatment. During the treatment, 34 patients developed hepatocellular carcinoma, among whom 30 patients had cirrhosis before treatment initiation. ETV treatment showed efficient virologic response as the treatment duration was extended, but off-treatment efficacy was not durable, and the antiviral treatment showed some limitation in preventing hepatocellular carcinoma among liver cirrhosis patients, implying that treatment cessation should be taken into consideration more carefully.. This study from a real-life cohort may provide data on treating chronic hepatitis B patients more close to everyday clinical practice.

Topics: Adolescent; Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Drug Administration Schedule; Electronic Health Records; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome; Viral Load; Young Adult

We created a model to predict the development of liver carcinogenesis in patients with chronic hepatitis B (CHB) undergoing entecavir (ETV) therapy and to validate the accuracy using an independent dataset.A total of 328 CHB subjects were analyzed. Subjects were randomly assigned into 2 groups: the training group (n = 164) and the validation group (n = 164). Using data from the training group, we built a predictive model for liver carcinogenesis by performing univariate and multivariate analyses using variables associated with liver carcinogenesis. We subsequently assessed the applicability of the constructed model in the validation group.The median (range) follow-up periods in the training and the validation groups were 5.03 years (1.03-9.98) and 4.84 years (1.10-9.97), respectively. The proportion of hepatitis B virus-DNA at 24 weeks <1.9 log IU/mL in the training group was 70.7% (116/164), while that in the validation group was 71.3% (117/164). For the entire cohort (n = 328), the median alpha-fetoprotein (AFP) value at 24 weeks (3.45 ng/mL; range, 0.9-102.7 ng/mL) significantly decreased compared to the baseline values (5.55 ng/mL; range, 0.9-1039.5 ng/mL), while the median alanine aminotransferase (ALT) value at 24 weeks (24 IU/mL; range, 6-251 IU/mL) also significantly decreased compared to baseline values (57 IU/mL; range, 7-1450 IU/mL). During the observation period, hepatocellular carcinoma (HCC) developed in 15 (9.1%) patients in the training group and in 17 (10.4%) patients in the validation group. The 3- and 5-year cumulative HCC incidence rates in the entire cohort were 4.48% and 9.52%, respectively. In the multivariate analysis of the training group, age ≥54 years (P = 0.0273), ALT level at 24 weeks (P = 0.0456), and AFP at 24 weeks (P = 0.0485) were found to be significant predictors linked to HCC. Using these independent predictors, the risk for HCC development was well stratified in the validation group (overall significance, P < 0.0001). Similar results were observed in subgroup analyses of patients with or without cirrhosis and HBe antigen positivity.In conclusion, our predictive model was well verified; hence, it may be a promising model for the prediction of the development of liver carcinogenesis in CHB patients undergoing ETV therapy.

Topics: Adult; Age Factors; Aged; Alanine Transaminase; alpha-Fetoproteins; Antiviral Agents; Carcinogenesis; Carcinoma, Hepatocellular; Female; Follow-Up Studies; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Incidence; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Models, Theoretical; Prognosis

Oral antiviral therapy may reduce the disease progression of chronic hepatitis B (CHB) patients. We aimed to further investigate the efficacy of long-term entecavir therapy in reduction of the risk of hepatocellular carcinoma (HCC), cirrhotic events and mortality in a large group of CHB-related cirrhosis patients.. The C-TEAM (Cirrhosis-Taiwanese EntecAvir Multicenter) study was a nationwide, multicenter, retrospective-prospective cohort study in Taiwan. We enrolled treatment-naïve patients with CHB-related cirrhosis and baseline HBV-DNA≥2000 IU/mL receiving long-term entecavir therapy and compared the development of HCC, cirrhotic events and mortality with that of a historical untreated cohort.. In total, 1315 entecavir-treated and 503 untreated patients with cirrhosis were enrolled, with median treatment and follow-up durations of 4 and 6 years respectively. Compared with the untreated cohort, entecavir therapy was associated with a 60% HCC risk reduction [hazard ratio (HR): 0.40, 95% confidence interval (CI): 0.28-0.57]. Additionally, an older age, the male gender, HBeAg positivity, alpha-fetoprotein (AFP)≥7 ng/mL before therapy were independent predictors of HCC development. Further analysis showed that entecavir therapy significantly reduced risks of variceal bleeding, spontaneous bacterial peritonitis, and liver-related and all-cause mortality. These findings were confirmed by propensity score-matched cohorts in sensitivity analysis. In patients under entecavir therapy, an older age, the male gender, HBeAg positivity, AFP level ≥7 ng/mL before therapy, and 1-year virological response were predictive of HCC development.. Four-year entecavir therapy significantly reduces the risk of HCC, cirrhotic events and mortality in patients with CHB-related cirrhosis.

Topics: Adult; alpha-Fetoproteins; Antiviral Agents; Carcinoma, Hepatocellular; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Prospective Studies; Retrospective Studies; Taiwan; Treatment Outcome

Topics: Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Drug Resistance, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver Neoplasms; Treatment Outcome

Hepatic damage during transarterial chemoembolization (TACE) is a critical complication in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Apart from its role in preventing HBV reactivation, there is some evidence for the benefits of preemptive antiviral therapy in TACE. This study evaluated the effect of preemptive antiviral therapy on acute hepatic deterioration following TACE.. This retrospective observational study included a prospectively collected cohort of 108 patients with HBV-related HCC who underwent TACE between January 2007 and January 2013. Acute hepatic deterioration following TACE was evaluated. Treatment-related hepatic decompensation was defined as newly developed encephalopathy, ascites, variceal bleeding, elevation of the bilirubin level, prolongation of prothrombin time, or elevation of the Child-Pugh score by ≥2 within 2 weeks following TACE. Univariate and multivariate analyses were conducted to identify factors influencing treatment-related decompensation. Preemptive antiviral therapy involves directing prophylaxis only toward high-risk chronic hepatitis B patients in an attempt to prevent the progression of liver disease. We regarded at least 6 months as a significant duration of preemptive antiviral treatment before diagnosis of HCC.. Of the 108 patients, 30 (27.8%) patients received preemptive antiviral therapy. Treatment-related decompensation was observed in 25 (23.1%) patients during the follow-up period. Treatment-related decompensation following TACE was observed more frequently in the nonpreemptive group than in the preemptive group (29.5% vs. 6.7%,. Our findings suggest that preemptive antiviral therapy significantly reduces the risk of acute hepatic deterioration. Preventing hepatic deterioration during TACE by applying such a preemptive approach may facilitate the continuation of anticancer therapy and thus improve long-term outcomes.

Topics: Aged; Antiviral Agents; Bilirubin; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Female; Gastrointestinal Hemorrhage; Guanine; Hepatitis B; Humans; Hypoalbuminemia; Incidence; Liver; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Proportional Hazards Models; Retrospective Studies; Risk Factors; Treatment Outcome

The aim of this study was to re-evaluate the diagnostic performance of alpha-foetoprotein (AFP) as a surveillance test for hepatocellular carcinoma (HCC) in patients with hepatitis B virus-related chronic liver disease who were treated with entecavir (ETV).. Between January 2007 and August 2012, we analysed 373 treatment-naïve patients with HBV-related chronic hepatitis (n = 229) or cirrhosis (n = 144) who were candidates for surveillance test, and were treated with ETV (0.5 mg/day) for longer than 12 months. To minimize the effect of AFP elevation caused by hepatitis activity, serum AFP levels were measured 12 months after the initiation of ETV treatment.. Hepatocellular carcinoma developed in 28 patients (7.5%) during a median follow-up period of 48.0 months (IQR = 40.5-57.3 months). The area under the receiver operating characteristic curve for AFP was 0.71 (95% CI = 0.59-0.84). The optimal AFP cut-off value was 13 ng/ml, leading to a sensitivity of 50.0%, specificity of 98.8%, positive predictive value of 77.8% and negative predictive value of 96.1%. In multivariate Cox analysis, an older age, the presence of cirrhosis and AFP levels of ≥20 ng/ml at 12 months after treatment were found to be significantly associated with an increased incidence of HCC.. The role of serum AFP as a surveillance test should be re-evaluated in patients with HBV-related chronic liver diseases who were treated with antiviral therapy.

Topics: Adult; alpha-Fetoproteins; Area Under Curve; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B; Humans; Liver Neoplasms; Male; Middle Aged; Predictive Value of Tests; Proportional Hazards Models; ROC Curve; Sensitivity and Specificity

Hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients treated with lamivudine. Whether HCC rates are comparable in patients treated with the current first-line antivirals remains uncertain. We estimated the incidence and evaluated predictors of HCC in a large nationwide prospective cohort (HepNet.Greece) of HBeAg-negative CHB patients treated with entecavir. HBeAg-negative CHB patients from the same cohort who were initially treated with lamivudine were used as controls. We included 321 patients treated with entecavir for a median of 40 months and 818 patients treated initially with lamivudine for a median of 60 months. In the entecavir group, HCC developed in 4 of 321 (1.2%) patients at a median of 1.5 (range: 1.0-4.5) years, while the cumulative HCC incidence was significantly higher in cirrhotics than noncirrhotics (1, 3, 5 years: 0%, 3%, 9% vs 1%, 1%, 1%; P = 0.024) and in older patients (P = 0.026). Entecavir compared with lamivudine group patients had lower HCC incidence (1, 3, 5 years: 0.3%, 1.2%, 2.8% vs 0.7%, 3.8%, 5.6%; P = 0.024). However, in multivariable Cox regression analysis, the HCC risk was independently associated with older age (P < 0.001), male gender (P = 0.011) and cirrhosis (P = 0.025), but not with the initial agent. In conclusion, our large nationwide study indicates that the HCC risk remains increased in entecavir-treated HBeAg-negative CHB patients with cirrhosis, particularly of older age, at least for the first 5 years. The HCC risk does not seem to be significantly reduced with entecavir compared with antiviral therapy starting with lamivudine.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Female; Greece; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Incidence; Lamivudine; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Risk Assessment; Treatment Outcome

The risk of hepatocellular carcinoma (HCC) in Caucasian patients with chronic hepatitis B (CHB), treated with entecavir (ETV) or tenofovir (TDF), is unclear. We evaluated the incidence and predictors of HCC and the accuracy of existing HCC risk scores in Caucasian CHB patients receiving ETV/TDF.. This large, multicentre, retrospective cohort study included 1666 adult Caucasian CHB patients under ETV/TDF for 39 months. CHB without cirrhosis, compensated and decompensated cirrhosis were present in 67%, 39%, and 3% of patients, respectively. The predictability of baseline parameters and three risk scores (GAG-HCC, CU-HCC, and REACH-B), developed in Asian patients, was assessed.. The cumulative probability of HCC was 1.3%, 3.4%, and 8.7% at year-1, year-3, and year-5 after ETV/TDF onset. Older age and lower platelets were strong independent HCC predictors in the total population and in the subgroups of cirrhotic and non-cirrhotic patients, while liver disease severity was an independent HCC predictor in the total population and in the cirrhotics. GAG-HCC, CU-HCC, and REACH-B risk scores were associated with HCC development only in the univariable but not in the multivariable analyses and offered poor to modest predictability.. HCC can still develop in Caucasian CHB patients treated with ETV/TDF. Besides the well-known predictors of HCC, such as older age, male gender and more advanced liver disease, lower platelets represent an independent factor of higher HCC risk. The applicability and predictability of HCC risk scores developed in Asian patients are poor or modest in Caucasian CHB patients, for whom different risk scores are required.

Topics: Adenine; Adult; Antiviral Agents; Carcinoma, Hepatocellular; Female; Follow-Up Studies; Greece; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Netherlands; Organophosphonates; Retrospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Spain; Tenofovir; Time Factors; Turkey; White People

Entecavir (ETV) is one of the first-line nucleoside analogs for treating patients with chronic hepatitis B virus (HBV) infection. However, the hepatocellular carcinoma (HCC) risk for ETV-treated patients remains unclear.. A total of 496 Japanese patients with chronic HBV infection undergoing ETV treatment were enrolled in this study. The baseline characteristics were as follows: age 52.6 ± 12.0 years, males 58%, positive for hepatitis B e antigen 45 %, cirrhosis 19%, and median HBV DNA level 6.9 log copies (LC) per milliliter. The mean treatment duration was 49.9 ± 17.5 months.. The proportions of HBV DNA negativity (below 2.6 LC/mL) were 68% at 24 weeks and 86% at 1 year, and the rates of alanine aminotransferase (ALT) level normalization were 62 and 72%, respectively. The mean serum alpha-fetoprotein (AFP) levels decreased significantly at 24 weeks after ETV treatment initiation (from 29.0 ± 137.1 to 5.7 ± 27.9 ng/mL, p < 0.001). The cumulative incidence of HCC at 3, 5, and 7 years was 6.0, 9.6, and 17.2%, respectively, among all enrolled patients. In a multivariate analysis, advanced age [55 years or older, hazard ratio (HR) 2.84; p = 0.018], cirrhosis (HR 5.59, p < 0.001), and a higher AFP level (10 ng/mL or greater) at 24 weeks (HR 2.38, p = 0.034) were independent risk factors for HCC incidence. HCC incidence was not affected by HBV DNA negativity or by ALT level normalization at 24 weeks.. The AFP level at 24 weeks after ETV treatment initiation can be the on-treatment predictive factor for HCC incidence among patients with chronic HBV infection.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; alpha-Fetoproteins; Antiviral Agents; Biomarkers, Tumor; Carcinoma, Hepatocellular; Female; Follow-Up Studies; Guanine; Hepatitis B, Chronic; Humans; Incidence; Japan; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Risk Factors; Young Adult

Hepatectomies may exacerbate chronic hepatitis B in patients with high hepatitis B viral (HBV) DNA levels, and could result in hepatic insufficiency. Antiviral treatment is effective for suppressing HBV virus loads. This study investigated whether perioperative antiviral therapy is warranted for resection of hepatocellular carcinoma (HCC) with concurrent HBV infections.. Patients with HBV-related HCC (n = 112) who underwent major liver resection were retrospectively divided into two groups based on treatment with perioperative antiviral therapy (antiviral group) (n = 72) or absence of antiviral treatment (control group) (n = 40).. Exacerbation of chronic hepatitis B occurred in 6 patients of the control group (15.0%). The prevalence of hepatic insufficiency in the antiviral group and control group were 1.4% (1/72) and 12.5% (5/40), respectively (p < 0.05). Five of them (4.5%) developed hepatic encephalopathy and 3 of them (2.7%) developed hepatorenal syndrome. The control group had significantly higher morbidity (75.0% vs. 34.7%, p < 0.01) than the antiviral group. The control group had significantly higher levels of postoperative alanine aminotransferase (ALT) and serum bilirubin than the antiviral group.. Perioperative antiviral treatment improves patient safety by decreasing morbidity and speeding recovery of postoperative liver function for HBV-related major HCC resection.

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatectomy; Hepatic Insufficiency; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Middle Aged; Perioperative Care; Retrospective Studies; Treatment Outcome; Viral Load

Low-dose hepatitis B immunoglobulin (HBIG) and nucleos(t)ides analogs (lamivudine/adefovir) used for the prevention of hepatitis B virus (HBV) recurrence after liver transplantation (LT) are associated with some risk of HBV recurrence and antiviral resistance.. The study cohort included 176 patients (at least >12 months follow-up) with HBV cirrhosis/hepatocellular carcinoma who received secondary prophylaxis with indefinite entecavir/tenofovir after living-donor LT (LDLT). All patients received 10,000 IU intravenous HBIG in anhepatic phase followed by 600-1000 IU intramuscularly daily for 7 days, weekly for 3 weeks, and then monthly, to keep antiHBs levels >100 mIU/mL for 1 year. Hepatitis B surface antigen (HBsAg) and HBV DNA were tested every 6 months.. The study cohort is composed of 157 men and 19 women, mean age 47.9 ± 10.1 years, all HBsAg positive, 35 (19.8%) had HBV DNA >2000 IU/mL before LT. After LT, patients received entecavir (n = 126, 71.5%), tenofovir (n = 20, 11.3%), or a combination of entecavir and tenofovir (n = 30, 17% for 3 months), followed by entecavir alone. During follow-up of 43 (12-117) months, 2 patients (including 1 with non-compliance) had HBV recurrence.. In a large cohort of LDLT recipients for HBV-related liver disease, use of low-dose short-term HBIG with high genetic barrier drugs results in a substantially lower incidence of HBV recurrence, even in high-risk patients.

Topics: Adenine; Adult; Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Drug Resistance, Viral; Drug Therapy, Combination; Female; Follow-Up Studies; Guanine; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Immunoglobulins; Lamivudine; Liver Transplantation; Male; Middle Aged; Organophosphonates; Prospective Studies; Recurrence; Tenofovir

Serum α-fetoprotein (AFP) is frequently elevated in patients with chronic hepatitis B (CHB) who do not have hepatocellular carcinoma (HCC). Entecavir (ETV) treatment reduces AFP levels in these patients, but the clinical significance of AFP response to ETV has not been fully studied. The aims of this study were to elucidate the temporal response of AFP to ETV therapy and to determine the relationship between AFP response and the subsequent development of HCC.. All consecutive nucleos(t)ide-naïve CHB patients who started ETV therapy between March 2007 and February 2009 were selected from an electronic medical record database at a tertiary referral center (BESTCare). Clinical, biochemical, and virologic parameters were evaluated in relation to the serial AFP levels tested during ETV treatment.. Among the 244 enrolled patients, 66 had elevated AFP levels before ETV therapy. Low serum albumin was a significant predictor for elevated AFP. During 12 months of ETV therapy, AFP levels normalized in approximately three fourths of these patients. The decrease in AFP was delayed in patients with high baseline hepatitis B virus titers and in patients who subsequently developed HCC during ETV therapy. Incidence of HCC was similar regardless of baseline AFP levels. Among patients with elevated AFP, however, HCC developed exclusively in the subgroup where elevated AFP persisted for more than 6 months of ETV therapy.. Delayed AFP response to ETV may serve as an indicator of high HCC risk.

Topics: Adult; Aged; alpha-Fetoproteins; Antiviral Agents; Biomarkers, Tumor; Carcinoma, Hepatocellular; Female; Forecasting; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Middle Aged; Risk; Time Factors

Chronic hepatitis B virus (HBV) infection is a major risk factor for the development of liver cirrhosis and hepatocellular carcinoma (HCC). Key Messages: In patients with advanced liver fibrosis or liver cirrhosis, antiviral therapy is mandatory to slow down, halt or reverse disease progression and possibly reduce the risk of HCC development. As in patients without advanced fibrosis, PEG-interferon and nucleoside/nucleotide analogues (NUCs) are available for antiviral therapy. NUC therapy should be performed indefinitely as the rates of HBs-Ag loss are low. Entecavir or tenofovir should be preferred due to their strong antiviral potency and their high barrier to resistance. PEG-interferon therapy can be administered to patients with compensated liver disease but should not be offered to patients with signs of hepatic decompensation.. Antiviral therapy in chronic HBV infection can reduce liver fibrosis and even revert overt cirrhosis. Whether it also reduces the risk of HCC development in cirrhotic patients remains elusive and might vary in different countries and ethnicities.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Disease Progression; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Polyethylene Glycols; Recombinant Proteins; Reverse Transcriptase Inhibitors; Tenofovir

Limited data is available from India on outcome and efficacy of tenofovir and entecavir in hepatitis B virus (HBV)-related cirrhosis when used for prolonged time. We report the long-term efficacy and outcome of these antiviral drugs in patients with chronic HBV infection, with compensated or decompensated cirrhosis.. We retrospectively analyzed laboratory and clinical data of 400 HBV-related cirrhotic patients without access to liver transplantation, who were treated with tenofovir/entecavir therapy, from January 2007 to January 2014. Two hundred and ten (52.5 %) patients had at least one of the components of decompensation at baseline. Two hundred and twenty (55 %) and 180 (45 %) patients were initiated tenofovir and entecavir, respectively. Follow up period was 45 (12-68) months for tenofovir and 36 (11-60) months for entecavir.. At the end of 1 year, levels of HBV DNA <20 IU/mL were achieved in 91.8 % and 88.8 % of patients, and alanine aminotransferase normalized in 54.5 % and 55.5 % of patients who received tenofovir and entecavir, respectively. At the last visit, Child-Turcotte-Pugh scores improved among 29.5 % of patients who received tenofovir, 25 % of those who received entecavir, and remained stable in 61.9 % and 65 % patients, respectively, in both groups. The 5-year cumulative rate of liver decompensation, hepatocellular carcinoma, and cirrhosis-related complications were 3.1 %, 1.9 %, and 2.1 % with an annual incidence of 0.8 %, 0.3 %, and 0.5 % per person-year, respectively.. Tenofovir and entecavir were effective and potent drugs for prolonged treatment of HBV cirrhosis and improved the overall clinical course.

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Female; Follow-Up Studies; Guanine; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Tenofovir; Time Factors; Treatment Outcome; Young Adult

Long-term nucleos(t)ide analogues therapy may reduce hepatocellular carcinoma (HCC) in chronic hepatitis B patients with advanced fibrosis or cirrhosis.. To investigate in a retrospective-prospective study whether this beneficial effect would be reduced in cirrhotic patients who discontinued a successful course of entecavir (ETV) therapy.. The study included 586 hepatitis B e antigen (HBeAg)-negative patients with compensated cirrhosis, mean age of 53.8 ± 10 years and 81% males, treated with ETV for at least 12 months. After ETV therapy for 46.5 ± 22.9 months, 205 patients who achieved hepatitis B virus (HBV) DNA suppression discontinued therapy. The clinical outcomes were assessed and HCC incidence was compared between propensity score (PS)-matched patients who continued and patients who discontinued ETV therapy by Asian Pacific Association for the Study of Liver stopping rule.. During a mean duration of 59.3 ± 19 months after start of ETV therapy, nine and six HCC developed in an estimated annual incidence of 2.3% and 1.6% in 154 PS-matched patients who continued and who discontinued ETV therapy, respectively (P = 0.587). Multivariate Cox proportional hazards regression analyses showed that age (HR 1.065, P < 0.001) and HBV DNA (HR 1.216, P = 0.048) were the significant factors for HCC development. The rates of adverse clinical outcomes were comparable.. The clinical outcomes, including HCC, after cessation of a successful course of entecavir therapy in patients with compensated cirrhosis were comparable to those who continued therapy. The results suggest that this strategy of finite therapy is safe and a feasible alternative to indefinite therapy, especially in a low resources setting.

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Incidence; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Retrospective Studies

At present, for adults with chronic hepatitis B virus (HBV) infection, two new analogues, entecavir (ETV) and tenofovir, are recommended as the first-line therapy by the EASL (European Association for the Study of the Liver), AASLD (American Association for the Study of Liver Diseases), and APASL (Asian Pacific Association for the Study of the Liver) guidelines. The use of pegylated interferon-α (PEG IFN-α) is recommended as the first-line therapy instead of standard IFN-α according to the above 3 guidelines. In this paper, the aim was to assess: (1) the long-term efficacy and safety as well as the resistance to ETV and tenofovir disoproxil fumarate (TDF); (2) the efficacy of PEG IFN-α; (3) the role of combination therapy with IFN plus two analogues, such as lamivudine and ETV; (4) the efficacy and safety of two analogues with cirrhosis, and (5) suppression of hepatocellular carcinoma (HCC) by ETV and IFN treatment. The results are as follows: (1) both ETV and TDF showed long-term efficacy and safety; (2) PEG IFN-α resulted in a greater decline in HBV DNA levels and a higher rate of HBeAg seroconversion; (3) combination therapy with IFN plus two analogues did not elevate the rate of sustained responses; (4) both ETV and TDF showed efficacy and safety with cirrhosis (ETV especially displayed efficacy and safety with decompensated cirrhosis), and (5) suppression of HCC was observed by ETV and IFN.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Clinical Trials as Topic; Disease Management; Drug Therapy, Combination; Guanine; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon-alpha; Japan; Liver Neoplasms; Practice Guidelines as Topic; Prognosis

Hepatitis B virus (HBV) reactivation was reported to be induced by transcatheter arterial chemoembolization (TACE) in HBV-related hepatocellular carcinonma (HCC) patients with a high incidence. The effective strategy to reduce hepatitis flares due to HBV reactivation in this specific group of patients was limited to lamivudine. This retrospective study was aimed to investigate the efficacy of prophylactic entecavir in HCC patients receiving TACE.. A consecutive series of 191 HBV-related HCC patients receiving TACE were analyzed including 44 patients received prophylactic entecavir. Virologic events, defined as an increase in serum HBV DNA level to more than 1 log10 copies/ml higher than nadir the level, and hepatitis flares due to HBV reactivation were the main endpoints.. Patients with or without prophylactic were similar in host factors and the majorities of characteristics regarding to tumor factors, HBV status, liver function and LMR. Notably, cycles of TACE were parallel between the groups. Ten (22.7%) patients receiving prophylactic entecavir reached virologic response. The patients receiving prophylactic entecavir presented significantly reduced virologic events (6.8% vs 54.4%, p=0.000) and hepatitis flares due to HBV reactivation (0.0% vs 11.6%, p=0.039) compared with patients without prophylaxis. Kaplan-Meier analysis illustrated that the patients in the entecavir group presented significantly improved virologic events free survival (p=0.000) and hepatitis flare free survival (p=0.017). Female and Eastern Cooperative Oncology Group (ECOG) performance status 2 was the only significant predictors for virological events in patients without prophylactic antiviral. Rescue antiviral therapy did not reduce the incidence of hepatitis flares due to HBV reactivation.. Prophylactic entecavir presented promising efficacy in HBV-related cancer patients receiving TACE. Lower performance status and female gender might be the predictors for HBV reactivation in these patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Carcinoma, Hepatocellular; Case-Control Studies; Chemoembolization, Therapeutic; Child; Female; Follow-Up Studies; Guanine; Hepatic Artery; Hepatitis B; Hepatitis B virus; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Prognosis; Retrospective Studies; Virus Activation; Young Adult

There are limited data comparing the clinical outcomes between telbivudine and entecavir. We consecutively enrolled 115 telbivudine-naive and 115 entecavir-naive chronic hepatitis B patients, who were matched for age, sex, hepatitis B e antigen (HBeAg) status and cirrhosis, and treated for at least 2 years or less than 2 years but had developed resistance. Except for the rate of HBeAg seroconversion, which was similar, patients in the entecavir group had better clinical outcomes than those in the telbivudine group for alanine aminotransferase normalization (85.2% vs 78.4%, p <0.048), undetectable HBV DNA (96.5% vs 74.8%, p <0.001), and viral resistance (0.9% vs 21.7%, p <0.001) after 2 years of treatment, After applying roadmap or super-responders concepts, entecavir still had better outcomes than telbivudine in undetectable HBV DNA and viral resistance. The cumulative incidence of hepatocellular carcinoma development was similar between telbivudine-naive and entecavir-naive patients (p 0.565). In renal function analysis, there were significantly more patients with estimated glomerular filtration rate (eGFR) category improvement in both the telbivudine and entecavir groups at year 1 (p 0.006 and p 0.047, respectively). The rate of virological improvement was significantly higher with entecavir than with telbivudine after 2 years of treatment, whether applying the concepts of roadmap or super-responders. The incidence of hepatocellular carcinoma was similar between telbivudine and entecavir. Both telbivudine and entecavir were associated with eGFR improvement, especially in patients with renal insufficiency.

Topics: Adult; Aged; Alanine Transaminase; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Drug Resistance, Viral; Drug-Related Side Effects and Adverse Reactions; Female; Glomerular Filtration Rate; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Telbivudine; Thymidine; Treatment Outcome

We investigated whether liver stiffness (LS) values can predict liver-related events (LREs) development in patients with chronic hepatitis B (CHB).. LS values using transient elastography provides accurate assessment of liver fibrosis in patients with chronic liver disease.. Between June 2007 and May 2010, a total of 162 patients with CHB who completed 2-year entecavir (ETV) treatment were evaluated. The primary endpoint was LRE development (hepatic decompensation, hepatocellular carcinoma, or liver-related death) during the 2-year ETV treatment.. The median age of the patients (99 men, 63 women) was 51 years, and the median LS value was 14.8 kPa. During the 2-year ETV treatment, 15 (9.3%) patients experienced LREs. On univariate analysis, age, the proportion of patients with liver cirrhosis, platelet counts, and baseline LS values were significantly associated with LRE development (all P<0.05). Together with age, multivariate analysis identified baseline LS values as an independent predictor of LRE development (P=0.046; hazard ratio, 1.040; 95% confidence interval, 1.101-1.084). The cutoff LS value maximizing the sum of sensitivity and specificity was 12.0 kPa (area under the receiver operating characteristics curve, 0.736; P=0.003; sensitivity, 93.3%; specificity, 42.2%). In addition, the changes in LS values between baseline and 1-year ETV treatment showed significant correlations with LRE development (P=0.030).. Our data suggest that LS values are predictive of LRE development during 2-year ETV treatment in patients with CHB. The potential role of LS value as a monitoring tool for predicting dynamic changes in the risk of LRE development during long-term ETV treatment should be investigated further.

Topics: Adult; Aged; Antiviral Agents; Area Under Curve; Biopsy; Carcinoma, Hepatocellular; Chi-Square Distribution; Elasticity Imaging Techniques; Female; Guanine; Hepatitis B, Chronic; Humans; Liver; Liver Cirrhosis; Liver Failure; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Prospective Studies; Risk Assessment; Risk Factors; ROC Curve; Time Factors; Treatment Outcome; Young Adult

Without effective prophylaxis, liver transplantation (LT) for hepatitis B virus (HBV)-related liver disease is frequently complicated by severe and rapidly progressive HBV recurrence. The combination of low-dose hepatitis B immunoglobulin (HBIG) and the new nucleos(t)ide analog, entecavir, as prophylaxis for HBV recurrence after living-donor LT (LDLT) were analyzed.. A total of 315 patients with positive hepatitis B surface antigen underwent LDLT at our transplant center between July 2003 and December 2011. Our protocol for post-transplantation HBV prophylaxis was a combination of low-dose HBIG and nucleos(t)ide analog.. During a median follow-up period of 49 months post-transplant, 10 patients (3.2%) had HBV recurrence, which was significantly related to hepatocellular carcinoma (HCC) at transplantation (P = 0.041) and post-LT antiviral agent (P < 0.001) in multivariate analysis. The level of HBV DNA and hepatitis B e antigen state at transplantation were not significant factors for HBV recurrence (P = 0.342 and P = 0.802, respectively). In 170 patients with HCC at LDLT, HCC recurrence was significantly related to HBV recurrence (P < 0.001). Among 10 patients with HBV recurrence, three are alive and two had lost hepatitis B surface antigen. The remaining seven patients died of HCC recurrence.. The combination of low-dose HBIG and nucleos(t)ide analogs is safe and effective for HBV prophylaxis after LDLT. As a post-LT antiviral treatment, entecavir is more effective than lamivudine. HCC at transplantation was significantly associated with HBV recurrence. HBV-related HCC patients who undergo LDLT require close virological monitoring.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Guanine; Hepatitis B; Humans; Immunoglobulins; Liver Neoplasms; Liver Transplantation; Living Donors; Male; Middle Aged; Nucleotides; Risk Factors; Secondary Prevention; Treatment Outcome

Liver transplantation (LT) for hepatitis B virus (HBV)-related disease can be complicated by HBV recurrence. The aim of this study was to evaluate the risk factors, prophylaxis treatment, and histological characteristics of HBV recurrence after LT when using long-term, low-dose hepatitis B immunoglobulin (HBIG) plus nucleoside analog (lamivudine [LAM] or entecavir [ETV]).. Retrospective data from 253 adult LT patients using long-term, low-dose HBIG plus nucleoside analog after LT, for a mean treatment duration of 1-72 months, were collected from a single center in Beijing, China. Univariate analyses were conducted to determine the association among gender, age, hepatocellular carcinoma, hepatitis B e antigen-positive status, HBV-DNA level and tyrosine-methionine-aspartate-aspartate (YMDD) mutations on HBV recurrence in these patients.. Overall, the HBV recurrence rate was 6.32% (16/253). There was no significant difference in the survival rate between the HBV recurrence and non-recurrence groups. Risk factors for HBV recurrence were: hepatitis B e antigen positivity, HBV-DNA > 10(5) copies/mL, hepatocellular carcinoma, and YMDD mutation. Sixteen patients receiving LAM had HBV recurrence (16/169; mean treatment duration: 61.8 ± 18.3 months). No HBV recurrence occurred in patients receiving ETV after LT (0/84; mean treatment duration: 57.1 ± 15.9 months). Differences in rate of mortality and HBV recurrence were not significant between the two groups.. LT is an effective treatment for HBV-related end-stage liver disease. The combination of ETV and intramuscular HBIG for HBV recurrence prophylaxis after LT was more effective than LAM, especially in Chinese patients with HBV recurrence risk factors.

Topics: Adult; Age Factors; Antiviral Agents; Aspartic Acid; Carcinoma, Hepatocellular; China; DNA, Viral; Drug Therapy, Combination; End Stage Liver Disease; Guanine; Hepatitis B; Hepatitis B e Antigens; Hepatitis B virus; Humans; Immunoglobulins; Lamivudine; Liver Neoplasms; Liver Transplantation; Male; Methionine; Middle Aged; Mutation; Retrospective Studies; Risk Factors; Secondary Prevention; Sex Factors; Tyrosine

Alpha-fetoprotein (AFP) is the most widely used biomarker for hepatocellular carcinoma (HCC) surveillance, which is criticized as neither sensitive nor specific in active hepatitis and liver cirrhosis. The aim of this study was to determine the performance of AFP as a tumor marker for HCC in entecavir-treated patients with chronic hepatitis B (CHB). This was a retrospective-prospective cohort study of 1,531 entecavir-treated patients under regular HCC surveillance with AFP and ultrasonography. Mean age was 52 ± 12 years; 1,099 (72%) patients were male and 332 (21.7%) had clinical evidence of cirrhosis. At a mean follow-up of 51 ± 13 months, 57 (2.9%) patients developed HCC (median size: 3.3 cm). AFP fluctuated with alanine aminotransferase (ALT) and peaked at the time of starting entecavir, then gradually decreased after. AFP started to increase 6 months before the diagnosis of HCC. The receiver operator characteristic curve (AUROC) of AFP was highest at the time of HCC diagnosis (0.85; 95% confidence interval [CI]: 0.73-0.98) and remained satisfactory at 3 (0.82; 95% CI: 0.73-0.91) and 6 months (0.79; 95% CI: 0.69-0.89) before the diagnosis. Using the conventional AFP cut-off (20 μg/L) at month 0, the sensitivity and specificity to diagnose HCC were 38.6% and 98.9%, respectively. Adopting the lower cut-off value (6 μg/L) of AFP level at month 0, sensitivity was increased to 80.7%, whereas specificity was decreased to 80.4%.. On-treatment AFP is a specific tumor marker for HCC in CHB patients receiving entecavir therapy. Adopting a lower cut-off value of AFP level at 6 μg/L would significantly increase the sensitivity for HCC detection.

Topics: Adult; Aged; alpha-Fetoproteins; Antiviral Agents; Biomarkers, Tumor; Carcinoma, Hepatocellular; Female; Follow-Up Studies; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Retrospective Studies; Sensitivity and Specificity

Little is known about the long-term clinical outcome and durability of HBsAg seroclearance following nucleos(t)ide analogue (NUC) therapy in patients with chronic hepatitis B (CHB).. During a median follow-up period of 6 years (33 567 patient-years) of 5409 CHB patients who were initially treated with lamivudine or entecavir, a total of 110 achieved HBsAg seroclearance (0.33% annual seroclearance rate) and were included in this study.. Baseline alanine aminotransferase (ALT) level >5 times of upper limit of normal was associated with higher probability of HBsAg seroclearance (HR 1.80, p<0.01), while HBeAg positivity (HR 0.46, p<0.01), high HBV DNA level (log(10) IU/mL; HR 0.61, p<0.01), and cirrhosis (HR 0.48, p<0.01) were inversely associated with the probability of HBsAg seroclearance by multivariable analysis. During follow-up for 287 patient-years after HBsAg seroclearance, only two patients with baseline cirrhosis developed hepatocellular carcinoma (HCC) or died (0.7% annual risk), which was of a significantly lower rate compared with propensity score-matched patients without HBsAg seroclearance (HR 0.09, p<0.01). HBsAg reversion and/or HBV DNA reversion occurred in 18 patients, most of which were transient with extremely low serum levels of HBsAg (0.05-1.00 IU/mL) and HBV DNA (17-1818 IU/mL). None required retreatment. The cumulative probability of anti-HBs seroconversion (detection of anti-HBs) at 4 years was 67.4% by Kaplan-Meier analysis. Selection for lamivudine-resistance HBV mutants during treatment was not associated with composite reversion (p=0.66).. HBsAg seroclearance achieved after NUC treatment was associated with favourable clinical outcomes and was durable in most cases during long-term follow-up.

Topics: Adult; Alanine Transaminase; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Female; Follow-Up Studies; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Kaplan-Meier Estimate; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Time Factors

Chronic hepatitis B (CHB) can progress to cirrhosis, hepatocellular carcinoma (HCC), and ultimately liver-related deaths. Recently, owing to potent antiviral therapy with minimal side-effects, sustained suppression of hepatitis B virus replication can be achieved, thereby preventing such complications. We aimed to reappraise clinical courses regarding disease progression in the era of antiviral therapy.. Between 2001 and 2005, treatment-naïve Korean CHB patients without cirrhosis were enrolled and followed up for at least 5 years. During follow up, antiviral therapy was commenced according to Korean Association for the Study of the Liver guidelines, if eligible, and ultrasonography and laboratory and clinical assessment were performed regularly. Primary end-points were development of cirrhosis, hepatic decompensation, HCC, or liver-related deaths.. Of 360 patients, 323 (89.7%) received antiviral therapy such as lamivudine (70.6%), entecavir (8.7%), or telbivudine (6.5%). During follow up, cirrhosis developed in 29 (8.1%), hepatic decompensation in 4 (1.1%), and HCC in 15 (4.2%) patients. Annual incidences of cirrhosis, hepatic decompensation, and HCC were 1.05%, 0.14%, and 0.53% per person-year, respectively. Age was an independent predictor for developing cirrhosis (hazard ratio [HR] 1.075, 95% confidence interval [CI] 1.037-1.116; P < 0.001), whereas age (HR 1.060, 95% CI 1.012-1.111; P = 0.014) and cirrhosis (HR 17.470, 95% CI 5.081-60.063; P < 0.001) were those for developing HCC.. In the era of antiviral therapy, overall clinical courses have been much improved since introduction of lamivudine in 1999. However, patients with older age or cirrhosis are still subject to HCC development despite appropriate antiviral therapy, necessitating cautious surveillance.

Topics: Adult; Age Factors; Antiviral Agents; Carcinoma, Hepatocellular; Disease Progression; Female; Follow-Up Studies; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Republic of Korea; Telbivudine; Thymidine; Time Factors; Treatment Outcome

Little is known about whether the antiviral agent entecavir is more effective than a less potent drug, lamivudine, in reducing the risk of death and hepatocellular carcinoma (HCC) in patients with chronic hepatitis B.. We performed a retrospective analysis of data from 5374 consecutive adult patients with chronic hepatitis B, treated with entecavir (n = 2000) or lamivudine (n = 3374), at a tertiary referral hospital in Seoul, Korea, from November 1, 1999, through December 31, 2011. Data were collected from patients for up to 6 years and analyzed by a multivariable Cox proportional hazards model for the entire cohort and for propensity score-matched cohorts.. During the study period, 302 patients (5.6%) died, 169 (3.1%) received a liver transplant, and 525 (9.8%) developed HCC. Multivariable analyses showed that compared with lamivudine, entecavir therapy was associated with a significantly lower risk of death or transplantation (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.38-0.64), but a similar risk of HCC (HR, 1.08; 95% CI, 0.87-1.34). In the 1792 overall propensity-matched pairs, entecavir again was associated with a significantly lower risk of death or transplantation (HR, 0.49; 95% CI, 0.37-0.64) and a similar risk of HCC (HR, 1.01; 95% CI, 0.80-1.27). Entecavir also reduced the risk of death or transplantation, compared with lamivudine, in 860 pairs of patients with cirrhosis (HR, 0.42; 95% CI, 0.31-0.57) but there were no differences in risk for HCC (HR, 1.00; 95% CI, 0.78-1.28). However, entecavir and lamivudine did not have significantly different effects on clinical outcome in 878 pairs of patients without cirrhosis.. In a retrospective study of 5374 patients with chronic hepatitis B virus infection, entecavir therapy was associated with a significantly lower risk of death or transplantation than lamivudine. However, the drugs did not have different effects on HCC risk.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Female; Follow-Up Studies; Guanine; Hepatitis B, Chronic; Humans; Incidence; Lamivudine; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Proportional Hazards Models; Republic of Korea; Retrospective Studies; Risk Factors; Survival Rate; Treatment Outcome

It is generally stated that oral antiviral therapy in patients with chronic hepatitis B (CHB) decreases the risk of developing hepatocellular carcinoma (HCC). Although oral nucleos(t)ide analogues (NUCs) may induce a state similar to inactive stage CHB, the long-term risk for HCC in patients treated with NUCs compared with inactive CHB is unclear.. A total of 1378 patients who were treatment naïve and started NUC therapy and 1014 patients with inactive stage CHB who were HBeAg-negative and continuously had hepatitis B DNA <2000 IU/mL during follow-up were enrolled. The NUC group was divided into two groups by continuous viral suppression: NUC complete responder (CR) group and NUC incomplete responder (IR) group. Cumulative HCC incidence rates were compared between the groups.. The risk of developing HCC was significantly higher in the NUC CR group compared with the inactive CHB group, regardless of the presence of baseline liver cirrhosis (p<0.001). Risk factors associated with the development of HCC were treatment groups (p<0.001), age (p<0.001), sex (p<0.001) and the presence of liver cirrhosis at baseline (p=0.005). Of the NUC group, the cumulative incidence of HCC in the NUC IR group was significantly higher compared with the NUC CR group (p=0.028).. The use of potent oral antiviral therapy can effectively suppress HBV replication in patients with CHB. However, the risk of HCC development in patients treated with oral antiviral agent is still significantly higher than patients with inactive stage CHB.

Topics: Adult; Antiviral Agents; Arabinofuranosyluracil; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Incidence; Kaplan-Meier Estimate; Lamivudine; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Outcome Assessment, Health Care; Patient Acuity; Republic of Korea; Retrospective Studies; Risk Assessment; Risk Factors; Time

Analysis of alpha-fetoprotein (AFP) levels affords limited diagnostic accuracy because of the high false-positive rates, especially in those with active chronic hepatitis B (CHB). We measured AFP levels before and after commencement of oral antiviral therapy and explored the utility of these data in terms of early detection of hepatocellular carcinoma (HCC) in patients with CHB.. A total of 207 patients with CHB who were treated with an oral antiviral agent were consecutively included. Dynamic changes in AFP levels and the diagnostic utility of such changes for HCC detection during the therapy were explored.. The proportions of patients showing elevated AFP levels (≥ 20 ng/mL) were 22.2%, 5.5%, and 1.3% at baseline; and at 6 and 12 months after commencement of antiviral therapy, respectively. All patients who did not suffer from HCC exhibited normalization of AFP levels at 12 months. The cumulative incidence of HCC was 9.5% during 36 months of follow-up. If AFP levels were over 20 ng/mL after 12 months of antiviral treatment, the probability of HCC development approached certainty. The positive predictive value for HCC development remained at 100% in patients prescribed long-term (≥ 12 months) antiviral therapy, if AFP levels persistently or abruptly elevated more than 12 ng/mL.. In the era of oral antiviral agents, AFP might be a useful biomarker for HCC surveillance in patients with CHB.

Topics: Administration, Oral; Adult; Aged; alpha-Fetoproteins; Antiviral Agents; Arabinofuranosyluracil; Biomarkers; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Liver Neoplasms; Male; Middle Aged; Predictive Value of Tests; Retrospective Studies; Sensitivity and Specificity; Time Factors

This study aimed to evaluate the risk of development of hepatocellular carcinoma (HCC) according to underlying liver status and virological response (VR) to entecavir (ETV) in chronic hepatitis B patients with cirrhosis. Procollagen III N-terminal peptide (PIIINP) concentration during ETV treatment and its association with HCC development were also evaluated.. A total of 306 patients with clinically diagnosed liver cirrhosis were treated with ETV for ≥12 months and were subsequently followed up for the occurrence of HCC (median follow-up duration: 37.0 months). Patients who developed HCC within 12 months were excluded. VR was defined as a hepatitis B virus DNA level <20 IU/ml at 12 months after ETV treatment.. A total of 209 patients (68.3%) had compensated cirrhosis, and the remaining patients (31.7%) had decompensated cirrhosis. The 5-year cumulative incidence of HCC was 26.8%. A multivariate Cox regression analysis identified the following independent risk factors for developing HCC in all the patients: age >50 years (hazard ratio (HR)=8.41; 95% confidence interval (CI)=3.86-18.28; P=0.000), male sex (HR=4.24; 95% CI=1.83-9.81; P=0.001), high serum PIIINP level at 12 months (HR=1.07; 95% CI=1.02-1.13; P=0.007), and no VR at 12 months (HR=2.10; 95% CI=1.02-4.33; P=0.043). The subgroup analyses showed that no VR at 12 months is a significant risk factor for developing HCC in the patients with decompensated cirrhosis (HR=7.74; 95% CI=1.34-44.78; P=0.022) but not in those with compensated cirrhosis (P=0.749).. The antiviral treatment with ETV did not completely eliminate the risk of developing HCC in our patients with cirrhosis. However, VR to ETV was associated with a low probability that the patients with decompensated cirrhosis would develop HCC.

Topics: Adult; Aged; Aged, 80 and over; Antiviral Agents; Biomarkers, Tumor; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Republic of Korea; Retrospective Studies; Risk Factors; Treatment Outcome

Little is known about the role of antiviral therapy for patients with hepatitis B who underwent curative hepatectomy for hepatocellular carcinoma (HCC). The aim of this study was to assess whether antiviral therapy after hepatectomy improves the prognosis of HCC in preoperatively antiviral-free patients.. This was a retrospective study of postoperative antiviral treatment in patients (n=87) who underwent curative hepatectomy for HCC. Clinicopathological features and disease-free survival (DFS) were assessed. Patients were followed up to monitor HCC recurrence (median of 31 months).. In patients with HCC up to 3 cm (n=36), antiviral therapy reduced serum alanine transminase levels after 6 months of treatment (-26.3%, P<0.01). Among these patients, there was a significant prolongation of DFS in patients who received antiviral therapy after hepatectomy compared with those who did not (P=0.006). However, in patients with HCC greater than 3 cm (n=51), antiviral therapy did not decrease alanine transminase levels (+32.8%, P<0.01). In these patients, antiviral therapy had no effect on DFS (P>0.05). Using multivariate analysis, postoperative antiviral therapy was found to be an independent prognostic factor that was associated with a better DFS in patients with HCC up to 3 cm (odds ratio=0.220, 95% confidence interval: 0.120-0.434, P=0.008).. Antiviral therapy improved the prognosis of hepatitis B virus-related HCC up to 3 cm. Antiviral therapy should be considered a standard postoperative adjuvant therapy of hepatitis B virus-related HCC.

Topics: Alanine Transaminase; Antiviral Agents; Carcinoma, Hepatocellular; Chi-Square Distribution; Disease-Free Survival; Female; Guanine; Hepatectomy; Hepatitis B; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Neoplasm Recurrence, Local; Odds Ratio; Proportional Hazards Models; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome; Tumor Burden

Since the licensing of lamivudine in 1999, the treatment of chronic hepatitis B has been revolutionized by the introduction of oral nucleoside and nucleotide analogues (NAs), which act as inhibitors of the HBV polymerase. The effectiveness of the first of these substances was limited by incomplete response and resistance development in many patients, but today, highly potent substances are available that make a reliable and durable suppression of HBV replication, a reduction of necroinflammatory activity in the liver, and even a reversion of liver fibrosis achievable for almost all patients. Beyond that, NA treatment can prevent the development of hepatocellular carcinoma in many patients. HBeAg seroconversion appears in approximately 50% of all HBeAg-positive patients during NA treatment. However, the ideal treatment endpoint, the serologic loss of HBsAg, remains a rare event almost exclusively achievable for HBeAg-positive patients. After cessation of the treatment, HBV replication tends to relapse in most patients, which is why the duration of NA treatment is indefinite. Future treatment strategies should aim at tailoring individual NA treatment regimens to increase HBs loss rates and optimize treatment duration.

Topics: Adenine; Antiviral Agents; Arabinofuranosyluracil; Carcinoma, Hepatocellular; Gene Products, pol; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver; Liver Cirrhosis; Liver Neoplasms; Organophosphonates; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase; Telbivudine; Tenofovir; Thymidine; Treatment Outcome; Virus Replication

North American data are lacking on the effect of nucleos(t)ide analogues (NA) in preventing chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC).. To determine the incidence of HCC in NA-treated patients and compare this risk with that predicted without treatment based on the REACH-B model.. In this retrospective study, the incidence of HCC was determined in CHB patients initiated on NA from 1999 to 2012. Pre-treatment data utilised in the REACH-B model were used to predict the annual HCC risk. The standardised incidence ratio (SIR) for HCC was calculated by comparing the observed to expected number of cases, and HCC risk factors determined by Cox proportional hazards regression.. Five hundred and forty nine initiated NA (14% lamivudine, 5% adefovir, 1.5% telbivudine, 39% entecavir, 41% tenofovir). Over a median follow-up of 3.2 years (IQR 1.9-4.6), 11 (3.2%) were diagnosed with HCC. Among 322 with data to calculate the REACH-B model, the median age at treatment initiation was 46 years (IQR 38-55), 65% were male, 32% HBeAg positive and 20% had cirrhosis. The median pre-treatment ALT was 71 U/L (IQR 41-127) and HBV DNA was 6.48 log10 copies/mL (4.95-8.04). The observed annual HCC incidence (0.9%; 95% CI 0.5-1.7) was significantly lower than predicted without treatment by the REACH-B model (SIR 0.46; 95% CI 0.23-0.82); this risk was reduced after 4 years of therapy (SIR 0.49; 95% CI 0.2-1.00).. In this Canadian study of nucleos(t)ide analogues-treated patients with chronic hepatitis B, the incidence of HCC was lower than expected, suggesting that NA reduce the risk of chronic hepatitis B-related HCC.

Topics: Adenine; Adult; Antiviral Agents; Canada; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Incidence; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Nucleosides; Organophosphonates; Retrospective Studies; Risk Factors; Telbivudine; Tenofovir; Thymidine

This retrospective study was aimed to investigate the efficacy of prophylactic agents in hepatocellular carcinoma (HCC) patients receiving TACE and compare the difference between lamivudine and entecavir.. A consecutive series of 203 HBV-related HCC patients receiving TACE were analyzed including 91 patients given prophylactic agents. Virologic events, defined as an increase in serum HBV DNA level to more than 1 log10 IU/ml higher than the nadir level, hepatitis flares due to HBV reactivation and progression free survival (PFS) were the main endpoints.. Some 48 (69.6%) reached virologic response. Prophylaxis significantly reduced virologic events (8.8% vs 58.0%, p=0.000) and hepatitis flares (1.1% vs 13.4%, p=0.001). Patients presenting undetectable HBV DNA levels displayed a significantly improved PFS as compared to those who never achieved undetectable HBV DNA. Prophylaxis and e-antigen positivity were the only significant variables associated with virologic events. In addition, prophylaxis was the only independent protective factor for hepatitis flares. Liver cirrhosis, more cycles of TACE, HBV DNA negativity, a lower Cancer of the Liver Italian Program score, non-metastasis and no hepatitis flares were protective factors for PFS. Prophylactic lamivudine demonstrated similar efficacy as entecavir.. Prophylactic agents are efficacious for prevention of HBV reactivation in HCC patients receiving TACE. Achievement of undetectable HBV DNA levels displayed a significant capability in improving PFS. Moreover, persistent tumor residual lesions, positive HBV DNA and hepatitis B flares might be causes of tumor progression in these patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Child; Disease-Free Survival; DNA, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Reverse Transcriptase Inhibitors; Young Adult

To evaluate the short-term effect and safety of entecavir for the treatment of chronic hepatitis B (CHB) virus carriers.. Ninety-three cases of CHB virus infection (hepatitis B surface antigen (HBsAg)-positive, hepatitis B e antigen (HBeAg)-positive, hepatitis B core antibody (HBcAb)-positive, HBV DNA≥1x10(5) copies/mL) were divided into two groups: CHB virus carrier (47 cases) and CHB (46 cases). All of the 93 cases were given 0.5 mg entecavir orally once a day for 48 weeks. Virology, serology and biochemistry tests were perrmed at treatment weeks 0, 4, 12, 24 and 48. Side effects of entecavir and the incidence of liver cirrhosis and hepatocellular carcinoma were recorded.. The CHB virus carrier and CHB group had complete virological response rates of 14.9% and 17.4% at week 4, 51.1% and 63.0% at week 12, 76.6% and 89.1% at week 24, and 97.9% and 100% at week 48, respectively; there was no significant difference between the two groups (P>0.05). The CHB virus carrier and CHB group had partial virological response rates of 42.6% and 47.8% at week 4, 57.44% and 65.2% at week 12, 85.0% and 89.1% at week 24, and 100% and 100% at week 48, respectively; there was no significant difference between the two groups (P>0.05). No cases in either group experienced virologic breakthrough during the treatment course. The CHB virus carrier and CHB group had serological response (HBeAg-negative) rates of 0 and 4.3% at week 4, 2.1% and 8.7% at week 12, 4.3% and 13.0% at week 24, and 8.5% and 21.7% at week 48, respectively; there was no significant difference between the two groups (P>0.05). The CHB virus carrier and CHB group had HBeAg seroconversion rates of 0 and 0 at week 4, 0 and 4.4% at week 12, 2.1% and 10.9% at week 24, and 6.4% and 17.4% at week 48, respectively; there was no significant difference between the two groups (P>0.05). No case in either group showed HBsAg-negativity and seroconversion during the treatment course. The CHB group had a biochemical response (alanine aminotransferase normalization) rate of 26.1% at week 4, 65.2% at week 12, 91.3% at week 24, and 97.8% at week 48.No case in either group showed biochemical breakthrough during the treatment course. There were no cases of liver cirrhosis or hepatocellular carcinoma in either group. There were no side effects of the entecavir treatment experienced in either group.. Antiviral therapy with entecavir is effective, safe and well tolerated in CHB virus carriers.

Topics: Alanine Transaminase; Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms

Little is known about the validity of hepatocellular carcinoma (HCC) risk scores derived from treatment-naïve patients with chronic hepatitis B for patients treated with entecavir.. We performed a retrospective-prospective cohort study of 1531 patients with chronic hepatitis B (age, 51 ± 12 years; 1099 male; 332 with clinical cirrhosis) who were treated with entecavir 0.5 mg daily for at least 12 months at Prince of Wales Hospital in Hong Kong from December 2005 to August 2012. The patients were assessed once every 3 to 6 months for symptoms, drug history, and adherence; blood samples were collected for biochemical analyses. We validated 3 HCC risk scores (CU-HCC, GAG-HCC, and REACH-B scores) based on data collected when patients began treatment with entecavir and 2 years later.. After 42 ± 13 months of follow-up, 47 patients (2.9%) developed HCC. The 5-year cumulative incidence of HCC was 4.3% (95% confidence interval [CI], 3.6%-5.0%). Older age, presence of cirrhosis, and virologic remission after 24 months or more of therapy were independently associated with HCC in the entire cohort; advanced age and hypoalbuminemia were associated with HCC in patients without cirrhosis. The area under the receiver operating characteristic curves (AUCs) for baseline CU-HCC, GAG-HCC, and REACH-B scores for HCC were 0.80 (95% CI, 0.75-0.86), 0.76 (95% CI, 0.70-0.82), and 0.71 (95% CI, 0.62-0.81), respectively; the time-dependent AUCs 1 to 4 years after patients started treatment were comparable to those at baseline. The cutoff value of the baseline CU-HCC score identified patients who would develop HCC with 93.6% sensitivity and 47.8% specificity, the baseline GAG-HCC score with 55.3% sensitivity and 78.9% specificity, and the baseline REACH-B score with 95.2% sensitivity and 16.5% specificity. Compared with patients with CU-HCC scores <5 at baseline, those with CU-HCC scores that either decreased from ≥5 to <5 or remained ≥5 had a higher risk of HCC (5-year cumulative incidences, 0% vs 3.9% and 7.3%; P = .002 and P < .001, respectively).. The CU-HCC, GAG-HCC, and REACH-B HCC risk scores accurately predict which patients with chronic hepatitis B treated with entecavir will develop HCC.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Confidence Intervals; DNA, Viral; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Hong Kong; Humans; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Reproducibility of Results; Retrospective Studies; Risk Assessment; Risk Factors

Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) is the most frequent and difficult-to-treat viral hepatitis worldwide. HBV DNA and hepatitis B surface antigen (HBsAg) serum levels, which help the early identification of non-responders to pegylated interferon (PEG-IFN), prompt more flexible individualized therapeutic strategies exploiting the benefits of both PEG-IFN and nucleoside/nucleotide analogues (NAs). We assessed the cost-effectiveness of week-12 HBV DNA/HBsAg stopping rule for early interruption and switch to currently most effective NA treatments (entecavir [ETV] or tenofovir disoproxil fumarate [TDF]).. A decision-analytic Markov model was developed in the following health-related states: CHB, compensated cirrhosis (CC) and decompensated cirrhosis, hepatocellular carcinoma, liver transplant, post-liver transplant, death, virological response, relapse and HBsAg clearance. Simulated strategies included: ETV/TDF in CHB; ETV/TDF delayed until CC; first-line PEG-IFN followed by switch to ETV/TDF for either patients meeting the week-12 stopping rule or week-48 null-responders/relapsers; and first-line PEG-IFN followed by switch to ETV/TDF delayed until CC. ETV and TDF were considered alternatively for a total of eight strategies. A lifetime simulation horizon was applied.. Early treatment strategies using NAs with or without first-line PEG-IFN provided the highest results (approximately 22 life-years and 15 quality-adjusted life years [QALYs]). Delayed treatments until cirrhosis development resulted in poorer outcomes. The average per-patient lifetime costs ranged from €33,500 (TDF in CC) to €68,900 (TDF in CHB). Costs using ETV were 20-50% higher. First-line PEG-IFN strategies ranged from dominant (that is, more effective and less costly) to highly cost-effective, although differences in QALYs were always very narrow.. The cost-effectiveness of antiviral therapy of HBeAg-negative CHB could be improved significantly using first-line PEG-IFN followed by a switch to NAs in either patients meeting the week-12 HBV DNA/HBsAg stopping rule or week-48 non-responders/relapsers.

Topics: Adenine; Adult; Antiviral Agents; Carcinoma, Hepatocellular; Cost-Benefit Analysis; Drug Administration Schedule; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Liver Cirrhosis; Liver Neoplasms; Male; Markov Chains; Organophosphonates; Polyethylene Glycols; Precision Medicine; Prognosis; Quality-Adjusted Life Years; Recombinant Proteins; Tenofovir; Viral Load

Hepatitis B virus (HBV) is responsible for 50%-80% of cases of hepatocellular carcinoma (HCC) worldwide. Entecavir (ET) is a potent inhibitor of chronic HBV-DNA polymerase, inhibiting both the priming and elongation steps of viral DNA replication. Sorafenib (SO) has proven efficacy in prolonging survival in patients with advanced HCC. In this frontier report we discuss a possible way to optimize treatment outcomes in patients with HBV and HCC by treatment with ET and SO, on the basis of our practice and published evidence from the literature.

Topics: Aged; Antineoplastic Agents; Antiviral Agents; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Sorafenib; Time Factors; Treatment Outcome

This study investigated the influence of virological response (VR) to entecavir on clinical liver disease progression in nucleos(t)ide analogue (NA)-naive and -experienced patients.. We investigated 487 chronic hepatitis B patients (323 NA-naive, 164 NA-experienced) treated with entecavir monotherapy for at least 12 months. VR was defined as hepatitis B virus DNA level <300 copies/mL during entecavir therapy. Clinical events were defined as hepatic decompensation, hepatocellular carcinoma (HCC), death and liver transplantation.. Of the 487 patients, 49 developed clinical events during entecavir treatment. Of those, 36 developed HCC. For all patients, Cox regression analysis showed that age, baseline cirrhosis, alanine aminotransferase level ≤200 U/L, albumin level and no VR during entecavir treatment were independent predictors for clinical events and HCC development. However, the benefit of VR to entecavir was significant for clinical events and HCC only in NA-experienced patients, but not in NA-naive patients. For the further analysis of the different subgroups of NA-experienced patients, the benefit of VR to entecavir was significant for clinical events or HCC only in patients with prior lamivudine- or adefovir-resistant mutants, but not in NA-experienced patients who had never developed lamivudine- or adefovir-resistant mutants. VR at month 12 (but not early VR at month 6) remained a significant predictor associated with the development of clinical events and HCC in NA-experienced patients.. VR to entecavir was associated with a reduced risk of clinical events and HCC in NA-experienced patients, particularly in those who had prior lamivudine- or adefovir-resistant mutants.

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Drug Resistance, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Risk Assessment; Treatment Outcome; Viral Load

Topics: Antiviral Agents; Asian People; Carcinoma, Hepatocellular; Cohort Studies; Guanine; Hepatitis B Antibodies; Hepatitis B Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Prognosis; Republic of Korea; Treatment Outcome

Entecavir (ETV) is a potent inhibitor of viral replication in chronic hepatitis B and prolonged treatment may result in regression of fibrosis. The aim of this study was to investigate the effect of ETV on disease progression.. In a multicentre cohort study, 372 ETV-treated patients were investigated. Clinical events were defined as development of hepatocellular carcinoma (HCC), hepatic decompensation or death. Virological response (VR) was defined as HBV DNA <80 IU/ml.. Patients were classified as having chronic hepatitis B without cirrhosis (n=274), compensated cirrhosis (n=89) and decompensated cirrhosis (n=9). The probability of VR was not influenced by severity of liver disease (p=0.62). During a median follow-up of 20 months (IQR 11-32), the probability of developing clinical events was higher for patients with cirrhosis (HR 15.41 (95% CI 3.42 to 69.54), p<0.001). VR was associated with a lower probability of disease progression (HR 0.29 (95% CI 0.08 to 1.00), p=0.05) which remained after correction for established risk factors such as age. The benefit of VR was only significant in patients with cirrhosis (HR 0.22 (95% CI 0.05 to 0.99), p=0.04) and remained after excluding decompensated patients (HR 0.15 (95% CI 0.03 to 0.81), p=0.03). A higher HBV DNA threshold of 2000 IU/ml was not associated with the probability of disease progression (HR 0.20 (95% CI 0.03 to 1.10), p=0.10).. VR to ETV is associated with a lower probability of disease progression in patients with cirrhosis, even after correction for possible baseline confounders. When using a threshold of 2000 IU/ml, the association between viral replication and disease progression was reduced, suggesting that complete viral suppression is essential for nucleoside/nucleotide analogue treatment, especially in patients with cirrhosis.

Topics: Adult; Aged; Algorithms; Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Disease Progression; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Guanine; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Risk Assessment; Risk Factors; Severity of Illness Index; Treatment Outcome; Virus Replication

Polymorphisms in estrogen receptor alpha (ESR1) are reported to be associated with the susceptibility to persistent HBV infection, HBV liver cirrhosis and HBV-related hepatocellular carcinoma (HCC).. To test the hypothesis that polymorphisms in estrogen receptor alpha (ESR1) might influence the virological response to entecavir (ETV) therapy, we examined two polymorphisms (PvuII and XbaI) in 76 nucleoside-naïve chronic hepatitis B (CHB) patients. All of the patients (52 HBeAg-positive and 24 HBeAg-negative) were treated with ETV 0.5 mg daily and followed up for a median time of 96 weeks (range 48-96). Polymorphisms were determined using the polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) method.. Under an additive model, the univariate analysis showed that patients carrying the PvuII T/C genotype might have higher virological responders than those carrying the T/T and C/C genotypes at week 48 (87.7 vs. 57.1 vs. 58.3 %; P = 0.012) and week 96 (96.7 vs. 64.3 vs. 24 87.5 %; P = 0.018), although this difference disappeared with the multiple analysis at week 48 [95 % confidence interval (CI) 0.687-3.841; P = 0.269] and week 96 (95 % CI 0.861-18.016; P = 0.077). Conversely, the univariate analysis suggests statistical significance between the recessive model of PvuII (TT vs. TC/CC) and virological response at week 48 (57.1 vs. 81.1 %; P = 0.033) and week 96 (64.3 vs. 94.7 %; P = 0.017). Multiple regression analysis affirmed the significant and independent association between the recessive model of PvuII and virological response. In other words, patients carrying at least one PvuII C allele (TC/CC) had a better likelihood of achieving virological response compared with those carrying the T/T genotype at week 48 (95 % CI 1.026-14.785, P = 0.046) and week 96 (95 % CI 1.456-57.509; P = 0.018). XbaI polymorphisms were not significantly associated with virological response.. Our results suggest that the PvuII polymorphism may play an important role in determining ETV efficacy after 48 and 96 weeks of treatment, at least in this study population.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Estrogen Receptor alpha; Female; Genetic Predisposition to Disease; Genotype; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Male; Medication Adherence; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Regression Analysis

Liver grafts from hepatitis B surface antigen-negative and anti-core antibody-positive donors are safe for liver transplant. However, the use of hepatitis B surface antigen-positive liver donors in liver transplants is controversial. We assessed the safety and effectiveness of liver transplants using hepatitis B surface antigen-positive liver grafts to patients with diseases related to hepatitis B virus.. We retrospectively reviewed 23 patients who had a deceased-donor liver transplant using hepatitis B surface antigen-positive liver grafts. All patients had end-stage liver disease secondary to hepatitis B virus infection. Recipients had oral entecavir and intravenous or intramuscular injection of hepatitis B immune globulin for >1 year after the transplant.. Two patients died from severe perioperative pneumonia, and the other 21 patients were followed for 9 to 38 months after transplant. All 21 patients remained hepatitis B surface antigen-positive. A repeat liver transplant was performed in 1 patient at 5 months after the initial transplant because of biliary ischemia. There were 3 patients who died from recurrent liver cancer at 9, 14, and 18 months after transplant. There were 18 patients (78%) who survived and 17 grafts (74%) that survived.. Liver transplant using hepatitis B surface antigen-positive liver grafts is safe for patients with end-stage liver disease secondary to hepatitis B virus infection.

Topics: Administration, Oral; Adult; Antiviral Agents; Biomarkers; Carcinoma, Hepatocellular; Donor Selection; Drug Administration Schedule; Guanine; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B Vaccines; Humans; Immunosuppressive Agents; Injections, Intramuscular; Injections, Intravenous; Kaplan-Meier Estimate; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Risk Factors; Time Factors; Tissue Donors; Treatment Outcome

Chronic hepatitis B virus (HBV) infection leads to cirrhosis and hepatocellular carcinoma (HCC). Antiviral agents are thought to reduce HCC development, but agents such as lamivudine (LAM) have a high rate of drug resistance. We compared the incidence of HCC in 472 entecavir (ETV)-treated patients and 1,143 nontreated HBV patients (control group). Propensity score matching eliminated the baseline differences, resulting in a sample size of 316 patients per cohort. The drug mutation resistance was 0.8% (4/472) in the ETV group. The cumulative HCC incidence rates at 5 years were 3.7% and 13.7% for the ETV and control groups, respectively (P < 0.001). Cox proportional hazard regression analysis, adjusted for a number of known HCC risk factors, showed that patients in the ETV group were less likely to develop HCC than those in the control group (hazard ratio: 0.37; 95% confidence interval: 0.15-0.91; P = 0.030). Both cohorts were applied in three previously reported risk scales and risk scores were generated based on age, gender, cirrhosis status, levels of alanine aminotransferase, hepatitis B e antigen, baseline HBV DNA, albumin, and bilirubin. The greatest HCC risk reduction occurred in high-risk patients who scored higher on respective risk scales. In sub analyses, we compared treatment effect between nucleos(t)ide analogs, which included matched LAM-treated patients without rescue therapy (n = 182). We found HCC suppression effect greater in ETV-treated (P < 0.001) than nonrescued LAM-treated (P = 0.019) cirrhosis patients when they were compared with the control group.. Long-term ETV treatment may reduce the incidence of HCC in HBV-infected patients. The treatment effect was greater in patients at higher risk of HCC.

Topics: Adult; Carcinoma, Hepatocellular; Cohort Studies; Drug Resistance, Viral; Female; Guanine; Hepatitis B, Chronic; Humans; Incidence; Lamivudine; Liver Neoplasms; Male; Middle Aged; Retrospective Studies

To correlate early HBV-DNA suppression by antiviral treatment with posthepatectomy long-term survivals in patients with HBV-related hepatocellular carcinoma (HCC).. A retrospective study was conducted on patients with a baseline HBV-DNA load of >2,000 IU/ml. The cumulative rates of HBV-DNA undetectability at weeks 24 and 48, as well as long-term tumor recurrence and overall survivals were determined.. Of 1,040 patients with a high baseline HBV-DNA load, 865 patients received antiviral treatment. At a median follow-up of 42 months, 616 patients (59.2 %) had developed HCC recurrence and 482 patients (46.3 %) had died. The median time to recurrence was 25 months. In patients who received antiviral treatment, the cumulative rates of HBV-DNA undetectability (<200 IU/ml) were 54.3 and 88.1 % at weeks 24 and 48, respectively. There was no significant difference between the two groups of patients who received antiviral treatment or not for disease-free survival. On multivariate analyses, tumor size >5 cm, blood transfusion, surgical margin <1 cm, presence of satellite nodules, presence of portal vein tumor thrombus and high Ishak inflammation score were significant risk factors of HCC recurrence. Also, tumor size >5 cm, surgical margin <1 cm, presence of satellite nodules, presence of portal vein tumor thrombus and high Ishak fibrosis score were significant factors associated with poor postoperative overall survival. On the other hand, an undetectable HBV-DNA level before week 24 was a significant protective factor of disease-free survival and overall survival.. Early HBV-DNA suppression with antiviral treatment improved prognosis of patients with HBV-related HCC.

Topics: Adenine; Adult; Antiviral Agents; Carcinoma, Hepatocellular; Disease-Free Survival; DNA, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Kaplan-Meier Estimate; Lamivudine; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Neoplasm Recurrence, Local; Organophosphonates; Portal Vein; Proportional Hazards Models; Retrospective Studies; Risk Factors; Viral Load

Entecavir is a potent antiviral agent with high genetic barrier to resistance, hence it is currently recommended as first-line antiviral therapy for chronic hepatitis B (CHB). The aim of this study was to investigate the efficacy of entecavir on clinical outcomes and deaths. It was a retrospective-prospective cohort study based on two cohorts of patients. The entecavir cohort included consecutive CHB patients who had received entecavir 0.5 mg/day for at least 12 months. The historical control cohort included untreated patients recruited since 1997 who underwent routine clinical care. The primary outcome was the 5-year cumulative probability of hepatic events, defined as any cirrhotic complications, hepatocellular carcinoma (HCC), and/or liver-related mortality. A total of 1,446 entecavir-treated patients (72% men; age, 51 ± 12 years; follow-up, 36 ± 13 months) and 424 treatment-naïve patients (65% men; age, 41 ± 13 years; follow-up, 114 ± 31 months) were studied. Overall, there was no difference in hepatic events between the entecavir and control cohorts. Among patients with liver cirrhosis (482 entecavir-treated, 69 treatment-naïve), entecavir-treated patients had reduced risks of all clinical outcomes when compared with treatment-naïve patients with cirrhosis after adjusted for model for end-stage liver disease score: hepatic events (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.34-0.78; P = 0.002), HCC (HR, 0.55; 95% CI, 0.31-0.99; P = 0.049), liver-related mortality (HR, 0.26; 95% CI, 0.13-0.55; P < 0.001), and all-cause mortality (HR, 0.34; 95% CI, 0.18-0.62; P < 0.001). Entecavir-treated patients with cirrhosis who failed to achieve undetectable hepatitis B virus DNA (105/482 [22%]) had comparable risk of hepatic events as the untreated patients.. Entecavir therapy reduces the risks of hepatic events, HCC, liver-related and all-cause mortality of CHB patients with liver cirrhosis in 5 years, particularly among those who had maintained viral suppression.

Topics: Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Female; Guanine; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Retrospective Studies

Topics: Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male

Tremendous healthcare resources have been spent on the management of chronic hepatitis B (CHB) and its related complications. Therefore, a proper evaluation of the cost-effectiveness of pharmacotherapy is vital in aid of decision-making. The aim of the present study was to examine the long-term economic and clinical influence if lamivudine was replaced by entecavir in a group of CHB patients.. A recently published decision analytic model was adapted to study the cost-effectiveness of 2 years of treatment of entecavir in a hypothetical cohort of 1000 hepatitis B e antigen (HBeAg)-negative CHB patients from a public hospital perspective. Compensated cirrhosis (CC) and de-compensated cirrhosis (DC) and hepatocellular carcinoma (HCC) events were projected to 10 years. Hong Kong-specific health care costs were used. Quality Adjusted Life Years (QALYs) were calculated using the utility values obtained from a local study.. In the base case analysis, compared with lamivudine, the use of entecavir was expected to reduce the incidences of CC, DC and HCC by 41.8%, 57.1% and 49.3%, respectively, and lead to a saving of $US 1.17 million in medical cost. The overall disease management cost for entecavir, which was 67.7% higher than lamivudine for 2 years treatment was reduced to 17.2% after projecting 2-year treatment duration to 10 years. The incremental cost per QALY gained for entecavir compared with lamivudine was $US 13 759.. Based on the recommended cost-effectiveness threshold of the World Health Organization, entecavir is considered cost-effective compared with lamivudine in treating CHB in Hong Kong when long term medical consequences were considered.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Cost-Benefit Analysis; DNA, Viral; Drug Costs; Drug Resistance, Viral; Guanine; Health Care Costs; Hepatitis B virus; Hepatitis B, Chronic; Hong Kong; Hospitals, Public; Humans; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Quality-Adjusted Life Years; Viral Load

To determine whether nucleoside analogue therapy is associated with improved survival in patients with hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) who are treated solely with transarterial chemoembolization.. A retrospective chart review of patients diagnosed with HBV-associated HCC was performed to identify patients treated solely with chemoembolization. Relevant demographic and clinical data were extracted and recorded. The influence of therapy with nucleoside analogues (lamivudine, adefovir dipivoxil, or entecavir) was determined by estimating the survival function using the Kaplan-Meier product-limit method.. The inclusion criteria for chemoembolization were met by 81 patients (67 men and 14 women, mean age 60.6 years ± 9.2); 21 (25.9%) of these patients had been treated with nucleoside analogues. The number of chemoembolization treatments was significantly greater in the patients who were treated with nucleoside analogues (3.43 ± 2.32) than in the patients who did not receive nucleoside analogues (1.82 ± 0.95; P = .0022). The 1-year, 3-year, and 5-year survival rates were 89.5%, 66.8%, and 40.5% in the patients treated with nucleoside analogues and 72.6%, 27.5%, and 14.3% in the patients not treated with nucleoside analogues. The survival rate was significantly higher in the patients who received nucleoside analogues (P = .0051). Nucleoside analogue intake was an independent factor that was associated with increased survival (P = .0063).. Administration of nucleoside analogues was associated with longer survival in patients with HBV-associated HCC who were treated with transarterial chemoembolization.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antiviral Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Chi-Square Distribution; Disease-Free Survival; Female; Guanine; Hepatitis B, Chronic; Humans; Japan; Kaplan-Meier Estimate; Lamivudine; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Nucleosides; Organophosphonates; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Risk Factors; Survival Rate; Time Factors; Treatment Outcome

Little information is available about the antiviral efficacy of lamivudine (LAM) and entecavir (ETV) in patients with hepatitis B virus (HBV)-related advanced hepatocellular carcinoma (HCC). Thus, we compared the antiviral efficacy of LAM and ETV in these patients.. The medical records of 134 antiviral therapy-naïve patients with HBV-related advanced HCC (modified Union for International Cancer Control [UICC] Tumor, Nodes, and Metastases [TNM] stages III-IV) treated between January 2005 and September 2009 were reviewed. After HCC diagnosis, 87 (64.9%) and 47 (35.1%) patients received LAM and ETV, respectively.. The mean age of patients (115 men, 19 women) was 53 years. Sixty-five (48.5%) and 69 (51.5%) patients had TNM stages III and IV HCC, respectively. Treatment outcomes during follow-up, including virologic, biochemical, and serologic responses and appearance of antiviral resistance, were similar in the LAM and ETV groups (all P>0.05). Multivariate analysis identified Child-Pugh class, α-fetoprotein, and TNM stage as independent predictors of overall survival (all P<0.05). Antiviral agent type (LAM vs ETV) did not influence overall survival (median 9.6 months in LAM vs 13.6 months in ETV group; P=0.493). HCC treatment was not interrupted due to HBV flare up in any patient.. The antiviral efficacy of LAM and ETV was similar and the type of antiviral agent did not influence overall survival in patients with HBV-related advanced HCC. Thus, LAM, which is less expensive than ETV in Korea, might be sufficient to control HBV in these patients.

Topics: Adult; Aged; alpha-Fetoproteins; Antiviral Agents; Carcinoma, Hepatocellular; Chi-Square Distribution; DNA, Viral; Drug Resistance, Viral; Female; Genotype; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Kaplan-Meier Estimate; Lamivudine; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Neoplasm Staging; Retrospective Studies; Severity of Illness Index

To assess whether commencement of antiviral therapy after hepatectomy improves the prognosis of hepatocellular carcinoma (HCC) in preoperatively antiviral-naive patients with chronic hepatitis B virus (HBV) infection.. Retrospective analysis of a prospectively collected database.. University teaching hospital.. Disease-free and overall survival rates.. One hundred thirty-six patients received major hepatectomy for HBV-related HCC from September 1, 2003, through December 31, 2007. Among them, 42 patients received antiviral therapy (treatment group) after hepatectomy, whereas 94 did not (control group). Patient demographics, preoperative liver function, tumor characteristics, and liver function at the time of tumor recurrence were comparable between the 2 groups. Disease-free and overall survival rates were significantly prolonged in the treatment group. The 1-, 3-, and 5-year overall survival rates in the treatment group were 88.1%, 79.1%, and 71.2%, respectively; in the control group, 76.5%, 47.5%, and 43.5%, respectively (P = .005). The 1-, 3-, and 5-year disease-free survival rates in the treatment group were 66.5%, 51.4%, and 51.4%, respectively; in the control group, 48.9%, 33.8%, and 33.8%, respectively (P = .05). Subgroup analysis stratified against tumor stage and major vascular invasion showed that posthepatectomy antiviral treatment conferred a significant survival benefit in stages I and II tumors or HCCs without major venous invasion.. Antiviral therapy improves the prognosis of HBV-related HCC. It should be considered after hepatectomy for HBV-related HCC, especially in early-stage tumors.

Topics: Adult; Aged; Aged, 80 and over; Antiviral Agents; Carcinoma, Hepatocellular; Disease-Free Survival; Female; Guanine; Hepatectomy; Hepatitis B, Chronic; Humans; Lamivudine; Liver Function Tests; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Survival Rate

We investigated the efficacy of entecavir, a cyclopentyl guanosine nucleoside analogue, as monoprophylaxis in patients with chronic hepatitis B who received a liver transplant.. We studied data from 80 consecutive patients who received a liver transplant (47 from living donors and 33 from deceased donors) for hepatitis B-related disease and entecavir monotherapy as prophylaxis. None of the patients received hepatitis B immunoglobulin. Indications for transplant included decompensation from cirrhosis (27.5%), acute-on-chronic hepatitis B (47.5%), and hepatocellular carcinoma (25%). The median follow-up time was 26 months (range, 5-40 months). Before transplant, 33 patients were not on antiviral therapy and 47 were on oral therapy (18 had received less than 3 months of treatment).. At the time of transplant, the median log HBV DNA level was 3.5 copies/mL (range, 1.54-8.81); 21 patients (26%) had undetectable levels of HBV DNA. The cumulative rate of hepatitis B surface antigen (HBsAg) loss was 86% and 91% after 1 and 2 years, respectively. Ten patients had reappearance of HBsAg. Eighteen patients (22.5%) were HBsAg positive at the time of their last examination; 17 of these had undetectable levels of HBV DNA, and the remaining patient had a low level of HBV DNA (217 copies/mL). There was no evidence of mutations at sites that confer resistance to entecavir among patients who were HBsAg positive.. Although only 26% of patients had complete viral suppression at the time of transplant, 91% lost HBsAg, with 98.8% achieving undetectable levels of HBV DNA. A hepatitis B immunoglobulin-free regimen of entecavir monotherapy is effective after liver transplantation for chronic hepatitis B.

Topics: Adult; Aged; Antiviral Agents; Biomarkers; Carcinoma, Hepatocellular; Chi-Square Distribution; DNA, Viral; Female; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hong Kong; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Magnetic Resonance Imaging; Male; Middle Aged; Postoperative Care; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Viral Load; Young Adult

We investigated the efficacy and effectiveness of entecavir in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients.. We enrolled 231 nucleoside-naïve chronic hepatitis B (CHB) patients primarily treated with entecavir 0.5 mg/day for at least 6 months in our institution. Of these, 71 patients had HCC at the start of entecavir treatment (HCC group) and 160 did not (non-HCC group). We compared antiviral responses to entecavir in the two groups, and evaluated the effects of entecavir on the clinical outcomes of curatively-treated HCC patients.. The HCC and non-HCC groups had similar cumulative rates of HBV-DNA negativity, alanine aminotransferase normalization, and hepatitis e antigen loss in year 2 (100% vs 95.4%, 94.7% vs 97.3%, and 40.8% vs 41.8%, respectively; P > 0.05). Entecavir treatment for 12 months decreased mean Model for End-Stage Liver Disease scores in patients with cirrhosis and HCC (7.2 vs 5.6, P < 0.001). Of the 71 HCC patients, 16 underwent curative therapies concurrently with entecavir; hepatectomy in six and radiofrequency ablation in 10, and the 55 remaining patients received transarterial chemoembolization or conservative treatment. In a subgroup of 16 HCC patients receiving curative treatments, patients who became serum HBV DNA negative by week 24 had better overall survival (P = 0.039), but not recurrence-free survival (P = 0.961), than those who did not.. First-line entecavir monotherapy is comparably effective in CHB patients with and without HCC, and improves hepatic function in HBV-related HCC patients. An early virological response to entecavir is prognostic of improved survival following curative therapy against HBV-related HCC.

Topics: Adult; Aged; Antiviral Agents; Biomarkers; Carcinoma, Hepatocellular; Catheter Ablation; Chemoembolization, Therapeutic; Chi-Square Distribution; Disease-Free Survival; DNA, Viral; Female; Guanine; Hepatectomy; Hepatitis B virus; Hepatitis B, Chronic; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Male; Middle Aged; Propensity Score; Proportional Hazards Models; Republic of Korea; Retrospective Studies; Risk Assessment; Risk Factors; Survival Rate; Time Factors; Treatment Outcome; Viral Load

Alpha-fetoprotein (AFP) is a marker of the presence of hepatocellular carcinoma (HCC), but is also elevated in advanced chronic hepatitis B. The detection and usage of AFP tests need to be improved. A cohort of 101 patients with advanced chronic hepatitis B and elevated AFP values was treated with entecavir (ETV) or peginterferon-alpha2a. ETV was more effective in reducing AFP levels; mean time to AFP normalization was 11.9 weeks after ETV treatment initiation vs 22.3 weeks in peginterferon treated patients (P = 0.000). An additional cohort of 93 hepatitis B virus (HBV) cirrhotic patients with elevated AFP were treated with ETV prospectively and maintained under intensive surveillance. HCC developed in 16 (17.2%) patients in whom the strongest independent predictor was a continued AFP rise in spite of ongoing treatment. In this context, nodules of sizes 10-14 mm and 15-20 mm were detected in 40% of patients each. In conclusion, HBV cirrhotic patients with rising AFP levels were at very high risk of HCC development. Early detection of minute lesions may be possible by monitoring AFP levels, whilst patients are on treatment in conjunction with enhanced computed tomography examination.

Topics: Adult; alpha-Fetoproteins; Antiviral Agents; Biomarkers, Tumor; Carcinoma, Hepatocellular; Early Diagnosis; Female; Guanine; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins

Topics: Aged; Antiviral Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Liver Neoplasms; Male; Treatment Outcome; Virus Replication

The recurrence rate of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is high even in patients receiving curative therapy. In this study, we analysed the risk factors for tumour recurrence after curative therapy for HBV-related HCC while under treatment with nucleot(s)ide analogues (NAs) by measuring serum HBcrAg and intrahepatic covalently closed circular DNA (cccDNA) levels to elucidate the viral status associated with HCC recurrence.. We enrolled 55 patients who developed HCC during NA therapy and underwent either curative resection or percutaneous ablation for HCC.. Hepatocellular carcinoma recurred in 21 (38%) of the patients over a period of 2.2 (range, 0.2-7.4) years. In multivariate analysis, serum HBcrAg levels ≥4.8 log U/ml at the time of HCC diagnosis (hazard ratio, 8.96; 95% confidential interval, 1.94-41.4) and portal vein invasion (3.94, 1.25-12.4) were independent factors for HCC recurrence. The recurrence-free survival rates of the high cccDNA group were significantly lower than those of the low cccDNA group only in patients who underwent resection (P=0.0438). A positive correlation (P=0.028; r=0.479) was observed between the intrahepatic cccDNA and the serum HBcrAg levels at the incidence of HCC.. HBcrAg is a predictor of the post-treatment recurrence of HCC during antiviral therapy. Serum HBcrAg and intrahepatic cccDNA suppression by NAs may be important to prevent HCC recurrence.

Topics: Adenine; Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; Catheter Ablation; Disease-Free Survival; Female; Guanine; Hepatectomy; Hepatitis B Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Japan; Kaplan-Meier Estimate; Lamivudine; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Organophosphonates; Proportional Hazards Models; Risk Assessment; Risk Factors; RNA, Viral; Survival Rate; Time Factors; Treatment Outcome

Topics: Adenine; Antiviral Agents; Carcinoma, Hepatocellular; Clinical Trials as Topic; Guanine; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Organophosphonates; Polyethylene Glycols; Recombinant Proteins; Tenofovir

Virologic resistance emerging during entecavir (ETV) therapy for hepatitis B virus (HBV) requires three substitutions in the viral reverse transcriptase (RT), signifying a high barrier to resistance. Two of these substitutions are associated with lamivudine resistance (LVDr) in the tyrosine-methionine-aspartate-aspartate (YMDD) motif (rtM204V and rtL180M), whereas the other occurs at one or more positions specifically associated with ETV resistance (ETVr): rtT184, rtS202, or rtM250. Although a variety of substitutions at these primary ETVr positions arise during ETV therapy, only a subset give rise to clinical virologic breakthrough. To determine the phenotypic impact of observed clinical and potential new ETVr substitutions, a comprehensive panel of clones containing every possible amino acid at the three primary ETVr positions in LVDr HBV was constructed and analyzed in vitro. A range of replication capacities was observed for the panel, but none of the mutations rescued replication of the LVDr mutant to the wild-type level. More clones with residue rtS202 substitutions were severely impaired than those at rtT184 or rtM250. A wide variety of ETV susceptibilities was observed, ranging from approximately eight-fold (no increase over the LVDr parent) to greater than 400-fold over the wild-type. A correlation was identified between clinically observed substitutions and those displaying higher in vitro replication and resistance, especially those from virologic breakthrough patients.. The high number of tolerated and resistant ETVr substitutions is consistent with models predicting that the mechanism for ETVr is through enhancement of LVDr changes in the RT deoxyribonucleotide triphosphate (dNTP)-binding pocket.

Topics: Amino Acid Substitution; Antiviral Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Drug Resistance, Viral; Enzyme-Linked Immunosorbent Assay; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Liver Neoplasms; Mutagenesis, Site-Directed; RNA-Directed DNA Polymerase; Virus Replication

Entecavir (ETV) is a guanosine nucleoside analogue with potent antiviral efficacy in woodchucks chronically infected with woodchuck hepatitis virus. To explore the consequences of prolonged virus suppression, woodchucks received ETV orally for 8 weeks and then weekly for 12 months. Of the 6 animals withdrawn from therapy and monitored for an additional 28 months, 3 had a sustained antiviral response and had no evidence of hepatocellular carcinoma (HCC). Of the 6 animals that continued on a weekly ETV regimen for an additional 22 months, 4 exhibited serum viral DNA levels near the lower limit of detection for >2 years and had no evidence of HCC. Viral antigens and covalently closed circular DNA levels in liver samples were significantly reduced in all animals. ETV was well tolerated, and there was no evidence of resistant variants. On the basis of historical data, long-term ETV treatment appeared to significantly prolong the life of treated animals and delay the emergence of HCC.

Topics: Animals; Antiviral Agents; Carcinoma, Hepatocellular; Disease Models, Animal; DNA, Circular; DNA, Viral; Guanine; Hepatitis B Surface Antigens; Hepatitis B Virus, Woodchuck; Hepatitis B, Chronic; Humans; Liver; Liver Neoplasms, Experimental; Marmota; Time Factors; Virus Replication