Background & Aims The incidence of hepatocellular carcinoma (HCC) increases with age, but protective antibody responses decrease with time after infants are immunized against hepatitis B virus (HBV). ...We investigated whether immunization of infants against HBV prevents their developing HCC as adults. We also searched for strategies to maximize the cancer-preventive effects. Methods We collected data from 2 Taiwan HCC registry systems on 1509 patients (6–26 years old) diagnosed with HCC from 1983 through 2011. Data on history of HBV immunization and prenatal maternal levels of HBV antigens of all HCC patients born after July 1984 were retrieved from the HBV immunization data bank of the Taiwan Center for Disease Control. We collected data on birth cohort-specific populations (6–26 years old) of Taiwan using the National Household Registry System. Rates of HCC incidence per 105 person-years were derived by dividing the number of patients with HCC by the person-years of the general population. Relative risks (RR) for HCC were estimated by Poisson regression analysis in vaccinated vs unvaccinated birth cohorts. We stratified patients by age group to evaluate the association of birth cohorts and HCC risks. Results Of the 1509 patients with HCC, 1343 were born before, and 166 were born after, the HBV vaccination program began. HCC incidence per 105 person-years was 0.92 in the unvaccinated cohort and 0.23 in the vaccinated birth cohorts. The RRs for HCC in patients 6–9 years old, 10–14 years old, 15–19 years old, and 20–26 years old who were vaccinated vs unvaccinated were 0.26 (95% confidence interval CI, 0.17–0.40), 0.34 (95% CI, 0.25–0.48), 0.37 (95% CI, 0.25–0.51), and 0.42 (95% CI, 0.32–0.56), respectively. The RR for HCC in 6- to 26-year-olds was lower in the later vs the earlier cohorts (born in 1992–2005 vs 1986–1992; P < .001 and 1986–1992 vs 1984–1986; P < .002). Transmission of HBV from highly infectious mothers and incomplete immunization were associated with development of HCC. Conclusions Based on an analysis of 1509 patients with HCC in Taiwan, immunization of infants against HBV reduces their risk of developing HCC as children and young adults. Improving HBV vaccination strategies and overcoming risk factors could reduce the incidence of liver cancer.
Background Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma. This population-based study aimed to investigate whether prevention of hepatocellular carcinoma by the ...universal Taiwanese HBV vaccine program, launched in July 1984, has extended beyond childhood and to identify the predictors of hepatocellular carcinoma for vaccinated birth cohorts. Methods Data on 1958 patients with hepatocellular carcinoma who were aged 6–29 years at diagnosis in Taiwan between 1983 and 2004 were collected from two national hepatocellular carcinoma registries. Age- and sex-specific incidence among vaccinated and unvaccinated birth cohorts were analyzed by using Poisson regression models. All statistical tests were two-sided. Records of 64 hepatocellular carcinoma patients and 5 524 435 HBV vaccinees who were born after the initiation of the vaccination program were compared for HBV immunization characteristics during infancy and prenatal maternal hepatitis B surface antigen (HBsAg) and e antigen (HBeAg) serostatus. Results Hepatocellular carcinoma incidence was statistically significantly lower among children aged 6–19 years in vaccinated compared with unvaccinated birth cohorts (64 hepatocellular cancers among vaccinees in 37 709 304 person-years vs 444 cancers in unvaccinated subjects in 78 496 406 person-years, showing an age- and sex-adjusted relative risk of 0.31, P < .001, for persons vaccinated at birth). The risk of developing hepatocellular carcinoma for vaccinated cohorts was statistically significantly associated with incomplete HBV vaccination (for those who received fewer than three doses of HBV vaccine, odds ratio OR = 4.32, 95% confidence interval CI = 2.34 to 7.91); with prenatal maternal HBsAg seropositivity (OR = 29.50, 95% CI = 13.98 to 62.60); with prenatal maternal HBeAg seropositivity (with administration of hepatitis B immunoglobulin at birth, OR = 5.13, 95% CI = 2.24 to 11.71; and without it, OR = 9.43, 95% CI = 3.54 to 25.11). Conclusion The prevention of hepatocellular carcinoma by this HBV vaccine extends from childhood to early adulthood. Failure to prevent hepatocellular carcinoma results mostly from unsuccessful control of HBV infection by highly infectious mothers.
Data are limited on the safety and effectiveness of oral antivirals other than lamivudine and adefovir dipivoxil for treatment of chronic hepatitis B (CHB) in patients with decompensated liver ...disease. This Phase 2, double‐blind study randomized 112 patients with CHB and decompensated liver disease to receive either tenofovir disoproxil fumarate (TDF; n = 45), emtricitabine (FTC)/TDF (fixed‐dose combination; n = 45), or entecavir (ETV; n = 22). The primary endpoint was safety; more specifically, tolerability failure (adverse events resulting in permanent treatment discontinuation) and confirmed serum creatinine increase ≥0.5 mg/dL from baseline or confirmed serum phosphorus <2 mg/dL. Patients with insufficient viral suppression (e.g., confirmed HBV DNA ≥400 copies/mL at week 8 or 24) could begin open‐label FTC/TDF but were considered failures in this interim week 48 analysis for efficacy endpoints. Tolerability failure was infrequent across arms: 6.7% TDF, 4.4% FTC/TDF, and 9.1% ETV (P = 0.622) as were confirmed renal parameters meeting threshold 8.9%, 6.7%, and 4.5% (P = 1.000), respectively. Six patients died (none considered related to study drug) and six received liver transplants (none had HBV recurrence). The adverse event and laboratory profiles were consistent with advanced liver disease and complications, with no unexpected safety signals. At week 48, HBV DNA was <400 copies/mL (69 IU/mL) in 70.5% (TDF), 87.8% (FTC/TDF), and 72.7% (ETV) of patients. Proportions with normal alanine aminotransferase were: 57% (TDF), 76% (FTC/TDF), and 55% (ETV). Hepatitis B e antigen (HBeAg) loss/seroconversion occurred in 21%/21% (TDF), 27%/13% (FTC/TDF), and 0%/0% (ETV). Child‐Turcotte‐Pugh and Modification for End‐stage Liver Disease scores improved in all groups. Conclusion: All treatments were well tolerated in patients with decompensated liver disease due to CHB with improvement in virologic, biochemical, and clinical parameters. (HEPATOLOGY 2011.)
Hepatocarcinogenesis is a multistep process that evolves from cirrhosis or dysplastic nodule (DN), and eventually leads to overt hepatocellular carcinoma (HCC). Differentiation between early HCC and ...DN is an important issue in the clinical setting. This study aims to investigate the potential of circulating microRNA (miRNA) levels in the diagnosis of early HCC. RNA was extracted from sera of 30 chronic hepatitis B patients with pathologically proven DN and 120 age‐ and sex‐matched patients with early HCC. Paired samples were collected from ten patients with DN who developed overt HCC in the follow‐up. A panel of ten cancer‐associated miRNAs was analyzed by quantitative real‐time reverse‐transcription polymerase chain reaction. Serum levels of miR‐16, miR‐122, miR‐221, let‐7b and miR‐15b were significantly lower in patients with DN than in the HCC group. When DN progressed to overt HCC, serum miR‐122, miR‐let‐7b and miR‐15b levels increased significantly (p = 0.046, 0.043 and 0.044, respectively). As a single marker, α‐fetoprotein (AFP) and miR‐122 as well as let‐7b had the similar performance for differentiate HCC from DN. As limited to subjects with normal AFP, let‐7b resulted in a sensitivity of 84.8% and a specificity of 50% in separating HCC and DN with a cutoff value of 3.5 (p = 0.001). In conclusion, miR‐122 and let‐7b, which are upregulated in the serum of early‐HCC patients, can be useful markers for differentiating early HCC from DN in chronic hepatitis B patients.
What's new?
Due to late detection, the prognosis for hepatocellular carcinoma (HCC) is generally dismal. HCC‐specific biomarkers are thus urgently needed, especially in areas where hepatitis B is endemic. In this study, the authors found that serum levels of certain microRNAs (miRNAs) are significantly higher in patients with early HCC, compared to those with dysplastic nodules of the liver. These specific miRNAs may therefore provide a useful screening tool for early detection of HCC, which could greatly improve treatment outcomes.
Background & Aims
Patients with chronic hepatitis C (CHC) after successful antiviral therapy remain at risk of hepatocellular carcinoma (HCC). This study was to determine whether liver stiffness ...measurement (LSM) was useful in HCC risk assessment and to develop a risk‐score system for clinical use.
Methods
This retrospective study enrolled patients with CHC achieving sustained virological response (SVR) after interferon‐based therapy with LSM at/after SVR determination. The demographics, clinical characteristics and HCC development were obtained from medical chart reviews. The diagnosis of HCC was based on recommended criteria.
Results
A total of 376 (M/F: 185/191, mean age: 54.1 years) patients, including 278 with pretreatment liver biopsy specimens, with a median follow‐up period of 7.6 years were enrolled. Twenty‐one patients developed HCC. The 5‐ and 10‐year cumulative HCC incidences were 1.4% and 7.8%, respectively. Multivariate analysis showed advanced fibrosis/cirrhosis, diabetes and LSM were associated with HCC developments with odds ratio (OR) of 12.38, 2.80 and 1.01, respectively. For LSM in HCC prediction, the performance and cut‐off were 0.783 and 12 kilopascal (kPa), respectively. For 278 patients with pretreatment biopsy, a risk‐score system (score 0–4) combining advanced fibrosis/cirrhosis, diabetes and LSM >12 kPa was developed. With the low‐risk group as a reference, patients in intermediate‐ (OR: 12.57) and high‐risk (OR: 197.33) groups carried higher risk of HCC development.
Conclusions
For patients with CHC achieving SVR, liver stiffness value at/after SVR determination was associated with HCC development independently. Patients with pretreatment advanced fibrosis/cirrhosis, diabetes and LSM >12 kPa after SVR were at high risk of HCC development.
There is strong evidence linking chronic hepatitis C virus (HCV) infection and Type 2 diabetes mellitus (DM). Recent studies have suggested that DM is associated with increased risk of developing ...hepatocellular carcinoma (HCC). The aim of our cohort study was to assess whether DM influence the incidence of HCC in chronic hepatitis C patients treated with interferon (IFN)‐based antiviral therapy. A total of 1,470 chronic hepatitis C patients treated with IFN or pegylated‐IFN plus ribavirin therapy were enrolled. Of them, 253 (17%) patients had DM at entry. Evaluation of HCC incidence was performed by Kaplan–Meier method and Cox proportional hazards analysis. Patients with baseline DM were significantly older and had higher body mass index, serum transaminase levels and fibrosis scores and lower platelet counts compared to non‐DM subjects. Sustained virological response (SVR) was achieved in 160 (63%) of DM and 867 (71%) of non‐DM patients (p = 0.008). During a median follow‐up period of 4.3 years, HCC developed in 21 (8.3%) of DM and 66 (5.4%) of non‐DM patients (p = 0.017). However, DM was not an independent covariate by Cox proportional hazards analysis. In a subgroup analysis, DM (hazard ratio, 4.32; 95% confidence interval, 1.23–15.25; p = 0.023) was an independent predictor of HCC in the SVR patients without baseline cirrhosis, despite a low HCC incidence. In conclusion, DM has a selective impact on HCC development among chronic hepatitis C patients after IFN‐based therapy. DM may increase the HCC risk in chronic hepatitis C without cirrhosis after eradication of HCV.
Background/Aims The long-term outcomes of interferon-alpha (IFN-α) therapy in hepatitis B e antigen (HBeAg) seropositive patients remain controversial. This study was conducted to address this issue. ...Methods The long-term outcomes were compared in 233 IFN-treated patients and 233 well-matched untreated controls. Results The cumulative incidence at the end of 15 years of follow-up (median 6.8 years, range 1.1–16.5 years) in the IFN-treated patients and controls was: HBeAg seroconversion 74.6% vs. 51.7% ( P = 0.031); hepatitis B surface antigen (HBsAg) seroclearance 3% vs. 0.4% ( P = 0.03); cirrhosis 17.8% vs. 33.7% ( P = 0.041); and hepatocellular carcinoma (HCC) 2.7% vs. 12.5% ( P = 0.011). Significant reduction of HCC was only observed in patients with pre-existing cirrhosis ( P < 0.01). Compared with untreated controls with persistent HBeAg, HBeAg seroconverters in untreated and IFN-treated group showed significantly lower incidence of cirrhosis and HCC ( P = 0.003–0.031), while non-seroconverters of IFN-treated group had marginally significant lower incidence of cirrhosis ( P = 0.065). Multivariate analysis showed that IFN therapy, HBeAg seroconversion and genotype B HBV infection are independent factors for better long-term outcomes. Conclusions IFN therapy reduces cirrhosis and HCC development.
Hepatitis B virus (HBV) reactivation is a well-known complication of lymphoma treatment in the pre-rituximab era. This complication has not been as well studied, however, since monoclonal anti-CD20 ...antibody became the standard regimen for B cell lymphoma. In this retrospective study, 115 B cell lymphoma patients who received rituximab-containing therapy were analyzed. Of 15 hepatitis B surface antigen (HBsAg)-positive patients, five received lamivudine prophylaxis and did not develop HBV-related hepatitis during lymphoma treatment. Eight of ten HBV carriers without lamivudine prophylaxis experienced HBV-related hepatitis, including one fatal hepatic failure. Four (4.2%) of 95 HBsAg-negative patients developed de novo HBV-related hepatitis and two died of fulminant hepatitis. In conclusion, rituximab-based therapy may cause serious HBV-related complications and even death in both HBsAg-positive and HBsAg-negative patients.
Background & Aims: This longitudinal study investigated the interactions and roles of hepatitis B virus (HBV) genotypes, pre-S deletions, and core promoter and precore mutations on the progression of ...liver disease in hepatitis B e antigen (HBeAg)-negative patients. Methods: A total of 141 HBeAg-negative patients without liver cirrhosis or hepatocellular carcinoma at study entry were recruited for this study, including 45 inactive HBV carriers and 96 patients with HBeAg-negative chronic hepatitis B. The HBV genotypes and the sequences of pre-S, core promoter, and precore regions were determined. Results: Compared with patients without developing liver cirrhosis, patients with the development of liver cirrhosis had higher rates of genotype C; pre-S deletions; C or G1753, T1762/A1764, T1766, and/or A1768 mutants; and G1799 variant. Cox regression analysis showed that older age, higher total bilirubin and HBV DNA levels, pre-S deletions, and T1766 and/or A1768 mutants were significantly associated with the development of liver cirrhosis. HBV with a complex mutation pattern (pre-S deletion, T1762/A1764, and T1766 and/or A1768 mutants) rather than a single mutation was associated with the development of liver cirrhosis, and the patterns of mutation combinations differed between HBV genotype B and C. Moreover, pre-S deletion was a significant risk factor for hepatocellular carcinoma. Conclusions: This study indicated that pre-S deletion and combined mutations of HBV are useful molecular markers for predicting the clinical outcomes of HBeAg-negative patients.
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.
PDF
