ASSOCIATION BETWEEN HYPOGLYCEMIA AND FALL-RELATED FRACTURES AND HEALTH CARE UTILIZATION IN OLDER VETERANS WITH TYPE 2 DIABETES.

OBJECTIVE: To examine the association between hypoglycemia and fall-related outcomes in older patients with type 2 diabetes mellitus (T2DM). METHODS: This retrospective cohort study used electronic medical records of T2DM patients (≥65 years) from the Veterans Integrated Service Network 16 (VISN 16) data warehouse (01/01/2004-06/30/2010). Patients in nonhypoglycemia group (non-HG) were 1:1 randomly matched with patients in hypoglycemia group (HG) by age (±5 years), sex, race, and medical center location. Fall-related events (i.e., fractures and head injuries) were identified, with a fall being the external cause within ±2 days. McNemar tests and generalized estimating equation (GEE) models were used to compare fall-related events in the 1-year outcome period after the index date (i.e., date of first hypoglycemic episode). We also examined fall-related healthcare utilization. RESULTS: A total of 4,215 patients in each group were studied, with the mean age of 76.5 years (SD: 5.85). The mean Charlson comorbidity index (CCI) scores were 5.73 (SD: 2.95) in the HG and 4.34 (SD: 2.40) in the non-HG. The HG had significantly higher rates of fall-related events than non-HG, 27 (0.64%) versus 1 (0.02%) and 89 (2.11%) versus 21 (0.50%) events within 30 days and 1 year, respectively. GEE models confirmed the elevated risk of fall-related events after controlling for sociodemographic and clinical characteristics, comorbidities, and medication use (adjusted odds ratio [aOR]: 2.70; 95% confidence interval [CI]: 1.64-4.47). The HG patients were more likely to have emergency department (ED) visits, hospital admissions, and long-term care placement compared to their counterparts. CONCLUSION: Hypoglycemia is associated with worse fall-related outcomes among the elderly veterans.

Cost-effectiveness of apixaban vs. current standard of care for stroke prevention in patients with atrial fibrillation.

AIMS: Warfarin, a vitamin K antagonist (VKA), has been the standard of care for stroke prevention in patients with atrial fibrillation (AF). Aspirin is recommended for low-risk patients and those unsuitable for warfarin. Apixaban is an oral anticoagulant that has demonstrated better efficacy than warfarin and aspirin in the ARISTOTLE and AVERROES studies, respectively, and causes less bleeding than warfarin. We evaluated the potential cost-effectiveness of apixaban against warfarin and aspirin from the perspective of the UK payer perspective. RESULTS AND METHODS: A lifetime Markov model was developed to evaluate the pharmacoeconomic impact of apixaban compared with warfarin and aspirin in VKA suitable and VKA unsuitable patients, respectively. Clinical events considered in the model include ischaemic stroke, haemorrhagic stroke, intracranial haemorrhage, other major bleed, clinically relevant non-major bleed, myocardial infarction, cardiovascular hospitalization and treatment discontinuations; data from the ARISTOTLE and AVERROES trials and published mortality rates and event-related utility rates were used in the model. Apixaban was projected to increase life expectancy and quality-adjusted life years (QALYs) compared with warfarin and aspirin. These gains were expected to be achieved at a drug acquisition-related cost increase over lifetime. The estimated incremental cost-effectiveness ratio was £11 909 and £7196 per QALY gained with apixaban compared with warfarin and aspirin, respectively. Sensitivity analyses indicated that results were robust to a wide range of inputs. CONCLUSIONS: Based on randomized trial data, apixaban is a cost-effective alternative to warfarin and aspirin, in VKA suitable and VKA unsuitable patients with AF, respectively.

Prediction models of long-term cirrhosis and hepatocellular carcinoma risk in chronic hepatitis B patients: risk scores integrating host and virus profiles.

UNLABELLED: Integrating host and HBV characteristics, this study aimed to develop models for predicting long-term cirrhosis and hepatocellular carcinoma (HCC) risk in chronic hepatitis B virus (HBV) patients. This analysis included hepatitis B surface antigen (HBsAg)-seropositive and anti-HCV-seronegative participants from the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer in HBV (R.E.V.E.A.L.-HBV) cohort. Newly developed cirrhosis and HCC were ascertained through regular follow-up ultrasonography, computerized linkage with national health databases, and medical chart reviews. Two-thirds of the participants were allocated for risk model derivation and another one-third for model validation. The risk prediction model included age, gender, HBV e antigen (HBeAg) serostatus, serum levels of HBV DNA, and alanine aminotransferase (ALT), quantitative serum HBsAg levels, and HBV genotypes. Additionally, the family history was included in the prediction model for HCC. Cox's proportional hazards regression coefficients for cirrhosis and HCC predictors were converted into risk scores. The areas under receiver operating curve (AUROCs) were used to evaluate the performance of risk models. Elder age, male, HBeAg, genotype C, and increasing levels of ALT, HBV DNA, and HBsAg were all significantly associated with an increased risk of cirrhosis and HCC. The risk scores estimated from the derivation set could accurately categorize participants with low, medium, and high cirrhosis and HCC risk in the validation set (P<0.001). The AUROCs for predicting 3-year, 5-year, and 10-year cirrhosis risk ranged 0.83-0.86 and 0.79-0.82 for the derivation and validation sets, respectively. The AUROC for predicting 5-year, 10-year, 15-year risk of HCC ranged 0.86-0.89 and 0.84-0.87 in the derivation and validation sets, respectively. CONCLUSION: The risk prediction models of cirrhosis and HCC by integrating host and HBV profiles have excellent prediction accuracy and discriminatory ability. They may be used for clinical management of chronic hepatitis B patients.

Synergism between obesity and alcohol in increasing the risk of hepatocellular carcinoma: a prospective cohort study.

Obesity and alcohol interact to increase the risk of death from liver failure in men. In the present study, we aimed to examine whether obesity and alcohol were multiplicative or additive in increasing the risk of hepatocellular carcinoma (HCC) in both men and women. We conducted a prospective, population-based study of 23,712 Taiwanese residents (50.3% men) from 7 townships who underwent an evaluation for liver disease and were followed for 11.6 years for incident HCC. The mean age was 47 (standard deviation, 10) years and the mean body mass index (weight (kg)/height (m)(2)) was 24 (standard deviation, 3). Overall, 305 cases of HCC were identified over 275,126 person-years of follow-up. Age, male sex, alcohol drinking, cigarette smoking, elevated alanine aminotransferase, serum hepatitis B surface antigen, anti-hepatitis C virus positivity, and diabetes mellitus were each statistically significant predictors of incident HCC in univariate analyses (P < 0.05). Alcohol use and obesity (body mass index ≥30) showed a synergistic association with the risk of incident HCC in both unadjusted analyses (hazard ratio = 7.19, 95% confidence interval: 3.69, 14.00; P < 0.01) and multivariable-adjusted analyses (age, sex, smoking, serum alanine aminotransferase, serum hepatitis B surface antigen, anti-hepatitis C virus antibody, and diabetes mellitus) (hazard ratio = 3.82, 95% confidence interval: 1.94, 7.52; P < 0.01). Relative excess risks due to interaction, attributable proportion, and synergy index were 4.83, 0.67, and 4.53, respectively, suggesting a multiplicative interaction between alcohol use and obesity. Obesity and alcohol synergistically increase the risk of incident HCC.

A predictive scoring system for the seroclearance of HBsAg in HBeAg-seronegative chronic hepatitis B patients with genotype B or C infection.

BACKGROUND & AIMS: Seroclearance of hepatitis B surface antigen (HBsAg) is the most ideal end point in the treatment of chronic hepatitis B. This study develops a predictive scoring system to assess whether the addition of serum levels HBsAg may improve the predictability of HBsAg loss. METHODS: This study included 2491 untreated participants with genotype B or C HBV infection, who were HBsAg-seropositive, HBeAg-seronegative, anti-HCV-seronegative, and cirrhosis free at study entry. Regression coefficients of predictors in Cox Regression models were converted into integer scores for predicting HBsAg seroclearance. Predictive accuracy was assessed with area under the receiver operating characteristic curves (AUROC), and predictive accuracies of models with and without serum HBsAg levels were compared. RESULTS: Low serum levels of both HBsAg and HBV DNA were the strongest predictors of spontaneous HBsAg seroclearance. Compared to baseline serum HBsAg levels ≥1000 IU/ml, the multivariate adjusted rate ratio of spontaneous HBsAg seroclearance was 10.96 (7.92-15.16) for those with baseline serum HBsAg levels <100 IU/ml. The predictive ability of HBsAg levels was modified by HBV viral load, showing a weaker effect in those with higher viral loads, and the strongest effect among those with undetectable viral loads. The inclusion of serum HBsAg levels greatly improved the AUROC for predicting HBsAg seroclearance at the fifth (from 0.79 [0.787-0.792] to 0.89 [0.889-0.891]) and tenth year (from 0.73 [0.728-0.732] to 0.84 [0.839-0.841]) after study entry. CONCLUSIONS: Incorporated into an easy-to-use scoring system, HBV viral load and quantitative serum HBsAg levels can accurately predict HBsAg seroclearance.

Synergistic effects of family history of hepatocellular carcinoma and hepatitis B virus infection on risk for incident hepatocellular carcinoma.

BACKGROUND & AIMS: Little is known about the effects of family history of hepatocellular carcinoma (HCC) on hepatitis B progression or risk of HCC. We examined how family HCC history and presence or stage of hepatitis B virus (HBV) infection affect risk for HCC. METHODS: We performed a population-based cohort study of 22,472 participants from 7 townships in Taiwan who underwent evaluation for liver disease from 1991 through 1992. Those who received a first diagnosis of HCC from January 1, 1991, to December 31, 2008, were identified from the Taiwanese cancer registry. RESULTS: There were 374 cases of incident HCC over 362,268 person-years of follow-up evaluation. The cumulative risk of HCC in hepatitis B surface antigen (HBsAg)-seronegative patients without a family history of HCC was 0.62%, in those with a family history of HCC the cumulative risk was 0.65%, in HBsAg-seropositive patients without a family history of HCC the cumulative risk was 7.5%, and in HBsAg-seropositive patients with a family history of HCC the cumulative risk was 15.8% (P < .001). The multivariate-adjusted hazard ratio for HBsAg-seropositive individuals with family history, compared with HBsAg-seronegative individuals without a family history of HCC, was 32.33 (95% confidence interval, 20.8-50.3; P < .001). The relative excess risk owing to interaction was 19, the attributable proportion was 0.59, and the synergy index value was 2.54. These findings indicate synergy between family HCC history and HBsAg serostatus. The synergy between these factors remained significant in stratification analyses by HBeAg serostatus and serum level of HBV DNA. CONCLUSIONS: Family history of HCC multiplies the risk of HCC at each stage of HBV infection. Patients with a family history of HCC require more intensive management of HBV infection and surveillance for liver cancer.

Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma.

BACKGROUND & AIMS: It is not clear whether risk for hepatocellular carcinoma can be accurately determined from long-term changes in serum levels of hepatitis B virus (HBV) DNA or alanine aminotransferase (ALT). METHODS: We measured serum levels of HBV DNA and ALT at enrollment and during follow-up analysis of 3160 participants in the REVEAL-HBV study. Development of hepatocellular carcinoma was determined from follow-up examinations and computerized linkage with National Cancer Registry and National Death Certification profiles. Multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models. RESULTS: During 38,330 person-years of follow-up, 81 participants developed hepatocellular carcinoma (incidence rate, 211.3/100,000 person-years). The risk for hepatocellular carcinoma was only slightly higher for participants whose follow-up levels of HBV DNA spontaneously decreased to <10,000 copies/mL compared with those with baseline levels of HBV DNA<10,000 copies/mL (control group; HR, 2.25; 95% CI, 0.68-7.37). Compared with the control group, the HRs (95% CI) for long-term levels of HBV DNA that persisted at 10,000 to 100,000 copies/mL, decreased to/persisted at 100,000 to 1,000,000 copies/mL, or decreased to/persisted at 1,000,000 to 10,000,000 copies/mL were 3.12 (1.09-8.89), 8.85 (3.85-20.35), and 16.78 (7.33-38.39), respectively. A gradient in ALT level was significantly associated with hepatocellular carcinoma risk: from all low-normal, to ever high-normal, to transient abnormal, to persistent abnormal (Ptrend<.001). CONCLUSIONS: Long-term changes in serum levels of HBV DNA and ALT are independent predictors of risk for hepatocellular carcinoma. Regular monitoring of levels of HBV DNA and ALT is important in clinical management of chronic carriers of HBV.

Incidence and determinants of spontaneous seroclearance of hepatitis B e antigen and DNA in patients with chronic hepatitis B.

BACKGROUND & AIMS: The spontaneous seroclearance of hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV) DNA are important markers of progression of chronic HBV infection. We performed a long-term cohort study to elucidate the incidence and determinants of HBeAg and HBV DNA seroclearance in patients with chronic hepatitis B. METHODS: A total of 1289 participants with a serum HBV DNA level of 10,000 copies/mL or more and without cirrhosis when the study began (1991-1992) were followed up until June 2004. A subset of patients that tested positive for HBeAg at baseline (n = 439) was included in the analysis of HBeAg seroclearance. Cox proportional hazards models were used to estimate seroclearance rate ratios for various determinants associated with the outcomes. RESULTS: After 3161.2 person-years of follow-up evaluation, HBeAg seroclearance occurred in 187 participants (incidence rate, 5.9 per 100 person-years). The cumulative lifetime incidence of HBeAg seroclearance among patients who were 30 to 40, or 50, 60, 70, or 74 years old was 38.8%, 69.4%, 81.9%, 89.1%, and 95.5%, respectively. Major predictors of HBeAg seroclearance included female sex, genotype B, the precore 1896 mutant, increased serum levels of alanine aminotransferase, and low baseline serum levels of HBV DNA. The median (interquartile range) serum level of HBV DNA at the time of HBeAg seroclearance was 177,801 copies/mL (4941-3,247,560 copies/mL). HBV DNA seroclearance occurred in 199 participants (15.4%) during the mean follow-up period of 7.8 years (incidence rate, 1.97 per 100 person-years). The cumulative lifetime incidence of HBV DNA seroclearance at 40, 50, 60, 70, and 77 years old was 10.0%, 25.0%, 38.8%, 54.2%, and 82.8%, respectively. Lower levels of HBV DNA at study entry and among those with the precore 1896 wild-type variant were associated with an increased rate of HBV DNA seroclearance. Among individuals who were HBeAg-seropositive at study entry and cleared serum HBV DNA during the follow-up period, 89% had cleared HBeAg by the time they had an undetectable serum level of HBV DNA. CONCLUSIONS: Serum level of HBV DNA is the most important predictor of seroclearance of HBeAg and HBV DNA. This finding supports current clinical guidelines for antiviral treatments of chronic hepatitis B.

Natural history of chronic hepatitis B: what exactly has REVEAL revealed?

Chronic hepatitis B virus (HBV) infection is a serious public health problem because of its worldwide prevalence and potential to cause adverse consequences. The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study carried out in Taiwan was used to investigate the natural history of chronic hepatitis B. The REVEAL-HBV study has established an HBV viral load paradigm in the natural history of chronic hepatitis B (CHB). Serum HBV DNA level has been shown to be significantly and independently associated with incidence of hepatocellular carcinoma (HCC) and cirrhosis and liver-related mortality across a biological gradient. It is also a major predictor of HBsAg seroclearance. Genetic features including HBV genotype and basal core promoter A1762T/G1764A mutant, and precore G1896A mutant were documented as predictors of HCC risk. Inactive HBV carriers still had an increased risk on HCC development and liver-related mortality compared with HBsAg -seronegatives. Nomograms focusing on facilitating risk communication between patients and clinicians were developed incorporating non-invasive clinical parameters to predict long-term HCC risk. These will hopefully contribute to evidence-based decisions in the clinical management of CHB patients. A somewhat provocative and novel finding from the REVEAL-HBV study is the association of chronic HBV infection in active replication with an increased pancreatic cancer risk especially in women less than 50 years old. This finding will hopefully spur further research in this area seeking confirmatory evidence. Finally, we hope that the REVEAL-HBV study will continue to be a source of data to answer other important questions in chronic hepatitis B research going forward.

Incidence and determinants of spontaneous hepatitis B surface antigen seroclearance: a community-based follow-up study.

BACKGROUND & AIMS: Seroclearance of hepatitis B surface antigen (HBsAg) is one of the most important clinical outcomes for chronic hepatitis B treatment trials. Few studies have explored the incidence and determinants of spontaneous seroclearance using a long-term follow-up study. This study aimed to examine the natural history and predictors of HBsAg seroclearance. METHODS: A total of 3087 individuals with chronic hepatitis B virus infection were enrolled between 1991 and 1992 in this community-based study. Serum samples collected at baseline and follow-up examinations were tested for HBsAg, hepatitis B e antigen (HBeAg), serum hepatitis B virus (HBV)-DNA levels, and anti-hepatitis C virus serostatus. Cox proportional hazards models were used to estimate HBsAg seroclearance rate ratios associated with various determinants. RESULTS: HBsAg seroclearance occurred in 562 participants during 24,829 person-years of follow-up evaluation, giving a 2.26% annual seroclearance rate. HBV-DNA levels at baseline and follow-up evaluation were the most significant predictor of seroclearance. Higher HBV viral loads conferred lower HBsAg seroclearance rates (P<.001). A spontaneous decrease in follow-up HBV-DNA level (>or=3 log) was associated significantly with seroclearance, showing an adjusted odds ratio of 4.17 (95% confidence interval, 2.55-6.82). Among those with seroclearance, 95.8% had undetectable HBV-DNA levels before seroclearance. Cumulative incidence of HBsAg seroclearance at 60 and 100 months after serum HBV-DNA level decreased to undetectable was 25.8% and 51.3%, respectively. CONCLUSIONS: This study reveals determinants of HBsAg seroclearance, and suggests that a low viral load is an important factor affecting the natural seroclearance of HBsAg, indicating significant clinical implications for the treatment of chronic HBV.

Long-term treatment with entecavir induces reversal of advanced fibrosis or cirrhosis in patients with chronic hepatitis B.

BACKGROUND & AIMS: Long-term treatment with entecavir resulted in durable virologic suppression and continued histologic improvement in nucleoside-naive chronic hepatitis B patients. Patients with advanced fibrosis or cirrhosis, who received long-term entecavir treatment, were evaluated for improvement in liver histology. METHODS: The study included a subset of patients from phase III and long-term rollover studies, who received entecavir for at least 3 years, had advanced fibrosis or cirrhosis, and evaluable biopsies at baseline and after long-term treatment. RESULTS: Ten patients had advanced fibrosis or cirrhosis at baseline (Ishak fibrosis score, ≥ 4). After approximately 6 years of cumulative entecavir therapy (range, 267-297 wk), all 10 patients showed improvement in liver histology and Ishak fibrosis score. The mean change from baseline in Ishak fibrosis and Knodell necroinflammatory scores were -2.2 and -7.6, respectively. A reduction in Ishak fibrosis score to 4 or less was observed for all 4 patients who had cirrhosis at baseline. CONCLUSIONS: Chronic hepatitis B patients with advanced fibrosis or cirrhosis demonstrated histologic improvement and reversal of fibrosis and cirrhosis after long-term treatment with entecavir.

Carriers of inactive hepatitis B virus are still at risk for hepatocellular carcinoma and liver-related death.

BACKGROUND & AIMS: The risk and the predictors of liver disease progression in carriers of inactive hepatitis B virus (HBV) are unclear. METHODS: Participants in the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study who were seronegative for hepatitis B e antigen; had serum levels of HBV DNA <10,000 copies/mL; and did not have cirrhosis, hepatocellular carcinoma, or increased serum levels of alanine aminotransferase were classified as carriers of inactive HBV (n = 1932). Study participants who were seronegative for HB surface antigen and antibodies against hepatitis C virus, yet had similar clinical liver features, were the controls (n = 18,137). Liver-related death and new cases of hepatocellular carcinoma were ascertained through computerized data linkage with National Cancer Registry and Death Certification profiles. The disease progression rates were estimated. The multivariate-adjusted hazard ratios for risk predictors were derived from Cox regression models. RESULTS: There were 20,069 participants, contributing a total of 262,122 person-years, with a mean follow-up of 13.1 years. Annual incidence rates of hepatocellular carcinoma and liver-related death were 0.06% and 0.04%, respectively, for inactive HBV carriers; rates were 0.02%, and 0.02% for controls, respectively. The multivariate-adjusted hazard ratios for carriers of inactive HBV, compared to controls, were 4.6 (95% confidence interval: 2.5-8.3) for hepatocellular carcinoma and 2.1 (95% confidence interval: 1.1-4.1) for liver-related death. Older age and alcohol drinking habits were independent predictors of risk for carriers of inactive HBV to develop hepatocellular carcinoma. CONCLUSIONS: Carriers of inactive HBV have a substantial risk of hepatocellular carcinoma and liver-related death compared with individuals not infected with HBV.

Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B.

UNLABELLED: One year of treatment with entecavir (0.5 mg daily) in nucleoside-naive patients with hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis B (CHB) resulted in significantly improved liver histology and virological and biochemical endpoints in comparison with lamivudine. Patients who received at least 3 years of cumulative entecavir therapy in phase 3 studies and a long-term rollover study and underwent long-term liver biopsy were evaluated for improvements in histological appearance. Sixty-nine patients [50 HBeAg-positive and 19 HBeAg-negative] receiving entecavir therapy underwent long-term liver biopsy (median time of biopsy = 6 years, range = 3-7 years). Histological improvement was analyzed for 57 patients who had adequate baseline biopsy samples, baseline Knodell necroinflammatory scores > or =2, and adequate long-term biopsy samples. At the time of long-term biopsy, all patients in the cohort had a hepatitis B virus DNA level <300 copies/mL, and 86% had a normalized alanine aminotransferase level. Histological improvement (> or =2-point decrease in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score) was observed in 96% of patients, and a > or =1-point improvement in the Ishak fibrosis score was found in 88% of patients, including all 10 patients with advanced fibrosis or cirrhosis at the phase 3 baseline. CONCLUSION: The majority of nucleoside-naive patients with CHB who were treated with entecavir in this long-term cohort achieved substantial histological improvement and regression of fibrosis or cirrhosis.

Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B.

UNLABELLED: Sustained virologic suppression is a primary goal of therapy for chronic hepatitis B (CHB). In study entecavir (ETV)-022, 48 weeks of entecavir 0.5 mg was superior to lamivudine for virologic suppression for hepatitis B e antigen (HBeAg)-positive CHB. A total of 183 entecavir-treated patients from ETV-022 subsequently enrolled in study ETV-901. We present the results after up to 5 years (240 weeks) of continuous entecavir therapy. The entecavir long-term cohort consists of patients who received >or=1 year of entecavir 0.5 mg in ETV-022 and then entered ETV-901 with a treatment gap

Obesity and alcohol synergize to increase the risk of incident hepatocellular carcinoma in men.

BACKGROUND & AIMS: Body mass index (BMI) and alcohol use are risk factors for hepatocellular carcinoma (HCC). We performed a prospective study to determine if these factors have synergistic effects on HCC risk. METHODS: Over 14 years, we followed up 2260 Taiwanese men from the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) Study Cohort who tested positive for the hepatitis B surface antigen (mean age, 46 ± 10 y; mean BMI, 24 ± 3 kg/m(2)); 20% reported alcohol use. Incident HCC cases were identified via linkage to the national cancer registry. Multivariate-adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using Cox-proportional hazards models. RESULTS: In univariate analysis, the interaction between BMI and alcohol predicted incident HCC (P = .029). Alcohol use and extreme obesity (BMI ≥30 kg/m(2)) had synergistic effects on the risk of incident HCC in analyses adjusted for age (HR, 3.41; 95% CI, 1.25-9.27; P < .025) and multivariables (HR, 3.40; 95% CI, 1.24-9.34; P < .025). The relative risk estimate for the interaction and the attributable proportion from the interaction and synergy index were 1.59, 0.52, and 4.40, respectively; these indicate a multiplicative interaction between alcohol use and extreme obesity. In an analysis stratified into 4 World Health Organization categories of BMI and alcohol use, the risk of incident HCC increased in overweight (HR, 2.4; 95% CI, 1.3-4.4), obese (HR, 2.0; 95% CI, 1.1-3.7), and extremely obese (HR, 2.9; 95% CI, 1.0-8.0) users of alcohol (P for trend = .046). CONCLUSIONS: Obesity and alcohol have synergistic effects to increase the risk of incident HCC in hepatitis B surface antigen-positive men. Lifestyle interventions might reduce the incidence of HCC.

Hepatitis B virus DNA levels and outcomes in chronic hepatitis B.

Serum hepatitis B virus (HBV) DNA levels can fluctuate markedly during the course of chronic HBV infection. Both case-control and cohort studies have shown a significant, dose-response association between serum HBV DNA levels measured at the time of initial evaluation and the subsequent risk of cirrhosis. A similar direct relationship has been shown for the risk of hepatocellular carcinoma (HCC) in cross-sectional, case-control, and cohort studies. Interventional studies have shown a strong correlation between the indices of disease activity seen on liver biopsy and levels of serum HBV DNA. These studies have also shown that reduction in HBV DNA levels correlate strongly with improvements in liver histology. For patients with HCC, prognosis (including risk of death, metastasis, and recurrence following surgery) is worse with higher serum HBV DNA levels. The preponderance of the evidence in the published literature demonstrates that serum HBV DNA level is an important and independent risk factor for disease progression in chronic hepatitis B. The relative importance of serial HBV DNA measurements, the loss of hepatitis B e and surface antigens, as well as the emergence of HBV mutants in the progression of chronic hepatitis B, especially in young patients, is an important need for future research.

Risk of pancreatic cancer in chronic hepatitis B virus infection: data from the REVEAL-HBV cohort study.

BACKGROUND AND AIMS: The relationship between the hepatitis B virus (HBV) and pancreatic cancer remains unclear. Because HBV has been isolated from pancreatic tissue, we hypothesized that HBV may play a role in the development of pancreatic carcinoma. METHODS: This cohort was recruited between 1991 and 1992. Serum samples obtained at enrolment were tested for HBsAg and HBeAg by radioimmunoassay. Pancreatic cancer diagnosis was ascertained through data linkage with profiles of the National Cancer Registry and Death Certification System in Taiwan from 1 January 1991 to 31 December 2007. Multivariate-adjusted hazards ratios (HR(adj)) with 95% confidence intervals (CI) were derived using Cox proportional hazards models. RESULTS: In total 22 471 subjects were followed up for 342 186 person-years and 48 had pancreatic cancer. Chronic carriers of HBsAg had a significantly increased risk of pancreatic cancer showing an HR(adj) (95% CI) of 1.95 (1.01-3.78). This association was most striking in females, individuals < or =50 years, non-smokers and non-drinkers. The HR(adj) (95% CI) of developing pancreatic cancer was 5.73 (1.73-19.05) for HBeAg-seropositive carriers and 1.64 (0.79-3.42) for HBeAg-seronegative carriers compared with HBsAg-seronegative non-carriers. An increased risk of pancreatic cancer was observed for HBsAg-seropositives with HBV DNA > or =300 copies/ml (HR(adj), 2.44; 95% CI, 1.20-4.95), but not for HBsAg-seropositives with HBV DNA <300 copies/ml (HR(adj), 0.64; 95% CI, 0.09-4.67). CONCLUSIONS: In addition to the well-established risk of hepatocellular carcinoma, chronic HBV infection may be associated with an increased risk of pancreatic cancer.

96-week efficacy and safety of atazanavir, with and without ritonavir, in a HAART regimen in treatment-naive patients.

This study assesses virologic response, safety, tolerability, and changes in health-related quality of life (HRQoL) in antiretroviral (ARV)-naive patients treated with 2 atazanavir (ATV)-based regimens over 96 weeks. Treatment-naive adult patients (n = 200) were randomized to receive either ATV 300 mg with ritonavir (RTV) 100 mg (ATV300/r, n = 95) or ATV 400 mg (ATV400; n = 105). At week 96, 75% of ATV300/r-treated and 70% of ATV400-treated patients achieved viral loads <400 copies/mL (difference estimate [95% confidence interval, CI] = 5.1 [-7.1 to 17.2]). Five and 20 patients, respectively, experienced virologic failure. Adverse event-related discontinuations occurred among 8% receiving ATV300/r and 3% receiving ATV400. Plasma lipid elevations were generally low. Both regimens were well tolerated and associated with sustained improvements in HRQoL. These findings demonstrate long-term efficacy, tolerability, and safety of both ATV300/r and ATV400 in ARV-naive patients through 96 weeks with improvements in HRQoL.

Economic implications of entecavir treatment in suppressing viral replication in chronic hepatitis B (CHB) patients in China from a perspective of the Chinese Social Security program.

OBJECTIVES: Of estimated 112 million persons infected with chronic hepatitis B (CHB) in China, 15% to 40% will eventually develop liver complications. Most patients do not actively seek antiviral agents for treatment due in part to lack of good understanding of the disease. Entecavir is a new therapeutic option for CHB patients and the purpose of this study was to evaluate the cost-effectiveness of entecavir treatment in China, based on projected clinical benefits from its superior viral suppression efficacy. METHODS: The analysis was based on the perspective of the Chinese Social Security program. Adjusted relative risks on the association between viral load (VL) and clinical end points (liver cirrhosis/hepatocellular carcinoma) were derived from a publication of a Taiwan CHB prospective cohort with 42,115 person-years of follow-up, and applied to patients enrolled in a randomized phase III trial in China. In this trial, hepatitis B virus (HBV) DNA (by polymerase chain reaction assay) was the key efficacy end point after 48 weeks of treatment with either entecavir or lamivudine monotherapy. Entecavir and lamivudine daily prices were assumed to be Renminbi Yuan (RMB) 40 and 16.71, respectively. Life expectancy tables were based on China vital statistics. Direct medical cost and utility scores for different phases of CHB were estimated from published China specific data, and costs were adjusted to 2006 values using the Chinese Consumer Price Index. Probabilistic sensitivity analyses were conducted to evaluate parameter uncertainty on event distribution and treatment failure rates beyond the trial period. RESULTS: A total of 519 subjects were enrolled in the study, comprising of 82% males, 87% HBeAg+, and a mean age of 30 years. Based on the efficacy measurement of the percentage of patients achieving HBV DNA <300 copies/ml at week 48, entecavir was superior to lamivudine (78.7% vs. 46.7%, respectively [P < 0.05]). In the base case, compared with lamivudine, 1 year of entecavir therapy gained 0.305 quality-adjusted life year (QALY) at an incremental cost of 5368 RMB, with a 3% annual discount. Compared with lamivudine, using entecavir cost an incremental 17,590 RMB per QALY gained (95% CI 6333-56,407). CONCLUSIONS: Based on the results of this study, entecavir is likely to be cost-effective in treating hepatitis B patients in China based on the World Health Organization's recommended maximum willingness to pay threshold.