Platform trial design for neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis: A potential model for rare diseases.

Background: Neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis (grouped under the abbreviation "NF") are rare hereditary tumor predisposition syndromes. Due to the low prevalence, variability in the range, and severity of manifestations, as well as limited treatment options, these conditions require innovative trial designs to accelerate the development of new treatments. Methods: Within European Patient-Centric Clinical Trial Platforms (EU-PEARL), we designed 2 platform-basket trials in NF. The trials were designed by a team of multidisciplinary NF experts and trial methodology experts. Results: The trial will consist of an observational and a treatment period. The observational period will serve as a longitudinal natural history study. The platform trial design and randomization to a sequence of available interventions allow for the addition of interventions during the trial. If a drug does not meet the predetermined efficacy endpoint or reveals unacceptable toxicities, participants may stop treatment on that arm and re-enter the observational period, where they can be re-randomized to a different treatment arm if eligible. Intervention-specific eligibility criteria and endpoints are listed in intervention-specific-appendices, allowing the flexibility and adaptability needed for highly variable and rare conditions like NF. Conclusions: These innovative platform-basket trials for NF may serve as a model for other rare diseases, as they will enhance the chance of identifying beneficial treatments through optimal learning from a small number of patients. The goal of these trials is to identify beneficial treatments for NF more rapidly and at a lower cost than traditional, single-agent clinical trials.

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.

Association between hypoglycemia and fall-related events in type 2 diabetes mellitus: analysis of a U.S. commercial database.

BACKGROUND: Hypoglycemia is a major barrier to achieving optimal glycemic control and managing diabetes successfully in patients with diabetes. Falls are the most significant consequences caused by hypoglycemia episodes. Both hypoglycemia and falls lead to substantial economic burden on the health care system in the United States. OBJECTIVE: To examine the association of hypoglycemia with fall-related outcomes in elderly patients with type 2 diabetes mellitus (T2DM). METHODS: Records were obtained for T2DM patients (N = 1,147,937) from January 1, 2008, to December 31, 2011. The nonhypoglycemia patients were randomly matched 1:1 by age and gender to the hypoglycemia patients. Fall-related events (composite of fall-related outcomes) were defined using ICD-9-CM codes. Conditional logistic regression models were used to compare the fall-related events within 30 days, 90 days, 180 days, and 365 days between the 2 cohorts. RESULTS: A total of 21,613 hypoglycemia patients were matched with 21,613 nonhypoglycemic patients. Patients with hypoglycemia had higher fall-related events within 30 days, 90 days, 180 days, and 365 days (P less than 0.001 for all frequency differences). Conditional logistic regression analyses showed an elevated risk for fall-related events over 365 days (aOR = 1.95, 95% CI = 1.70-2.24). Subgroup analysis showed elevated risk for patients aged less than 75 years and ≥ 75 years. Elevated risks were also seen for individual fall-related outcomes of fractures, head injuries, long-term care placement, and hospital admissions. CONCLUSIONS: The risk of fall-related events over 365 days increased 2-fold among elderly patients with diabetes who experienced hypoglycemia.

Preventable coronary heart disease events from control of cardiovascular risk factors in US adults with diabetes (projections from utilizing the UKPDS risk engine).

Type 2 diabetes mellitus (T2DM) carries significant risks for coronary heart disease (CHD). We examined the potential US population impact of single and composite risk factor control. Among US adults with diagnosed T2DM aged≥30 years in the National Health and Nutrition Examination Survey 2007 to 2012, we assessed CHD events preventable using the United Kingdom Prospective Diabetes Study CHD risk engine. We examined in all those not at goal the impact of statistical control of smoking, glycated hemoglobin, systolic blood pressure, and total and high-density lipoprotein cholesterol, according to the predefined criteria setting risk factors at different levels of control representing (1) "All to Goal," (2) at "Nominal Control," or (3) at "Aggressive Control." Preventable CHD events represented the difference between the number of events estimated from the control of these risk factors versus current levels of the risk factors. Of 606 men (representing 6.2 million) and 603 women (6.3 million) with DM and no previous CHD, 1.3 million men and 0.7 million women would develop a CHD event within 10 years if left uncontrolled. Controlling all risk factors to goal was projected to prevent 35% and 45% of CHD events in men and women, respectively. Nominal risk factor control was projected to prevent 36% and 38% and aggressive control 51% and 61% of CHD events, respectively. In conclusion, a significant proportion of CHD events in adults with T2DM could be prevented from composite control of risk factors often not at goal.

Cost-effectiveness of apixaban versus other new oral anticoagulants for stroke prevention in atrial fibrillation.

BACKGROUND: Apixaban (5 mg BID), dabigatran (available as 150 mg and 110 mg BID in Europe), and rivaroxaban (20 mg once daily) are 3 novel oral anticoagulants (NOACs) currently approved for stroke prevention in patients with atrial fibrillation (AF). OBJECTIVE: The objective of this study was to evaluate the cost-effectiveness of apixaban against other NOACs from the perspective of the United Kingdom National Health Services. METHODS: A Markov model was developed to evaluate the pharmacoeconomic impact of apixaban versus other NOACs over a lifetime. Pair-wise indirect treatment comparisons were conducted against other NOACs by using ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation), RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy), and ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial results for the following end points: ischemic stroke, hemorrhagic stroke, intracranial hemorrhage, other major bleeds, clinically relevant nonmajor bleeds, myocardial infarction, and treatment discontinuations. Outcomes were life-years, quality-adjusted life years gained, direct health care costs, and incremental cost-effectiveness ratios. RESULTS: Apixaban was projected to increase life expectancy versus other NOACs, including dabigatran (both doses) and rivaroxaban. A small increase in therapeutic management costs was observed with apixaban due to projected gains in life expectancy and lower discontinuation rates anticipated on apixaban versus other NOACs through lifetime. The estimated incremental cost-effectiveness ratio was £9611, £4497, and £5305 per quality-adjusted life-year gained with apixaban compared with dabigatran 150 mg BID, dabigatran 110 mg BID, and rivaroxaban 20 mg once daily, respectively. Sensitivity analyses indicated that results were robust over a wide range of inputs. CONCLUSIONS: Although our analysis was limited by the absence of head-to-head trials, based on the indirect comparison data available, our model projects that apixaban may be a cost-effective alternative to dabigatran 150 mg BID, dabigatran 110 mg BID, and rivaroxaban 20 mg once daily for stroke prevention in AF patients from the perspective of the United Kingdom National Health Services.

Evaluation of the relationship between weight change and glycemic control after initiation of antidiabetic therapy in patients with type 2 diabetes using electronic medical record data.

AIMS: This study evaluates the relationship between HbA1c and weight change outcomes by anti-diabetic weight-effect properties in patients newly treated for type 2 diabetes; a relationship not previously characterized. METHODS: Electronic medical records of patients with type 2 diabetes newly prescribed anti-diabetic monotherapy were assessed to identify HbA1c goal attainment [(<53 mmol/mol)] and weight change at 1-year. Anti-diabetics were categorized by weight-effect properties: weight-gain (sulfonylureas, thiazolidinediones) and weight-loss/neutral (metformin, DPP-4 inhibitors, GLP-1 agonists). Logistic regression analyses identified likelihood of attaining HbA1c goal or ≥3% weight loss by anti-diabetic category controlling for baseline characteristics. MANOVA was used to identify correlation between changes in weight and HbA1c. RESULTS: The study included 28,290 patients. Mean age ± sd was 61 years ±11.8. Baseline HbA1c was 7.4% ± 1.6 (57 mmol/mol ± 17); 67.3% were prescribed a weight-loss/neutral anti-diabetic. At 1-year, more patients in the weight-loss/neutral anti-diabetic category lost weight (≥3%) than in the weight-gain anti-diabetic category (40.4% vs. 24.2%, p<0.001) or had an HbA1c<7.0% (<53 mmol/mol) (71.1% vs. 63.8%, p<0.001). Those prescribed a weight-gain anti-diabetic were 53% less likely to lose weight and 29% less likely to be at HbA1c goal than those prescribed a weight-loss/neutral anti-diabetic (p<0.001). Weight loss and HbA1c outcomes were significantly correlated (p<0.001). CONCLUSIONS: Weight loss of ≥3% was associated with better glycemic control in patients newly treated for type 2 diabetes. Anti-diabetics associated with weight-loss/neutrality were associated with greater weight loss and HbA1c goal attainment and may facilitate efforts to co-manage weight and glycemia in the ambulatory-care setting.

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.

Trends in control of cardiovascular risk factors among US adults with type 2 diabetes from 1999 to 2010: comparison by prevalent cardiovascular disease status.

BACKGROUND: Most patients with type 2 diabetes mellitus (T2DM) suffer from cardiovascular disease (CVD). Whether CVD risk factors have improved in those with DM with and without CVD is not established. We compared risk factor levels and goal attainment in US adults with diabetes with and without CVD. METHODS: We examined 2403 adults (aged ≥ 18 years) in the United States with T2DM (n = 654, 27% with CVD) across 1999-2010 using the US National Health and Nutrition Examination Survey (NHANES) and evaluated control of hemoglobin A1c (HbA1c), blood pressure (BP), low-density lipoprotein cholesterol (LDL-C) and body mass index (BMI) in those with DM with versus without CVD. RESULTS: The proportions controlled for HbA1c, BP and LDL-C have improved (p < 0.001) overall between 1999 and 2010, but only 24% were at goal for all three factors in 2009-2010. There were improvements in BP, triglycerides and LDL-C in those with CVD, and in those without CVD, there were also improvements in control of all parameters, although changes in mean levels of risk factors were less impressive. CONCLUSION: Despite modest improvement over time, in most CVD risk factors, only one-fourth of those with T2DM are at goal for HbA1c, BP and LDL-C, with improvements seen in those without CVD more often than those with CVD.

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.

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.

Comparison of demographic factors and cardiovascular risk factor control among U.S. adults with type 2 diabetes by insulin treatment classification.

AIMS: Data on glucose and cardiovascular disease (CVD) risk factor control among persons with type 2 diabetes mellitus (DM) according to insulin treatment status are lacking. We examined DM control, risk factors, and comorbidities among U.S. persons according to insulin treatment status. METHODS: In the U.S. National Health and Nutrition Examination Surveys 2003-2006, we examined in 10,637 adults aged ≥30 with type 2 DM the extent of control of A1c, LDL-C, HDL-C, triglycerides, and blood pressure (BP) and composite goal attainment by insulin use status. RESULTS: 6.6% (n=889, projected to 14.3 million) had type 2 DM; of these, 22.9% were insulin users and 57.2% were treated only by other diabetes medications. Overall, 58.2% had an A1c<7% (53 mmol/mol) (insulin users 33.1%, non-insulin treated 66.1%, and 77.9% of those not on medication, p<0.0001). Overall, 44.2% were at a BP goal of <130/80 mmHg, 43.8% had an LDL-C<100 mg/dl (2.6 mmol/L), and 13.9% a BMI<25 kg/m(2). Only 10.2% were simultaneously at A1c, LDL, and BP goals (5.4% of those on insulin). CONCLUSIONS: U.S. adults with type 2 DM, especially those treated with insulin remain inadequately controlled for A1c and CVD risk factors and have a high prevalence of comorbidities.

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.

Global cardiovascular disease risk assessment in United States adults with diabetes.

BACKGROUND: Diabetes mellitus (DM) is often considered a risk equivalent for cardiovascular disease (CVD); however, the variation in CVD risk in adults with DM has not been described. METHODS: We studied 1114 US adults aged ≥18 years with DM from national survey data and the proportion at low (<10%), intermediate (10-20%) and high (>20%) risk, or with CVD, by age, gender, ethnicity and diabetes type and treatment, and glycaemic and risk factor control by risk group. RESULTS: Overall, 22.9% were low, 17.5% intermediate, 31.4% high risk and 28.2% had pre-existing CVD (total 59.6% high risk/CVD). More Hispanics (32.4%) and Blacks (30.6%) versus Whites (18.8%) were at lower risk (p<0.0001). Among type 1 versus 2 DM, 35% vs. 65% (p<0.0001) and among insulin users 68.1% were high risk or with CVD. However, among low-intermediate risk, >50% have metabolic syndrome and 7% chronic kidney disease, increasing the high risk/CVD group to 86.8%. Simultaneous achievement of HbA1c, blood pressure and low density lipoprotein-cholesterol goals was low (<15%) regardless of risk group. CONCLUSIONS: Many DM patients are not at high 10-year CVD risk, but metabolic factors may place them at greater long-term risk. Risk assessment could help target the intensity of treatment.

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.

Absenteeism and productivity among employees being treated for hepatitis C.

OBJECTIVES: To compare productivity, absence days, and absence costs for treated (HCV-Tx) and untreated (HCV-NoTx) US employees with hepatitis C virus (HCV) infection. STUDY DESIGN: Retrospective database study. METHODS: Employee records from multiple large employers in the United States with data about demographics, jobs, and healthcare use in the Human Capital Management Services database were assessed. HCV subjects were identified by International Classification of Diseases, 9th Revision codes. To test differences between cohorts, t tests and χ2 tests were used. Regression modeling was used to compare absence days, costs,and objectively measured productivity, while controlling for confounding factors. For HCV-Tx employees, the index date was the date of the first treatment with interferon, peginterferon, and/or ribavirin. For HCV-NoTx employees, the index date was the average date by company among HCV-Tx employees. Absence and productivity were measured from each employee's index date to the last date the employee was enrolled in health benefits coverage. RESULTS: A total of 441 HCV-Tx and 1223 HCV-NoTx employees were evaluated. HCV-Tx workers had 0.52 more total monthly absence days and $31.31 in additional monthly absence payments per employee than untreated employees. Treated employees' productivity was lower, with treated subjects processing 11.7% fewer units per hour and 17.4% fewer units per month than untreated employees. CONCLUSIONS: This study quantified the substantial indirect burden of illness associated with use of current HCV treatments. New treatments are needed with improved adverse effect profiles that result in reduced absence from work and improved productivity among HCV-infected persons.

Lifetime risk and sex difference of hepatocellular carcinoma among patients with chronic hepatitis B and C.

PURPOSE: Both hepatitis B (HBV) and C viruses (HCV) are causes of hepatocellular carcinoma (HCC), but lifetime risk and sex difference remain unclear. This study aimed to assess the lifetime risk and sex difference of HCC among patients with chronic HBV and/or HCV. METHODS: A prospective cohort of 23,820 residents of Taiwan age 30 to 65 years were enrolled from 1991 to 1992, with 477 instances of HCC occurring subsequently. Serum samples collected at enrollment were tested for seromarkers and viral load of HBV and HCV. Newly developed HCC was ascertained through computerized data linkage with national cancer registry and death certification systems. RESULTS: The cumulative lifetime (age 30 to 75 years) incidences of HCC for men and women positive for both HBV surface antigen (HBsAg) and antibodies against HCV (anti-HCV) were 38.35% and 27.40%; for those positive for HBsAg only, 27.38% and 7.99%; for those positive for anti-HCV only, 23.73% and 16.71%; and for those positive for neither, 1.55% and 1.03%, respectively. There was a significant male predominance in incidence of HCC for chronic HBV carriers but not for chronic carriers of HCV or both. Multivariate adjusted hazard ratio of developing HCC decreased with age in HBsAg-seropositive men but increased with age in anti-HCV-seropositive women. Among dual-infected participants, there was an inverse association between HBV and HCV viral load. Risk of HCC increased significantly with increasing viral load of HBV and HCV. CONCLUSION: There exists a suppressive effect of HCV on HBV viral load. Individual and combined effects of the two viruses on HCC vary with sex and age.

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.