Associations Between Hepatitis B Virus Genotype and Mutants and the Risk of Hepatocellular Carcinoma

Background The risk of hepatocellular carcinoma (HCC) increases with increasing level of hepatitis B virus (HBV) in serum (viral load). However , it is unclear whether genetic characteristics of HBV, including HBV genotype and specific genetic mutations, contribute to the risk of HCC. We examined the HCC risk associated with HBV genotypes and common variants in the precore and basal core promoter (BCP) regions. Methods From January 5, 1991, to December 21, 1992 , baseline blood samples were collected from 2762 Taiwanese men and women who were seropositive for HBV surface antigen but had not been diagnosed with HCC; the samples were tested for HBV viral load by real-time polymerase chain reaction and genotyped by melting curve analysis. Participants who had a baseline serum HBV DNA level greater than 101 copies/ mL (n = 1526) were tested for the precore G 1896A and BCP A 1762T/G1764A mutants by direct sequencing. Incident cases of HCC were ascertained through follow-up examinations and computerized linkage to the National Cancer Registry and death certification profiles. A Cox proportional hazards model was used to estimate the risk of HCC associated with HBV genotype and precore and BCP mutants after adjustment for other risk factors. All statistical tests were two-sided . Results A total of 153 HCC cases occurred during 33847 person-years of follow-up. The HCC incidence rates per 100000 person-years for participants infected with HBV genotype B or C were 305.6 (95% confidence interval [CI] = 236.9 to 388.1) and 785.8 (95% CI = 626.8 to 972.9), respectively. Among participants with a baseline HBV DNA level of at least 10(4) copies/mL, HCC incidence per 100000 person-years was higher for those with the precore G1896 ( wild-type) variant than for those with the G1896A variant ( 955.5 [95% CI = 749.0 to 1201.4] vs 269.4 [95% CI = 172.6 to 400.9]) and for those with the BCP A1762T/G1764A double mutant than for those with BCP A1762/G1764 (wild-type) variant (1149.2 [95% CI = 872.6 to 1485.6] vs 358.7 [95% Cl = 255.1 to 490.4]). The multivariable-adjusted hazard ratio of developing HCC was 1.76 (95% CI = 1.19 to 2.61) for genotype C vs genotype B, 0.34 (95% CI = 0.21 to 0.57) for precore G1896A vs wild type, and 1.73 (95% CI = 1.13 to 2.67 ) for BCP A1762T/G1764A vs wild type. Risk was highest among participants infected with genotype C HBV and wild type for the precore 1896 variant and mutant for the BCP 1762/1764 variant ( adjusted hazard ratio = 2.99, 95% CI = 1.57 to 5.70 , P<.001). Conclusions HBV genotype C and specific alleles of BCP and precore were associated with risk of HCC. These associations were independent of serum HBV DNA level

Cost-Effectiveness Analysis of Entecavir versus Lamivudine in the First-Line Treatment of Australian Patients with Chronic Hepatitis B

Background: Chronic hepatitis B (CHB) virus infection is a major global healthcare problem. The recent introduction of entecavir in Australia for the treatment of CHB patients in the naive treatment setting has triggered significant optimism with regards to improved clinical outcomes for CHB patients. Abstract: Objective: To estimate, from an Australian healthcare perspective, the cost effectiveness of entecavir 0.5 mg/day versus lamivudine 100 mg/day in the treatment of CHB patients naive to nucleos(t)ide therapy. Abstract: Methods: A cost-utility analysis to project the clinical and economic outcomes associated with CHB disease and treatment was conducted by developing two decision-tree models specific to hepatitis B e antigen-positive (HBeAg+ve) and HBeAg-ve CHB patient subsets. This analysis was constructed using the Australian payer perspective of direct costs and outcomes, with indirect medical costs and lost productivity not being included. The study population comprised a hypothetical cohort of 1000 antiviral treatment-naive CHB patients who received either entecavir 0.5 mg/day or lamivudine 100 mg/day at model entry. The population of patients used in this analysis was representative of those patients likely to receive initial antiviral therapy in clinical practice in Australia. The long-term cost effectiveness of entecavir compared with lamivudine in the first-line treatment of CHB patients was expressed as an incremental cost per life-year gained (LYG) or QALY gained. Abstract: Results: Results revealed that the availability of entecavir 0.5 mg/day as part of the Australian hepatologist's treatment armamentarium should result in significantly lower future rates of compensated cirrhosis (CC), decompensated cirrhosis (DC), and hepatocellular carcinoma (HCC) events (i.e. 54 fewer cases of CC, seven fewer cases of DC, and 20 fewer cases of HCC over the model's timeframe for HBeAg+ve CHB patients, and 69 fewer cases of CC, eight fewer cases of DC and 25 fewer cases of HCC over the model's timeframe for HBeAg-ve CHB patients). Compared with lamivudine 100 mg/day, entecavir 0.5 mg/day generated an estimated incremental cost per LYG of Australian dollars ($A, year 2006 values) 5046 and an estimated incremental cost per QALY of$A5952 in the HBeAg+ve CHB patient population, an estimated incremental cost per LYG of $A7063 and an estimated incremental cost per QALY of$A8003 in the HBeAg-ve CHB patient population, and an overall estimated incremental cost per LYG of $A5853 and an estimated incremental cost per QALY of$A6772 in the general CHB population. Abstract: Conclusion: The availability of entecavir in Australian clinical practice should make long-term suppression of hepatitis B virus replication increasingly attainable, resulting in fewer CHB sequelae, at an acceptable financial cost.

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 &lt; 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

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

BackgroundMost 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.MethodsWe 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.ResultsThe proportions controlled for HbA1c, BP and LDL-C have improved (p &lt; 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.ConclusionDespite 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

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 A(1c) (HbA(1c)), 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 HbA(1c), 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 HbA(1c), BP and LDL-C, with improvements seen in those without CVD more often than those with CVD

Changes in lipids over twelve months after initiating protease inhibitor therapy among persons treated for HIV/AIDS

Background: Protease inhibitors are known to alter the lipid profiles in subjects treated for HIV/AIDS. However, the magnitude of this effect on plasma lipoproteins and lipids has not been adequately quantified. Objective: To estimate the changes in plasma lipoproteins and triglycerides occurring within 12 months of initiating PI-based antiretroviral therapy among HIV/AIDS afflicted subjects. Methods: We included all antiretroviral naïve HIV-infected persons treated at St-Paul's Hospital, British Columbia, Canada, who initiated therapy with protease inhibitor antiretroviral (ARV) drugs between August 1996 and January 2002 and who had at least one plasma lipid measurement. Longitudinal associations between medication use and plasma lipids were estimated using mixed effects models that accounted for repeated measures on the same subjects and were adjusted for age, sex, time dependent CD4+ T-cell count, and time dependent cumulative use of non-nucleoside reverse transcriptase inhibitors and adherence. The cumulative number of prescriptions filled for PIs was considered time dependent. We estimated the changes in the 12 months following any initiation of a PI based regimen. Results: A total of 679 eligible subjects were dispensed nucleoside analogues and PI at the initiation of therapy. Over a median 47 months of follow-up (interquartile range (IQR): 29–62), subjects had a median of 3 (IQR: 1–6) blood lipid measurements. Twelve months after treatment initiation of PI use, there was an estimated 20% (95% confidence interval: 17% – 24%) increase in total cholesterol and 22% (12% – 33%) increase in triglycerides. Conclusions: Twelve months after treatment initiation with PIs, statistically significant increases in total cholesterol and triglycerides levels were observed in HIV-infected patients under conditions of standard treatment. Our results contribute to the growing body of evidence implicating PIs in the development of blood lipid abnormalities. In conjunction with the predominance or men, high rates of smoking, and aging of the treated HIV-positive population, elevated lipoproteins and triglycerides may mean that patients such as these are at elevated risk for cardiovascular events in the future.Health Care and Epidemiology, Department ofMedicine, Department ofMedicine, Faculty ofOther UBCNon UBCReviewedFacult