Comparison of renal safety and efficacy of telbivudine, entecavir and tenofovir treatment in chronic hepatitis B patients: real world experience.

This study aims to assess the nephrotoxicity and efficacy of tenofovir disoproxil fumarate (tenofovir), telbivudine and entecavir. A retrospective study of 587 patients with chronic hepatitis B treated with tenofovir (n = 170), telbivudine (n = 184) and entecavir (n = 233) for at least 1 year. Renal function and efficacy were assessed. The estimated glomerular filtration rate (eGFR) decreased significantly in the tenofovir group after a mean of 17 months treatment (from 92.2 to 85.6 mL/min/1.73 m(2), p < 0.001), but increased in the telbivudine group after a mean of 32 months of treatment (from 86.1 to 95 mL/min/1.73 m(2), p < 0.001). There was no significant change in eGFR in the entecavir group after a mean of 44 months. By multivariate analysis, pre-existing renal insufficiency (p = 0.003), tenofovir (p = 0.007) and diuretic treatment (p = 0.001) were independent predictors for renal function deterioration. Cumulative virological breakthrough was 0% in tenofovir after 2 years, 3.4% in entecavir after 7 years and 22.9% in telbivudine after 5 years. Liver cirrhosis (p = 0.008) and virological breakthrough (p = 0.040) were independently associated with increased risk of hepatocellular carcinoma development. Tenofovir may lead to deterioration in renal function as assessed by serial eGFR measurements. Although telbivudine appeared to be associated with an improvement in eGFR, it was associated with high rates of virological breakthrough, which was an independent risk factor for HCC development. With low rates of virological breakthrough and preservation of renal function, entecavir could be the best choice among these three agents.

A comparison of efficacy and safety of 2-year telbivudine and entecavir treatment in patients with chronic hepatitis B: a match-control study.

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

Clinical-guide risk prediction of hepatocellular carcinoma development in chronic hepatitis C patients after interferon-based therapy.

BACKGROUND: Interferon (IFN)-based therapies could eradicate hepatitis C (HCV) and reduce the risk of hepatocellular carcinoma (HCC). However, HCC could still happen after sustained virological response (SVR). We aimed to develop a simple scoring system to predict the risk of HCC development among HCV patients after antiviral therapies. METHODS: From 1999 to 2009, 1879 patients with biopsy-proven HCV infection treated with IFN-based therapies were analyzed. RESULTS: Multivariable analysis showed old age (adjusted HR (aHR)=1.73, 95% CI=1.13-2.65 for aged 60-69 and aHR=2.20, 95% CI=1.43-3.37 for aged ≥ 70), Male gender (aHR=1.74, 95% CI=1.26-2.41), platelet count <150 × 10(9)/l (HR=1.91, 95% CI=1.27-2.86), α-fetoprotein ≥ 20 ng ml(-1) (HR=2.23, 95% CI=1.58-3.14), high fibrotic stage (HR=3.32, 95% CI=2.10-5.22), HCV genotype 1b (HR=1.53, 95% CI=1.10-2.14), and non SVR (HR=2.40, 95% CI=1.70-3.38) were independent risk factors for HCC. Regression coefficients were used to build up a risk score and the accuracy was evaluated by using the area under the receiver operating characteristic curve (AUC). Three groups as low-, intermediate-, and high-risk are classified based on the risk scores. One hundred sixty patients (12.78%) in the derivation and 82 patients (13.08%) in the validation cohort developed HCC with AUC of 79.4%, sensitivity of 84.38%, and specificity of 60.66%. In the validation cohort, the 5-year HCC incidence was 1.81%, 12.92%, and 29.95% in low-, intermediate-, and high-risk groups, with hazard ratios 4.49 in intermediate- and 16.14 in high-risk group respectively. The risk reduction of HCC is greatest in patients with SVR, with a 5-year and 10-year risk reduction of 28.91% and 27.99% respectively. CONCLUSION: The risk scoring system is accurate in predicting HCC development for HCV patients after antiviral therapies.

Trends in the use of immunosuppressive agents by outpatients after renal transplantation at a medical center in southern Taiwan.

Kidney transplantation has become an effective treatment for end-stage renal failure. This study analyzed trends in immunosuppressive agent use after renal transplantation at a medical center in southern Taiwan over a 9-year period (2000-2008) seeking to determine whether the trends were consistent with clinical trial outcomes and published guidelines. We identified adult outpatients who had diagnoses of renal transplantation and who had concurrent immunosuppressive drug claims. From 2000-2008, we discovered 39,189 prescriptions related to kidney transplantation. The overall medication consumption showed an increase from 4.9% to 31.9%. Cyclosporine was the main determinant of overall drug costs during these 9 years. The long-term prescribing trend for immunosuppressive use among renal transplantation outpatients showed a clear change during the course of the study. Tacrolimus and sodium mycophenolate/mycophenolate mofetil were used increasingly as combination therapy. However, our survey revealed that management of this transplantation population, especially regarding the use of either calcineurin inhibitor or corticosteroids, was based on potential long-term side effects.

Using the pharmacoepidemiology approach to evaluate the first-year posttransplantation ambulatory health care cost from the Longitudinal Health Insurance Database (2001 to 2006) in Taiwan.

This research evaluated the total first-year posttransplantation ambulatory health care cost using a countrywide health claims database. We searched all health reimbursement claims of posttransplantation patients from 2001 to 2006 using the ICD-9-CM codes (V42.0, V42.1, V42.6, V42.7, V42.8) for kidney, heart, lung, liver, and other specified organ transplantations. We excluded patients undergoing transplantation surgery>12 months before 2001 or with <1 year of or irregular follow-up visits. All of the studied ambulatory care expenditures by visit files were based on the Taiwan Longitudinal Health Insurance Database (2005), which contained the claims of 1,000,000 beneficiaries who were randomly sampled from the Registry for Beneficiaries of the National Health Insurance Research Database. During this 6-year period we identified 336 transplant patients with 145 new cases having consecutive and >12 months of follow-up ambulatory visits to calculate the first-year posttransplantation cost. Among them, the first-year posttransplantation drug costs and total health care costs of the kidney, heart, lung, liver, and other organ transplantations were (m NTs) 346,396.6+/-170,806.9 and 404,241.9+/-182,499.1, 242,878.5+/-128,772.7 and 302,325+/-129,609.9, 345,792+/-185,940.8 and 387,840.5+/-184,244.5, 404,441.8+/-299,311.7 and 471,631.5+/-306,936.3 and 40,718.2+/-50,740.2 and 67,469.8+/-70,765.7, respectively. Drug expenditures were approximately 80% of the total health care cost except for the other specified organ transplant, i.e., bone marrow, wherein they were 60%. The mean differences between drug expenditures and total costs of various organ transplants were significant (P<.01; ANOVA). Despite the first-year health care cost a the posttransplantation patient being less than dialysis costs in Taiwan, most end-stage renal disease patients are still a waiting organ donation; therefore, some candidates are seeking a transplants outside Taiwan.

A retrospective study on the utilization of and expenditure for immunosuppressants for organ transplant recipients in Taiwan--updated to 2006.

We sought to examine the utilization of and expenditure for immunosuppressants among transplant recipients under the Taiwan global budget system updated from 2004 to 2006, as provided by the Taiwan Longitudinal Health Insurance Database (2005). By using all ambulatory care orders (OO) of files from 2002 to 2006, we identified immunosuppressive agents by the Anatomic Therapeutic Chemical (ATC) code. We selected and analyzed all immunosuppressants classified into the L04 group. For the analytic work, a generalized linear model was developed to examine the effect of time and different ATC subgroup immunosuppressants on drug expenditures. Compared with the previous report covering 1999-2003, wherein the most frequently prescribed immunosuppressive agents were cyclosporine (43%), mycophenolate (30.8%), and tacrolimus (21.3%), the updated information showed cyclosporine 36.8%, tacrolimus 30.17%, and mycophenolate 21.46%. In 2005, the total drug expenditure for tacrolimus was higher than for cyclosporine which was the major immunosuppressive agent used previously. Wald chi-square tests on the effect of time from 2001 to 2006 with different immunosuppressive drug classes showed a significant result (P<.01), namely, increased drug expenditures over time owing to different ATC classes of immunosuppressants. Projecting drug expenditure using a pharmacoepidemiology approach could show the overall picture of cost utilization, including the complex determinants of price inflation, utilization, and physician behavior.

Gender issues and drug use pattern in kidney transplantation: experience of a medical center in southern Taiwan.

Gender issues in clinical transplantation affect outcomes at many levels beyond immunologic concerns; for example, immunosuppressive drugs may influence hormone levels. Most immunosuppressive agents are categorized as "C" by the U.S. Food and Drug Administration, meaning that risks can not be excluded. To optimize renal allograft survival is crucially important in Taiwan because of the limited resources to treat irreversible renal failure. This survey sought to investigate which gender undergoing renal transplantation required greater health care expenditures, using the records of a medical center in Southern Taiwan. We analyzed not only the number of female and male recipients, but also the health care costs. All of the recipients were categorized into 4 groups based on gender and age (40 years). The prescribing patterns in this study were separated into 2 groups by gender to examine differences. From 2000 to 2008, a total of 145 outpatient visits and 8,446 prescriptions met the criteria of renal transplant cases. We also computed the gender proportion of our patients. In conclusion, gender did not influence graft recipient expenditures in our hospital.

Fendiline-evoked [Ca2+]i rises and non-Ca2+-triggered cell death in human oral cancer cells.

The effect of fendiline on cytosolic free Ca(2+) concentrations ([Ca(2+)](i)) and proliferation has not been explored in human oral cancer cells. This study examined whether fendiline altered Ca(2+) levels and caused cell death in OC2 human oral cancer cells. [Ca(2+)](i) and cell viability were measured using the fluorescent dyes fura-2 and WST-1, respectively. Fendiline at concentrations above 10 microM increased [Ca(2+)](i) in a concentration-dependent manner. The Ca(2+) signal was reduced partly by removing extracellular Ca(2+). The fendiline-induced Ca(2+) influx was sensitive to blockade of L-type Ca(2+) channel blockers. In Ca(2+)-free medium, after pretreatment with 50 microM fendiline, 1 microM thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor)-induced [Ca(2+)](i) rises were inhibited; and conversely, thapsigargin pretreatment nearly abolished fendiline-induced [Ca(2+)](i) rises. Inhibition of phospholipase C with 2 microM U73122 did not change fendiline-induced [Ca(2+)](i) rises. At concentrations between 5 and 25 microM, fendiline killed cells in a concentration-dependent manner. The cytotoxic effect of 15 microM fendiline was not reversed by prechelating cytosolic Ca(2+) with BAPTA/AM. Collectively, in OC2 cells, fendiline induced [Ca(2+)](i) rises by causing Ca(2+) release from the endoplasmic reticulum and Ca(2+) influx from L-type Ca(2+) channels. Furthermore, fendiline-caused cytotoxicity was not via a preceding [Ca(2+)](i) rise.