Clinical experience with nonstandard doses ofinterferon alfa-2b and ribavirin in the treatment of chronic hepatitis C infection: A retrospective analysis.

BACKGROUND: Hepatitis C virus (HCV) infection is the most common blood-borne virus in the United States. Several mono- and combination therapies have been approved by the US Food and Drug Administration for the treatment of HCV, but their routes of administration, dosing approaches, eras of introduction, and actual use in clinical practice and resulting effectiveness have not yet been reported. OBJECTIVES: The aim of this article was to characterize clinical use and virologic response (VR) of the HCV treatments interferon alfa-2b plus ribavirin (IFN + RBV) and peginterferon alfa-2b plus ribavirin (peg-IFN + RBV). METHODS: This retrospective chart review of office-based practices in theUnited States was conducted at 200 physicians' offices across the United States. We collected data concerning dosing patterns, VR (HCV RNA load, ≤1000 IU/mL or "negative" on polymerase chain reaction qualitative analysis), and adverse events (AEs) from the medical records of a geographically diverse sample of patients receiving treatment for chronic HCV infection in the United States from July 2001 to June 2002. For efficacy assessment, factors that were statistically different at baseline were adjusted using logistic regression. Providers also reviewed the medical records for symptoms or signs consistent with HCV treatment-related AEs. RESULTS: Data from the records of 675 patients (423 men, 252 women; mean [SD] age of 45.5 [8.2] years; mean [SD] body weight, 80.8 [19.4] kg) were analyzed. At baseline, the IFN + RBV treatment group (330 patients) had significantly higher percentages of black patients (22.1% vs 15.7%; P = 0.032) and patients with hepatic disease based on clinician-reported cirrhosis and liver dysfunction (18.8% vs 9.9%; P < 0.001), and a significantly lower percentage of white patients (60.3% vs 69.6%; P = 0.012) compared with the peg-IFN + RBV treatment group (345 patients). The difference in log-transformed baseline HCV RNA loads between the 2 treatment groups in this study was <1 log unit. A significantly higher percentage of IFN + RBV-treated patients compared with peg-IFN + RBV-treated patients were prescribed HCV therapy on diagnosis (37.3% vs 29.9%; P = 0.041), and the mean (SD) duration of treatment was significantly different between the 2 treatment groups (52.5 [37.0] vs 27.5 [15.0] weeks; P < 0.001). Peg-IFN + RBV was associated with a higher rate of VR compared with IFN + RBV on univariate analysis (28.5% vs 17.5%; P = 0.018). Recommended doses of peg-IFN and higher-than-recommended doses of RBV were associated with an increased likelihood of VR. Higher-than-recommended doses of peg-IFN without a concomitant increase in RBV was not associated with an increased likelihood of VR. The incidences of the 3 most commonly reported AEs in the IFN + RSV group were significantly higher compared with those in the peg-IFN + RSV group: fatigue, 217 (65.8%) versus 185 (53.6%) patients (P = 0.001); depression, 147 (44.5%) versus 120 (34.8%) (P = 0.009); and anxiety, 87 (26.4%) versus 64 (18.6%) (P = 0.014). Nausea, however, was reported in a significantly higher number of patients in the peg-IFN group compared with the IFN + RBV group (74 [21.4%] vs 51 [15.5%]; P = 0.045). The frequencies of dose modification and treatment discontinuation due to AEs were similar between the 2 treatments and were similar to or less than those reported in other studies. CONCLUSIONS: In this retrospective data analysis of US office-based practicesconcerning HCV treatment, clinicians were observed to prescribe IFN + RBV at doses that differ from recommendations in the product information (PI), as well as prescribe the RBV component of peg-IFN + RBV at doses that differed from PI recommendations. Although patients treated with peg-IFN + RBV appeared to achieve higher VR compared with those treated with IFN + RBV in our analysis of data from clinical practice, peg-IFN + RBV was associated with lower VR rates compared with those reported in clinical studies.

Mycophenolate mofetil versus azathioprine therapy is associated with a significant protection against long-term renal allograft function deterioration.

BACKGROUND: To evaluate the association of long-term continuous mycophenolate mofetil (MMF) versus azathioprine (AZA) therapy and renal allograft function, as measured by the slope of reciprocal creatinine, we analyzed 49,666 primary renal allograft recipients reported to the United States Renal Data System between October 31, 1988 and June 30, 1998. METHODS: The primary study endpoint was defined as a greater than 20% decrease below a 6-month baseline of 1/serum creatinine (SCr) (slope of reciprocal creatinine) at or beyond 1 year after transplantation. A secondary endpoint was defined as reaching an SCr value greater than 1.6 mg/dL. Univariate Kaplan-Meier analysis and multivariate Cox proportional hazard models were used to investigate the risk of reaching the study endpoints. Multivariate analyses were corrected for potential confounding covariates. RESULTS: According to the Cox proportional hazard model, 12-month continued therapy of MMF versus AZA was associated with a protective effect against declining renal function, as measured by the slope of reciprocal creatinine (relative risk [RR]=0.84, confidence interval 0.78-0.91, P<0.001). For 24-month continued therapy of MMF versus AZA, MMF was associated with a further decreased risk for a decline in renal function (RR=0.66, confidence interval=0.57-0.77, P<0.001). Furthermore, MMF was associated with a protective effect against reaching the SCr threshold of 1.6 mg/dL (RR=0.80, P<0.001) beyond 12 months posttransplantation. CONCLUSIONS: Continuous use of MMF versus AZA was associated with a protective effect against declining renal function beyond 1 year after transplantation. Further study is needed to confirm that continued MMF therapy is protective against long-term deterioration in renal function.

Retrospective study of the renal effects of amphotericin B lipid complex when used at higher-than-recommended dosages and longer durations compared with lower dosages and shorter durations in patients with systemic fungal infections.

BACKGROUND: Patients with fungal infections who are treated with amphotericin B lipid complex (ABLC) often receive dosages less than that recommended in the product information (5 mg/kg.d). This occurs despite the described safety and increased efficacy in select patients treated with higher ABLC dosages. OBJECTIVE: The purpose of this study was to compare the renal effects of high-dosage/long-duration (HDos/LDur) ABLC therapy (>5 mg/kg.d for >12 days) with those of low-dosage/short-duration (LDos/SDur) ABLC therapy (or=4 ABLC doses according to a large, multicenter patient database, the Collaborative Exchange of Antifungal Research (CLEAR) registry. The safety profile of each dosage was evaluated using serum creatinine concentration (S-Cr) and calculated creatinine clearance (CCcr). RESULTS: A total of 1726 patients were studied. The HDos/LDur group included 309 patients and theLDos/SDur group included 1417 patients. The median ages of the HDos/LDur and LDos/SDur groups were 42 and 48 years, respectively (ranges, <1 to 83 and <1 to 95 years; P < 0.001); females comprised 51% and 42% of the 2 populations (P = 0.004); and 6% and 12% had solid tumors (P = 0.002). The HDos/LDur group was more likely than the LDos/SDur group to have been treated for multiple systemic fungal pathogen infections (16% and 9%, respectively) and for mold infections (28% and 12%, respectively) (both, P < 0.001). The median change in S-Cr from baseline was 0.1 mg/dL in both groups (range, -4.9 to 5 mg/dL in the HDos/LDur group and -3.96 to 4.7 mg/dL in the LDos/SDur group). No increased risk for renal dysfunction, as reflected in the median change from baseline in CCcr, was observed in either cohort (-3 mL/min [range, -118.65 to 69.03 mL/min] in the HDos/LDur group; -2.17 mL/min [range, -107.48 to 104.45 mL/min] in the LDos/SDur group). CONCLUSION: These data suggest that higher ABLC dosages appear to be as well tolerated as lower dosages, warranting further study of ABLC dosages >5 mg/kg.d for >12 days in the treatment of systemic fungal infections.

Intensive lifestyle modification: impact on cardiovascular disease risk factors in subjects with and without clinical cardiovascular disease.

Intensive lifestyle modification programs are intended to stabilize or promote regression of coronary artery disease; however, clinical response is often nonuniform, complicating appropriate utilization of resources and prediction of outcome. This study assessed physiological and psychological benefits to 72 persons participating in a prospective, nonrandomized, four-component lifestyle change program and compared response between patients with clinical cardiovascular disease (CVD) and patients with elevated risk factors for CVD but without clinical manifestations of disease. Subjects entering the program due to elevated risk factor levels alone demonstrated equal or greater benefit, in terms of improvement in primary CVD risk factors and reduction in measures of coronary disease risk developed in the Framingham Heart Study, than those with clinical CVD. These findings suggest that intensive lifestyle change programs may be important for primary prevention in individuals at increased risk of CVD.

Development and evaluation of a common data model enabling active drug safety surveillance using disparate healthcare databases.

OBJECTIVE: Active drug safety surveillance may be enhanced by analysis of multiple observational healthcare databases, including administrative claims and electronic health records. The objective of this study was to develop and evaluate a common data model (CDM) enabling rapid, comparable, systematic analyses across disparate observational data sources to identify and evaluate the effects of medicines. DESIGN: The CDM uses a person-centric design, with attributes for demographics, drug exposures, and condition occurrence. Drug eras, constructed to represent periods of persistent drug use, are derived from available elements from pharmacy dispensings, prescriptions written, and other medication history. Condition eras aggregate diagnoses that occur within a single episode of care. Drugs and conditions from source data are mapped to biomedical ontologies to standardize terminologies and enable analyses of higher-order effects. MEASUREMENTS: The CDM was applied to two source types: an administrative claims and an electronic medical record database. Descriptive statistics were used to evaluate transformation rules. Two case studies demonstrate the ability of the CDM to enable standard analyses across disparate sources: analyses of persons exposed to rofecoxib and persons with an acute myocardial infarction. RESULTS: Over 43 million persons, with nearly 1 billion drug exposures and 3.7 billion condition occurrences from both databases were successfully transformed into the CDM. An analysis routine applied to transformed data from each database produced consistent, comparable results. CONCLUSION: A CDM can normalize the structure and content of disparate observational data, enabling standardized analyses that are meaningfully comparable when assessing the effects of medicines.

Comparison of characteristics of treated and non-treated patients with Hepatitis C infection.

OBJECTIVES: This study compares the characteristics of treated and non-treated patients with Hepatitis C (HCV) infection. METHODS: Information on patient demographics, clinical data, and treatment regimens were collected from a retrospective medical record review of 998 patients diagnosed with HCV, representing a diverse geographic sample of 200 U.S. physicians including 130 gastroenterologists, 50 infectious disease physicians, and 20 hepatologists. A total of 551 patients were randomly selected and 447 were provided as an augmented sample in an intent-to-treat analysis based on treatment decisions. Pretreatment factors examined included age, gender, race, weight, HCV genotype, HCV viral load, serum ALT levels, liver biopsy results, cirrhosis, HIV co-infection, HBV co-infection, IV drug use, and insurance status. Univariate analyses were performed using Chi-squared or ANOVA tests. Factors that were significant in univariate analyses were entered into a multivariate logistic regression model with HCV treatment as the outcome variable. RESULTS: Of the 998 patients reviewed, 778 were treated for HCV and 220 were not treated. In univariate analyses, non-treated patients were more likely to be African American, HBV co-infected, HIV co-infected, IDUs, alcoholics, Medicaid insured, and were less likely to have had biopsies. The multivariate regression analysis demonstrated that performance of a liver biopsy, treatment with psychiatric medications (antidepressants and anxiolytics), and patient weight were independently associated with treatment, while Medicaid insurance and HIV co-infection were independently associated with a decreased likelihood of receiving HCV therapy. CONCLUSION: This study suggests that it is not the clinical stage of HCV infection but the patient's demographic characteristics and co-morbid conditions that impact the decision to initiate HCV therapy.

Mycophenolate mofetil vs. azathioprine is associated with decreased acute rejection, late acute rejection, and risk for cardiovascular death in renal transplant recipients with pre-transplant diabetes.

Outcomes specifically in mycophenolate mofetil (MMF)-treated diabetic renal transplant patients have not been previously reported. This study compared acute rejection (AR), late acute rejection (LAR), patient survival [and specifically death from cardiovascular (CV), infectious and malignant causes], incidence of post-transplant malignancies, and graft loss in MMF- or azathioprine (AZA)-treated renal transplant patients with pre-transplant diabetes. Outcomes were compared between MMF- (n = 14 144) and AZA- (n = 3001) treated diabetic patients using the Scientific Registry of Transplant Recipients data on all U.S. adult renal transplants performed between 1995 and 2002. Statistical analyses included Kaplan-Meier survival analysis, Cox multivariable regression and chi-square tests. MMF patients had less AR compared with AZA-treated patients (23.5% vs. 28.3%, p < 0.001) and less risk for LAR over 4 yr [hazard ratio (HR): 0.64, 95% CI 0.44, 0.92; p = 0.02]. While time to any-cause death did not differ between the groups, MMF treatment was associated with a 20% decreased risk of CV death (HR: 0.80, 95% CI 0.67, 0.97; p = 0.020) compared with AZA treatment. MMF patients also had a lower incidence of malignancies than AZA patients (2.2% vs. 3.7%, p < 0.001). These results suggest treatment with MMF compared with treatment with AZA in diabetic transplant patients is associated with less AR, less risk of LAR, a decreased risk of CV death, and a lower incidence of malignancies.

Mycophenolate mofetil vs azathioprine in a large population of elderly renal transplant patients.

BACKGROUND: Mycophenolate mofetil (MMF) has been shown to decrease acute rejection episodes after kidney transplantation, and has been associated with better graft and patient survival vs azathioprine (AZA). Previous studies reported a higher risk of death due to infection in elderly recipients treated with MMF-based immunosuppression. METHODS: We analysed 5069 elderly ( > 65 years of age) primary renal allograft recipients treated with either MMF or AZA reported to the Scientific Registry of Transplant Recipients between 1988 and 2000, and compared rates of acute rejection, late acute rejection, graft survival, death-censored graft survival, patient survival and death with a functioning graft. RESULTS: In Cox proportional hazard models, MMF was associated with lower rates of late acute rejection with 12 (RR = 0.72, P = 0.11) and 24 months (RR = 0.50, P = 0.028) of continuous therapy. In univariate analysis (Kaplan-Meier), MMF was associated with improved patient (P = 0.0003) and graft (P<0.0001) survival vs AZA, and trends toward improved patient and graft survival in multivariate analyses. CONCLUSIONS: These findings demonstrate the efficacy of MMF-based immunosuppression in elderly transplant recipients and do not suggest an increased risk of death compared to treatment with AZA.

Sirolimus with neoral versus mycophenolate mofetil with neoral is associated with decreased renal allograft survival.

To evaluate the association between a regimen of cyclosporine microemulsion (CsA) + sirolimus (Rapa) treatment versus CsA and mycophenolate mofetil (MMF) and renal allograft survival, we analyzed 23 016 primary recipients reported to the Scientific Registry of Transplant Recipients between January 1, 1998 and July 26, 2003. Univariate Kaplan-Meier analysis and multivariate Cox proportional hazard models correcting for demographic and clinical covariates were used to estimate the relative risks for CsA+Rapa versus CsA+MMF-treated patients reaching study endpoints. Subgroup analyses were conducted for recipient ethnicity and donor type. CsA+Rapa was associated with significantly lower graft survival (74.6% vs. 79.3% at 4 years, p = 0.002) and death-censored graft survival (83.7% vs. 87.2%, p = 0.003) compared to CsA+MMF. In multivariate analyses, CsA+Rapa was associated with a significantly increased risk for graft loss, death-censored graft loss and decline in renal function (HR = 1.22, p = 0.002; HR = 1.22, p = 0.018 and HR = 1.25, p < 0.001, respectively). Similar results were obtained in recipient ethnicity and donor type subgroups. In summary, CsA+Rapa was associated with significantly worse graft survival and death-censored graft survival compared to CsA+MMF, and likely reflects full-dose CsA +Rapa. Outcomes regarding alternative strategies of Rapa utilization with reduced CsA, with alternative agents or with no calcineurin inhibitor cannot be extrapolated from these data.

Long-term use of mycophenolate mofetil is associated with a reduction in the incidence and risk of late rejection.

To evaluate the association of long-term continuous (minimum 1 year) mycophenolate mofetil (MMF) vs. azathioprine (AZA) therapy with the incidence of late acute rejection, we analyzed 47 693 primary renal allograft recipients reported to the United States Renal Data System between 1988 and 1998. The primary study endpoint was acute rejection beyond 1 year after transplantation. Univariate Kaplan-Meier analysis and multivariate Cox proportional hazard models were used to investigate the risk of reaching the study endpoints. All multivariate analyses were corrected for potential confounding covariates. Mycophenolate mofetil was associated with a 65% decreased risk of developing late acute rejection as compared to AZA (RR = 0.35, CI 0.27-0.45, p < 0.001). The incidence of acute rejection episodes at 2 and 3 years post-transplantation was significantly lower in the MMF group (0.9% at 2 years, 1.1% at 3 years) than the AZA group (6.1% at 2 years, 9.3% at 3 years). In the primary vs. repeat late rejection analysis, MMF patients exhibited a decreased late acute rejection risk of 72% (RR = 0.28, p < 0.001) and 60%, respectively (RR = 0.40, p < 0.001). In African Americans, the late acute rejection risk was 70% lower in MMF patients than AZA patients (RR = 0.30, p < 0.001). Further study is indicated to determine the optimal duration of MMF therapy after renal allograft transplantation.