Chronic hepatitis C genotype 1 patients with insulin resistance treated with pioglitazone and peginterferon alpha-2a plus ribavirin.

UNLABELLED: Patients with chronic hepatitis C and insulin resistance are less likely to respond to anti-hepatitis C virus (HCV) therapy and are at risk for more rapid fibrosis progression. Coadministration of pioglitazone with peginterferon/ribavirin improves insulin sensitivity and increases virologic response rates in insulin-resistant HCV genotype 4 patients, but it is unclear whether this finding applies to genotype 1 patients. For this reason we randomized treatment-naive HCV genotype 1 patients with insulin resistance to receive either standard care (peginterferon alpha-2a plus ribavirin for 48 weeks, n = 73) or pioglitazone 30-45 mg/day plus standard care (n = 77) in an open-label multicenter trial. Patients randomized to pioglitazone received the drug during a 16-week run-in phase, the 48-week standard-care phase, and the 24-week untreated follow-up phase. Pioglitazone treatment improved hemoglobin A1c (HbA1c), plasma glucose, insulin levels, and homeostasis model assessment of insulin resistance score and increased serum adiponectin levels during the 16-week run-in phase and maintained these improvements during the standard-care phase. However, we observed no statistically significant difference between the two groups in the primary efficacy endpoint, the decrease from baseline to Week 12 of peginterferon alpha-2a/ribavirin treatment in mean log(10) HCV RNA titer (-3.5 ± 1.71 and -3.7 ± 1.62 IU/mL in the pioglitazone and standard-care groups, respectively, Δ = 0.21 IU/mL, P = 0.4394). CONCLUSION: Treatment with pioglitazone before and during treatment with peginterferon alpha-2a plus ribavirin improved several indices of glycemic control in patients with chronic hepatitis C and insulin resistance, but did not improve virologic response rates compared with peginterferon alpha-2a plus ribavirin alone.

Impact of disease severity on healthcare costs in patients with chronic hepatitis C (CHC) virus infection.

UNLABELLED: Hepatitis C virus (HCV) infection increases total healthcare costs but the effect of the severity of liver disease associated with chronic hepatitis C (CHC) on healthcare costs has not been well studied. We analyzed the demographics, healthcare utilization, and healthcare costs of CHC patients in a large U.S. private insurance database (January, 2002 to August, 2010), with at least 1 year of baseline enrollment and 30 days of continuous follow-up. Patients were stratified by liver disease severity: noncirrhotic liver disease (NCD), compensated cirrhosis (CC), and endstage liver disease (ESLD), as defined by the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9) codes. Mean all-cause and HCV-related healthcare costs per-patient-per-month (PPPM) during follow-up (mean 634 days) are reported in 2010 U.S.$ from the payer's perspective. A total of 53,796 patients with CHC were included (NCD: 41,858 [78%]; CC: 3,718 [7%]; and ESLD: 8,220 [15%]). Mean all-cause PPPM healthcare costs were 32% and 247% higher for patients with CC and ESLD compared to those with NCD ($1,870 and $4,931 versus $1,420; P < 0.001) and were independent of age or comorbid conditions. Pharmacy, ambulatory, and inpatient care collectively accounted for 90% of NCD costs and 93% of CC and ESLD costs. The largest cost components were inpatient costs for those with ESLD (56%) and ambulatory costs for those with CC and NCD (37% and 36%, respectively). Overall, 56% of costs were HCV-related and this proportion increased with severity (46%, 57%, and 71% for patients with NCD, CC, and ESLD, respectively). CONCLUSION: The direct healthcare costs associated with CHC are high, increase in association with the progression of liver disease, and are highest in those with ESLD.

Peginterferon alfa-2a and ribavirin in Latino and non-Latino whites with hepatitis C.

BACKGROUND: Race has been shown to be a factor in the response to therapy for hepatitis C virus (HCV) infection, and limited data suggest that ethnic group may be as well; however, Latinos and other ethnic subpopulations have been underrepresented in clinical trials. We evaluated the effect of Latino ethnic background on the response to treatment with peginterferon alfa-2a and ribavirin in patients infected with HCV genotype 1 who had not been treated previously. METHODS: In a multicenter, open-label, nonrandomized, prospective study, 269 Latino and 300 non-Latino whites with HCV infection received peginterferon alfa-2a, at a dose of 180 microg per week, and ribavirin, at a dose of 1000 or 1200 mg per day, for 48 weeks, and were followed through 72 weeks. The primary end point was a sustained virologic response. We enrolled Latinos whose parents and grandparents spoke Spanish as their primary language; nonwhite Latinos were excluded. RESULTS: Baseline characteristics were similar in the Latino and non-Latino groups, although higher proportions of Latino patients were 40 years of age or younger, had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of more than 27 or more than 30, and had cirrhosis. The rate of sustained virologic response was higher among non-Latino whites than among Latinos (49% vs. 34%, P<0.001). The absence of HCV RNA in serum was more frequent in non-Latino whites at week 4 (P=0.045) and throughout the treatment period (P<0.001 for all other comparisons). Latino or non-Latino background was an independent predictor of the rate of sustained virologic response in an analysis adjusted for baseline differences in BMI, cirrhosis, and other characteristics. Adherence to treatment did not differ significantly between the two groups. The numbers of patients with adverse events and dose modifications were similar in the two groups, but fewer Latino patients discontinued therapy because of adverse events. CONCLUSIONS: Treatment with peginterferon alfa-2a and ribavirin for 48 weeks resulted in rates of sustained virologic response among patients infected with HCV genotype 1 that were lower among Latino whites than among non-Latino whites. Strategies to improve the sustained virologic response in Latinos are needed. (ClinicalTrials.gov number, NCT00107653.)

Histologic outcomes in hepatitis C-infected patients with varying degrees of virologic response to interferon-based treatments.

UNLABELLED: Patients with chronic hepatitis C with partial virologic response or nonresponse to interferon-based therapies can experience treatment-related improvements in liver histology. This retrospective analysis assessed the histologic response to treatment in patients with varying degrees of virologic response (sustained virologic response [SVR], breakthrough, relapse, or nonresponse), time to hepatitis C virus (HCV) RNA undetectability, and duration of viral suppression. Patients (HCV genotypes 1-6) with baseline and follow-up liver biopsies from eight phase 2 to phase 4 interferon-based trials were analyzed. Blinded biopsies were evaluated by a single pathologist. Improvements or worsening of METAVIR necroinflammatory activity and fibrosis were defined as increase or decrease of ≥1 grading category from baseline to 24 weeks after end of treatment. A majority of the 1571 patients with paired biopsy data were white, male, with HCV genotype 1/4, baseline HCV RNA levels >800,000 IU/mL, and baseline alanine aminotransferase levels ≤3 × upper limit of the normal range; mean baseline activity and fibrosis scores were 1.8 and 1.7, respectively. Overall, 80% of patients received peginterferon alfa-2a monotherapy or peginterferon alfa-2a/ribavirin combination therapy. Mean treatment duration was 46 weeks. There was a positive correlation between the degree of virologic response and improvements in METAVIR activity and fibrosis, and an inverse correlation with worsening activity and fibrosis (all comparisons, P < 0.0001). Patients with SVR had the greatest histologic benefit. As a combined group, relapsers and patients with breakthrough had significantly greater benefits than nonresponders (activity, P = 0.0001; fibrosis, P = 0.003). Consistent with these results, a better histologic response was correlated with a shorter time to undetectable HCV RNA and a longer duration of viral suppression (all comparisons, P < 0.0001). CONCLUSION: In patients with chronic hepatitis C who were treated with interferon-based therapies, histologic benefits may be observed even in the absence of an SVR.

Peginterferon α-2a plus ribavirin in Latino and Non-Latino Whites with HCV genotype 1: Histologic outcomes and tolerability from the LATINO Study.

OBJECTIVES: We sought to compare the histologic response, safety, and tolerability in Latino and non-Latino patients with hepatitis C virus (HCV) genotype 1 treated with peginterferon α-2a plus ribavirin (LATINO study). METHODS: LATINO was a prospective, open-label, multicenter study that enrolled 269 Latinos and 300 non-Latinos receiving peginterferon α-2a 180 µg/week and ribavirin 1,000/1,200 mg/day for 48 weeks. Liver biopsies were obtained within 18 months of baseline and at week 72. Improved or worsened liver fibrosis and necroinflammatory activity were assessed by the Ishak-modified histologic activity index scoring system. Efficacy and safety parameters were monitored during treatment and the 24-week follow-up period. RESULTS: The primary study results published elsewhere showed a higher sustained virologic response (SVR) rate among non-Latinos than Latinos (49% vs. 34%; P<0.001). Paired biopsy data were available for 157 Latinos and 201 non-Latinos. At baseline, more Latinos vs. non-Latinos had alanine aminotransferase (ALT) >3 × the upper limit of normal (20% vs. 18%) and cirrhosis (13% vs. 10%). Both groups experienced improvement in Ishak activity at week 72, although the improvement rates were higher in non-Latinos than Latinos (59% vs. 47%; P=0.03). For both groups, more patients with SVR compared with non-responders had improved Ishak fibrosis scores. In both groups, baseline Ishak activity score (P<0.0001 for both) was predictive of Ishak activity response. Additional predictors in Latinos were age (P=0.0023), body mass index (BMI) (P=0.068), baseline ALT quotient (P=0.031), and baseline Ishak fibrosis scores (P=0.021). There were no significant differences in steatosis changes between the two groups. Adverse events (AEs) and withdrawals due to AEs were more frequent in non-Latinos. CONCLUSIONS: Significant proportions of patients in both groups had histologic response to peginterferon α-2a plus ribavirin. However, histologic response was higher in non-Latinos than in Latinos regardless of virologic response. This study highlights the need for additional strategies to improve virologic response in Latinos.

Impact of ribavirin dose reductions in hepatitis C virus genotype 1 patients completing peginterferon alfa-2a/ribavirin treatment.

BACKGROUND & AIMS: To maximize sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) infection, treatment with pegylated interferon and ribavirin has been genotype-specific (1 vs non-1). We evaluated the effects of ribavirin and peginterferon alfa-2a dose reductions on SVR in patients infected with HCV genotype 1. METHODS: Data were pooled from 569 patients enrolled in 2 phase III trials of 48 weeks of treatment with peginterferon alfa-2a and ribavirin. All patients were evaluated for the effect of cumulative drug exposure on 4- and 12-week responses, and the 427 patients who completed treatment were evaluated for effect of drug exposure on SVR. RESULTS: Of patients who completed treatment, more had reductions (< or =97% cumulative dose) of ribavirin than of peginterferon alfa-2a (43% vs 27%). Neither early virologic response nor SVR was affected adversely by ribavirin reductions when the cumulative ribavirin exposure was greater than 60%. The SVR was reduced significantly (P = .0006) in patients with less than the 60% cumulative ribavirin dose and was associated with prolonged periods of dose reduction, temporary interruptions, or premature cessation of ribavirin. Ribavirin dose reductions had minimal impact on SVR in patients who achieved rapid virologic response, defined as undetectable HCV RNA levels after 4 weeks, even when they received less than the 60% cumulative ribavirin dose. In contrast, SVR was reduced markedly in patients who had ribavirin dose reductions and did not achieve rapid virologic response. CONCLUSIONS: Minor ribavirin dose reductions to manage adverse events do not appear to affect SVR adversely, unless cumulative exposure is less than 60%. Prospective studies, however, are required to establish the impact of ribavirin dose reduction on SVR.

Steady-state pharmacokinetic interaction of modified-dose indinavir and rifabutin.

BACKGROUND: Combined administration of the human immunodeficiency virus protease inhibitor indinavir (800 mg every 8 hours) with the antimycobacterial rifabutin (300 mg daily) results in a significant decrease in indinavir concentrations with subsequent risk of treatment failure, as well as a significant increase in rifabutin concentrations with increased toxicity. Therefore this study was designed to evaluate alternative dosing regimens. METHODS: Eighteen healthy volunteers received 300 mg rifabutin daily alone for 14 days and then 1000 mg indinavir every 8 hours plus rifabutin at a reduced dose of 150 mg daily, given at 8 am or noon in a randomized crossover sequence for 14 days. Ten human immunodeficiency virus-infected subjects received 800 mg indinavir every 8 hours for 14 days and then 1000 mg indinavir every 8 hours plus 150 mg rifabutin daily at 8 am for 14 days. Twenty-four-hour pharmacokinetic sampling was performed at the end of each 14-day study period. RESULTS: Indinavir, 1000 mg every 8 hours, coadministered with 150 mg rifabutin daily produced an area under the concentration-time curve similar to that of 800 mg indinavir every 8 hours. The mean area under the concentration-time curve values of rifabutin and 25-desacetyl rifabutin, when 150 mg rifabutin every morning was coadministered simultaneously with 1000 mg indinavir every 8 hours, were 70% and 120% higher than with 300 mg rifabutin daily alone. Drug concentrations were not different when rifabutin and indinavir were administered simultaneously at 8 am or staggered by 4 hours. CONCLUSIONS: Increasing indinavir's dose to 1000 mg every 8 hours when coadministered with rifabutin at a reduced dose of 150 mg daily compensates for rifabutin induction of indinavir metabolism. Rifabutin concentrations were still higher than with rifabutin alone despite a 50% reduction of rifabutin dose, which is the current recommendation when these 2 drugs are combined. The clinical significance of the increase in rifabutin and 25-desacetyl rifabutin concentrations is not known.

Factors affecting serum concentrations of hepatitis C virus (HCV) RNA in HCV genotype 1-infected patients with chronic hepatitis.

The serum concentration of hepatitis C virus (HCV) RNA is usually stable (4 to 8 log(10) IU/ml) in untreated patients with chronic hepatitis C. While this baseline HCV RNA concentration ([HCV RNA](BL)) is predictive of a sustained virologic response to treatment, its determinants are only partially identified. We therefore analyzed the baseline characteristics of 2,472 HCV genotype 1-infected patients to identify correlations with gender, age, race, weight, body mass index (BMI), HCV acquisition mode, HCV subtype, alanine aminotransferase concentration, or histopathologic changes in the liver. After separation of the data according to four [HCV RNA](BL) groups (< or =5.0, >5.0 to 5.6, >5.6 to 5.9, and >5.9 log(10) IU/ml), we determined that increasing [HCV RNA](BL) correlated (P < 0.05) with increasing proportions of patients who were male, >40 years of age, or heavier (a weight of >85 kg or a BMI of >27 kg/m(2)). Histologic activity index (HAI) data were available for 1,304 of these patients: increasing [HCV RNA](BL) correlated with higher fibrosis and necrosis-inflammation scores. As a continuous variable, [HCV RNA](BL) correlated with age, gender, weight (continuous or < or =85 versus >85 kg), BMI (continuous or < or =27 versus >27 kg/m(2)), subtype, fibrosis score, and necrosis-inflammation score; however, multiple-regression analysis yielded P values of <0.1 only for age, gender, BMI (< or =27 versus >27 kg/m(2)), and fibrosis score. While our findings are suggestive of a role for these factors in maintenance of the pretreatment state of HCV infection, the multiple-regression model accounted for only < or =4.6% of the [HCV RNA](BL) differences between individuals (R(2) = 0.046 for 1,304 patients with HAI scores; 0.043 for all 2,472 patients).

Stability of nevirapine suspension in prefilled oral syringes used for reduction of mother-to-child HIV transmission.

OBJECTIVE: To reduce mother-to-child transmission (MTCT) of HIV, we assessed the stability of nevirapine suspension in an oral dosing syringe over a range of storage conditions. DESIGN: A mother-to-child transmission dosing kit, containing a maternal nevirapine tablet and infant nevirapine suspension in an oral syringe that can be dispensed to the pregnant woman to use at delivery. However, the manufacturer only packages nevirapine in 240 mL, multidose containers and there are no published stability data for nevirapine suspension repackaged in an oral syringe. METHODS: Nevirapine suspension 6 mg/0.6 mL in 3 mL amber BAXA Exacta-Med Oral Dispensers (Baxa Corporation, Englewood, CO) were stored under the following conditions: 26 degrees C/high relative humidity (RH), 40 degrees C/low RH, 40 degrees C/high RH, refrigerated and frozen -30 degrees C for 6 months. The samples were assayed monthly for nevirapine by HPLC-UV. At 3, 4, and 6 months the samples were cultured for pathogens. RESULTS: : There were no significant decreases in nevirapine concentrations in the prefilled syringes compared with baseline. Nevirapine became more concentrated in syringes incubated at 40 degrees C/low RH due to evaporation resulting in the suspension becoming more viscous. No pathogens were cultured. CONCLUSIONS: Nevirapine suspension is stable and pathogen free at varying conditions for 6 months in Baxa Exacta-Med Oral Dispensers.

Modeling in vivo pharmacokinetics and pharmacodynamics of moxifloxacin therapy for Mycobacterium tuberculosis infection by using a novel cartridge system.

To study the efficacy of moxifloxacin treatment for tuberculosis, we utilized a novel cartridge system to simulate in vivo pharmacokinetics. We found this system to be a robust method for modeling in vivo pharmacokinetics and present data supporting the utility of intermittent moxifloxacin treatment as a component of antituberculosis chemotherapy.