Received Peginterferon Alfa-2b Research Articles

Peginterferon alfa-2b in the treatment of Chinese patients with HBeAg-positive chronic hepatitis B: A randomized trial

BackgroundIn mainland China, peginterferon (PEG-IFN) alfa-2b 1.0μg/kg/wk for 24 weeks is the approved treatment for HBeAg-positive chronic hepatitis B. ObjectiveThis multicenter, randomized trial evaluated the safety and efficacy of regimens utilizing increased dose or treatment duration in treatment-naive Chinese patients with chronic hepatitis B. Study design670 HBeAg-positive patients from China, Malaysia, Taiwan area, Singapore, and Thailand were enrolled. Patients received PEG-IFN alfa-2b 1.0μg/kg/wk (arm A) or 1.5μg/kg/wk (arm B) for 24 weeks, or 1.5μg/kg/wk for 48 weeks (arm C). The primary end point was loss of HBeAg 24 weeks after end of treatment. ResultsAt the end of follow-up, HBeAg loss was significantly greater in arm C compared with arm A (31.3% vs. 17.3%; P=0.001) and arm B (31.3% vs. 18.1%; P=0.001). No significant difference in the rate of HBeAg loss was observed between arms A and B. The proportions of patients with HBe seroconversion, HBV DNA levels <20,000IU/mL, and ALT normalization at the end of follow-up were significantly higher in arm C compared with arm A and arm B. In arms A, B, and C, rates of early treatment discontinuation were 6.3%, 4.9%, and 8.9%; of discontinuation due to an AE, 2%, 3%, and 3%; and of AEs requiring dose modification, 3%, 6%, and 10%, respectively. ConclusionsIn Chinese patients with HBeAg-positive chronic hepatitis B, PEG-IFN alfa-2b 1.5μg/kg/wk for 48 weeks is more efficacious compared with 1.0 and 1.5μg/kg/wk for 24 weeks.

Peginterferon alfa-2a and peginterferon alfa-2b combined with ribavirin in patients with genotype 1 chronic hepatitis C: Results of a prospective single-centre study

PurposeThis prospective, randomized, single-centre study compared peginterferons alfa-2a and alfa-2b, combined with ribavirin, in treating patients infected with hepatitis C virus (HCV) genotype 1. Material/methodsHundred-and-one patients received 48 weeks of open-label treatment with peginterferon alfa-2a (180μg/week) and 111 patients received peginterferon alfa-2b (1.5μg/kg/week). All patients received the same dose of ribavirin 1000/1200mg/day, depending on weight. The primary efficacy endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA (<50IU/mL) 24 weeks after the end of treatment. ResultsEarly virologic response (EVR), defined as at least 2log10IU/mL reduction of viral load at 12 weeks, was more common in patients treated with peginterferon alfa-2a (88% vs. 74.8%; p=0.04). However, the difference in SVR was not statistically significant (49.5% vs. 44.1%; p=0.43). ConclusionsPeginterferon alfa-2a treated patients were also more likely to be HCV RNA negative at the end of treatment (67.3% vs. 57.7%), but this difference did not reach statistical significance. Multivariate logistic regression analysis found that SVR was associated with low fibrosis stage (F1–2 by Scheuer; p=0.001) and low serum HCV RNA level (<400,000IU/L; p=0.023). While both forms of peginterferon showed similar efficacy as measured by SVR, use of peginterferon alfa-2b could lower the number of patients receiving unnecessary treatment beyond 12 weeks.

Efficacy and Safety of Pegylated Interferon Alfa-2b and Ribavirin Combination Therapy Versus Pegylated Interferon Monotherapy in Hemodialysis Patients: A Comparison of 2 Sequentially Treated Cohorts

Pegylated interferon (peginterferon; interferon with an attached polyethylene glycol molecule) monotherapy is the recommended treatment for chronic hepatitis C virus (HCV) infection in hemodialysis patients. Limited data concerning peginterferon alfa-2b and ribavirin treatment in this population are available. 2 prospective observational cohort studies. From 2007-2009, a total of 26 patients received peginterferon alfa-2b monotherapy. From 2009-2012, an additional 26 patients were treated with peginterferon alfa-2b and ribavirin. Peginterferon alfa-2b monotherapy, 1.0 μg/kg/wk, versus peginterferon alfa-2b, 1.0 μg/kg/wk, and ribavirin, 200 mg, 3 times per week. Treatment durations were 24 and 48 weeks for HCV genotypes non-1 and 1, respectively. End-of-treatment virologic response and sustained virologic response (SVR) were undetectable HCV RNA at the end of treatment and 24 weeks after treatment ended, respectively. SVR and treatment-related withdrawal rate were evaluated by intention-to-treat (ITT) and per-protocol (PP) analyses. Severe anemia was defined as nadir hemoglobin level <8 g/dL. Patients who received combination therapy had a higher end-of-treatment virologic response than patients who received monotherapy (85% vs 62% in ITT [P = 0.03] and 100% vs 80% in PP [P = 0.03]). The SVR rate was higher in the combination-treatment cohort than in the monotherapy cohort (62% vs 27% in ITT [P = 0.01] and 73% vs 35% in PP [P = 0.01]). Patients who received combination therapy had a significantly higher rate of severe anemia than those who received monotherapy (58% vs 27%; P = 0.03). However, treatment withdrawal rates were similar between the combination (15%) and monotherapy (23%) groups. Comparison of 2 sequential cohorts rather than a randomized control study. Peginterferon alfa-2b and ribavirin combination therapy provided a higher SVR rate than peginterferon alfa-2b monotherapy for treatment-naive dialysis patients with chronic HCV infection through careful monitoring of hematologic parameters and ribavirin dose modification. Severe anemia was significantly higher in patients receiving combination therapy than patients treated with monotherapy.

Serum proteins in chronic hepatitis B patients treated with peginterferon alfa-2b

To study the differential protein profile in serum of hepatitis B patients. Serum samples were obtained from patients with chronic hepatitis B who were receiving peginterferon alfa-2b. The serum samples were subjected to albumin depletion and analyzed by two-dimensional gel electrophoresis (2-DE). Differentially expressed protein spots were identified by electrospray ionization-quadrupole time-of-flight mass spectrometry. Alpha-2-HS-glycoprotein, complement component C3c and CD5 antigen were further analyzed by an enzyme-linked immunosorbent assay and immunonephelometry. Nineteen patients with HBeAg-positive chronic hepatitis B (CHB) were studied. These patients were followed for at least 1 year after treatment and were classified according to their treatment response: responders (n = 9) and non-responders (n = 10). 2-DE and MS/MS analysis were performed to compare the serum proteins before initiating peginterferon alfa-2b. From the quantitative analysis of the 2-D gel, 7 proteins were detected between the two groups at different levels before treatment. Among these potential candidates, serum levels of alpha-2-HS-glycoprotein, complement component C3c and CD5 antigen-like precursor were further analyzed. In the validation phase, 23 subjects, 9 sustained responders and 14 non-responders, were recruited. Interestingly, the levels of alpha-2-HS-glycoprotein and complement component C3c were elevated in the serum of the non-responders compared to the responders. Serum alpha-2-HS-glycoprotein and complement component C3c may be potential serum biomarkers in predicting the treatment response of peginterferon alfa-2b in patients with CHB prior to treatment.

XVIII Latin American Congress

XVIII Latin American Congress

Comparison of peginterferon pharmacokinetic and pharmacodynamic profiles

The pharmacokinetics and in dosing regimens of the currently available pegylated interferon (peginterferon) alfa molecules differ greatly, depending on the size and nature of their polyethylene glycol (PEG) moiety. Peginterferon alfa-2a has a branched 40 kDa PEG chain covalently attached to lysine residues and circulates as an intact molecule. On the other hand, peginterferon alfa-2b has a linear 12 kDa PEG chain covalently attached to interferon-a-2b via an unstable urethane bond that is hydrolysed after injection, releasing native interferon alfa-2b. The difference in pegylation between the two peginterferons has a significant impact on their pharmacokinetic properties. Data from comparative and non-comparative studies indicate that peginterferon alfa-2b has a shorter half-life in serum than peginterferon alfa-2a, and a significant proportion of patients receiving peginterferon alfa-2b may have trough concentrations below the limit of detection during the latter part of the 7-day dosing schedule. However, the pharmacodynamic parameters of the two drugs appear to be similar.

Peginterferon alfa and ribavirin for chronic hepatitis C in patients eligible for shortened treatment, re-treatment or in HCV/HIV co-infection: a systematic review and economic evaluation

The aim of this health technology assessment is to assess the clinical-effectiveness and cost-effectiveness of peginterferon alfa and ribavirin for the treatment of chronic hepatitis C. Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of moderate to severe hepatitis C was appraised by NICE in 2004 (TA751) and an appraisal specifically for mild hepatitis C was carried out in 2006 (TA1062). Both appraisals were based on independent assessment reports conducted by SHTAC.3,4 Since NICE's clinical guidance was published, there have been extensions to the licences for peginterferon alfa-2a and -2b. This health technology assessment is a part-review of the current NICE guidance and will be restricted to the patient subgroups that are affected by the licence extensions for the peginterferons. This includes people who have been previously treated with peginterferon alfa and ribavirin in combination and who either did not respond or who responded but relapsed, people who meet the licensed criteria for receiving shortened courses of combination therapy and people with HCV/HIV co-infection The HTA Programme commissioned this technology assessment report on behalf of the National Institute for Health and Clinical Excellence.

Maintenance Therapy With Peginterferon Alfa-2b Does Not Prevent Hepatocellular Carcinoma in Cirrhotic Patients With Chronic Hepatitis C

Several studies have reported that low doses of interferon can delay the development of hepatocellular carcinoma (HCC) and progression of chronic hepatitis C. We investigated the incidence of clinical events among participants of the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis (EPIC)3 program. Data were analyzed from an open-label randomized study of patients with chronic hepatitis C who had failed to respond to interferon alfa plus ribavirin. All patients had compensated cirrhosis with no evidence of HCC. Patients received peginterferon alfa-2b (0.5 μg/kg/week; n=311) or no treatment (controls, n=315) for a maximum period of 5 years or until 98 patients had a clinical event (hepatic decompensation, HCC, death, or liver transplantation). The primary measure of efficacy was time until the first clinical event. There was no significant difference in time to first clinical event among patients who received peginterferon alfa-2b compared with controls (hazard ratio [HR], 1.452; 95% confidence interval [CI]: 0.880-2.396). There was no decrease in the development of HCC with therapy. The time to disease progression (clinical events or new or enlarged varices) was significantly longer for patients who received peginterferon alfa-2b compared with controls (HR, 1.564; 95% CI: 1.130-2.166). In a prospectively defined subanalysis of patients with baseline portal hypertension, peginterferon alfa-2b significantly increased the time to first clinical event compared with controls (P=.016). There were no new safety observations. Maintenance therapy with peginterferon alfa-2b is not warranted in all patients and does not prevent HCC. However, there is a potential clinical benefit of long-term suppressive therapy in patients with preexisting portal hypertension.

757 OUTCOME OF PEGINTERFERON ALFA-2B AND RIBAVIRIN THERAPY FOLLOWING MP-424 (TELAPREVIR) MONOTHERAPY FOR 24 WEEKS IN JAPANESE PATIENTS WITH CHRONIC HEPATITIS C VIRUS GENOTYPE 1B INFECTION

Background: MP-424 (telaprevir) is a highly selective inhibitor of the hepatitis C virus (HCV) NS3–4A protease which is currently investigated in phase 3 trial in combination with peginterferon and ribavirin. We reported the first clinical study examining telaprevir monotherapy with an extended dosing period of 24 weeks in Japan (Ozeki I, et al: EASL 2009). After completing study drug therapy, patients were treated with peginterferon alfa-2b and ribavirin. Methods: Five naive patients were treated with telaprevir monotherapy at 750 mg every 8 hours for up to 24 weeks. All patients, 48 to 68 years of age, had a chronic infection with HCV genotype 1b and their baseline serum HCV RNA levels were at least 1×10 5 IU/ml. Patients who met the definition of viral breakthrough (>2-log increase in HCV RNA above nadir) discontinued telaprevir dosing. RNA sequence was analyzed using the clonal sequencing method. After a withdrawal of MP-424, 4 of the 5 patients were enrolled in the off-study treatment with peginterferon alfa-2b and ribavirin within 4 weeks after the last administration of study drug. Results: At the initiation of off-study treatment, major NS3 protease variants in the patients were T54A, T54S+A156T, and A156V+V158I. All patients achieved undetectable HCV RNA levels by 12 weeks regardless of selected telaprevir-resistant variants. Sustained virologic response (SVR) was achieved in 2 patients who completed the assigned treatment for 48 weeks. The other 2 patients are now receiving peginterferon alfa-2b and ribavirin beyond 48 weeks for extended treatment period to 72 weeks. HCV RNA levels in these 2 patients continue to be undetectable. Conclusions: By the off-study treatment of standard peginterferon alfa-2b and ribavirin, all patients achieved complete EVR regardless of selected drug-resistant variants. Two patients who were typically treated for 48 weeks achieved an SVR. Updated results of this study will be presented.

758 CHARACTERIZATION OF RESISTANT MUTANTS SELECTED IN VITRO BY THE HCV NS3/4A PROTEASE INHIBITOR BI 201335

Background: MP-424 (telaprevir) is a highly selective inhibitor of the hepatitis C virus (HCV) NS3–4A protease which is currently investigated in phase 3 trial in combination with peginterferon and ribavirin. We reported the first clinical study examining telaprevir monotherapy with an extended dosing period of 24 weeks in Japan (Ozeki I, et al: EASL 2009). After completing study drug therapy, patients were treated with peginterferon alfa-2b and ribavirin. Methods: Five naive patients were treated with telaprevir monotherapy at 750mg every 8 hours for up to 24 weeks. All patients, 48 to 68 years of age, had a chronic infection with HCV genotype 1b and their baseline serum HCVRNA levels were at least 1×105 IU/ml. Patients who met the definition of viral breakthrough (>2-log increase in HCVRNA above nadir) discontinued telaprevir dosing. RNA sequence was analyzed using the clonal sequencing method. After a withdrawal of MP-424, 4 of the 5 patients were enrolled in the off-study treatment with peginterferon alfa-2b and ribavirin within 4 weeks after the last administration of study drug. Results: At the initiation of off-study treatment, major NS3 protease variants in the patients were T54A, T54S+A156T, and A156V+V158I. All patients achieved undetectable HCVRNA levels by 12 weeks regardless of selected telaprevir-resistant variants. Sustained virologic response (SVR) was achieved in 2 patients who completed the assigned treatment for 48 weeks. The other 2 patients are now receiving peginterferon alfa-2b and ribavirin beyond 48 weeks for extended treatment period to 72 weeks. HCVRNA levels in these 2 patients continue to be undetectable. Conclusions: By the off-study treatment of standard peginterferon alfa-2b and ribavirin, all patients achieved complete EVR regardless of selected drug-resistant variants. Two patients who were typically treated for 48 weeks achieved an SVR. Updated results of this study will be presented.

759 COMBINATION OF TMC435 WITH TWO NOVEL NS5B INHIBITORS INCREASES ANTI HCV ACTIVITY AND RESULTS IN A HIGHER GENETIC BARRIER IN VITRO

Background: MP-424 (telaprevir) is a highly selective inhibitor of the hepatitis C virus (HCV) NS3–4A protease which is currently investigated in phase 3 trial in combination with peginterferon and ribavirin. We reported the first clinical study examining telaprevir monotherapy with an extended dosing period of 24 weeks in Japan (Ozeki I, et al: EASL 2009). After completing study drug therapy, patients were treated with peginterferon alfa-2b and ribavirin. Methods: Five naive patients were treated with telaprevir monotherapy at 750mg every 8 hours for up to 24 weeks. All patients, 48 to 68 years of age, had a chronic infection with HCV genotype 1b and their baseline serum HCVRNA levels were at least 1×105 IU/ml. Patients who met the definition of viral breakthrough (>2-log increase in HCVRNA above nadir) discontinued telaprevir dosing. RNA sequence was analyzed using the clonal sequencing method. After a withdrawal of MP-424, 4 of the 5 patients were enrolled in the off-study treatment with peginterferon alfa-2b and ribavirin within 4 weeks after the last administration of study drug. Results: At the initiation of off-study treatment, major NS3 protease variants in the patients were T54A, T54S+A156T, and A156V+V158I. All patients achieved undetectable HCVRNA levels by 12 weeks regardless of selected telaprevir-resistant variants. Sustained virologic response (SVR) was achieved in 2 patients who completed the assigned treatment for 48 weeks. The other 2 patients are now receiving peginterferon alfa-2b and ribavirin beyond 48 weeks for extended treatment period to 72 weeks. HCVRNA levels in these 2 patients continue to be undetectable. Conclusions: By the off-study treatment of standard peginterferon alfa-2b and ribavirin, all patients achieved complete EVR regardless of selected drug-resistant variants. Two patients who were typically treated for 48 weeks achieved an SVR. Updated results of this study will be presented.

High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alfa-2b plus ribavirin

Pegylated interferon (PEG-IFN) alfa-2b plus ribavirin (RBV) is the standard of care for adults with chronic hepatitis C but was not approved for the treatment of children at the time of this study. The aim of this study was to evaluate the efficacy and safety of PEG-IFN alfa-2b plus RBV in children. Children and adolescents ages 3-17 years were treated with PEG-IFN alfa-2b (60microg/m(2)/week) plus RBV (15mg/kg/day). The duration of therapy was 24 weeks for genotype (G) 2 and G3 patients with low viral load (<600,000IU/ml) and 48 weeks for G1, G4, and G3 with high viral load (>or=600,000IU/ml). The primary end point was sustained virologic response (SVR), defined as undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of therapy. SVR was attained by 70 (65%) children. Genotype was the main predictor of response: G1, 53%; G2/3, 93%; G4, 80%. SVRs were similar in younger and older children. Baseline viral load was the main predictor of response in the G1 cohort. No new safety signals were identified, and adverse events (AEs) were generally mild or moderate in severity. Dose was modified because of AEs in 25% of children; 1 child discontinued because of an AE (thrombocytopenia). No serious AEs related to study drugs were reported. Therapy with PEG-IFN alfa-2b plus RBV in children and adolescents with chronic hepatitis C offers favorable efficacy, reduced injection frequency, and an acceptable safety profile.

Durability of peginterferon alfa-2b treatment at 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B

Approximately 30%-40% of patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B treated with peginterferon and/or lamivudine achieve HBeAg seroconversion 6 months after the end of treatment. The durability and long-term effect of treatment are unknown. In this study, 85 HBeAg-positive patients who received peginterferon alfa-2b 1.5 microg/kg/week for 32 weeks and lamivudine 100 mg/day for 52 or 104 weeks were prospectively followed for 6.1 +/- 1.7 years posttreatment. Twenty-five (29%) patients had virologic response (HBeAg seroconversion and HBV DNA <10,000 copies/mL) at 5 years. The rate of HBeAg seroconversion rose progressively from 37% at the end of treatment to 60% at 5 years. Twenty-seven (32%) and 11 (13%) patients had undetectable HBV DNA (<100 copies/mL) at the end of peginterferon treatment and at 5 years, respectively. Two (2.4%) patients achieved hepatitis B surface antigen (HBsAg) seroclearance at 2.6 and 84 months posttreatment. Among virologic responders at the end of treatment, 82% and 57% and sustained HBeAg seroconversion and virologic response at 5 years. End-of-treatment serum quantitative HBsAg was significantly lower in patients with sustained virologic response at 5 years (median 1,431 IU/mL versus 2,689 IU/mL [P = 0.041]). At the last follow-up, the liver stiffness measurement by transient elastography was 5.8 +/- 2.7 kPa. Only two patients had liver stiffness suggestive of advanced fibrosis. Week 16 HBV DNA, end-of-treatment HBeAg seroconversion, and undetectable HBV DNA were independent factors associated with virologic response at 5 years. The duration of concomitant lamivudine treatment had no impact on any long-term response. Peginterferon has high durability in HBeAg-positive chronic hepatitis B patients with end-of-treatment virologic response.

Propensity Score Matching in the Evaluation of Drug Therapy Management Programs

This retrospective cohort analysis demonstrates the application of propensity score methods in the Be In Charge (BIC) program, a drug therapy management program for patients with hepatitis C. Data were drawn from BIC participant records and program utilization and from a longitudinal database of administrative claims for pharmacy and medical services. Eligible patients must have received peginterferon alfa-2b (PEG-IFN alfa-2b) and ribavirin, but analyses evaluated only PEG-IFN alfa-2b use; BIC enrollees were matched with patients not enrolled in BIC (controls). Adherence was measured on the basis of the number of injections dispensed and the proportion of patients for whom an average of at least 1 injection per week was dispensed during follow-up. BIC subjects refilled 1.2 more injections than did controls (P < .001) within 12 weeks, 2.7 more (P < .001) within 24 weeks, and 6.7 more (P < .001) within 48 weeks. BIC enrollees were more likely than controls to refill the indicated dose (1 injection per week) within 12 weeks (72% vs 64%, P < .001), 24 weeks (52% vs 41%, P < .001), and 48 weeks (22% vs 13%, P = .002) of initiation. These data suggest that the BIC program may significantly improve adherence to PEG-IFN alfa-2b.

Treatment persistence in and cost of therapy for patients with chronic hepatitis C: Peginterferon alfa-2a plus ribavirin versus peginterferon alfa-2b plus ribavirin

Treatment persistence and cost of therapy for patients with chronic hepatitis C (CHC) treated with peginterferon alfa-2a plus ribavirin and peginterferon alfa-2b plus ribavirin were evaluated. This retrospective database analysis used eligibility, pharmacy, and medical claims data from a large U.S. health plan for patients with CHC treated with peginterferon alfa-2a plus ribavirin and peginterferon alfa-2b plus ribavirin from January 2002 through June 2006. For the purposes of this analysis, the study population included all hepatitis C virus (HCV) genotypes. Comparable groups for assessment of outcomes were constructed using propensity score matching to reduce the effect of known sources of bias. Outcome variables included treatment persistence and annualized overall and HCV-attributable health care costs. A total of 1783 matched pairs were analyzed. Compared with patients receiving peginterferon alfa-2a plus ribavirin, patients receiving peginterferon alfa-2b plus ribavirin were 18% less likely to be persistent with therapy at week 48 (p = 0.013). During the first six months of follow-up, mean all-cause costs (p = 0.0368) and HCV-attributable costs (p < 0.0001) were significantly lower for peginterferon alfa-2a plus ribavirin than for peginterferon alfa-2b plus ribavirin. Mean annualized all-cause costs (p = 0.0060) and HCV-attributable costs (p = 0.0167) over the entire follow-up period were significantly lower for patients treated with peginterferon alfa-2a plus ribavirin versus peginterferon alfa-2b plus ribavirin. Analysis of information from a health care claims database suggests that treating CHC with peginterferon alfa-2a plus ribavirin may improve treatment persistence and help reduce the health care costs imposed by CHC compared with treatment with peginterferon alfa-2b plus ribavirin.

Patient education improves adherence to peg-interferon and ribavirin in chronic genotype 2 or 3 hepatitis C virus infection: A prospective, real-life, observational study

To evaluate the impact of therapeutic education on adherence to antiviral treatment and sustained virological response (SVR) in a real-life setting in genotype 2/3 hepatitis C, as there are few adherence data in genotype 2/3 infection, even from randomized trials. This prospective survey included genotype 2/3 patients who received peg-interferon alfa-2b and ribavirin. There was no intervention. Adherence was self-reported over the past 4 wk (peg-interferon) or 7 d (ribavirin). Adherence to bitherapy was defined as adherence to the two drugs for >or= 20 wk. SVR was defined as undetectable RNA >or= 12 wk after the end of treatment. 370/674 patients received education during the first 3 mo of treatment. After 6 mo, adherence to bitherapy was higher in educated patients (61% vs 47%, P = 0.01). Adherence to peg-interferon was 78% vs 69% (P = 0.06). Adherence to ribavirin was 70% vs 56% (P = 0.006). The SVR (77% vs 70%, P = 0.05) and relapse (10% vs 16%, P = 0.09) rates tended to be improved. After adjustment for baseline differences, education improved adherence [Odds ratio (OR) 1.58, P = 0.04] but not the SVR (OR 1.54, P = 0.06). In genotype 2/3 patients, therapeutic education helped maintain real-life adherence to bitherapy.

The Effect of Multiple Doses of Peginterferon alfa‐2b on the Steady‐State Pharmacokinetics of Methadone in Patients With Chronic Hepatitis C Undergoing Methadone Maintenance Therapy

This multicenter, open-label study evaluated the effects of multiple doses of peginterferon alfa-2b on the steadystate pharmacokinetics of methadone in 20 adults with hepatitis C virus infection who were enrolled in a methadone maintenance program. All subjects received peginterferon alfa-2b 1.5 mug/kg/wk for 4 weeks and maintained their normal methadone regimen. Serial blood samples were collected immediately before the first and after the fourth peginterferon alfa-2b dose (day 23). At day 23, exposure to the active methadone R-enantiomer increased by approximately 15% following administration of peginterferon alfa-2b, with 90% confidence intervals just outside the bioequivalence criteria (range, 80%-125%). Similar increases in exposure (C(max), AUC(0-24), and AUC(last)) were observed with S-methadone and total methadone. Peginterferon alfa-2b was well tolerated. Peginterferon alfa-2b is associated with minor increases in exposure to methadone in individuals with hepatitis C virus infection; however, these increases are unlikely to be clinically meaningful and are not associated with any safety concerns.

Peginterferon alfa-2b and ribavirin in patients with hepatitis C virus and decompensated cirrhosis: A controlled study

To evaluate long-term outcomes in decompensated HCV-related cirrhotic patients treated with antiviral therapy. Of 129 eligible patients, 66 received peginterferon alfa-2b and ribavirin for 24 weeks, and 63 were controls. Survival and recurrence of liver failure events after therapy were main outcomes. Therapy was tolerated by 27 patients, dose reduced in 26 for toxicity, and discontinued in 13 for intolerance. End-of-therapy and sustained virological response (SVR) rates were 82.6% and 43.5% for HCV 2/3 patients, and 30.2% and 7.0% for HCV 1/4 patients. During therapy, odds ratios for severe infections or deaths due to infection were 2.95 (95% C.I. 0.93-9.3) and 1.97 (95% C.I. 0.40-9.51) in treated patients as compared with controls. During a follow-up of 30 months off-therapy, decompensated events occurred in 52, 33, and 3 of controls, non-responders, and SVR patients. Odds ratios for ascites, encephalopathy, and oesophageal bleeding in treated patients significantly decreased as compared with controls. Annualized incidence of death was 2.34, 1.91, and 0 per 1000 patient-years, respectively, in controls, non-responders, and SVR patients. Survival curves showed early separation of SVR patients from both non-responders and controls at approximately 6 months. In decompensated cirrhotics, HCV clearance by therapy is life-saving and reduces disease progression.

Sertaline for the Prevention of Depression with HCV Therapy

Purpose: Current HCV treatment with peginterferon alfa and ribavirin is associated with severe side effects, including depression. The aim of this study was to evaluate if treatment with Sertraline prior to initiation of HCV therapy decreases the risk of depression during HCV treatment. Methods: This was a randomized, double blind, placebo-controlled trial conducted at the Durham VAMC Liver Clinic. All patients had chronic HCV infection with no previous treatment and no symptoms of depression. Patients received peginterferon alfa-2b 1.5 mcg/kg weekly and ribavirin 13 ± 2 mg/kg divided twice daily. Patients received Sertraline 50 mg (or placebo) two weeks prior to the initiation of HCV treatment and then throughout treatment. Depression and anxiety were assessed using the Hamilton Depression Scale, Beck Depression Inventory, and the Hamilton Anxiety Scale. Results: Forty patients were randomized, and the two groups had similar characteristics (Table 1). All patients in the Sertraline group completed at least 12 weeks of HCV therapy. Three of 20 patients in the placebo group did not complete 12 weeks of therapy. One patient withdrew prior to starting HCV therapy. Another relapsed to substance abuse, and the third had hyperglycemia. Clinical outcomes in the two groups were similar with early virologic response of 60% in each group, and sustained virologic response 50% in the placebo group and 45% in the Sertraline group. No severe episodes of depression occurred. Episodes of mild depression were significantly lower in the Sertraline group (Table 2). No differences were seen in anxiety scores.Table 1: Patient CharacteristicsTable 2: Results at 12 weeksConclusions: This pilot study found that Sertraline decreased the incidence of depression during HCV treatment. No benefit in virologic outcomes was noted, but larger studies are needed to further assess the role of prophylactic antidepressants during HCV therapy.

A randomised trial to compare the pharmacokinetic, pharmacodynamic, and antiviral effects of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C (COMPARE)

To compare the pharmacokinetics, pharmacodynamics, and antiviral activity of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C virus genotype 1. Thirty-six patients were randomised to peginterferon alfa-2b (1.5 microg/kg/week) or peginterferon alfa-2a (180 microg/week) for 4 weeks, then in combination with ribavirin (13 mg/kg/day) for a further 4 weeks. The pharmacokinetic profile of both peginterferons, mRNA expression of a selected group of interferon-induced gene transcripts, and serum HCV-RNA levels were assessed. Patients receiving peginterferon alfa-2b had significantly greater up-regulation of interferon-alfa response genes compared with those receiving peginterferon alfa-2a. Correspondingly, patients treated with peginterferon alfa-2b also had a significantly greater log10 maximum and log10 time-weighted average decrease in serum HCV-RNA. A greater proportion of peginterferon alfa-2b patients achieved a > or = 2.0 log10 reduction in serum HCV-RNA levels by week 8 (72% vs 44% of peginterferon alfa-2a patients, P = 0.09). There was an approximately 16-fold greater exposure to peginterferon in the serum of patients treated with peginterferon alfa-2a. These findings suggest that the biological activity, measured by early interferon-induced gene transcripts and early antiviral responsiveness, may have been greater in patients treated with peginterferon alfa-2b despite their lower exposure to the drug compared with patients treated with peginterferon alfa-2a.