Search

Aim: To evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin (pegIFN/RBV), in treatment-naive hepatitis C virus (HCV) genotype (GT) 1-infected patients., Methods: In this phase 3, randomized, open-label, noninferiority study, 602 patients were randomly assigned (2:1) to daclatasvir vs telaprevir, stratified by IL28B rs12979860 host genotype (CC vs non-CC), cirrhosis status (compensated cirrhosis vs no cirrhosis), and HCV GT1 subtype (GT1a vs GT1b). Patients were selected by study inclusion criteria from a total of 793 enrolled patients. Patients received daclatasvir 60 mg once daily or telaprevir 750 mg 3 times daily plus pegIFN/RBV. Daclatasvir recipients received 24 wk of daclatasvir plus pegIFN/RBV; those without an extended rapid virologic response (eRVR; undetectable HCV-RNA at weeks 4 and 12) received an additional 24 wk of pegIFN/RBV. Telaprevir-treated patients received 12 wk of telaprevir plus pegIFN/RBV followed by 12 (with eRVR) or 36 (no eRVR) wk of pegIFN/RBV. The primary objective was to compare for noninferiority of sustained virologic response rates at posttreatment week 12 (SVR12) in GT1b-infected patients. Key secondary objectives were to demonstrate that the rates of anemia (hemoglobin < 10 g/dL) and rash-related events, through week 12, were lower with daclatasvir + pegIFN/RBV than with telaprevir + pegIFN/RBV among GT1b-infected patients. Resistance testing was performed using population-based sequencing of the NS5A region for all patients at baseline, and for patients with virologic failure or relapse and HCV-RNA ≥ 1000 IU/mL, to investigate any link between NS5A polymorphisms associated with daclatasvir resistance and virologic outcome., Results: Patient demographics and disease characteristics were generally balanced across treatment arms; however, there was a higher proportion of black/African Americans in the daclatasvir groups (6.0% and 8.2% in the GT1b and GT1a groups, respectively) than in the telaprevir groups (2.2% and 3.0%). Among GT1b-infected patients, daclatasvir plus pegIFN/RBV was noninferior to telaprevir plus pegIFN/RBV for SVR12 [85% (228/268) vs 81% (109/134); difference, 4.3% (95%CI: -3.3% to 11.9%)]. Anemia (hemoglobin < 10 g/dL) was significantly less frequent with daclatasvir than with telaprevir [difference, -29.1% (95%CI: -38.8% to -19.4%)]. Rash-related events were also less common with daclatasvir than with telaprevir, but the difference was not statistically significant. In GT1a-infected patients, SVR12 was 64.9% with daclatasvir and 69.7% with telaprevir. Among both daclatasvir and telaprevir treatment groups, across GT1b- or GT1a-infected patients, lower response rates were observed in patients with IL28B non-CC and cirrhosis - factors known to affect response to pegIFN/RBV. Consistent with these observations, a multivariate logistic regression analysis in GT1b-infected patients demonstrated that SVR12 was associated with IL28B host genotype (CC vs non-CC, P = 0.011) and cirrhosis status (absent vs present, P = 0.031). NS5A polymorphisms associated with daclatasvir resistance (at L28, R30, L31, or Y93) were observed in 17.3% of GT1b-infected patients at baseline; such variants did not appear to be absolute predictors of failure since 72.1% of these patients achieved SVR12 compared with 86.9% without these polymorphisms. Among GT1b-infected patients, treatment was completed by 85.4% (229/268) in the daclatasvir group, and by 85.1% (114/134) in the telaprevir group, and among GT1a-infected patients, by 67.2% (90/134) and 69.7% (46/66), respectively. Discontinuations (of all 3 agents) due to an AE were more frequent with telaprevir than with daclatasvir, whereas discontinuations due to lack of efficacy were more frequent with daclatasvir, due, in part, to differences in futility criteria., Conclusion: Daclatasvir plus pegIFN/RBV demonstrated noninferiority to telaprevir plus pegIFN/RBV for SVR12 and was well-tolerated in treatment-naive GT1b-infected patients, supporting the use of daclatasvir with other direct-acting antivirals.

Unlabelled: Retreatment of patients who have not achieved sustained virological response (SVR) after treatment with investigational direct-acting antiviral agents (DAAs) has not been extensively studied. We conducted an open-label trial to assess the efficacy and safety of sofosbuvir (SOF) plus pegylated interferon (Peg-IFN) and ribavirin (RBV) in patients with genotype 1 hepatitis C virus (HCV) who participated in previous studies of one or more Gilead investigational DAAs in combination with RBV with or without Peg-IFN. We enrolled 80 patients at 40 sites. All patients received SOF 400 mg once daily plus Peg-IFN-α 180 μg/week and weight-based ribavirin (1,000 or 1,200 mg/day) for 12 weeks. The efficacy endpoint was the proportion of patients with SVR 12 weeks after discontinuation of therapy (SVR12). Of the 80 patients enrolled, 36 (45%) had received two or more courses of earlier treatment for HCV and 74 (93%) had at least one resistance-associated variant (RAV) at baseline. SVR12 was achieved by 63 of the 80 patients (79%) treated. Rates of SVR12 were similar across patient subgroups. Presence of RAVs at baseline did not appear to be associated with treatment failure. Seventy-one of eighty patients (89%) experienced at least one adverse event (AE), but most events were mild to moderate in severity. The most common AEs were fatigue, headache, and nausea. No patients discontinued all treatment because of AEs., Conclusion: These findings suggest that SOF plus Peg-IFN and RBV for 12 weeks is effective and safe in patients who have not achieved SVR with earlier regimens of one or more DAAs plus Peg-IFN and RBV., (© 2015 by the American Association for the Study of Liver Diseases.)

Background & Aims: Chronic hepatitis C treatment for prior non-responders to peginterferon (PegIFN)/ribavirin remains suboptimal. The MATTERHORN study evaluated regimens containing ritonavir-boosted danoprevir (danoprevir/r) in prior PegIFN alfa/ribavirin non-responders., Methods: Prior partial responders (N=152) were randomized to 24 weeks of twice-daily danoprevir/r 100/100mg, mericitabine 1000 mg and ribavirin 1000/1200 mg (IFN-free); danoprevir/r plus PegIFN alfa-2a/ribavirin (triple); or danoprevir/r, mericitabine and PegIFN alfa-2a/ribavirin (Quad). Prior null responders (N=229) were randomized to 24 weeks of IFN-free therapy, or quad alone (Quad 24) or quad plus 24-weeks of PegIFN alfa-2a/ribavirin (Quad 48). The primary endpoint was sustained virological response (HCV RNA <25 IU/ml) 24 weeks after end-of-treatment (SVR24). Due to high relapse rates, genotype (G) 1a patients in IFN-free arms were offered additional PegIFN alfa-2a/ribavirin., Results: Among prior partial responders, SVR24 rates were 46.2%, 51.0%, and 86.0%, in the IFN-free, Triple and Quad arms, respectively; among prior null responders, SVR24 rates were 45.5%, 80.5%, and 83.8% respectively. Relapse rates were lower and SVR24 rates higher in G1b-infected than G1a-infected patients. SVR24 rates in G1a and G1b patients randomized to Quad were 75.0% and 96.2%, respectively, in the partial Quad arm, and 68.1% and 100%, respectively, in the null Quad 24 arm. Treatment failure was associated with resistance to danoprevir, but not to mericitabine, and was more common in G1a infected patients. Treatment was well-tolerated., Conclusions: Danoprevir/r, mericitabine plus PegIFN alfa-2a/ribavirin was well-tolerated and produced high overall SVR24 rates in prior partial and null responders to PegIFN alfa/ribavirin. In contrast, IFN-free regimens were associated with unacceptably high relapse rates., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Although the addition of the HCV NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (peginterferon) alfa plus ribavirin has improved sustained virological response (SVR) in treatment-naive and treatment-experienced patients infected with hepatitis C virus (HCV) genotype 1, the regimens have a high pill burden and are associated with increased rates and severity of adverse events, such as anaemia and rash. The efficacy and safety of the combination of simeprevir, a one pill, once-daily, oral HCV NS3/4A protease inhibitor, plus peginterferon alfa 2a plus ribavirin were assessed in treatment-naive patients with HCV genotype 1 infection., Methods: In QUEST-1, a phase 3, randomised, double-blind multicentre trial undertaken in 13 countries (Australia, Europe, North America, Puerto Rico, and New Zealand), 394 patients (aged ≥18 years) with chronic HCV genotype 1 infection and no history of HCV treatment, stratified by HCV subtype and host IL28B genotype, were randomly assigned in a 2:1 ratio with a computer-generated allocation sequence to receive simeprevir (150 mg once daily, orally) plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (simeprevir group), or placebo orally plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (placebo group). Treatment duration was 24 weeks or 48 weeks in the simeprevir group according to criteria for response-guided therapy (ie, HCV RNA <25 IU/mL [undetectable or detectable] at week 4 and <25 IU/mL undetectable at week 12) and 48 weeks in the placebo group. Patients, study personnel, and the sponsor were masked to the treatment group assignment. The primary efficacy endpoint was sustained virological response 12 weeks after the planned end of treatment (SVR12) and was assessed with an intention-to-treat analysis. The results of the primary analysis (week 60) are presented for safety and SVR12. This trial is registered with ClinicalTrials.gov, number NCT01289782., Findings: Treatment with simeprevir, peginterferon alfa 2a, and ribavirin was superior to placebo, peginterferon alfa 2a, and ribavirin (SVR12 in 210 [80%] patients of 264 vs 65 [50%] of 130, respectively, adjusted difference 29·3% [95% CI 20·1-38·6; p<0·0001). Adverse events in the first 12 weeks of treatment led to discontinuation of simeprevir in two (<1%) patients and discontinuation of placebo in one patient (<1%); fatigue (106 [40%] vs 49 [38%] patients, respectively) and headache (81 [31%] vs 48 [37%], respectively) were the most common adverse events. The prevalences of anaemia (42 [16%] vs 14 [11%], respectively) and rash (72 [27%] vs 33 [25%]) were similar in the simeprevir and placebo groups. Addition of simeprevir did not increase severity of patient-reported fatigue and functioning limitations, but shortened their duration., Interpretation: Simeprevir once daily with peginterferon alfa 2a and ribavirin shortens therapy in treatment-naive patients with HCV genotype 1 infection without worsening the adverse event profiles associated with peginterferon alfa 2a plus ribavirin., Funding: Janssen Infectious Diseases-Diagnostics., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background & Aims: Boceprevir with peginterferon/ribavirin (BOC/PR) leads to significantly higher sustained virological response (SVR) rates in patients with chronic hepatitis C and partial response or relapse after prior treatment with peginterferon/ribavirin. We studied the efficacy of BOC/PR in patients with prior treatment failure, including those with a null response (<2-log10 decline in HCV RNA), to peginterferon/ribavirin., Methods: Patients in the control arms of boceprevir Phase 2/3 studies who did not achieve SVR were re-treated with BOC/PR for up to 44 weeks. Patients enrolling >2 weeks after end-of-treatment in the prior study received PR for 4 weeks before adding boceprevir., Results: Of 168 patients enrolled, four discontinued from the PR lead-in and 164 received BOC/PR. Baseline viral load was >800,000 IU/ml in 77% of patients; 62% had HCV genotype 1a, and 10% were cirrhotic. In the ITT analysis (all 168 patients), SVR was achieved in 20 (38%) of 52 patients with prior null response, 57 (67%) of 85 with prior partial response, and 27 (93%) of 29 with prior relapse. In the mITT analysis (164 BOC/PR-treated patients), SVR rates were 41% (20/49), 67% (57/85), and 96% (27/28), respectively. SVR was achieved by 48% of patients with <1-log10 decline in HCV-RNA after lead-in and 76% of those with ⩾ 1-log10 decline or undetectable HCV-RNA after lead-in. The most common adverse events were anemia (49%), fatigue (48%), and dysgeusia (35%); 8% of patients discontinued due to adverse events., Conclusions: Re-treatment with BOC/PR improved SVR rates in all patient subgroups, including those with prior null response., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Simeprevir (TMC435) is an oral NS3/4 protease inhibitor in phase III trials for chronic hepatitis C virus (HCV) infection. We performed a phase IIb, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of the combination of simeprevir, peginterferon-α2a (PegIFN), and ribavirin (RBV) in patients with HCV genotype-1 infection previously treated with PegIFN and RBV., Methods: We analyzed data from patients who did not respond (null response), had a partial response, or relapsed after treatment with PegIFN and RBV, randomly assigned to receive simeprevir (100 or 150 mg, once daily) for 12, 24, or 48 weeks plus PegIFN and RBV for 48 weeks (n = 396), or placebo plus PegIFN and RBV for 48 weeks (n = 66). All patients were followed for 24 weeks after planned end of treatment; the primary end point was the proportion of patients with sustained virologic response (SVR; undetectable HCV RNA) at that time point., Results: Overall, rates of SVR at 24 weeks were significantly higher in the groups given simeprevir than those given placebo (61%-80% vs 23%; P < .001), regardless of prior response to PegIFN and RBV (simeprevir vs placebo: prior null response, 38%-59% vs 19%; prior partial response, 48%-86% vs 9%; prior relapse, 77%-89% vs 37%). All groups had comparable numbers of adverse events; these led to discontinuation of simeprevir or placebo and/or PegIFN and RBV in 8.8% of patients given simeprevir and 4.5% of those given placebo., Conclusions: In treatment-experienced patients, 12, 24, or 48 weeks simeprevir (100 mg or 150 mg once daily) in combination with 48 weeks PegIFN and RBV significantly increased rates of SVR at 24 weeks compared with patients given placebo, PegIFN, and RBV and was generally well tolerated. ClinicalTrials.gov number: NCT00980330., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Unlabelled: The phase IIb, double-blind, placebo-controlled PILLAR trial investigated the efficacy and safety of two different simeprevir (SMV) doses administered once-daily (QD) with pegylated interferon (Peg-IFN)-α-2a and ribavirin (RBV) in treatment-naïve patients with HCV genotype 1 infection. Patients were randomized to one of five treatments: SMV (75 or 150 mg QD) for 12 or 24 weeks or placebo, plus Peg-IFN and RBV. Patients in the SMV arms stopped all treatment at week 24 if response-guided therapy (RGT) criteria were met; patients not meeting RGT continued with Peg-IFN and RBV until week 48, as did patients in the placebo control group. Sustained virologic response (SVR) rates measured 24 weeks after the planned end of treatment (SVR24) were 74.7%-86.1% in the SMV groups versus 64.9% in the control group (P < 0.05 for all comparisons [SMV versus placebo], except SMV 75 mg for 24 weeks). Rapid virologic response (HCV RNA <25 IU/mL undetectable at week 4) was achieved by 68.0%-75.6% of SMV-treated and 5.2% of placebo control patients. According to RGT criteria, 79.2%-86.1% of SMV-treated patients completed treatment by week 24; 85.2%-95.6% of these subsequently achieved SVR24. The adverse event profile was generally similar across the SMV and placebo control groups, with the exception of mild reversible hyperbilirubinemia, without serum aminotransferase abnormalities, associated with higher doses of SMV., Conclusion: SMV QD in combination with Peg-IFN and RBV significantly improves SVR rates, compared with Peg-IFN and RBV alone, and allows the majority of patients to shorten their therapy duration to 24 weeks., (© 2013 by the American Association for the Study of Liver Diseases.)

Resolution of chronic hepatitis C is considered when serum HCV RNA becomes repeatedly undetectable and liver enzymes normalize. However, long-term persistence of HCV following therapy with pegylated interferon-α/ribavirin (PegIFN/R) was reported when more sensitive assays and testing of serial plasma, lymphoid cells (PBMC) and/or liver biopsies was applied. Our aim was to reassess plasma and PBMCs collected during and after standard PegIFN/R therapy from individuals who became HCV RNA nonreactive by clinical testing. Of particular interest was to determine if HCV genome and its replication remain detectable during ongoing treatment with PegIFN/R when evaluated by more sensitive detection approaches. Plasma acquired before (n = 11), during (n = 25) and up to 12-88 weeks post-treatment (n = 20) from 9 patients and PBMC (n = 23) from 3 of them were reanalyzed for HCV RNA with sensitivity <2 IU/mL. Clone sequencing of the HCV 5'-untranslated region from plasma and PBMCs was done in 2 patients. HCV RNA was detected in 17/25 (68%) plasma and 8/10 (80%) PBMC samples collected from 8 of 9 patients during therapy, although only 5.4% plasma samples were positive by clinical assays. Among post-treatment HCV RNA-negative plasma samples, 9 of 20 (45.3%) were HCV reactive for up to 59 weeks post-treatment. Molecularly evident replication was found in 6/12 (50%) among PBMC reactive for virus RNA positive strand collected during or after treatment. Pre-treatment point mutations persisted in plasma and/or PBMC throughout therapy and follow-up. Therefore, HCV is not completely cleared during ongoing administration of PegIFN/R otherwise capable of ceasing progression of CHC and virus commonly persists at levels not detectable by the current clinical testing. The findings suggest the need for continued evaluation even after patients achieve undetectable HCV RNA post-treatment.

Background: The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV., Methods: For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800,000 IU/mL vs ≥800,000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01329978., Results: We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5). In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77-96) in cohort A, 97 patients (89%, 82-94) in cohort B, and by 135 (87%, 81-92) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0·94), or in cohort C (p=0·78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug--anaemia and neutropenia--were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event., Interpretation: Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis., Funding: Gilead Sciences., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: In phase 2 trials, the nucleotide polymerase inhibitor sofosbuvir was effective in previously untreated patients with chronic hepatitis C virus (HCV) genotype 1, 2, or 3 infection., Methods: We conducted two phase 3 studies in previously untreated patients with HCV infection. In a single-group, open-label study, we administered a 12-week regimen of sofosbuvir plus peginterferon alfa-2a and ribavirin in 327 patients with HCV genotype 1, 4, 5, or 6 (of whom 98% had genotype 1 or 4). In a noninferiority trial, 499 patients with HCV genotype 2 or 3 infection were randomly assigned to receive sofosbuvir plus ribavirin for 12 weeks or peginterferon alfa-2a plus ribavirin for 24 weeks. In the two studies, the primary end point was a sustained virologic response at 12 weeks after the end of therapy., Results: In the single-group study, a sustained virologic response was reported in 90% of patients (95% confidence interval, 87 to 93). In the noninferiority trial, a sustained response was reported in 67% of patients in both the sofosbuvir-ribavirin group and the peginterferon-ribavirin group. Response rates in the sofosbuvir-ribavirin group were lower among patients with genotype 3 infection than among those with genotype 2 infection (56% vs. 97%). Adverse events (including fatigue, headache, nausea, and neutropenia) were less common with sofosbuvir than with peginterferon., Conclusions: In a single-group study of sofosbuvir combined with peginterferon-ribavirin, patients with predominantly genotype 1 or 4 HCV infection had a rate of sustained virologic response of 90% at 12 weeks. In a noninferiority trial, patients with genotype 2 or 3 infection who received either sofosbuvir or peginterferon with ribavirin had nearly identical rates of response (67%). Adverse events were less frequent with sofosbuvir than with peginterferon. (Funded by Gilead Sciences; FISSION and NEUTRINO ClinicalTrials.gov numbers, NCT01497366 and NCT01641640, respectively.).

Background: Protease inhibitors have improved treatment of infection with hepatitis C virus (HCV), but dosing, a low barrier to resistance, drug interactions, and side-effects restrict their use. We assessed the safety and efficacy of sofosbuvir, a uridine nucleotide analogue, in treatment-naive patients with genotype 1-3 HCV infection., Methods: In this two-cohort, phase 2 trial, we recruited treatment-naive patients with HCV genotypes 1-3 from 22 centres in the USA. All patients were recruited between Aug 16, 2010, and Dec 13, 2010, and were eligible for inclusion if they were aged 18-70 years, had an HCV RNA concentration of 50,000 IU/mL or greater, and had no cirrhosis. We randomly allocated all eligible patients with HCV genotype 1 (cohort A) to receive sofosbuvir 200 mg, sofosbuvir 400 mg, or placebo (2:2:1) for 12 weeks in combination with peginterferon (180 μg per week) and ribavirin (1000-1200 mg daily), after which they continued peginterferon and ribavirin for an additional 12 weeks or 36 weeks (depending on viral response). Randomisation was done by use of a computer-generated randomisation sequence and patients and investigators were masked to treatment allocation until week 12. Patients with genotypes 2 or 3 (cohort B) received open-label sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks. Our primary outcomes were safety and tolerability. Secondary efficacy analyses were by intention to treat and endpoints included sustained virological response, defined as undetectable HCV RNA at post-treatment weeks 12 and 24. This study is registered with ClinicalTrials.gov, number NCT01188772., Findings: In cohort A, 122 patients were assigned 200 mg sofosbuvir (48 patients), 400 mg sofosbuvir (48), or placebo (26). We enrolled 25 patients into cohort B. The most common adverse events--fatigue, headache, nausea, and chills--were consistent with those associated with peginterferon and ribavirin. Eight patients discontinued treatment due to adverse events, two (4%) receiving sofosbuvir 200 mg, three (6%) receiving sofosbuvir 400 mg, and three (12%) receiving placebo. In cohort A, HCV RNA was undetectable at post-treatment week 12 in 43 (90%; 95% CI 77-97) of 48 patients in the 200 mg sofosbuvir group; 43 (91%; 80-98) of 47 patients in the 400 mg sofosbuvir group, and 15 (58%; 37-77) of 26 patients in the placebo group. In cohort B, 23 (92%) of 25 patients had undetectable HCV RNA at post-treatment week 12., Interpretation: Our findings lend support to the further assessment, in phase 2 and 3 trials, of sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks in treatment-naive patients with HCV genotype-1., Funding: Gilead Sciences., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Unlabelled: Boceprevir (BOC) added to peginterferon alfa-2b (PegIFN) and ribavirin (RBV) significantly increases sustained virologic response (SVR) rates over PegIFN/RBV alone in previously untreated adults with chronic hepatitis C genotype 1. We evaluate the relationship of incident anemia with triple therapy. A total of 1,097 patients received a 4-week lead-in of PegIFN/RBV followed by: (1) placebo plus PegIFN/RBV for 44 weeks (PR48); (2) BOC plus PegIFN/RBV using response-guided therapy (BOC/RGT); and (3) BOC plus PegIFN/RBV for 44 weeks (BOC/PR48). The management of anemia (hemoglobin [Hb]<10 g/dL) included RBV dose reduction and/or erythropoietin (EPO) use. A total of 1,080 patients had ≥1 Hb measurement during treatment. The incidence of anemia was 50% in the BOC arms combined (363/726) and 31% in the PR48 arm (108/354, P<0.001). Among BOC recipients, lower baseline Hb and creatinine clearance were associated with incident anemia. In the BOC-containing arms, anemia was managed by the site investigators as follows: EPO without RBV dose reduction, 38%; RBV dose reduction without EPO, 8%; EPO with RBV dose reduction, 40%; and neither RBV dose reduction nor EPO, 14%. SVR rates were not significantly affected by management strategy (70%-74%), and overall patients with anemia had higher rates of SVR than those who did not develop anemia (58%). Serious and life-threatening adverse events (AEs) and discontinuations due to AEs among BOC-treated patients did not differ by EPO use., Conclusion: With BOC/PR therapy, SVR rates in patients with incident anemia were higher than nonanemic patients and did not vary significantly according to the investigator-selected approach for anemia management. Prospective studies are needed to confirm this observation., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Background & Aims: The addition of boceprevir to therapy with peginterferon alfa-2b and ribavirin results in significantly higher rates of sustained virologic response (SVR) in previously treated patients with chronic hepatitis C virus (HCV) genotype-1 infection, compared with peginterferon alfa-2b and ribavirin alone. We assessed SVR with boceprevir plus peginterferon alfa-2a-ribavirin (PEG2a/R) in patients with identical study entry criteria., Methods: In a double-blind, placebo-controlled trial, 201 patients with HCV genotype-1 who had relapsed or not responded to previous therapy were assigned to groups (1:2) and given a 4-week lead-in phase of PEG2a/R, followed by placebo plus PEG2a/R for 44 weeks (PEG2a/R) or boceprevir plus PEG2a/R for 44 weeks (BOC/PEG2a/R). The primary end point was SVR 24 weeks after therapy ended., Results: The addition of boceprevir after 4 weeks of lead-in therapy with PEG2a/R significantly increased the rate of SVR from 21% in the PEG2a/R group to 64% in the BOC/PEG2a/R group (P < .0001). Among patients with poor response to interferon therapy (<1-log(10) decline in HCV RNA at week 4), 39% in the BOC/PEG2a/R group had SVRs, compared with none of the patients in the PEG2a/R group. Among patients with good response to interferon (≥1-log(10) decline), 71% in the BOC/PEG2a/R group had SVRs, compared with 25% in the PEG2a/R group. A ≥1-log(10) decline in HCV RNA at treatment week 4 was the strongest independent predictor of SVR, exceeding that of IL-28B genotype. Among 8 patients who began the study with HCV amino acid variants associated with boceprevir resistance, 3 (38%) achieved SVRs. Fifty percent of patients in the BOC/PEG2a/R group developed anemia (hemoglobin <10.0 g/dL), compared with 27% in the PEG2a/R group; 43% vs 21%, respectively, developed neutropenia (neutrophil count <750/mm(3))., Conclusions: The addition of boceprevir after 4 weeks of lead-in therapy with PEG2a/R caused significantly higher rates of SVR in previously treated patients with chronic HCV genotype-1 infection, compared with patients given only PEG2a/R. ClinicalTrials.gov Identifier: NCT00845065., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Resistance to direct-acting antivirals represents a new challenge in the treatment of chronic hepatitis C., Methods: SPRINT-1 was a randomized study of treatment-naive patients with genotype (G) 1 hepatitis C infection (n=595) that evaluated the safety and efficacy of boceprevir (BOC) when added to pegylated interferon-α2b plus ribavirin (PR). Plasma samples collected at protocol-specified visits were analysed by population sequencing for detection of BOC-associated resistance-associated variants (RAVs)., Results: A total of 17/24 (71%) patients randomized to BOC with baseline RAVs achieved sustained virological response (SVR). V55A/I (n=14), Q41H (n=11) and T54S (n=9) were the most frequently detected polymorphisms at baseline. Seven non-SVR patients with baseline RAVs had V55A (relapse, n=3; breakthrough, n=1; and non-response, n=1) and/or R155K (non-response, n=2). In total, 63/144 (44%) patients with sequenced post-baseline samples (2 SVR, 61 non-SVR) had detectable RAVs after BOC treatment (G1a: R155K [39/49; 80%], V36M [37/49; 76%] and T54S [24/49; 49%]; G1b: T54S [3/11; 27%], T54A [4/11; 35%], A156S [2/11; 18%] and V170A [2/11; 18%]). RAV frequency varied according to the virological response: 90%, 67%, 27% and 37% of breakthrough, incomplete virological response, relapse and non-responder patients, respectively, had post-baseline RAVs present. Similar RAVs were identified in both the PR lead-in and no-lead-in arms and the frequency of post-baseline RAVs was highest in the low-dose ribavirin arm., Conclusions: SVR rates were not compromised among patients with RAVs at baseline; however, a lower starting mg/kg dose of ribavirin was associated with a higher frequency of post-baseline RAVs.

Background: Shortened courses of treatment with pegylated interferon alfa and ribavirin for patients with hepatitis C virus infection who experience rapid virologic response can be effective in appropriately selected patients. The cost-effectiveness of truncated therapy is not known., Objective: To assess the cost-effectiveness of response-guided therapy versus standard-duration therapy on the basis of best available evidence., Methods: We developed a decision model for chronic hepatitis C virus infection representing two treatment strategies: 1) standard-duration therapy with pegylated interferon alfa and ribavirin for 48 weeks in patients with genotype 1 or 4 and for 24 weeks in patients with genotype 2 or 3 and 2) truncated therapy (i.e., 50% decrease in treatment duration) in patients with rapid virologic response. Patients for whom truncated therapy failed began standard-duration therapy guided by genotype. We used a Markov model to estimate lifetime costs and quality-adjusted life-years., Results: In the base-case analysis, mean lifetime costs were $46,623 ± $2,483 with standard-duration therapy and $42,354 ± $2,489 with truncated therapy. Mean lifetime quality-adjusted life-years were similar between the groups (17.1 ± 0.7 with standard therapy; 17.2 ± 0.7 with truncated therapy). Across model simulations, the probability of truncated therapy being economically dominant (i.e., both cost saving and more effective) was 78.6%. The results were consistent when we stratified the data by genotype. In one-way sensitivity analyses, the results were sensitive only to changes in treatment efficacy., Conclusion: Truncated therapy based on rapid virologic response is likely to be cost saving for treatment-naive patients with chronic hepatitis C virus infection. Cost-effectiveness varied with small changes in relative treatment efficacy., (Copyright © 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Unlabelled: In comparison with peginterferon/ribavirin alone, boceprevir with peginterferon/ribavirin significantly improves sustained virological response (SVR) rates in patients with chronic hepatitis C virus (HCV) genotype 1 infections, but treatment failure remains a significant problem. Using phase 3 trial databases, we sought to develop stopping rules for patients destined to fail boceprevir-based combination therapy in order to minimize drug toxicity, resistance, and costs in the face of ultimate futility. Exploratory post hoc analyses using data from the Serine Protease Inhibitor Therapy 2 (SPRINT-2) study (treatment-naive patients) and the Retreatment With HCV Serine Protease Inhibitor Boceprevir and Pegintron/Rebetol 2 (RESPOND-2) study (treatment-experienced patients) were undertaken to determine whether protocol-specified stopping rules (detectable HCV RNA at week 24 for SPRINT-2 and at week 12 for RESPOND-2) could be refined and harmonized. In SPRINT-2, a week 12 rule with an HCV RNA cutoff of ≥ 100 IU/mL would have discontinued therapy in 65 of 195 failures (sensitivity = 33%) without sacrificing a single SVR among 475 successes (specificity = 100%). Viral variants emerged after week 12 in 36 of the 49 evaluable patients (73%) who would have discontinued at week 12 using a ≥ 100 IU/mL stopping rule. In RESPOND-2, five of six patients with week 12 HCV RNA levels between the lower limit of detection (9.3 IU/mL) and the lower limit of quantification (25 IU/mL) who continued therapy despite the protocol-stipulated futility rule achieved SVR; one additional patient with a week 12 HCV RNA level of 148 IU/mL also continued therapy, had undetectable HCV RNA at week 16, and attained SVR., Conclusion: Although a stopping rule of detectable HCV RNA at week 12 would have forfeited some SVR cases, week 12 HCV RNA levels ≥ 100 IU/mL almost universally predicted a failure to achieve SVR in both treatment-naive and treatment-experienced patients. In boceprevir recipients, the combination of 2 stopping rules-an HCV RNA level ≥ 100 IU/mL at week 12 and detectable HCV RNA at week 24--maximized the early discontinuation of futile therapy and minimized premature treatment discontinuation., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Telaprevir is a potent HCV NS3/4A protease inhibitor. A completed development program has demonstrated the superior efficacy of a regimen of telaprevir combined with pegylated interferon alfa and ribavirin (PR) over PR alone in patients with HCV genotype 1. In the ADVANCE trial in treatment-naïve patients, 12 weeks of telaprevir, peginterferon alfa-2a and ribavirin followed by either 12 or 36 weeks of PR alone (depending upon extended rapid virologic response, or eRVR, i.e. HCV RNA undetectability at weeks 4 and 12), was associated with sustained virological response (SVR) in 75% of patients compared with 46% receiving PR for 48 weeks. The ILLUMINATE trial established the foundation for response-guided therapy in patients with eRVR. The REALIZE trial in treatment-experienced patients showed a gradient of SVR from prior relapsers (86%) to partial responders (57%) to null responders (31%), with rates of virologic failure and emergent resistance highest in the latter group. Incremental adverse effects of telaprevir include rash, anemia, pruritus, diarrhea, and nausea. Treatment naïve patients and relapsers are eligible for response-guided therapy. Stopping rules of telaprevir-based treatment include HCV RNA > 1000 IU/ml at weeks 4 and 12., (© 2012 John Wiley & Sons A/S.)

Background & Aims: Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-α (pegIFN)-related thrombocytopenia, neutropenia, and leukopenia., Methods: 1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (Pl) count ≥80×10(9)/L and an absolute neutrophil count (ANC) ≥1500/mm(3). Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts (Pl, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n=1294)., Results: 6 SNPs on chromosome 20 were positively associated with Pl reduction (top SNP rs965469, p=10(-10)). These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV)-induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with Pl reduction (p=10(-12), p=10(-7)) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with Pl reduction (r=-0.28, p=10(-17)) and Hb change largely attenuated the association between the ITPA variants and Pl reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia., Conclusions: Two ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Pegylated-interferon (PEG-IFN) and ribavirin (RBV), current standard treatment for hepatitis C virus (HCV) infection, are frequently associated with neutropenia and anemia, leading to high treatment discontinuation rates in HIV/HCV-coinfected patients. Our objective was to compare the effectiveness of intervening with hematologic growth factors versus dose reductions of standard HCV therapy for the management of treatment-induced hematologic disorders., Methods: Ninety-two HIV/HCV-coinfected, therapy-naive subjects received PEG-IFN alfa-2b 1.5 μg·kg⁻¹·wk⁻¹ and RBV 13 ± 2 mg·kg⁻¹·d⁻¹ for up to 48 weeks. Before treatment initiation, subjects were randomized to subsequently receive growth factors, recombinant human erythropoietin (rHuEPO) and/or granulocyte colony-stimulating factor, or dose reduction (RBV and/or PEG-IFN) for anemia and neutropenia management, respectively. We analyzed the ability of each management strategy to control anemia and neutropenia and the percentage of subjects who achieved a successful treatment outcome according to the different management strategies., Results: During treatment, 43 subjects developed anemia (human erythropoietin, n = 24; dose reduction, n = 19), whereas 25 subjects developed neutropenia (granulocyte colony-stimulating factor, n = 10; dose reduction, n = 15). After the intervention, the increase in both hemoglobin and absolute neutrophil counts did not differ between the 2 side effect management strategies. Sustained response percentages were similar comparing anemic and neutropenic subjects regardless of management strategy (anemia: recombinant human erythropoietin, 29% versus dose reduction, 21%, P = 0.92; neutropenia: granulocyte colony-stimulating factor, 40% versus dose reduction, 20%, P = 0.46)., Conclusions: Growth factor supplementation and dose reduction do not seem to differ as management strategies for anemia and neutropenia in HIV/HCV-coinfected individuals treated with PEG-IFN/RBV.

Background and Aims: African American ethnicity is a well-described negative predictor of treatment outcome for chronic hepatitis C (CHC); however, less is known about the influence of Hispanic and Asian ethnicity. The aim of this subanalysis of the Weight-based Dosing of PegINterferon α-2b and Ribavirin (WIN-R) study was to assess the impact of Asian (n=118), Hispanic (n=289), and white (n=3919) ethnicity on CHC treatment outcomes., Methods: WIN-R was an investigator-initiated trial in which patients with CHC received pegylated interferon α-2b (1.5 μg/kg/wk) plus a fixed ribavirin dose (800 mg/d) or a weight-based ribavirin dose (800 to 1400 mg/d) for 24 or 48 weeks., Results: Sustained virologic response was higher in Asian patients than in white patients (56% vs 46%, P=0.041), and higher in Asian and white patients than in Hispanic patients (56% vs 35%, P=0.0001; and 46% vs 35%, P=0.0002, respectively). In genotype 1 patients, sustained virologic response was higher in white and Asian patients than in Hispanic patients (36% and 45% vs 25%, P<0.001 for both comparisons); however, in genotype 2/3 patients, there were no significant differences among ethnic groups. Psychiatric adverse events were less common and anemia was more common in Asians than in white or Hispanic patients. Ribavirin dose reductions were less frequent in Hispanic patients than in white patients, whereas pegylated interferonα-2b dose reductions were more common in white patients than Hispanic patients., Conclusion: These observations highlight the importance of ethnicity as an integral component of the tailored treatment approach to CHC.

Background: In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients., Methods: In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8 weeks and placebo with peginterferon-ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12 weeks, followed by 36 weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response)., Results: Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group., Conclusions: Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.).

Background: Seizures are reported as an uncommon side effect of interferon therapy., Aim: To determine the frequency and presentation of seizures occurring during pegylated interferon-α (PEG-IFNα) and ribavirin therapy for chronic hepatitis C., Methods: Patients were identified using data from the WIN-R trial database, a US multicenter study comparing fixed (800 mg) versus weight-based (800 to 1400 mg) daily dosing of ribavirin in combination with PEG-IFNα-2b (1.5 μg/kg/wk)., Results: Of the 4913 enrolled patients, 8 (0.16%) had a seizure. Three patients had a grand mal seizure and the seizure type was unknown in 5 patients. At the time of seizure, 6 patients were taking antidepressants (including 3 on bupropion), 1 was hyponatremic, and 1 had consumed a significant amount of alcohol. One patient had a history of seizures. Neuroimaging and electroencephalographic studies were negative. Antiepileptic medications were continued in the patient with a history of seizures and initiated in 1 patient. PEG-IFNα-2b plus ribavirin therapy was continued in 2 patients following seizure and neither experienced a recurrent seizure., Conclusions: Seizures occur infrequently in patients receiving PEG-IFNα-2b plus ribavirin, and appear to be associated with other risk factors including antidepressant use.

Background: Peginterferon plus ribavirin achieves sustained virological response (SVR) in fewer than half of patients with genotype 1 chronic hepatitis C virus infection treated for 48 weeks. We tested the efficacy of boceprevir, an NS3 hepatitis C virus oral protease inhibitor, when added to peginterferon alfa-2b and ribavirin., Methods: In part 1 of this trial, undertaken in 67 sites in the USA, Canada, and Europe, 520 treatment-naive patients with genotype 1 hepatitis C virus infection were randomly assigned to receive peginterferon alfa-2b 1.5 mug/kg plus ribavirin 800-1400 mg daily for 48 weeks (PR48; n=104); peginterferon alfa-2b and ribavirin daily for 4 weeks, followed by peginterferon alfa-2b, ribavirin, and boceprevir 800 mg three times a day for 24 weeks (PR4/PRB24; n=103) or 44 weeks (PR4/PRB44; n=103); or peginterferon alfa-2b, ribavirin, and boceprevir three times a day for 28 weeks (PRB28; n=107) or 48 weeks (PRB48; n=103). In part 2, 75 patients were randomly assigned to receive either PRB48 (n=16) or low-dose ribavirin (400-1000 mg) plus peginterferon alfa-2b and boceprevir three times a day for 48 weeks (low-dose PRB48; n=59). Randomisation was by computer-generated code, and study personnel and patients were not masked to group assignment. The primary endpoint was SVR 24 weeks after treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00423670., Findings: Patients in all four boceprevir groups had higher rates of SVR than did the control group (58/107 [54%, 95% CI 44-64], p=0.013 for PRB28; 58/103 [56%, 44-66], p=0.005 for PR4/PRB24; 69/103 [67%, 57-76], p<0.0001 for PRB48; and 77/103 [75%, 65-83], p<0.0001 for PR4/PRB44; vs 39/104 [38%, 28-48] for PR48 control). Low-dose ribavirin was associated with a high rate of viral breakthrough (16/59 [27%]), and a rate of relapse (six of 27 [22%]) similar to control (12/51 [24%]). Boceprevir-based groups had higher rates of anaemia (227/416 [55%] vs 35/104 [34%]) and dysgeusia (111/416 [27%] vs nine of 104 [9%]) than did the control group., Interpretation: In patients with untreated genotype 1 chronic hepatitis C infection, the addition of the direct-acting antiviral agent boceprevir to standard treatment with peginterferon and ribavirin after a 4-week lead-in seems to have the potential to double the sustained response rate compared with that recorded with standard treatment alone., Funding: Merck., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Prospective, randomized, controlled, phase 3 clinical trials establish pegylated interferon (PEG-IFN) alfa plus ribavirin as the standard of care for patients with chronic hepatitis C. Such clinical trials are conducted in a highly regimented manner; patients must meet strict inclusion/exclusion criteria, and treatment is administered under rigid protocols with close monitoring by study personnel. Whether the results of phase 3 trials can be generalized or achieved in everyday clinical practice is questioned in several therapeutic areas. The efficacy of PEG-IFN alfa plus ribavirin therapy observed in pivotal phase 3 trials has been confirmed in several community-based trials conducted in North America and Europe, demonstrating consistent overall rates of sustained virologic response across a wide range of patient populations. Sustained virologic response rates stratified by genotype, viral load, fibrosis score, age, and ethnicity, factors known to impact treatment outcome, are consistent between these trials and comparable to those reported in clinical trials. The United States-based WIN-R trial confirmed the value of combining weight-based ribavirin dosing with weight-based PEG-IFN alfa-2b dosing across a spectrum of patient body weights. Large Canadian trials (POWeR and EAP), a German trial (AWB), a French study (Hepatys), and an Italian study demonstrated that PEG-IFN alfa plus ribavirin produces excellent efficacy in difficult-to-treat patient populations. Collectively, these results confirm the efficacy of current standard treatment regimens in a wide range of community-based settings, affording clinicians confidence that they can attain results similar to those of rigidly controlled randomized trials.

Background: Current therapy for chronic hepatitis C virus (HCV) infection is effective in less than 50% of patients infected with HCV genotype 1. Telaprevir, a protease inhibitor specific to the HCV nonstructural 3/4A serine protease, rapidly reduced HCV RNA levels in early studies., Methods: We randomly assigned patients infected with HCV genotype 1 to one of three telaprevir groups or to the control group. The control group (called the PR48 group) received peginterferon alfa-2a (180 microg per week) and ribavirin (1000 or 1200 mg per day, according to body weight) for 48 weeks, plus telaprevir-matched placebo for the first 12 weeks (75 patients). The telaprevir groups received telaprevir (1250 mg on day 1 and 750 mg every 8 hours thereafter) for 12 weeks, as well as peginterferon alfa-2a and ribavirin (at the same doses as in the PR48 group) for the same 12 weeks (the T12PR12 group, 17 patients) or for a total of 24 weeks (the T12PR24 group, 79 patients) or 48 weeks (the T12PR48 group, 79 patients). The primary outcome was a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy)., Results: The rate of sustained virologic response was 41% (31 of 75 patients) in the PR48 group, as compared with 61% (48 of 79 patients) in the T12PR24 group (P=0.02), 67% (53 of 79 patients) in the T12PR48 group (P=0.002), and 35% (6 of 17 patients) in the T12PR12 group (this group was exploratory and not compared with the control group). Viral breakthrough occurred in 7% of patients receiving telaprevir. The rate of discontinuation because of adverse events was higher in the three telaprevir-based groups (21%, vs. 11% in the PR48 group), with rash the most common reason for discontinuation., Conclusions: Treatment with a telaprevir-based regimen significantly improved sustained virologic response rates in patients with genotype 1 HCV, albeit with higher rates of discontinuation because of adverse events. (ClinicalTrials.gov number, NCT00336479.), (2009 Massachusetts Medical Society)

Unlabelled: This prospective, multicenter, community-based and academic-based, open-label, investigator-initiated, U.S. study evaluated efficacy and safety of pegylated interferon (PEG-IFN) alfa-2b plus a flat or weight-based dose of ribavirin (RBV) in adults with chronic hepatitis C. Patients (n = 5027) were randomly assigned to receive PEG-IFN alfa-2b 1.5 microg/kg/week plus flat-dose (800 mg/day) or weight-based (800-1400 mg/day) RBV for 48 weeks (patients with genotype 1, 4, 5, or 6) and for 24 or 48 weeks (genotype 2/3 patients). Primary end point was sustained virologic response (undetectable [<125 IU/mL] serum hepatitis C virus RNA at 24-week follow-up). Sustained virologic response, but not end-of-treatment, rates were significantly higher with weight-based than with flat-dose RBV (44.2% versus 40.5%; P = 0.008). Sustained virologic response rates by intention-to-treat analysis were 34.0% and 28.9%, respectively, in genotype 1 patients (P = 0.005) and 31.2% and 26.7%, respectively, in genotype 1 patients with high baseline viral load (P = 0.056). In genotype 2/3 patients, rates were not significantly different (61.8% and 59.5%, respectively) regardless of treatment duration. Besides greater hemoglobin reductions with weight-based RBV, safety profiles were similar across RBV dosing groups, including the 1400-mg/day group., Conclusion: PEG-IFN alfa-2b plus weight-based RBV is more effective than flat-dose RBV, particularly in genotype 1 patients, providing equivalent efficacy across all weight groups. RBV 1400 mg/day is appropriate for patients 105 to 125 kg. For genotype 2/3 patients, 24 weeks of treatment with flat-dose RBV is adequate; no evidence of additional benefit of extending treatment to 48 weeks was demonstrated.

Unlabelled: WIN-R (Weight-based dosing of pegINterferon alfa-2b and Ribavirin) was a multicenter, randomized, open-label, investigator-initiated trial involving 236 community and academic sites in the United States, comparing response to pegylated interferon (PEG-IFN) alfa-2b plus a flat or weight-based dose of ribavirin (RBV) in treatment-naive patients with chronic hepatitis C and compensated liver disease. Patients were randomized to receive PEG-IFN alfa-2b at 1.5 microg/kg/week plus flat-dose (800 mg/day) or weight-based-dose RBV (800 mg/day for weight <65 kg, 1000 mg/day for 65-85 kg, 1200 mg/day for >85-105 kg, or 1400 mg/day for >105-<125 kg). Sustained virologic response (SVR; undetectable [<125 IU/mL] hepatitis C virus [HCV] RNA at end of follow-up) in patients > or =65 kg was the primary end point. Low SVR rates have been reported among African American individuals, in whom there is a preponderance of HCV genotype 1. This subanalysis of WIN-R was conducted to evaluate the efficacy of weight-based dosing among African American individuals with genotype 1 infection enrolled in the trial. Of 362 African American patients in the primary efficacy analysis, 188 received RBV flat dosing and 174 received weight-based dosing. SVR rates were higher (21% versus 10%; P = 0.0006) and relapse rates were lower (22% versus 30%) in the weight-based-dose group than in the flat-dose group. Safety and rates of drug discontinuation were similar between the 2 groups., Conclusion: Weight-based dosing of RBV is more effective than flat dosing in combination with PEG-IFN alfa-2b in African American individuals with HCV genotype 1. Even with weight-based dosing, response rates in African American individuals are lower than reported in other ethnic groups.

The lower limit of detection of most polymerase chain reaction (PCR) assays for hepatitis C virus (HCV) RNA is 50 IU/ml, compared to 5 IU/ml for the transcription-mediated amplification (TMA) method. We retrospectively reviewed 57 patients to assess the predictive value of a positive TMA in the setting of a negative PCR during antiviral therapy. Patients were divided into (1) PCR-/TMA+ (discordant; n=21) and (2) PCR-/TMA-(concordant; n=36). Sustained virologic response (SVR) was decreased in the discordant group (48% vs. 75%; P=0.04). In discordant patients, SVR was more frequent in patients who had one positive TMA than in those who had two or more positive TMAs or one positive TMA and recurrent HCV RNA detectability by PCR during treatment (78% vs. 25%; P=0.03). Breakthrough occurred more frequently in discordant patients (24% vs. 3%; P=0.02). A positive TMA on two or more occasions in patients who have become PCR-negative on therapy indicates a high likelihood of treatment failure.

Objectives: The efficacy of combination therapy with pegylated interferon (PEG IFN) alpha plus ribavirin (RBV) in the retreatment of chronic hepatitis C (CHC) in patients who previously failed combination standard IFN plus RBV or IFN monotherapy has not been well established., Methods: Three hundred and twenty-one CHC patients including virologic nonresponders to combination IFN plus RBV (n = 219) or IFN monotherapy (n = 47), and relapsers to combination therapy (n = 55) were randomized to receive PEG IFN alpha-2b 1.5 microg/kg per wk plus RBV 800 mg per day (Regimen A, n = 160) or PEG IFN alpha-2b 1.0 microg/kg per wk plus RBV 1,000-1,200 mg per day (Regimen B, n = 161) for 48 wks., Results: Sustained virologic response (SVR) occurred in 16% of the overall study population (Regimen A vs B, 18%vs 13%, p= 0.21), in 8% of the combination therapy nonresponders (10%vs 6%, p= 0.35), in 21% of the IFN monotherapy nonresponders (16%vs 27%, p= 0.35), and in 42% of the combination therapy relapsers (50%vs 32%, p= 0.18). In nonresponders to prior combination therapy, HCV ribonucleic acid levels <100,000 copies/mL at the end of the prior treatment course were associated with an increased SVR compared with levels >or=100,000 copies/mL (21%vs 5%, p= 0.002). In the overall study population, genotype 1 patients had lower SVR rates than others (14%vs 33%, p= 0.01), and African Americans had lower SVR than Caucasians (4%vs 18%, p= 0.01)., Conclusion: Combination therapy with PEG IFN alpha-2b plus RBV is more effective in patients who relapsed after combination standard IFN plus RBV than in nonresponders to either combination therapy or IFN monotherapy. There was no significant effect of dosing regimen.

Background: Interferon-alpha (IFN-alpha) plus ribavirin is used to treat hepatitis C virus (HCV) infection and is associated with a high rate of depression. Newer, pegylated preparations of IFN-alpha have a longer half-life, require once-per-week dosing, and may be associated with reduced neuropsychiatric burden. Limited data exist on depression during pegylated IFN-alpha therapy., Method: Depressive symptoms were assessed using the Zung Self-Rating Depression Scale (SDS) in 162 HCV-infected patients at baseline and after 4, 8, 12, and 24 weeks of treatment with pegylated IFN alpha-2b (PEG IFN) plus weight-based (N = 86) versus standard dose (N = 76) ribavirin. Data were collected from March 2001 to April 2003., Results: Compared with baseline, mean SDS index scores were significantly increased by week 4 and remained elevated throughout the study. Thirty-nine percent of the sample experienced moderate to severe depressive symptoms (SDS index score > or = 60) at some point during PEG IFN/ribavirin therapy. Baseline depression scores significantly predicted severity of depressive symptoms during PEG IFN/ribavirin treatment (simple regression analysis: Y = 0.55X + 32.7, p < .0001). In addition, assignment to weight-based ribavirin treatment and history of depression were associated with increased likelihood of developing moderate to severe depressive symptoms (odds ratio [OR] = 2.7, 95% CI = 1.3 to 5.6, p < .01, and OR = 3.3, 95% CI = 1.3 to 8.1, p < .01, respectively)., Conclusions: Development of moderate to severe depressive symptoms occurred frequently during PEG IFN/ribavirin treatment and was predicted by baseline depression scores and higher doses of ribavirin. History of major depressive disorder was also a significant predictive factor, but only through association with elevated baseline depression status. All of these factors can be evaluated and addressed to limit neuropsychiatric morbidity during HCV treatment.

Interferon (IFN)-alpha plus ribavirin is an effective treatment for hepatitis C virus (HCV) infection, but is associated with a high rate of depression. Depression has been linked to a worse outcome in multiple medical disorders including viral illnesses. We examined whether increased symptoms of depression during IFN-alpha/ribavirin therapy were associated with a reduced treatment response as assessed by clearance of HCV. Depressive symptoms were evaluated in 102 HCV-infected patients at baseline and after 4, 8, 12, and 24 weeks of pegylated IFN-alpha-2b plus ribavirin therapy using the Zung self-rating depression scale (SDS). Viral clearance was determined at 24 weeks by polymerase chain reaction (PCR). Only 34% of subjects (10 out of 29) with a 20-point or greater increase in SDS Index score were HCV PCR negative at 24 weeks, compared to 59% (24 out of 41) of patients with a 10-19 point increase in SDS Index and 69% (22 out of 32) of patients with a less than 10 point increase (chi2=7.6, df=2, p <0.05). In addition, a 20-point or greater increase in SDS Index score during IFN-alpha/ribavirin therapy significantly predicted failure to clear virus when considered alone [crude odds ratio (OR), 3.2; 95% confidence interval (CI), 1.3-8.0; p <0.01] or when controlling for other factors that affected IFN-alpha treatment response (adjusted OR, 3.6; 95% CI, 1.3-9.5; p=0.01). These preliminary findings suggest that individuals who experience significant increases in depressive symptoms during IFN-alpha/ribavirin therapy may be less likely to clear virus, highlighting the importance of identifying and treating depressive symptoms in this patient population.

Objectives: Most studies establishing the role of antiviral therapy in patients with chronic hepatitis C (CHC) excluded the patients with normal ALT levels. Small trials with interferon monotherapy suggested a limited efficacy and/or de novo ALT elevations. We sought to evaluate the efficacy of two doses of interferon alfa-2b (IFN) with ribavirin (RBV) in patients with normal ALT [correction]., Methods: Patients with biopsy-proven CHC with detectable HCV RNA and at least two normal ALT levels three or more months apart were randomized to receive either 3 or 5 million units of IFN thrice a week plus RBV 1,000-1,200 mg. Therapy was stopped at 24 wk if HCV RNA remained detectable and continued for an additional 24 wk if HCV RNA was undetectable. A final HCV RNA level was obtained 24 wk after discontinuation of therapy., Results: Fifty-six patients were randomized and received at least one dose of treatment. The overall rate of sustained virologic response (SVR) was 32%. SVR rates were higher in genotype 2 and 3 patients (80%) than in genotype 1 patients (24%, p = 0.002). There was a tendency toward higher SVR in genotype 1 patients treated with the higher IFN dose (36%vs 10%, p = 0.07). Five patients had mild, transient ALT elevations. No sustained ALT elevations were noted., Conclusions: Patients with normal ALT had a rate of SVR comparable to that reported in patients with elevated ALT. Higher dose of interferon tended to be more effective in genotype 1 infected patients. De novo ALT elevations were transient and not clinically significant. Patients with CHC should not be excluded from treatment on the basis of ALT alone. Combination therapy with pegylated interferon and ribavirin should be evaluated in these patients.