Sofosbuvir for previously untreated chronic hepatitis C infection.

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.).

Faldaprevir, pegylated interferon, and ribavirin for treatment-naïve HCV genotype-1: pooled analysis of two phase 3 trials.

INTRODUCTION & AIM: Faldaprevir is a potent once-daily (q.d.) hepatitis C virus (HCV) NS3/4A protease inhibitor. The STARTVerso1 and STARTVerso2 phase 3 studies evaluated faldaprevir plus peginterferon alfa-2a/ribavirin (PegIFN/RBV) in treatment-naïve patients with chronic HCV genotype-1 infection. MATERIAL AND METHODS: Patients were randomized 1:2:2 to receive placebo, faldaprevir 120 mg q.d. (12 or 24 weeks) or faldaprevir 240 mg q.d. (12 weeks) all with PegIFN/RBV (24-48 weeks). Faldaprevir 120 mg for 12 weeks only (STARTVerso1 only) required early treatment success (ETS, HCV RNA < 25 IU/mL at week 4 and undetected at week 8). All faldaprevir-treated patients with ETS stopped PegIFN/RBV at week 24. Primary endpoint: sustained virologic response 12 weeks post-treatment (SVR12). RESULTS: SVR12 rates were significantly higher for patients treated with faldaprevir 120 or 240 mg (72% and 73%, respectively) compared with placebo (50%); estimated differences (adjusted for trial, race, and genotype-1 subtype) faldaprevir 120 mg 24% (95% CI: 17-31%, P < 0.0001), faldaprevir 240 mg 23% (95% CI: 16-30%, P < 0.0001). Subgroup analyses consistently showed higher SVR12 rates for patients receiving faldaprevir compared with placebo. The incidence of adverse events (AEs) was similar in faldaprevir 120-mg and placebo groups and slightly higher in the faldaprevir 240-mg group. Serious Aes were reported in 6%, 7%, and 8% of patients in placebo, faldaprevir 120-mg, and faldaprevir 240-mg groups, respectively. CONCLUSION: Addition of faldaprevir to PegIFN/RBV increased SVR12 in patients with HCV genotype-1, and was well tolerated. Faldaprevir 120 mg is effective in the treatment of HCV genotype-1. ClinicalTrials.gov: NCT01343888 and NCT01297270.

A randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection.

BACKGROUND & AIMS: Peginterferon lambda-1a (Lambda) is a type-III interferon with similar antiviral activity to alfa interferons but with a diminished extrahepatic receptor distribution, reducing the risk for extrahepatic adverse events. METHODS: This was a randomized, blinded, actively-controlled, multicentre phase 2b dose-ranging study in patients chronically infected with HCV genotypes 1-4. Treatment-naive patients received Lambda (120/180/240 µg) or peginterferon alfa-2a (alfa; 180 µg) once-weekly with ribavirin for 24 (genotypes [GT] 2,3) or 48 (GT1,4) weeks. RESULTS: Rates of undetectable HCV-RNA at week 12 (complete early virologic response [cEVR]; primary end point) were significantly higher in GT1,4 patients receiving Lambda vs. alfa (170/304, 56% vs. 38/103, 37%); with similar cEVR rates for GT2,3 (80/88, 91% vs. 26/30, 87%). Rates of undetectable HCV-RNA at week 4 were significantly higher on 180 µg (15/102, 15% GT1,4; 22/29, 76% GT2,3) and 240 µg (17/104, 16% GT1,4; 20/30, 67% GT2,3) Lambda than alfa (6/103, 6% GT1,4; 9/30, 30% GT2,3). Sustained virologic responses (post-treatment week 24) were comparable between Lambda and alfa for GT1,4 (37-46% Lambda; 37% alfa) and GT2,3 (60-76% Lambda; 53% alfa). Aminotransferase and/or bilirubin elevations were the primary dose-limiting abnormalities for Lambda; a sponsor-mandated 240 to 180 µg dose reduction was therefore implemented. Serious adverse events were comparable (3-13% Lambda; 3-7% alfa). Grade 3-4 haemoglobin, neutrophil, and platelet reductions were lower on Lambda than alfa. Among alfa patients, 28/133 (21%) had peginterferon and 31/133 (23%) had ribavirin dose reductions for haematologic abnormalities vs. 0/392 and 8/392 (2%) on Lambda. Lambda demonstrated fewer musculoskeletal (16-28% vs. 47-63%) and influenza-like events (8-23% vs. 40-46%) than alfa. CONCLUSION: Lambda was associated with improved or similar rates of virologic response with fewer extrahepatic adverse events than alfa in chronic HCV infection.

Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial.

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.

Persistent neurocognitive decline in a clinic sample of hepatitis C virus-infected persons receiving interferon and ribavirin treatment.

Treatment of hepatitis C virus (HCV) with pegylated interferon and ribavirin (IFN/RBV) can be associated with neuropsychiatric side effects, which may necessitate dose reductions or treatment discontinuation. This study aimed to characterize the time course and predictors of cognitive and affective/mood symptoms after IFN/RBV treatment initiation. Forty individuals enrolled in a longitudinal project underwent comprehensive cognitive, medical, and psychiatric assessment at baseline and 10 weeks, 6 months, 12 months, and 18 months after treatment initiation. Analyses were conducted to determine the prevalence of neurocognitive impairment over time; explicate the relationship between neurocognitive impairment, neuropsychiatric symptoms, and liver disease at each time point; and identify predictors of neurocognitive decline as well as cognitive effects of viral clearance. By 10 weeks after initiating IFN/RBV, the prevalence of neurocognitive impairment rose from 22.5 to 47.4% (p < 0.05). Infection with genotype 1 and premorbid depression were associated with more severe declines (p < 0.05). After 18 months, 42.5% remained neurocognitively impaired, independent of viral clearance, severity of liver disease, and current depressive symptoms. Undetectable viral load was not associated with improvement 18 months after initiating treatment (p > 0.10). Results of the current study indicate that IFN/RBV treatment-emergent neurocognitive declines are significant, prevalent, and may persist long after treatment cessation. Clinicians should monitor cognition throughout the course of treatment for HCV, noting that early declines may indicate individuals at elevated risk for persistent neurocognitive impairment. Longer-term studies are needed to determine whether lasting declines may remit over longer intervals or with newer direct acting agents.

Peginterferon alfa-2a plus ribavirin for HIV-HCV genotype 1 coinfected patients: a randomized international trial.

BACKGROUND: The safety and efficacy of weight-based ribavirin (RBV) dosing regimens in patients with HIV-HCV coinfection has not been demonstrated in randomized clinical trials. OBJECTIVE: This randomized, double-blind, international, parallel-group study in specialist outpatient clinics in the United States, Spain, and Portugal compares the efficacy and safety of 2 RBV dose regimens (800 mg/day and 1000/1200 mg/day) combined with peginterferon alfa-2a (40KD) in patients with HIV-HCV (genotype 1) coinfection. METHODS: Patients with HIV-HCV coinfection, quantifiable HCV RNA in serum, HCV genotype-1 infection, compensated liver disease, and stable HIV disease (CD4+ count ≥100 cells/µL) with or without ongoing antiretroviral therapy were randomized to 48 weeks' treatment with RBV at standard dose (800 mg/day) or weight-based dose (1000 mg/day for patients weighing <75 kg; 1200 mg/day for patients weighing ≥75 kg) in combination with peginterferon alfa-2a (40KD) 180 µg once a week. Planned enrollment was 400 patients with ≥100 non-Latino African Americans. The primary endpoint was sustained virological response (SVR) (undetectable HCV RNA [<20 IU/mL] at the end of a 24-week untreated follow-up period [week 72]). RESULTS: SVR rates were 19% (26/135) and 22% (60/275) in patients randomized to RBV 800 mg/day and 1000/1200 mg/day, respectively (odds ratio, 1.15; 95% CI, 0.68-1.93; P = .6119). In the 1000/1200 mg/day RBV dose group, the incidence of hemoglobin reductions <100 g/L and anaemia reported as an adverse event were higher versus the standard 800 mg/day RBV dose group. CONCLUSIONS: Compared with the standard RBV dose (800 mg/day), weight-based RBV dosing (1000/1200 mg/day) did not significantly increase SVR rates, but did increase the incidence of anemia in HIV-HCV (genotype 1) coinfected patients.

Association of host pharmacodynamic effects with virologic response to pegylated interferon alfa-2a/ribavirin in chronic hepatitis C.

UNLABELLED: Patients receiving therapy for chronic hepatitis C virus (HCV) infection frequently experience cytopenias and weight loss. We retrospectively assessed the pharmacodynamic effects of pegylated interferon (PEG-IFN) alfa-2a and ribavirin by evaluating the relationship between changes in hematologic parameters, body weight, and virologic response. Patients with HCV genotypes 1, 4, 5, or 6 receiving 24 or 48 weeks of PEG-IFN alfa-2a and ribavirin therapy were pooled from four phase 3/4 trials. Maximum decreases in hemoglobin level, neutrophil count, platelet count, and weight during therapy were assessed according to virologic response category (sustained virologic response [SVR], relapse, breakthrough, and nonresponder) and race/ethnicity. Of 1,778 patients analyzed, more than half were male, non-Hispanic Caucasian, and infected with HCV genotype 1; had a baseline HCV RNA >800,000; and had alanine aminotransferase levels ≤3 × the upper limit of normal. Virologic responders (SVR, relapse, and breakthrough) experienced greater maximum decreases from baseline in hemoglobin level, neutrophil count, platelet count, and weight compared with nonresponders; however, no clear trend was observed between SVR, relapse, and breakthrough. After adjusting for drug exposure and treatment duration, only decreases in neutrophil count remained associated with virologic response. Significantly greater declines in neutrophil (P < 0.0001) and platelet (P < 0.005) count were observed at weeks 4, 12, and 24 of therapy in virologic responders compared with nonresponders. This difference between responders and nonresponders was also observed among racial/ethnic groups, although statistical significance was not consistent across all groups. CONCLUSION: This post hoc analysis of HCV patients treated with PEG-IFN alfa-2a and ribavirin shows that maximum decreases from baseline in hematologic parameters and weight loss were associated with virologic response. However, after adjusting for drug exposure and accounting for duration of therapy, only neutropenia was independently associated with virologic response.

Virologic response rates of weight-based taribavirin versus ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C.

UNLABELLED: Ribavirin-induced hemolytic anemia can prompt dose reductions and lower sustained virologic response (SVR) rates in the treatment of patients with chronic hepatitis C. The study aimed to determine if weight-based dosing of taribavirin (TBV), an oral prodrug of ribavirin (RBV), demonstrated efficacy comparable to RBV while maintaining its previously demonstrated anemia advantage with fixed dose administration. A U.S. phase 2b randomized, open-label, active-controlled, parallel-group study was conducted in 278 treatment-naive patients infected with genotype 1 who were stratified by body weight and baseline viral load. Patients were randomized 1:1:1:1 to receive TBV (20, 25, or 30 mg/kg/day) or RBV (800-1400 mg/day) with pegylated interferon alfa-2b for 48 weeks. The SVR rates in this difficult-to-cure patient demographics (mean age, 49 years; 61% male; 30% African American or Latino; high viral load; advanced fibrosis; and mean weight, 82 kg) were 28.4%, 24.3%, 20.6%, and 21.4% in the 20, 25, and 30 mg/kg TBV groups and the RBV group, respectively. There were no statistical differences in the efficacy analyses. Anemia rates were significantly lower (P < 0.05) in the 20 and 25 mg/kg/day TBV treatment groups (13.4% and 15.7%, respectively) compared to RBV (32.9%). The most common adverse events in all groups were fatigue, diarrhea, and insomnia. Diarrhea, reported in 38% of TBV patients versus 21% of RBV patients, was generally mild and not dose-limiting. CONCLUSION: All TBV doses demonstrated efficacy and tolerability comparable to that of RBV; however, the 25 mg/kg dose demonstrated the optimal balance of safety and efficacy. Anemia rates were significantly lower for TBV given at 20-25 mg/kg than RBV. These data suggest weight-based dosing with TBV provides a safe and effective treatment alternative to RBV for chronic hepatitis C. American Association for the Study of Liver Diseases.

Retreating chronic hepatitis C with daily interferon alfacon-1/ribavirin after nonresponse to pegylated interferon/ribavirin: DIRECT results.

UNLABELLED: Up to 50% of patients with chronic hepatitis C fail to respond to initial therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV). With unsuccessful viral eradication, these patients remain at risk for developing progression of their liver disease. Retreatment with PEG-IFN/RBV yields sustained virologic response (SVR) rates that are under 10%. A wholly synthetic interferon, interferon alfacon-1 or consensus interferon (CIFN) given with RBV, was evaluated in patients who failed initial PEG-IFN/RBV therapy. The intent-to-treat analysis included 487 patients; 245 received CIFN 9 microg/day and RBV, and 242 received CIFN 15 microg/day and RBV. Within this group of patients, 59.3% had documented advanced fibrosis at baseline liver biopsy (stage F3 or F4). SVR rates were 6.9% (17/245 patients) in the 9 microg group and 10.7% (26/242) in the 15 microg group. In the intent-to-treat analysis, SVR rates were higher among patients with a >2-log(10) decrease in hepatitis C virus RNA during prior PEG-IFN/RBV therapy: 11% (4/38) in the 9 mug group and 23% (7/31) in the 15 microg group. Among patients with lower baseline fibrosis scores (F0-F3), SVR rates were 7.8% (15/192) in the 9 microg group and 13.1% (23/175) in the 15 microg group. In this same group of patients (F0-F3), if a >2-log(10) decrease in hepatitis C virus RNA with previous PEG-IFN/RBV treatment was achieved, SVR rates improved to 10.7% and 31.6% in the 9 microg and 15 microg groups, respectively. CIFN/RBV combination retreatment was safe and well tolerated. CONCLUSION: Retreatment of PEG-IFN and RBV nonresponders with CIFN and RBV is safe and efficacious and can be considered a retreatment strategy for patients failing previous therapy with PEG-IFN/RBV, especially in interferon-sensitive patients with lower baseline fibrosis scores.

Impact of Safety-Related Dose Reductions or Discontinuations on Sustained Virologic Response in HCV-Infected Patients: Results from the GUARD-C Cohort.

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced ≥1 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with ≥1 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not ≥5. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin.

Ritonavir-boosted danoprevir-based regimens in treatment-naive and prior null responders with HCV genotype 1 or 4 and compensated cirrhosis.

BACKGROUND AND AIM: Effective and safe antiviral treatment regimens are needed for patients with chronic hepatitis C (CHC) and cirrhosis. METHODS: An international open-label trial was conducted in CHC patients with genotype (G)1/4 infection, compensated cirrhosis, HCV RNA ≥ 50,000 IU/mL and body mass index 18-35 kg/m(2). Treatment-naive patients (Cohort 1) received a triple therapy regimen [danoprevir/r 100/100 mg twice daily (bid), ribavirin 1000/1200 mg/day and peginterferon alfa-2a 180 µg/week] for 24 weeks. Prior null responders (Cohort 2) received a quadruple therapy regimen (danoprevir/r 100/100 mg bid, mericitabine 1000 mg bid and peginterferon alfa-2a/ribavirin). The primary efficacy outcome was sustained virological response (HCV RNA < limit of quantification, target not detected) at end of the 24-week follow-up period (SVR24). RESULTS: In Cohort 1 (n = 23), 73.9 and 65.2 % of patients had a virological response at Weeks 4 and 24, respectively; 39.1 % achieved SVR24 (G1a = 1/13; G1b = 8/9; G4 = 0/1). In Cohort 2 (n = 20), 100 % achieved virological response at Weeks 4 and 24; 65 % achieved SVR24 (G1a = 4/8; G1b = 7/10; G4 = 2/2). Treatment failure was more common in G1a than G1b-infected patients and less common in patients receiving quadruple therapy. Treatment failure was associated with emergence of resistance to danoprevir, but not mericitabine. The safety profile was typical of that associated with peginterferon alfa-2a/ribavirin. No deaths/episodes of hepatic decompensation occurred. CONCLUSIONS: Treatment with danoprevir/r-based regimens for 24 weeks is safe and well tolerated in CHC patients with compensated cirrhosis. A quadruple therapy regimen (danoprevir/r, mericitabine, peginterferon alfa/ribavirin) produced high SVR24 rates in prior null responders, particularly among G1b patients.

Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial.

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.

Randomized trial comparing dose reduction and growth factor supplementation for management of hematological side effects in HIV/hepatitis C virus patients receiving pegylated-interferon and ribavirin.

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.

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

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The molecular adsorbents recycling system as a liver support system based on albumin dialysis: a summary of preclinical investigations, prospective, randomized, controlled clinical trial, and clinical experience from 19 centers.

Artificial liver support aims to prolong survival time of patients with liver failure by detoxification. Albumin as a molecular adsorbent in dialysis solution is capable of attracting even tightly albumin-bound toxins from blood into the dialysate if a specific dialysis membrane is used and if the albumin's binding sites are on-line-purified by a sorbent/dialysis-based recycling system (i.e., molecular adsorbents recycling system, or MARS). The MARS technology has been shown to remove water-soluble and albumin-bound toxins and to provide renal support in case of renal failure. Fourteen centers have reported that MARS treatment improved mental status of patients with liver failure and hepatic encephalopathy. In treating liver failure and cholestasis, MARS was associated with hemodynamic stabilization, improvement of hepatic and kidney function, and disappearance of pruritus. In hepatic failure and hepatorenal syndrome, a prospective, randomized, controlled trial of MARS treatment was able to prolong survival time significantly. MARS has been used in 26 patients with acute liver failure or primary graft dysfunction. Nineteen centers reporting on 103 patients have shown that MARS treatment is safe, easy to handle, feasible, and effective.

The impact of peginterferon alfa-2a plus ribavirin combination therapy on health-related quality of life in chronic hepatitis C.

BACKGROUND/AIMS: Peginterferon alfa-2a plus ribavirin improves sustained virological responses compared with interferon alfa-2b and ribavirin, or peginterferon alfa-2a alone in chronic hepatitis C. We examined the impact of these treatments on health related quality of life (HRQOL). METHODS: Patients (n=1121) were randomized to peginterferon alfa-2a weekly plus ribavirin or placebo, or interferon alfa-2b thrice weekly plus ribavirin. HRQOL was assessed with the SF-36 Health Survey and Fatigue Severity Scale (FSS). RESULTS: Patients receiving peginterferon alfa-2a plus ribavirin reported better HRQOL than those receiving interferon alfa-2b plus ribavirin. These differences were statistically significant for three SF-36 domains and both FSS scores (p<=0.05). Patients receiving peginterferon alfa-2a plus placebo had the least impairment; adding ribavirin significantly decreased five domains of the SF-36 and both FSS scores. Sustained virological response was associated with improvement at follow-up on all SF-36 and FSS scores. CONCLUSIONS: The effects of combination therapy on HRQOL and fatigue are less with peginterferon alfa-2a plus ribavirin than interferon alfa-2b plus ribavirin. Each medication in combination therapy with interferon and ribavirin, affects patients' quality of life differently. Understanding the relationship of specific therapeutic options to HRQOL may help physicians minimize the impact of therapy on HRQOL.