Improvement in hepatic fibrosis estimated by Fibrosis-4 index in pegloticase treated chronic refractory gout patients.

OBJECTIVES: To determine whether lowering serum urate (SU) affects the course of non-alcoholic fatty liver disease (NAFLD). METHODS: Retrospective data analysis from chronic refractory gout patients who participated in two 6-month pegloticase randomised clinical trials compared patients who received pegloticase biweekly to those who received placebo. Patients with persistent urate-lowering to <1 mg/dL in response to biweekly pegloticase (responders, n=36) were compared to those who received placebo (n=43). NAFLD was assessed using the Fibrosis-4 (Fib-4) index. Comparisons between groups were carried out using 2 sample Wilcoxon tests or regression analysis. RESULTS: At baseline the mean (standard deviation [SD]) Fib-4 values were 1.40 (0.86) in pegloticase responders, and 1.04 (0.53) in patients receiving placebo. Patients receiving placebo exhibited a change of 0.26 (0.41) in Fib-4 score over 6 months vs 0.13 (0.62) for pegloticase responders (p=0.048). When only patients with a Fib-4 value >1.3 were considered (n=27), a significant difference in the change in the Fib-4 values between pegloticase responders vs. placebo was observed (-0.15 [0.67] vs. 0.7 [0.42], p=0.04). The correlation between the SU area under the curve (AUC) over the 6-month trial period and the change in Fib-4 value was R=0.33 (p=0.0004). Multivariable analysis indicated SU AUC was the only significant contributor to the change in Fib-4 values (p=0.018). CONCLUSIONS: Persistent lowering of SU significantly reduced Fib-4 scores, implying a possible effect on NAFLD progression. These results support the consideration of a complete analysis of the impact of profound urate-lowering on NAFLD as measured by the Fib-4 index.

Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study.

OBJECTIVE: To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin. DESIGN: In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNA

Viral clearance is associated with improved insulin resistance in genotype 1 chronic hepatitis C but not genotype 2/3.

OBJECTIVES: Genotype-specific associations between hepatitis C virus (HCV) and insulin resistance (IR) have been described, but a causal relationship remains unclear. This study investigated the association between a sustained virological response (SVR) and IR after chronic HCV therapy. METHODS: 2255 treatment-naive patients with chronic HCV genotype 1 or 2/3 were enrolled in two phase 3 trials of albinterferon alpha-2b versus pegylated interferon alpha-2a for 48 or 24 weeks, respectively. IR was measured before treatment and 12 weeks after treatment using homeostasis model assessment (HOMA)-IR. RESULTS: Paired HOMA-IR measurements were available in 1038 non-diabetic patients (497 with genotype 1; 541 with genotype 2/3). At baseline the prevalence of HOMA-IR >3 was greater in patients with genotype 1 than 2/3 (33% vs 27%; p=0.048). There was a significant reduction in the prevalence of IR in patients with genotype 1 achieving SVR (δ 10%; p<0.001), but not in genotype 1 non-responders or those with genotype 2/3. Multivariate analysis indicated that SVR was associated with a significant reduction in mean HOMA-IR in patients with genotype 1 (p=0.004), but not in those with genotype 2/3, which was independent of body mass index, alanine transaminase, γ-glutamyl transpeptidase and lipid level changes. CONCLUSIONS: SVR is associated with a reduction in HOMA-IR in patients with HCV genotype 1 but not in those with genotype 2/3. Genotype 1 may have a direct effect on the development of IR, independent of host metabolic factors, and may be partially reversed by viral eradication.

Balapiravir plus peginterferon alfa-2a (40KD)/ribavirin in a randomized trial of hepatitis C genotype 1 patients.

INTRODUCTION: Balapiravir (R1626, RG1626) is the prodrug of a nucleoside analogue inhibitor of the hepatitis C virus (HCV) RNA-dependent RNA polymerase (R1479, RG1479). This phase 2, double-blind international trial evaluated the optimal treatment regimen of balapiravir plus peginterferon alfa-2a (40KD)/ribavirin. MATERIAL AND METHODS: Treatment-naive genotype 1 patients (N = 516) were randomized to one of seven treatment groups in which they received balapiravir 500, 1,000, or 1,500 mg twice daily, peginterferon alfa-2a (40KD) 180 or 90 µg/week and ribavirin 1,000/1,200 mg/day or peginterferon alfa-2a (40KD)/ribavirin. The planned treatment duration with balapiravir was reduced from 24 to 12 weeks due to safety concerns. RESULTS: The percentage of patients with undetectable HCV RNA was consistently higher in all balapiravir groups from week 2 to 12. However, high rates of dose modifications and discontinuations of one/all study drugs compromised the efficacy assessment and resulted in similar sustained virological response rates in the balapiravir groups (range 32-50%) and the peginterferon alfa-2a (40KD)/ribavirin group (43%). Balapiravir was discontinued for safety reasons in 28-36% of patients (most often for lymphopenia) and the percentage of patients with serious adverse events (especially hematological, infection, ocular events) was dose related. Serious hematological adverse events (particularly neutropenia, lymphopenia) were more common in balapiravir recipients. Two deaths in the balapiravir/peginterferon alfa-2a/ribavirin combination groups were considered possibly related to study medication. CONCLUSION: Further development of balapiravir for the treatment of chronic hepatitis C has been halted because of the unacceptable benefit to risk ratio revealed in this study (www.ClinicalTrials.gov NCT 00517439).

Albinterferon Alfa-2b was not inferior to pegylated interferon-α in a randomized trial of patients with chronic hepatitis C virus genotype 1.

BACKGROUND & AIMS: The current standard of care for patients with chronic hepatitis C virus (HCV) genotype 1 is once-weekly pegylated interferon-α (Peg-IFNα) plus daily ribavirin for 48 weeks. We evaluated the efficacy/safety of albinterferon alfa-2b (albIFN), a novel, long-acting, genetic fusion polypeptide of albumin and IFNα-2b. METHODS: In the phase 3 ACHIEVE-1 trial, 1331 patients were assigned equally to 3 open-label, 48-week treatment groups: Peg-IFNα-2a 180 µg every week, or albIFN 900 or 1200 µg every 2 weeks administered subcutaneously, with weight-based oral ribavirin 1000-1200 mg/day. During the study, the data monitoring committee recommended dose modification for all patients receiving albIFN 1200 µg to 900 µg because of increased pulmonary adverse events (AEs) in the 1200-µg arms of both ACHIEVE studies. Main outcome measure was sustained virologic response (SVR; undetectable serum HCV RNA at week 72). RESULTS: Intention-to-treat SVR rates were 51.0% (225/441), 48.2% (213/442), and 47.3% (208/440) with Peg-IFNα-2a, and albIFN 900 and 1200 µg, respectively. The primary objective of showing noninferiority of albIFN 900 µg (P < .001) and 1200 µg (P = .003) vs Peg-IFNα-2a for SVR was achieved. Multivariate modeling indicated consistency of treatment effect across subgroups. Serious/severe AE rates were 23.1%, 24.0%, 28.2%; treatment discontinuation rates because of AEs were 4.1%, 10.4%, 10.0%; discontinuation rates because of respiratory AEs were 0%, 0.9%, 1.6%; with Peg-IFNα-2a, and albIFN 900 and 1200 µg, respectively. Hematologic abnormality rates were comparable across the Peg-IFNα-2a and albIFN 900-µg groups. CONCLUSIONS: albIFN 900 µg every 2 weeks showed comparable efficacy, with similar serious/severe AE rates, although with a higher discontinuation rate, vs Peg-IFNα-2a in patients with chronic HCV genotype 1.

Seizures during pegylated interferon and ribavirin therapy for chronic Hepatitis C: observations from the WIN-R trial.

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.

Merimepodib, pegylated interferon, and ribavirin in genotype 1 chronic hepatitis C pegylated interferon and ribavirin nonresponders.

UNLABELLED: Merimepodib (MMPD) is an orally administered, inosine monophosphate dehydrogenase inhibitor that has shown antiviral activity in nonresponders with chronic hepatitis C (CHC) when combined with pegylated interferon alfa 2a (Peg-IFN-alfa-2a) and ribavirin (RBV). We conducted a randomized, double-blind, multicenter, phase 2b study to evaluate the antiviral activity, safety, and tolerability of MMPD in combination with Peg-IFN-alfa-2a and RBV in patients with genotype 1 CHC who were nonresponders to prior therapy with Peg-IFN and RBV. Patients received 50 mg MMPD, 100 mg MMPD, or placebo every 12 hours, in addition to Peg-IFN-alfa-2a and RBV, for 24 weeks. Patients with a 2-log or more decrease from baseline or undetectable hepatitis C virus (HCV) RNA levels at week 24 were then eligible to continue Peg-IFN-alfa-2a and RBV for a further 24 weeks, followed by 24 weeks of follow-up. The primary efficacy endpoint was sustained virological response (SVR) rate at week 72 in all randomized patients who received at least one dose of study drug and had a history of nonresponse to standard therapy. A total of 354 patients were randomized to treatment (117 to placebo; 119 to 50 mg MMPD; 118 to 100 mg MMPD), and 286 completed the core study. The proportion of patients who achieved SVR was similar among the treatment groups: 6% (6/107) for 50 mg MMPD, 4% (5/112) for 100 mg MMPD, and 5% (5/104) for placebo (P = 0.8431). Adverse-event profiles for the MMPD combination groups were similar to that for Peg-IFN-alfa and RBV alone. Nausea, arthralgia, cough, dyspnea, neutropenia, and anemia were more common in patients taking MMPD. CONCLUSION: The addition of MMPD to Peg-IFN-alfa-2a and RBV combination therapy did not increase the proportion of nonresponder patients with genotype 1 CHC achieving an SVR.

Thymalfasin for the treatment of chronic hepatitis C infection.

The purpose of this review article is to examine previous and ongoing studies of thymalfasin in combination with peginterferon-alpha2a and peginterferon-alpha2a plus ribavirin in difficult-to-treat hepatitis C virus (HCV) patients. The following studies will be reviewed in detail: (1) Sherman and colleagues conducted a study in 109 HCV RNA positive HVC patients comparing the combination of thymalfasin + IFN versus IFN alone versus placebo. (2) Rustgi et al. evaluated the efficacy and safety of thymalfasin and peg-IFN-alpha2a in 31 genotype 1, high viral load, HCV nonresponders in a 12-week viral kinetic study. (3) Di Bisceglie, Sherman et al. performed a study of previous HCV nonresponders being retreated with either peginterferon-alpha2a plus thymalfasin or peginterferon-alpha2a plus placebo. (4) Poo and colleagues in Mexico evaluated triple combination therapy using thymalfasin, peginterferon-alpha2a, and ribavirin for the treatment of Hispanic HCV nonresponders.

Randomized study of asunaprevir plus pegylated interferon-α and ribavirin for previously untreated genotype 1 chronic hepatitis C.

BACKGROUND: Asunaprevir is a selective NS3 protease inhibitor with in vitro activity against HCV genotypes 1 and 4. METHODS: In this Phase IIa double-blind study, treatment-naive HCV genotype-1-infected patients in the United States and France were randomly assigned 1:1:1:1 to placebo or asunaprevir 200 mg twice daily, 600 mg twice daily or 600 mg once daily in combination with pegylated interferon (PEG-IFN)-α2a and ribavirin for 48 weeks. The primary efficacy end point was undetectable HCV RNA at weeks 4 and 12 (extended rapid virological response [eRVR]). Other end points included safety and undetectable HCV RNA at 24 weeks post-treatment (24-week sustained virological response [SVR24]). RESULTS: A total of 47 patients were randomized and treated. eRVR was achieved by 75% (9/12), 75% (9/12) and 92% (11/12) of patients in the asunaprevir 200 mg twice-daily, 600 mg twice-daily and 600 mg once-daily groups, respectively, versus 0% (0/11) in the placebo group. Corresponding SVR24 rates were 83% (10/12), 83% (10/12) and 92% (11/12) in the asunaprevir groups and 46% (5/11) in the placebo group. There was no virological breakthrough in any asunaprevir group. Following the 12-week analysis, the 600 mg doses were reduced to 200 mg twice daily because of a greater frequency of transaminase elevations at the 600 mg dose. The most common grade 3-4 laboratory abnormalities were consistent with those reported for PEG-IFN and ribavirin. CONCLUSIONS: Asunaprevir plus PEG-IFN and ribavirin achieved higher response rates than placebo plus PEG-IFN and ribavirin, with a tolerable adverse event profile at the 200 mg twice-daily dose. This dose is being evaluated in the Phase IIb and Phase III studies.

Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial.

BACKGROUND: Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV. METHODS: In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 µg per week) and ribavirin (1000-1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with ClinicalTrials.gov, number NCT00874770. FINDINGS: 48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22-64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61-96%) who received 10 mg daclatasvir, nine of 12 (75%, 53-90%) who received 60 mg daclatasvir, and one of 12 (8%, 1-29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups. INTERPRETATION: Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection. FUNDING: Bristol-Myers Squibb.

Safety of small molecules in combination with interferon-based therapy for hepatitis C virus.

IMPORTANCE OF THE FIELD: HCV is a leading cause of liver disease in the US, where ~3.4 million people are chronically infected. The standard of care (SOC) of pegylated IFN and ribavirin combination therapy has limited efficacy with ~50% sustained viral response, and is associated with a considerable adverse event profile in many patients. New drugs that directly target the virus are in development, and promise more effective therapies for chronic HCV infection. AREAS COVERED IN THIS REVIEW: Patient sub-classes with poor prognosis with SOC are identified, as are their associated adverse event profiles. Novel drugs, known as specifically targeted antiviral therapy for HCV (STAT-C), are currently being evaluated in clinical trials in multidrug combinations. Emerging safety signals and strategies to identify and prevent viral resistance to STAT-C drugs are also addressed. WHAT THE READER WILL GAIN: How the multidrug combinations are being developed and tested, what their relative strengths and weakness are, and which patient groups will benefit the most. TAKE HOME MESSAGE: The central questions to successful multidrug combination therapies including novel small molecules will be their composite safety and efficacy profiles. Carefully conducted clinical trials and timely updates will be needed for ongoing improvements in patient care.