A Randomized Controlled Trial Adding Fluvastatin to Peginterferon and Ribavirin for Naïve Genotype 1 Hepatitis C Patients

T. Bader; L. D. Hughes; J. Fazili; B. Frost; M. Dunnam; A. Gonterman; M. Madhoun; C. E. Aston

Disclosures

J Viral Hepat. 2013;20(9):622-627. 

In This Article

Abstract and Introduction

Abstract

Fluvastatin or simvastatin has demonstrable antiviral activity against hepatitis C virus (HCV) as monotherapy. The safety and efficacy of adding fluvastatin or simvastatin to peginterferon/ribavirin for 48 weeks was tested in HCV genotype 1 naïve-to-treatment veterans. Thirty-seven naïve-to-treatment genotype 1 HCV patients were randomized to either a control group (n = 20) to receive peginterferon alfa plus ribavirin or an experimental group (n = 18) to similarly receive peginterferon alfa plus ribavirin as well as fluvastatin 20 mg/day. In addition, seven patients who presented for HCV treatment already were on simvastatin and could not be withdrawn. These simvastatin users were not randomized but were entered into a concurrent prospective pilot arm. There were no unique safety issues with fluvastatin or simvastatin when these drugs were given with peginterferon/ribavirin for 48 weeks. Thirteen of 25 statin patients achieved sustained viral response (SVR), while 5 of 20 control patients achieved SVR. Analysis of SVR by intention-to-treat showed P = 0.078. In this phase 2 study, there were no safety issues with the addition of fluvastatin or simvastatin to peginterferon and ribavirin for 48 weeks. There was a trend towards improvement in SVR when fluvastatin or simvastatin was administered with peginterferon/ribavirin. The size of the groups did not reach the prestudy size thought needed to show significant difference (type II error). These results support the significant results of two other larger randomized controlled trials reported using the same dose of fluvastatin in naïve-to-treatment genotype 1 HCV patients.

Introduction

Brown and Goldstein won the Nobel Prize in 1985 for their work on isolating and characterizing low-density lipoprotein (LDL). Brown and Goldstein also were the first to suggest that a statin, lovastatin, possessed an anti-HCV effect in a hepatitis C virus (HCV) replicon culture system.[1] Ikeda et al.[2] then performed an in vitro dose vs antiviral effect for all available statins. They reported that fluvastatin had the strongest anti-HCV activity.

Under a phase 1 Food and Drug Administration (FDA), USA licence, we previously were able to demonstrate an antiviral dose for fluvastatin in humans infected with chronic hepatitis C virus.[3] The FDA-approved doses of fluvastatin for use against hypercholesterolaemia are 20–80 mg/day. As Ikeda et al. had suggested that higher concentrations of statin in vitro possessed more anti-HCV activity, we tested doses up to 4 × the upper limit approved by the FDA for hypercholesterolaemia (i.e. 320 mg/day). Paradoxically, we determined that the lowest approved dose of fluvastatin, 20 mg/day, was the most active anti-HCV dose in humans when used as monotherapy. The anti-HCV effect with fluvastatin monotherapy is modest with decrements of HCV RNA in the range of 0.5–1.0 logs. It usually lasts a few days to a few weeks, although one patient experienced a 3-log HCV RNA drop 1 year later.[3] For comparison, this direct antiviral effect of fluvastatin monotherapy is significantly stronger and longer-lasting than the direct antiviral effect of ribavirin used alone.[4,5]

Our phase 1 FDA monotherapy trials of statins in patients with chronic HCV did not show safety problems. Specifically, we did not note any symptomatic or laboratory evidence of myopathy, although our numbers were small (n = 50). Unexpectedly, we saw uniform improvement in abnormal alanine aminotransferase (ALT) values that often normalized and lasted the duration of the statin use.[3,6]

The primary purpose of this phase 2 FDA-licensed trial was to examine safety issues occurring when fluvastatin was combined with peginterferon/ribavirin over 48 weeks. Phase 2 trials are small so as to limit exposure of subjects and not sized to prove efficacy as in the case of phase 3 trials. The FDA does not require randomization of subjects for phase 2 trials, but reviewers permit it. We randomized the cohort to better compare the development of safety issues. A secondary prestudy goal was to evaluate efficacy by intention-to-treat with the realization that our enrolment may not achieve an adequate size to reduce type 2 error below the typically accepted level of 20%.

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