Statins potentiate the in vitro anti-hepatitis C virus activity of selective hepatitis C virus inhibitors and delay or prevent resistance development #

Abstract

Worldwide approximately 170 million people (or almost 3% of the global population) are chronically infected with HCV. Chronically infected patients are at increased risk of developing liver cirrhosis and hepatocellular carcinoma. 1 In Western countries, infection with HCV is the most common cause of liver transplantation. The current standard therapy for chronic hepatitis C consists of the combination of pegylated interferon alpha (IFN-␣) and ribavirin. This therapy is only effective in 50% to 60% of infected patients and is associated with serious side effects. 2 There is thus an urgent need for more selective, potent, and better-tolerated therapies for chronic hepatitis C.Most antiviral drugs that are currently in clinical trials are inhibitors of the viral polymerase or serine protease. The design of antiviral drugs that inhibit the function of the HCV protease and polymerase therefore appears to be logical. The first HCV nonstructural (NS)3/4A serine protease inhibitor to enter clinical trials was

Statin intolerance – an attempt at a unified definition. Position paper from an International Lipid Expert Panel

“…It has been also shown that the combination of statins (except pravastatin) with interferon exhibited strong inhibitory effects on HCV RNA replication [120]. This was the first time when statins, especially fluvastatin, were shown to be potentially useful as new anti-HCV agents in combination with interferon [120], and that was confirmed in other studies [121]. Statin use (especially simvastatin, lovastatin and atorvastatin) in HCV patients is also associated with a 28% decrease in risk of HCC.…”

“…The percentage of patients who fail to receive statins because of fear of hepatotoxicity ranges between 10-30% [126]. On the other hand statins contribute to the clearance of viral hepatitis [120][121][122], and substantially reduce the risk of HCC [119,122,123]. Thus, the fear of a possible drug adverse effect, which is extremely rare, might be a reason that many patients needlessly suffer or die from cirrhosis, HCC or CVD events [126].…”

Serum Cholesterol and Statin Use Predict Virological Response to Peginterferon and Ribavirin Therapy†,‡

“…22 Conflicting evidence suggests that the opposite may be true, with less efficient uptake of HCV pseudoparticles (34%) seen in hepatoma cells treated with mevastatin as well as less efficient (48% inhibition) internalization of HCV into cells treated with statins. 20 Clearly, a better understanding of the role of the LDL receptor in HCV infectivity is required, and it is possible that the pleiotropic effects of statins may prove to be more relevant. Evidence suggests that HCV replicates within hepatocytes after an HCV replication complex is formed on lipid rafts within the endoplasmic reticulum.…”

“…The possibility that statins may play a role is intriguing. Delang et al 20 showed that statins delay or prevent development of resistance. Another finding of this study is the small number of patients with CHC who were actually on a statin.…”

“…However, cell culture models of HCV infection have demonstrated that anti-HCV activity is not the same for all statins: fluvastatin, atorvastatin, simvastatin, and lovastatin inhibit viral replication to variable extents, whereas pravastatin and rosuvastatin have little to no anti-HCV activity. [18][19][20][21] The underlying mechanism remains unclear; however, data suggest that HCV enters hepatocytes via several lipoprotein receptors (LDL and scavenger receptor class B type 1). At first glance, this appears to be counterintuitive because the statins increase LDL receptors on hepatocytes and in theory increase HCV infectivity.…”