Statins Active against HCV, Especially When Combined with Interferon

A new study published in the July 2006 issue of Hepatology showed that statin drugs, which are used to manage high blood cholesterol, are active against hepatitis C virus (HCV) in laboratory cell cultures; the anti-HCV effect was even stronger when combined with interferon.

Because HCV is difficult to maintain in the laboratory, the authors developed a genome-length HCV RNA replication system, or "replicon," dubbed OR6. They used the OR6 assay system to evaluate the anti-HCV activity of several drugs in the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor class, popularly known as statins:

- atorvastatin (Lipitor)
- fluvastatin (Lescol)
- lovastatin (Mevacor)
- pravastatin (Pravachol)
- simvastatin (Zocor)

Results

Fluvastatin demonstrated the strongest anti-HCV activity, with a 50% inhibitory concentration (IC₅₀) of 0.9 micromoles/L.

Atorvastatin and simvastatin showed moderate anti-HCV inhibitory activity.

Lovastatin exhibited the weakest anti-HCV activity (although a previous study found that this agent inhibited HCV replication).

Pravastatin demonstrated no anti-HCV activity, though it worked as an inhibitor of HMG-CoA reductase.

When administered with pegylated interferon, all the statins except for pravastatin exhibited an even stronger inhibitory effect on HCV replication.

Fluvastatin plus pegylated interferon produced a synergistic anti-HCV inhibitory effect.

Conclusion

The authors concluded that statins, especially fluvastatin, "could be potentially useful as new anti-HCV reagents in combination with interferon." In fact, they suggested that fluvastatin plus pegylated interferon is more effective against HCV than pegylated interferon monotherapy or pegylated interferon plus ribavirin.

The reason for the statins' inhibitory effect on HCV is unclear. The statins did not kill the host cells, so the anti-HCV activity was not due to cytotoxicity. The fact that pravastatin did not inhibit HCV replication despite its effect on HMG-CoA reductase suggests that the anti-HCV activity of the other statins is not directly due to inhibition of HMG-CoA reductase.

The researchers suggested that "the statins possess the ability to inhibit the replication of HCV RNA via a specific antiviral mechanism." The statins' anti-HCV activity was reversed by the addition of mevalonate or geranylgeraniol (two compounds that play a role in the HMG-CoA reductase biosynthesis pathway), suggesting that inhibition of these proteins may somehow block HCV replication.

While this research is still in the preclinical stage, it suggests that statins may in the future be used in hepatitis C treatment regimens with interferon, either in addition to or instead of ribavirin and experimental agents - such as protease and polymerase inhibitors - that directly target HCV.

07/11/06

Reference
M Ikeda, A Ken-ichi, M Yamada, and others. Different Anti-HCV Profiles of Statins and Their Potential for Combination Therapy with Interferon. Hepatology 44(1): 117-125. July 2006.