Vere CC et al. by inhibiting HMG-CoA reductase activity, statins reduce the intracellular concentration of geranylgeranyl pyro- phosphate, which lowers the level of mevalonate neces- sary in cholesterol synthesis. A strong argument in favor of this theory is the fact that adding geranylgeraniol and mevalonate in cell cultures treated with statins leads to the restoration of viral replication. In the same study, Ikeda et al. (2) evaluated the possibil- ity of replacing ribavirin with statins in the treatment of chronic hepatitis C. The efficacy of each tested statin was evaluated in combination therapy with interferon. All the statins, except pravastatin, showed higher inhibition of HCV replication when used in combination with inter- feron than when used as monotherapy. Interferon–fluv- astatin combination therapy had the strongest antiviral effect, and the authors consider that this treatment is su- perior to standard therapy with interferon and ribavirin (3). Another recently published study (10), which evalu- ated in vitro anti-HCV activity of 5 statins, confirmed the Japanese authors’ findings. According to these authors, mevastatin and simvastatin administered as mono- therapy have the strongest antiviral activity; lovastatin and fluvastatin have a moderate antiviral effect, while pravastatin has no antiviral activity. In addition, mevas- tatin and simvastatin enhance the antiviral activity of interferon α and of drugs that inhibit viral replication; mevastatin also prevents or reduces resistance to ther- apy with viral replication inhibitors (10). Results of in vivo studies are controversial. According to the Initiating Dialysis Early and Late (IDEAL) study published in 2009, statins combined with peginterferon–ribavirin therapy significantly increase the sustained virological response rate, which is independent of serum lipid levels before the initiation of antiviral therapy. The findings of this retrospective study were not conclusive because of the small sample size; only 66 of the 3070 patients infected with HCV genotype 1 received treatment with statins (11). Another prospective study (12) on 31 patients with chron- ic hepatitis C infection has shown that fluvastatin alone (in commonly used doses) has a moderate, variable, and short-term antiviral effect. However, the findings of the in vivo studies were not consistent with those of the in vitro studies. In 2007, O’Leary et al. published a prospec- tive study on 10 patients and reported that atorvastatin (in commonly used doses) does not inhibit viral replica- tion (13). In 2009, Forde et al. (4) published a retrospec- tive study including 6463 HCV seropositive patients; this study showed that statins do not inhibit viral replication in vivo. According to these authors, the discrepancy be- tween the results of the in vivo and in vitro studies may be attributable to several factors; one such factor is the low level of statins in the serum than in the cell cultures, because of the pharmacokinetic properties of statins. All statins, except pravastatin, are largely retained in the first pass through the liver. The in vitro anti-HCV action may be because of an adaptation of the cell cultures that Treatment of Hepatitis C makes the cells sensitive to interferon action and increas- es their sensitivity to statins. As an adaptive mechanism, HCV could undergo in vivo mutations and become resis- tant to statins; paradoxically, statins could exert proviral effects by promoting the expression of low-density lipo- protein (LDL) receptors, thereby facilitating HCV pen- etration into noninfected hepatocytes (4). Further, the same study showed that triglyceride-reducing agents, such as niacin, may have anti-HCV activity in vivo. There may be a direct relationship between triglyceride level and virus titer, considering that triglycerides metabo- lism is an intermediate step in the life cycle of HCV. The virus is released together with very low-density lipopro- tein (VLDL) particles, and therefore, drugs such as niacin inhibit viral replication by lowering serum triglyceride levels (14-16). Elucidating the role of statins in the treatment of chronic hepatitis C is important, and can be achieved by conducting prospective studies in large groups of pa- tients. Extensive research is required to determine the effectiveness of triglyceride-reducing agents for inhibit- ing HCV replication. Until the approval of new therapeu- tic agents, the peginterferon–ribavirin combination rep- resented the therapy of choice for chronic viral hepatitis C. Recent data have shown that the addition of protease inhibitors such as boceprevir or telaprevir to the classic peginterferon-ribavirin combination therapy decreases the duration of treatment, thereby reducing the cost of treatment and the number of adverse effects (17, 18). Further, an increase of up to 30% was observed in the sus- tained virological response rates in non-responders, with naïve and genotype 1 HCV infection, and a corresponding increase of up to 40–50% was observed in patients show- ing relapse (19, 20). These recent advances have shown that statins play a role in improving treatment outcome and increasing the quality of life of HCV patients; how- ever, the exact mechanism underlying their role is yet to be determined. Authors’ Contribution Al authors contributed equally to preparing this manu- script. Financial Disclosure None declared. References 1. Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH. Pathogenesis, natural history, treatment, and prevention of hepatitis C. Ann Intern Med. 2000;132(4):296-305. 2. Gao B, Hong F, Radaeva S. Host factors and failure of interferon- alpha treatment in hepatitis C virus. Hepatology. 2004;39(4):880- 90. 3. Ikeda M, Abe K, Yamada M, Dansako H, Naka K, Kato N. Different anti-HCV profiles of statins and their potential for combination therapy with interferon. Hepatology. 2006;44(1):117-25. 4. Forde KA, Law C, O’Flynn R, Kaplan DE. Do statins reduce hepati- 370 Hepat Mon. 2012:12(6)