An Open-label Randomized Controlled Study of Pegylated Interferon/Ribavirin Combination Therapy for Chronic Hepatitis C With Versus Without Fluvastatin

C. Kondo; M. Atsukawa; A. Tsubota; N. Itokawa; T. Fukuda; Y. Matsushita; H. Kidokoro; T. Kobayashi; Y. Narahara; K. Nakatsuka; H. Kanazawa; C. Sakamoto

Disclosures

J Viral Hepat. 2012;19(9):615-622. 

In This Article

Discussion

In the present study, we, for the first time, show that fluvastatin significantly improved the SVR rate in a randomized controlled open-labeled study, and identified the patient characteristics that would have a likelihood of achieving SVR with addition of fluvastatin. So far, several studies have shown that concomitant addition of statins to the SOC treatment yielded a more favorable treatment outcome than SOC treatment alone.[10–13] However, some limitations still remained in these studies: a small number of study patients, a retrospective or pilot study, or a non-randomized controlled trial for the use of fluvastatin. Moreover, these studies have yet to clarify which patients would benefit from the additional effect of statins, or what are the factors that could contribute to the therapeutic benefit. This randomized controlled study designed to solve these limitations showed that fluvastatin, when added to PEG-IFN/ribavirin combination therapy, significantly improved SVR rates in patients with genotype 1b and high viral load chronic hepatitis C.

In the present study, the striking effect of fluvastatin with more than 80% SVR rate was observed in male patients, in patients who had a history of relapse, or in patients with more than two mutations in the ISDR. It has already been shown that various host and viral factors influence the therapeutic effect. As for host factors, patient age, gender, blood cell count, and IL28B SNPs have been reported to influence the therapeutic effect.[14–18] As for HCV-related factors, the virus genotype, viral load, amino acid substitution in the core region,[19] and number of ISDR mutations appear to influence the therapeutic effect.[20–22]

Interestingly, the sub-analysis stratifying these factors showed that a high SVR rate was also observed in patients with these favorable factors among the fluvastatin compared to the non-fluvastatin group; i.e., male, core aa70 wild type, 2 or more ISDR mutations, low HCV-RNA level, and IL28B major genotype. Of note, the outcome of the fluvastatin combination therapy was also markedly favorable in patients who had a history of relapse after previous IFN therapy. These data suggest that the concomitant fluvastatin treatment may assure or consolidate a virological response when added to the SOC treatment.

When the treatment response was compared between the two groups, no significant differences were noted in the RVR, EVR, or ETR rate. Furthermore, there was no significant difference in early HCV dynamics during the first 12 week treatment period (24 h, 48 h, and 1, 2, 4, 8, and 12 weeks) between the groups (data not shown). Nevertheless, the concomitant use of fluvastatin significantly improved the SVR rate, suggesting that it might inhibit relapse after treatment completion in patients who were virological responders during treatment. Therefore it would be reasonable to speculate that the inhibition of viral relapse might be responsible, at least in part, for the significant improvement of the SVR rate with concomitant addition of fluvastatin.

Many studies have recently reported that the effect of antiviral therapy on chronic hepatitis C could be predicted at a high rate by focusing on IL28B SNPs.[14–16] However, there has been no report in which IL28B SNPs were investigated in patients treated with PEG-IFN/ribavirin/fluvastatin therapy. SVR rates in patients with the major genotype were significantly increased in the fluvastatin group as compared with the non-fluvastatin group, while no significant difference was noted in patients with the minor genotypes between the groups. In addition, the major IL28B SNP genotype was also an independent predictor for SVR among patients treated with fluvastatin combination therapy. Therefore, fluvastatin combination therapy, though highly effective in patients with the major genotype, does not appear to be effective for patients with such difficult-to-treat factors.

For genotype 1 chronic hepatitis C with a high viral load, PEG-IFN/ribavirin/protease inhibitor, such as telaprevir and boceprevir, combination therapy would become the standard of care quite soon. The addition of a protease inhibitor to PEG-IFN/ribavirin has been shown to result in SVR rates of around 80% in genotype 1 chronic hepatitis C with a high viral load. However, the noteworthy fact is that a marked number of cases developed anemia and severe rash during treatment, resulting in discontinuation of the therapy. According to a recent report, the rate of treatment interruption due to the adverse reactions of PEG-IFN/ribavirin with telaprevir was 21%, compared to 11% in PEG-IFN/ribavirin without telaprevir.[23] That is to say, concomitant addition of other agents to the standard treatment may cause the development of adverse effects due to the agents added or the risk of deterioration in already-known adverse effects. With regard to adverse events, on the other hand, no apparent severe adverse event was observed in any of the patients treated with fluvastatin in the present study. Thus, PEG-IFN/ribavirin with fluvastatin could be one therapeutic options that can be safely administered for chronic hepatitis C patients. Therefore, we would like to propose based on the present results, an algorithm in which future treatment for chronic hepatitis C patients with genotype 1b and high viral load would be selected. In cases for which the novel therapy with a concomitant protease is not applicable due to adverse reactions, PEG-IFN/ribavirin with concomitant use of fluvastatin may be useful. Specifically, the fluvastatin combination therapy may be recommended for male patients and patients with the major IL28B SNPgenotype. By contrast, the therapeutic effect may not be improved by the concomitant addition of fluvastatin in intractable cases such as those with core amino acid 70 mutant type, with IL28B minor genotype, and female patients. For these patients, new combination therapies with protease,[13,23–26] polymerase,[27–29] or N5A inhibitors[30] currently under development would be recommended.

Lastly, in vitro comparisons of the anti-HCV activity among various statins have been reported,[8] and the superiority of fluvastatin has been demonstrated. On the other hand, there has been no comparison of the clinical effect among statins, and which statin should be added to IFN therapy to obtain favorable results in hepatitis C patients.

In conclusion, fluvastatin-combined PEG-IFN/ribavirin therapy was safe and improved SVR rate in chronic hepatitis C patients with genotype 1b and high viral load.It was highly effective for male patients, patients with more than two mutations in the ISDR and patients who had a history of relapse after previous IFN treatment. Being male and major IL28B SNP genotype were independent predictors for SVR among patients on fluvastatin combination therapy.

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