Journal of Viral Hepatitis
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. AstonDisclosures
J Viral Hepat. 2013;20(9):622-627.
Discussion Only
Full Text Available @ Medscape
Safety
The primary purpose of the trial was to evaluate the safety issues involved when fluvastatin or simvastatin was added to peginterferon/ribavirin for 48 weeks. When we combined either fluvastatin or simvastatin prospectively with peginterferon/ribavirin in 25 patients for 48 weeks, we did not observe any unique difficulty and no patient discontinued therapy. Other groups who have combined 20 mg/day of fluvastatin with peginterferon/ribavirin in larger randomized control trials (RCTs) (noted later) also have failed to report any unique side effects or the occurrence of myopathy with the use of fluvastatin. The worldwide prospective RCT experience with 20 mg/day fluvastatin when combined with peginterferon/ribavirin and used against HCV for 48-week therapy now totals 181 patients for 8 688 weeks of drug exposure without incident. The latter fluvastatin total does not include our seven simvastatin patients or nonrandomized prospective studies of fluvastatin/peginterferon/ribavirin.[7]
Efficacy
When fluvastatin or simvastatin was added to peginterferon/ribavirin, 13 of 25 (52%) obtained sustained viral response (SVR), whereas in the control group using peginterferon/ribavirin, 5 of 20 (25%) reached SVR (P = 0.078). This indicates a strong trend favouring the addition of fluvastatin. We did not reach our enrolment goal of 80 patients that was based on the results of a retrospective study of patients who by chance took a statin along with peginterferon and ribavirin.[8] Thus, it is likely that an insufficient sample was accumulated. Enrolling patients became difficult when the promise of direct antiviral agents became a reality. Notably, maintaining the observed proportion of SVR in each group and artificially increasing the total sample size to 80 gave P = 0.021.
As with any RCT, a positive statistical effect favouring the intervention can be disguised by poor performance of the control group. Our current control group achieved a 25% SVR rate. This is identical to our previous retrospective report of naïve-to-treatment genotype 1 patients not on a statin of 25% (16/65).[8] The national VA database for this same classification of genotype 1 patients (n = 20 477) has been reported to have an SVR rate of 26%.[9] Thus, our control group performed the same as our own published historical group or the national VA database.
The 52% SVR rate for the statin group in the current report compares similarly to our retrospective SVR report of 55%. Throughout the time period encompassed by both the retrospective database and prospective trial, the statin used almost exclusively for hypercholesterolaemia in the VA system was simvastatin. Accordingly, 20 of 25 HCV patients in the retrospective statin report were taking simvastatin.[8]
In any case, our results serve to support the results of two other RCTs of fluvastatin published that have tested the addition of our discovered dose of 20 mg/day of fluvastatin to peginterferon/ribavirin. Georgescu et al. gave fluvastatin 20 mg/day combined with peginterferon/ribavirin in an RCT to 104 naïve-to-treatment genotype 1 patients and compared the outcome with 105 control patients. The SVR rates were 63.5% and 49.5% (P = 0.05), respectively. When the 50 patients with metabolic syndrome (as defined by National Cholesterol Education Program Adult Treatment Panel III criteria) were subtracted from each arm in a post hoc analysis, the SVR rates were 74.4% and 58.4%, respectively (P = 0.049).[10]
The second trial reported by Kondo et al.[11] also used 20 mg/day of fluvastatin with peginterferon/ribavirin in 94 naïve-to-treatment genotype 1b patients with high viral loads. The reported SVR rates in the fluvastatin and control arms were 63% and 42% (P = 0.047), respectively.
Combining all three studies (Georgescu et al., Kondo et al. and ours, total sample size = 348), the reported SVR rates in the fluvastatin and control arms were 62% and 45% (P = 0.0018).
When our trial is viewed together with the two other RCTs using fluvastatin at 20 mg/day, the evidence is growing that fluvastatin improves the SVR rate when given to naïve-to-treatment genotype 1 HCV patients.
The mechanism of statin action against hepatitis C is poorly understood. Hypothetically, if the effect is related to changes in extracellular cholesterol, one has to account for the observation that fluvastatin is the weakest LDL-lowering statin and yet it has the strongest anti-HCV effect of all the statins tested.[2] Moreover, it is at the lowest approved dose for hypercholesterolaemia, 20 mg, for which fluvastatin has the greatest anti-HCV effect.[3] In retrospective analysis, some have tried to relate outcomes of peginterferon alfa/ribavirin double therapy to the baseline serum LDL or baseline total cholesterol. In the largest post hoc analysis of statin and serum cholesterol (IDEAL trial), statin use was determined to be an independent factor from cholesterol as a predictor of response to peginterferon/ribavirin.[12] Later analysis of a smaller group from the IDEAL trial suggested that serum LDL cholesterol was strongly associated with the IL28B genotype and that it was this latter parameter that was more directly related to SVR outcome with peginterferon/ribavirin than cholesterol.[13] In our prospective work that delineated fluvastatin to have the strongest anti-HCV effect at 20 mg/day, we were unable to relate baseline LDL or changes in serum LDL to antiviral effect[3] In the current work, there were no differences between groups in regard to baseline serum LDL or total cholesterol (Table 1).
The limitations of our study include a time period before which IL28B genotypes were appreciated or commercially available. As with many VA studies, ours tested only men. Liver biopsies were not performed; however, platelet counts are a practical surrogate, and these counts did not differ between groups. Based upon our retrospective study of statins8, we planned an enrolment of 80 patients to reduce the possibility of type 2 error below the typically accepted level of 20%. With the prospective advent of protease inhibitors, it became increasingly difficult to enrol patients. Our closing study number was 45. Finally, the data reported for simvastatin are only preliminary in nature.
The relevance of the addition of fluvastatin to peginterferon/ribavirin in the era of HCV protease inhibitors may be greatest as cost-effective improvement in SVR for resource-limited areas. The current price for adding only the cost of the tablets for boceprevir or telaprevir ranges from US $28 000 to $55 000 per treated patient, respectively.[14] This does not include the cost of the peginterferon/ribavirin component or the expense of medical management. In contrast, the 20-mg capsule of fluvastatin was approved in generic form by the FDA on 13 April 2012. Prices for the generic version are not immediately available, but will likely become a US dollar per capsule as in other countries.[15] The 48-week cost of fluvastatin will then be US $336. There has not been a noninferiority head-to-head trial of fluvastatin triple therapy vs protease inhibitor triple therapy to compare SVR outcome.
Development of fluvastatin for HCV purposes has been slowed by the nonproprietary status of the drug and the persisting mythological paradigm of statin-induced hepatotoxicity.[16–19] It is relevant that the FDA recently revised all statin labels to state that monitoring of statins with liver tests is no longer recommended.[19] The 20-mg dose of fluvastatin has thus far been shown to be safe in HCV patients either alone or when added to peginterferon/ribavirin for 48 weeks.
The future of hepatitis C treatment seems to be heading towards combinations of oral antiviral agents. Given the positive results of the three randomized controlled trials reported here, further studies of fluvastatin for use against HCV as part of a multidrug regimen are needed.
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