Hepatitis C: Fluvastatin, Peginterferon, and Ribavirin for Naive Genotype 1 HCV

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.

Abstract and Introduction

Methods

Results 

Discussion

Hepatitis C Peg/Riba Therapy: With versus Without Fluvastatin-An Open-Label Randomized Controlled Study

From Journal of Viral Hepatitis

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

Posted: 08/23/2012; J Viral Hepat. 2012;19(9):615-622. © 2012 Blackwell Publishing

Discussion Only

Full text available at Medscape

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.

Full text available at Medscape

EASL; Fluvastatin Enhances Chronic Hepatitis C Treatment Response In Combination With Pegylated Interferon-Alpha And Ribavirin

Fluvastatin Enhances Chronic Hepatitis C Treatment Response In Combination With Pegylated Interferon-Alpha And Ribavirin

First Vaccine for Viral Hepatitis C Could Become a Reality


Anna Ohlden

FLUVASTATIN ENHANCES CHRONIC HEPATITIS C TREATMENT RESPONSE IN COMBINATION WITH PEGYLATED INTERFERON-ALPHA AND RIBAVIRIN

Well-known statin could be recycled as HCV therapy supplement

Berlin, Germany, Thursday 31 March 2011: /PRNewswire/ — New data presented today at the International Liver CongressTM confirm the antiviral activity of fluvastatin – commonly used as a cholesterol-lowering treatment – in patients with chronic hepatitis C (HCV).1

Patients had improved early and sustained virological response (EVR and SVR) when treated with the current standard of care – pegylated Interferon-alpha and ribavirin (PegIFNα/RBV) – and fluvastatin. The results show patients receiving fluvastatin and PegIFNα/RBV achieve higher rates of EVR and SVR – 75.96% and 63.46% – to those receiving placebo and PegIFNα/RBV – 61.9% and 49.52% respectively.

EASL’s Secretary General, Professor Heiner Wedemeyer, said: “We know that metabolic syndrome (MS), the main treatment indication for statins, is associated with severe fibrosis and lower treatment responses in chronic HCV patients.2 The confirmation that the combination of fluvastatin and PegIFNα/RBV could provide better clinical outcomes for those patients with co-morbid chronic HCV and MS is very exciting for clinicians."

Even in patients without MS, the study shows that responses to treatment are still higher in patients treated with fluvastatin and PegIFNα/RBV (EVR 85.36% versus 71.42% and SVR 74.39% vs. 58.44).

"Today, healthcare professionals have to be mindful when considering health provision and treatment costs. We cannot overlook the importance of opportunities to maximise more affordable drugs’ potential to complement the current standard of care for chronic HCV management," said Professor Wedemeyer.

This new study concludes that the synergistic effects between fluvastatin and PegIFNα/RBV shows lipid lowering drugs may favour HCV clearance and be useful as a chronic HCV treatment, irrespective of the presence of metabolic syndrome.

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Notes to Editors
About the study

In the double-blind pilot study, 209 treatment naïve HCV genotype 1b patients were given either PegIFNα/RBV and 20 mg of fluvastatin (104 patients) or PegIFNα/RBV and 20 mg of placebo (105 patients) for 48 weeks. Study medication was administered for 72 weeks (48 weeks in association with PegIFN-ribavirin plus 24 weeks in follow-up) in all patients, irrespective their lipid profile.

Both EVR and SVR are makers of a drug’s efficacy as an HCV treatment: EVR is measured by detectable HCV RNA at week 4, but undetectable HCV RNA at week 12, maintained to the end of treatment; SVR is measured by undetectable HCV RNA 24 weeks after the end of treatment.

About fluvastatin

Fluvastatin has previously shown promise as an HCV treatment: a 2008 study of 31 patients found the drug exhibited antiviral activity against HCV, although the authors described the effect as modest, variable, and often short-lived.3

Fluvastatin is a statin, a class of drug that improves blood cholesterol levels primarily by inhibiting a liver enzyme called HMG Co-A reductase, thus reducing the liver's ability to make cholesterol.4

About metabolic syndrome

Metabolic syndrome (MS) is a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes. It is also linked with a higher risk to develop severe fibrosis in chronic HCV patients.2

About EASL

EASL is the leading European scientific society involved in promoting research and education in hepatology. EASL attracts the foremost hepatology experts and has an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

EASL’s main focus on education and research is delivered through numerous events and initiatives, including:

The International Liver CongressTM which is the main scientific and professional event in hepatology worldwide

Meetings including Monothematic and Special conferences, Post Graduate courses and other endorsed meetings that take place throughout the year

Clinical and Basic Schools of Hepatology, a series of events covering different aspects in the field of hepatology

Journal of Hepatology published monthly

Participation in a number of policy initiatives at European level

About The International Liver CongressTM 2011

The International Liver Congress™ 2011, the 46th annual meeting of the European Association for the study of the Liver, is being held at the Internationales Congress Centrum, Berlin, Germany from March 30 – April 3, 2011. The congress annually attracts over 7,500 clinicians and scientists from around the world and provides an opportunity to hear the latest research, perspectives and treatments of liver disease from principal experts in the field.

For further information on the studies, or to request an interview, please do not hesitate to contact the EASL Press Office on:

Email: easlpressoffice@cohnwolfe.com

Travis Taylor: Onsite tel: +44 7843 069 451

Vicky O'Conner: Offsite tel: +44 20 7331 5342

References
1. Georgescu, E. et al. Potential enhancement of both early (EVR) and sustained (SVR) virological response by fluvastatin in chronic hepatitis C trated [sic] with standard pegifn-ribavirin therapy. A pilot study. Abstract presented at The International Liver CongressTM 2011

2. Tsochatzis E et al. Metabolic syndrome is associated with severe fibrosis in chronic viral hepatitis and non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2008 Jan 1;27(1):80-9. Epub 2007 Oct 5

3. Bader T, Fazili J, Madhoun M, et al. (April 2008). Fluvastatin Inhibits Hepatitis C Replication in Humans. Am. J. Gastroenterol. 103 (6): 1383. doi:10.1111/j.1572-0241.2008.01876.x. PMID 18410471

4. http://heartdisease.about.com/cs/cholesterol/a/statins.htm.  Accessed  16.03.2011

http://multivu.prnewswire.com/mnr/prne/easl/48894/