Journal Mobile Options
Table of Contents
Vol. 57, No. 1, 2014
Issue release date: December 2013
Section title: Original Paper
Intervirology 2014;57:23-30
(DOI:10.1159/000354541)

Impact of Added Fluvastatin to Standard-of-Care Treatment on Sustained Virological Response in Naïve Chronic Hepatitis C Patients Infected with Genotypes 1 and 3

Selic Kurincic T.a · Lesnicar G.a · Poljak M.b · Meglic Volkar J.c · Rajter M.c · Prah J.c · Baklan Z.d · Kotar Z.c · Maticic M.c
aDepartment of Infectious Diseases and Febrile Conditions, General Hospital Celje, Celje, bInstitute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, and cClinic for Infectious Diseases and Febrile Illnesses, University Medical Centre Ljubljana, Ljubljana, and dDepartment of Infectious Diseases and Febrile Illnesses, University Clinical Centre Maribor, Maribor, Slovenia
email Corresponding Author

Mojca Maticic

Clinic for Infectious Diseases and Febrile Illnesses

University Medical Centre Ljubljana, Japljeva ulica 2

SI-1525 Ljubljana (Slovenia)

E-Mail mojca.maticic@kclj.si


Abstract

Objectives: The combination of pegylated interferon-α and ribavirin is a standard-of-care (SOC) treatment for chronic hepatitis C (CHC), and it achieves a sustained virological response (SVR) in 41-52% of genotype 1 and in 73-79% of genotype 3 patients. In a few clinical trials, the combination of fluvastatin and SOC increased the SVR in genotype 1 patients. Methods: This prospective study enrolled 179 naïve CHC patients. In the fluvastatin group patients received the combination of SOC and fluvastatin 80 mg daily; historical controls matching the study group in genotype, age and gender were treated with the SOC treatment only. Results: On-treatment viral responses as well as the SVR did not differ significantly between the two groups, except for the genotype 1 patients with a high viral load presenting a significantly higher SVR rate in the fluvastatin group (75%) compared to the control group (41%; p = 0.024). Multivariate logistic regression identified hepatitis C virus (HCV) genotype 3 infection (p < 0.001), age ≤40 years (p < 0.001), liver steatosis <5% (p < 0.01) and low viral load (p < 0.001) as independent predictors of an SVR. Conclusion: A combination of fluvastatin and SOC significantly improved the SVR in naïve CHC patients infected with HCV genotype 1 and high viral load, but it did not improve the SVR in patients infected with HCV genotype 3.

© 2013 S. Karger AG, Basel


Related Articles for ""

Close Related Articles


Introduction

In Central Europe the prevalence of hepatitis C virus (HCV) infection is intermediate, ranging from 0.2-1.2%, with intravenous drug use being the primary mode of transmission during the last years [1,2]. In Slovenia, which has a population of 2 million inhabitants, the prevalence of HCV infection is estimated to be below 1%, with a predominance of HCV genotype 1 (56%), followed by genotype 3 (37.8%), genotype 2 (5%) and genotype 4 (1.2%) [3,4].

For the last 10 years, the combination of pegylated interferon-α (PEG-IFNα) and ribavirin (RBV) has presented a standard-of-care (SOC) treatment for chronic hepatitis C (CHC) [5]. Patients who achieve a sustained virological response (SVR) are considered cured in more than 99% of the cases according to long-term follow-up studies [6,7]. In pivotal clinical studies, an SVR was achieved in 41-52% of genotype 1 patients and in 73-82% of genotypes 2 and 3 patients treated with a SOC treatment [8,9,10]. In other clinical trials, genotype 1 patients achieved an SVR in 47-50% [11,12], and those infected with genotype 3 in 69-79% [13,14]. The most potent pretreatment factors for an SVR were viral genotype, baseline serum viral load, age, gender, BMI, stage of liver fibrosis and recently found genetic polymorphisms for interleukin 28B located on chromosome 19 [5,15,16,17].

In vitro studies have shown that elements of cholesterol-biosynthetic pathways play a critical role in HCV replication, especially geranylgeranyl which is required for HCV replication. It has been demonstrated that statins (3-hydroxyl-3-methylglutaryl-coenzyme A reductase inhibitors) disrupt HCV-RNA replication in cultured hepatoma cells [18,19]. Fluvastatin showed the strongest inhibition on viral replication, and in combination with interferon it had a synergistic inhibitory effect on HCV replication [20].

The aim of the present study was to investigate the impact of adding fluvastatin to SOC treatment on the SVR in a cohort of Slovene patients infected with HCV genotypes 1 and 3, and to determine how safe fluvastatin is for patients with CHC.

Patients and Methods

Study Design

This prospective, open-labeled, historically controlled study enrolled naïve intent-to-treat patients treated for CHC genotypes 1 and 3 according to the 2007 Slovene national consensus guidelines [21]. From September 2009 to February 2011, all of the eligible patients who agreed to participate in the study and who had provided informed consent received fluvastatin in combination with SOC treatment. All of the patients presented with baseline viremia detected by polymerase chain reaction determined by automated COBAS AmpliPrep/COBAS AMPLICOR HCV Test (Roche Diagnostic Systems) with a limit of detection of 30 IU/ml HCV-RNA, carried out at the national reference laboratory. Baseline patient characteristics were evaluated including the viral load, with a high viral load presenting >400,000 IU/ml. Pretreatment liver biopsy was performed in all patients except in those with contraindications. Histological diagnosis was performed according to METAVIR scoring system with the fibrosis stage ranging from 0 to 4 [22].

Patients with the following were excluded: decompensated cirrhosis, coinfection with HIV or HBV, any other cause of liver disease, leucocyte count <3,000/mm3, platelet count <75,000/mm3, hemoglobin <13 g/dl for men and <12 g/dl for women, uncontrolled depression, untreated thyroid disease and autoimmune diseases, clinically significant cardiovascular diseases, malignant neoplastic diseases, previous therapy with statins, and poorly controlled diabetes.

Eligible patients in the study group were treated with a combination of a weight-based dose of RBV 15 mg/kg body weight per day plus either PEG IFNα-2a 180 μg or PEG IFNα-2b 1.5 μg/kg once weekly subcutaneously since no conclusive evidence showing a preference for one of the two PEG-IFNα had been reported [5,23]. According to the viral genotype, baseline HCV-RNA and on-treatment virological response, the treatment duration was 24-72 weeks for genotype 1 and 24 weeks for genotype 3. All patients were additionally treated with fluvastatin 80 mg daily.

The historical control group consisted of all naïve patients with CHC genotypes 1 and 3 who completed treatment and follow-up; they were recruited from the national registry of treated patients and matched the study group in genotype, age and gender. Patients in the control group were treated with SOC treatment according to the same regime as the studied group regarding the treatment optimization (virological response-guided therapy, weight-based dose of RBV and aggressive management of side effects) which is in line with the Slovenian national guidelines [21].

Complete blood count and liver function tests were performed on a 2-week basis until week 8 of treatment and thereafter monthly until the end of treatment as well as at weeks 12 and 24 after cessation of treatment. HCV-RNA concentrations were determined at baseline; weeks 4, 12 and 24; at the end of treatment, and 24 weeks after cessation of treatment. In the fluvastatin group, the creatine kinase level was checked during the treatment.

The study was approved by The National Medical Ethics Committee of the Republic of Slovenia according to the Declaration of Helsinki and in compliance with the ICH/GCP requirements of good clinical practice and all the applicable regulations of the Republic of Slovenia.

Statistical Analysis

Due to the case-control design of the study, only the patients that completed treatment of CHC and a 24-week follow-up period were analyzed in both the study and the control groups. Firstly, the matching of both groups regarding significant SVR predictors was tested using the Mantel-Haenszel test for 2 × 2 × 2 comparisons, the likelihood ratio test for both groups per each specified stratum for categorical variables, and the Kruskal-Wallis test (both groups with respect to genotype and type of therapy) or t/Mann-Whitney U test for both groups per stratum [considering (non)normality of data distribution]. Analysis of the primary outcome, i.e. virological response according to genotype, viral load, pathohistological liver changes and mode of therapy, was performed using the likelihood ratio test. Statistical significance was set at p < 0.05.

Results

The study enrolled 179 naïve CHC genotypes 1 and 3 Caucasian patients: 81 treated with SOC treatment and fluvastatin, and 98 historical controls treated with SOC treatment only. In the study group, 17 patients discontinued treatment prematurely and were excluded from further analysis (fig. 1). Table 1 shows the baseline patient characteristics of the two groups.

Table 1

Baseline patient characteristics of the fluvastatin (n = 64) and the control (n = 98) groups

http://www.karger.com/WebMaterial/ShowPic/162004

Fig. 1

Trial profile.

http://www.karger.com/WebMaterial/ShowPic/162002

Response to Therapy

The overall SVR was 89% in the study group and 79.6% in the control group (p = 0.12). Since the study was designed in a case-control manner, a preliminary comparison of the main SVR predictor balance between the two groups was performed using bivariate testing of the following: HCV genotype, low/high viral load (≤400,000 IU/ml/>400,000 IU/ml), low/high BMI (≤30/>30), low/high age (≤40 years/>40 years), baseline low-density lipoprotein and baseline triglycerides. No significant overall difference was found (χ2 = 2.5; p = 0.114). However, a significant difference between the two groups was established in viral load with the fluvastatin group presenting a higher load, controlled for genotype (Mantel-Haenszel test: OR = 2.32, 95% CI: 1.17-4.59, p = 0.023). Kruskal-Wallis tests of absolute viral load (controlled for genotype) also showed a significant difference (p = 0.01), suggesting that groups do differ both in proportion of low/high viral load as well as in the absolute viral load. The results imply that the viral load should be considered as a possible confounder.

To further examine the possible confounders, data on SVR predictors were compared in both patient groups by the following four strata: (1) low viral load/genotype 1, (2) high viral load/genotype 1, (3) low viral load/genotype 3 and (4) high viral load/genotype 3. Except for the imbalance in higher triglyceride levels of the control group in strata 3, no significant differences were found between the two groups with respect to any of the compared variables (age, BMI, liver fibrosis, baseline low-density lipoprotein and baseline triglyceride levels) in any of the four strata.

The rapid (RVR), early (EVR) and end-of-treatment (ETR) virological responses in the fluvastatin group genotype 1 were 35, 92 and 85%, respectively, while in the control group they were 42, 93 and 87%, respectively. In genotype 3 patients, RVR, EVR and ETR were 89, 100 and 100%, respectively, compared to 92, 100 and 98% in the control group, respectively. RVR, EVR and ETR did not differ significantly between the two groups (fig. 2). In the fluvastatin group, genotype 1 patients achieved an SVR in 81% of the cases compared to 64% in the control group (p = 0.138). In genotype 3 patients, the SVR was 95% in the fluvastatin group versus 92% in the control group (p = 0.661).

Fig. 2

Comparison of virological response rates between the fluvastatin and the control groups in patients infected with HCV genotypes 1 (a) and 3 (b).

http://www.karger.com/WebMaterial/ShowPic/162001

Data on the SVRs of the study group were tested unconditioned on HCV genotype and viral load using the χ2 test. No significant overall difference was found (χ2 = 2.5; p = 0.114). Subsequently, data were tested separately by strata corresponding to the strata 1-4 with respect to the following virological responses: RVR, EVR, ETR and SVR. In the majority of subsets, virological responses did not differ significantly, except for the SVR among genotype 1 patients presenting a high viral load. In this subset, an SVR was achieved in 15 of 20 patients (75%) in the fluvastatin group and in 9 of 22 patients (41%) in the control group (likelihood ratio test: 5.104, p = 0.024).

In order to investigate the predictive factors of an SVR, we analyzed the viral and the pretreatment host factors. Overall, the proportion of patients achieving an SVR was higher in HCV genotype 3 infection versus genotype 1 infection (93 vs. 70%, respectively), higher among patients receiving SOC treatment with added fluvastatin versus patients receiving SOC treatment only (89 vs. 80%, respectively), higher in case of liver steatosis <5% versus steatosis ≥5% (89 vs. 69%, respectively), higher in case of liver fibrosis METAVIR stages 0-1 versus METAVIR stages 2-4 (87 vs. 79%, respectively), considerably higher among younger patients (≤40 years) versus older ones (95 vs. 41%, respectively), higher in BMI ≤30 versus BMI >30 (84 vs. 75%, respectively), and considerably higher among patients with a baseline viral load ≤400,000 IU/ml versus patients with a baseline viral load >400,000 IU/ml (94 vs. 77%, respectively). The differences reached significance using a multivariate logistic regression in four variables: HCV genotype 3 infection, patients ≤40 years old, steatosis <5% and baseline viral load ≤400,000 IU/ml, all being associated with higher odds of an SVR (table 2).

Table 2

Results of bivariate and multivariate logistic regression in predicting failure in reaching the SVR

http://www.karger.com/WebMaterial/ShowPic/162003

Safety and Tolerability

In the fluvastatin group, RBV dose reduction due to anemia was necessary in 8 of 64 patients (12.5%) compared to 4 of 98 (4%) in the control group (p = 0.06). Erythropoietin was administered in 4 of 64 patients (6%) in the fluvastatin group versus 3 of 98 (3%) in the control group (p = 0.36). Granulocyte colony-stimulating factor was prescribed in 1 patient out of 64 (1.6%) in the fluvastatin group versus 4 of 98 (4%) in the control group (p = 0.42). Most patients had mild or moderate psychiatric adverse events, although 1 patient in each group needed hospitalization at a psychiatric medical hospital. Hypothyroidism was seen in 2 of 64 patients (3%) in the fluvastatin group compared to 2 of 98 (2%) in the control group (p = 0.69), while hyperthyroidism presented in 3 of 64 (4.7%) of the fluvastatin group versus 2 of 98 (2%) in the control group (p = 0.39). One patient in the fluvastatin group (1.6%), who had also received other hepatotoxic drugs, discontinued treatment 5 months after the introduction of treatment due to an increase in γ-glutamyl transferase level (p = 0.40). No significant differences in side effects were detected between the two groups.

Discussion

This is the first report on the efficacy of optimized SOC treatment with added fluvastatin in HCV genotype 3-infected patients, as well as the first report on HCV genotype 1 monoinfected patients treated with a fluvastatin dose of 80 mg daily. Eligible patients received a maximal daily dose of fluvastatin approved by the FDA since there are no published data on the correlation between the oral dose of statins and the level of statins in human hepatocytes. In the last 4 years, only a few studies have been published evaluating the clinical effect of fluvastatin on viral response; however, the results have been controversial. In the first clinical trial, Bader et al. [24] reported that monotherapy with fluvastatin showed variable and often short-lived suppressive effects on viral load. In a pilot study, Sezaki et al. [25] demonstrated that the addition of fluvastatin 20 mg daily to SOC treatment might increase the SVR in patients infected with HCV genotype 1b and a high viral load. Recently, Georgescu et al. [26] and Kondo et al. [27 ]reported that the addition of fluvastatin 20 mg daily to SOC treatment significantly improved the SVR in patients infected with HCV genotype 1b. However, Milazzo et al. [28] reported that the addition of fluvastatin 80 mg daily to SOC treatment did not significantly improve the SVR among HIV/HCV-coinfected patients, but significantly improved RVR. According to our knowledge, no studies have been performed regarding the use of fluvastatin in genotype 3 patients.

In the present study, an SVR was achieved in more than 90% of genotype 3 patients with or without fluvastatin added to the optimized SOC treatment. In the previous studies using various regimens of SOC treatment optimization, the SVR was shown to be 68-74% [13,29]. Overall, the combination of fluvastatin and optimized SOC treatment showed no significant improvement in the SVR among genotype 3 patients.

In genotype 1 patients, an SVR was achieved in 81% in the fluvastatin group, which is much higher compared to 37-50% in other clinical studies [12,29]. However, compared to 64% in the control group, the difference was not significant. Interestingly, further analysis of the subgroups showed that the addition of fluvastatin to the optimized SOC treatment significantly improved the SVR in genotype 1 patients and high viral load (>400,000 IU/ml), which is in accordance with published studies [26,27].

One of the reasons for high SVR in our study and control patients was the study design since only the patients who completed treatment and follow-up were analyzed. In addition, favorable pretreatment factors, including a high rate of patients with genotype 3 infection, age ≤40 years (in 79%), BMI ≤30 (in >95%), liver steatosis <5% (in 65%) and liver fibrosis METAVIR stages 0-1 (in 51%), also contributed to the results, which is in agreement with the relevant studies [5,14,29].

Another reason for the high SVR rate was probably the optimization of the SOC treatment in both groups, including a weight-based dose of RBV in genotypes 1 and 3, viral response-guided treatment duration according to RVR and EVR, and the aggressive management of side effects [5,30,31]. All of the included drug users were treated according to the Slovenian national consensus guidelines for the management of HCV infection in drug users [21]. Regular monitoring and follow-up visits of the patients enabled optimal treatment adherence to both PEG-IFN plus RBV and prescription of erythropoietin, granulocyte colony-stimulating factor and antidepressants to avoid premature treatment discontinuation due to side effects.

Discontinuation of fluvastatin therapy as a result of severe hepatotoxicity was needed in 1 patient only (1.6%). According to the National Lipid Association Statin Safety Task Force, patients with chronic liver disease may safely receive statin therapy [32]. Khorashadi et al. [33] reported that statin use did not increase severe hepatotoxicity in patients with HCV infection. In the present study, fluvastatin use in patients with CHC proved to be safe.

We are fully aware of some study limitations, particularly the design of a nonrandomized trial for the use of fluvastatin and a small number of patients after performing stratification and logistic regression. As a general rule, an adequate sample size for logistic regression should comprise at least 10 events per included independent variable [34]. Therefore, three predictors at most were included in the present analysis to obtain valid results. However, as this is not in accordance with the general rule, this should be borne in mind when generalizing the results to the population. Due to a relatively small total number of known CHC patients in Slovenia, a historical-control study design was performed as it was also used in other pivotal clinical trials [12,14].

In conclusion, the present study contributes new data on the SVR in patients with CHC treated with the optimized SOC treatment plus fluvastatin. Moreover, addition of fluvastatin to SOC treatment might be an advantageous therapeutic option for the treatment of genotype 1 patients and high baseline viral load. It should also be noted that despite new treatment options for CHC, the combination of statins with protease inhibitors may result in a more potent antiviral activity, and this combination may also delay or prevent the development of resistance to protease inhibitors [35]. Moreover, fluvastatin is not contraindicated with protease inhibitors because it is mainly metabolized by cytochrome P450 2C9 and not by the cytochrome P450 3A isoenzyme, which is strongly inhibited by boceprevir and telaprevir [36,37]. As for the genotype 3 patients, according to previously reported SVR rates, further clinical research on the combination of SOC treatment and fluvastatin is warranted.


References

  1. Shepard CW, Finelli L, Alter MJ: Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005;5:558-567.
  2. Esteban JI, Sauleda S, Quer J: The changing epidemiology of hepatitis C virus infection in Europe. J Hepatol 2008;48:148-162.
  3. Maticic M, Poljak M, Lunder T, Rener-Sitar K, Stojanovic L: Lichen planus and other cutaneous manifestation in chronic hepatitis C: pre- and post-interferon-based treatment prevalence vary in a cohort of patients from low hepatitis C virus endemic area. J Eur Acad Dermatol Venereal 2008;22:779-788.
  4. Seme K, Vrhovac M, Mocilnik T, Maticic M, Lesnicar G, Baklan Z, Meglic Volkar M, Rajter M, Stepec S, Lunar M, Poljak M: Hepatitis C virus genotypes in 1,504 patients in Slovenia, 1993-2007. J Med Virol 2009;81:634-639.
  5. European Association for the Study of the Liver: EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2011;55:245-264.
  6. Swain MG, Lai MY, Shiffman ML, Cooksley GE, Zeuzem S, Dietrich DT, Abergel A, Pessoa MG, Lin A, Tietz A, Connell EV, Diago M: A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology 2010;139:1593-1601.
  7. Giannini EG, Basso M, Savarino V, Piccotto A: Sustained virological response to pegylated interferon and ribavirin is maintained during long-term follow-up of chronic hepatitis C patients. Aliment Pharmacol Ther 2010;31:502-508.
  8. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales F, Haeussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975-982.
  9. Hadziyannis SJ, Sette H, Morgan TR, Balan V, Diago M, Marcellin P, Ramadori G, Bodenheimer H, Bernstein D, Rizzetto M, Zeuzem S, Pockros PJ, Lin A, Ackrill AM: Peginterferon-α2a and ribavirin combination therapy in chronic hepatitis C. Ann Intern Med 2004;140:346-355.
  10. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958-965.
  11. Abadir N, Marotta P, Feinman SV, Scully JL, Varenbut M, Daiter J, Farley JD: Pegetron prospective optimal weight-based dosing response program (POWER): preliminary results. Hepatology 2005;42:693A.
  12. Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y, Cianciara J, Ibranyi E, Weiland O, Noviello S, Brass C, Albrecht J: Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol 2006;44:97-103.
  13. Manns M, Zeuzem S, Sood A, Lurie Y, Cornberg M, Klinker H, Buggisch P, Rössle M, Hinrichsen H, Merican I, Ilan Y, Mauss S, Abu-Mouch S, Horban A, Müller TH, Welsch C, Chen R, Faruqi R, Pedicone LD, Wedemeyer H: Reduced dose and duration of peginterferon alfa-2b and weight-based ribavirin in patients with genotype 2 and 3 chronic hepatitis C. J Hepatol 2011;55:554-563.
  14. Zeuzem S, Hultcrantz R, Bourliere M, Goeser T, Marcellin P, Sanchez-Tapias J, Sarrazin C, Harvey J, Brass C, Albrecht J: Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 2004;40:993-999.
  15. Manns MP, Wedemeyer H, Cornberg M: Treating viral hepatitis C: efficacy, side effects, and complications. Gut 2006;55:1350-1359.
  16. Bressler BL, Guindi M, Tomlinson G, Heathcote J: High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology 2003;38:639-644.
  17. Ghany MG, Strader DB, Thomas DL, Seeff LB: Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009;49:1335-1374.
  18. Kapadia SB, Chisari FV: Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids. Proc Natl Acad Sci USA 2005;102:2561-2566.
  19. Ye J, Wang C, Sumpter R Jr, Brown MS, Goldstein JL, Gale M Jr: Disruption of hepatits C virus RNA replication through inhibition of host protein geranylgeranylation. Proc Natl Acad Sci USA 2003;100:15865-15870.
  20. Ikeda M, Abe K, Yamada M, Danasko H, Naka K, Kato N: Different anti-HCV profiles of statins and their potential for combination therapy with interferon. Hepatology 2006;44:117-125.
  21. Maticic M, Kastelic A: National guidelines for the management of hepatitis C virus infection in drug users in Slovenia. Zdrav Vestn 2009;78:529-539.
  22. Bedossa P, Poynard T: An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996;24:289-293.
  23. McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, Nyberg LM, Lee WM, Ghalib RH, Schiff ER, Galati JS, Bacon BR, Davis MN, Mukhopadhyay P, Koury K, Noviello S, Pedicone LD, Brass CA, Albrecht JK, Sulkowski MS, IDEAL Study Team: Peginterferon alfa-2a or alfa-2b with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361:580-593.
  24. Bader T, Fazili J, Madhoun M, Aston C, Hughes D, Rizvi S, Seres K, Hasan M: Fluvastatin inhibits hepatitis C replication in humans. Am J Gastroenterol 2008;103:1383-1389.
  25. Sezaki H, Suzuki F, Akuta N, Yatsuji H, Hosaka T, Kobayashi M, Suzuki Y, Arase Y, Ikeda K, Miyakawa Y, Kumada H: An open pilot study exploring the efficacy of fluvastatin, pegylated interferon and ribavirin in patients with hepatitis C virus genotype 1b in high viral loads. Intervirology 2009;52:43-48.
  26. Georgescu EF, Streba L, Teodorescu R, Mateescu G, Tataru Abagiu M: Potential enhancement of both early (EVR) and sustained (SVR) virological response by fluvastatin in chronic hepatitis C treated with standard PEGIFN-RIBAVIRIN therapy. A pilot study. J Hepatol 2011;54:S5-S6.

    External Resources

  27. Kondo C, Atsukawa M, Tsubota A, Itokawa N, Fukuda T, Matsushita Y, Kidokoro H, Kobayashi T, Narahara Y, Nakatsuka K, Kanazawa H, Sakamoto C: An open-label randomized controlled study of pegylated interferon/ribavirin combination therapy for chronic hepatitis C with versus without fluvastatin. J Viral Hepat 2012;19:615-622.
  28. Milazzo L, Caramma I, Mazzali C, Cesari M, Olivetti M, Galli M, Antinori S: Fluvastatin as an adjuvant to pegylated interferon and ribavirin in HIV/hepatitis C genotype 1 co-infected patients: an open-label randomized controlled study. J Antimicrob Chemother 2010;65:735-740.
  29. Jacobson IM, Brown RS Jr, Freilich B, Afdhal N, Kwo PY, Santoro J, Becker S, Wakil AE, Pound D, Godofsky E, Strauss R, Bernstein D, Flamm S, Pauly MP, Mukhopadhyay P, Griffel LH, Brass CA, WIN-R Study Group: Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology 2007;46:971-981.
  30. Thevenot T, Cadranel JF, Di Martino V, Pariente A, Causse X, Renou C, Hagege H, Denis J, Lunel-Fabiani F: A national French survey on the use of growth factors as adjuvant treatment of chronic hepatitis C. Hepatology 2007;45:377-383.
  31. Schaefer M, Capuron L, Friebe A, Diez-Quevedo C, Robaeys G, Neri S, Foster GR, Kautz A, Forton D, Pariante CM: Hepatitis C infection, antiviral treatment and mental health: a European expert consensus statement. J Hepatol 2012;57:1379-1390.
  32. McKenney JM, Davidson MH, Jacobson TA, Guyton JR: Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006;97:89C-94C.
  33. Khorashadi S, Hasson NK, Cheung RC: Incidence of statin hepatotoxicity in patients with hepatitis C. Clin Gastroenterol Hepatol 2006;4:902-907.
  34. Agresti A: Building and applying logistic regression models; in Agresti A (ed): An Introduction to Categorical Data Analysis. Hoboken, John Wiley, 2007, p 138.

    External Resources

  35. Delang L, Paeshuyse J, Vliegen I, Leyssen P, Obeid S, Durantel D, Zoulim F, Op de Beeck A, Neyts J: Statins potentiate the in vitro anti-hepatitis C virus activity of selective hepatitis C virus inhibitors and delay or prevent resistance development. Hepatology 2009;50:6-16.
  36. Burger D, Back D, Buggisch P, Buti M, Craxi A, Foster G, Klinker H, Larrey D, Nikitin I, Pol S, Puoti M, Romero-Gomez M, Wedemeyer H, Zeuzem S: Clinical management of drug-drug interactions in HCV therapy: challenges and solutions. J Hepatol 2012;58:792-800.
  37. Fischer V, Johanson L, Heitz F, Tullman R, Graham E, Baldeck JP, Robinson WT: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin: effect on human cytochrome P-450 and implications for metabolic drug interactions. Drug Metab Dispos 1999;27:410-416.

    External Resources


Author Contacts

Mojca Maticic

Clinic for Infectious Diseases and Febrile Illnesses

University Medical Centre Ljubljana, Japljeva ulica 2

SI-1525 Ljubljana (Slovenia)

E-Mail mojca.maticic@kclj.si


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 5/22/2013 11:54:58 AM
Accepted: 7/16/2013
Published online: 9/26/2013
Issue release date: December 2013

Number of Print Pages: 8
Number of Figures: 2
Number of Tables: 2

ISSN: 0300-5526 (Print)
eISSN: 1423-0100 (Online)

For additional information: http://www.karger.com/INT


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Shepard CW, Finelli L, Alter MJ: Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005;5:558-567.
  2. Esteban JI, Sauleda S, Quer J: The changing epidemiology of hepatitis C virus infection in Europe. J Hepatol 2008;48:148-162.
  3. Maticic M, Poljak M, Lunder T, Rener-Sitar K, Stojanovic L: Lichen planus and other cutaneous manifestation in chronic hepatitis C: pre- and post-interferon-based treatment prevalence vary in a cohort of patients from low hepatitis C virus endemic area. J Eur Acad Dermatol Venereal 2008;22:779-788.
  4. Seme K, Vrhovac M, Mocilnik T, Maticic M, Lesnicar G, Baklan Z, Meglic Volkar M, Rajter M, Stepec S, Lunar M, Poljak M: Hepatitis C virus genotypes in 1,504 patients in Slovenia, 1993-2007. J Med Virol 2009;81:634-639.
  5. European Association for the Study of the Liver: EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2011;55:245-264.
  6. Swain MG, Lai MY, Shiffman ML, Cooksley GE, Zeuzem S, Dietrich DT, Abergel A, Pessoa MG, Lin A, Tietz A, Connell EV, Diago M: A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology 2010;139:1593-1601.
  7. Giannini EG, Basso M, Savarino V, Piccotto A: Sustained virological response to pegylated interferon and ribavirin is maintained during long-term follow-up of chronic hepatitis C patients. Aliment Pharmacol Ther 2010;31:502-508.
  8. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales F, Haeussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975-982.
  9. Hadziyannis SJ, Sette H, Morgan TR, Balan V, Diago M, Marcellin P, Ramadori G, Bodenheimer H, Bernstein D, Rizzetto M, Zeuzem S, Pockros PJ, Lin A, Ackrill AM: Peginterferon-α2a and ribavirin combination therapy in chronic hepatitis C. Ann Intern Med 2004;140:346-355.
  10. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958-965.
  11. Abadir N, Marotta P, Feinman SV, Scully JL, Varenbut M, Daiter J, Farley JD: Pegetron prospective optimal weight-based dosing response program (POWER): preliminary results. Hepatology 2005;42:693A.
  12. Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y, Cianciara J, Ibranyi E, Weiland O, Noviello S, Brass C, Albrecht J: Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol 2006;44:97-103.
  13. Manns M, Zeuzem S, Sood A, Lurie Y, Cornberg M, Klinker H, Buggisch P, Rössle M, Hinrichsen H, Merican I, Ilan Y, Mauss S, Abu-Mouch S, Horban A, Müller TH, Welsch C, Chen R, Faruqi R, Pedicone LD, Wedemeyer H: Reduced dose and duration of peginterferon alfa-2b and weight-based ribavirin in patients with genotype 2 and 3 chronic hepatitis C. J Hepatol 2011;55:554-563.
  14. Zeuzem S, Hultcrantz R, Bourliere M, Goeser T, Marcellin P, Sanchez-Tapias J, Sarrazin C, Harvey J, Brass C, Albrecht J: Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 2004;40:993-999.
  15. Manns MP, Wedemeyer H, Cornberg M: Treating viral hepatitis C: efficacy, side effects, and complications. Gut 2006;55:1350-1359.
  16. Bressler BL, Guindi M, Tomlinson G, Heathcote J: High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology 2003;38:639-644.
  17. Ghany MG, Strader DB, Thomas DL, Seeff LB: Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009;49:1335-1374.
  18. Kapadia SB, Chisari FV: Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids. Proc Natl Acad Sci USA 2005;102:2561-2566.
  19. Ye J, Wang C, Sumpter R Jr, Brown MS, Goldstein JL, Gale M Jr: Disruption of hepatits C virus RNA replication through inhibition of host protein geranylgeranylation. Proc Natl Acad Sci USA 2003;100:15865-15870.
  20. Ikeda M, Abe K, Yamada M, Danasko H, Naka K, Kato N: Different anti-HCV profiles of statins and their potential for combination therapy with interferon. Hepatology 2006;44:117-125.
  21. Maticic M, Kastelic A: National guidelines for the management of hepatitis C virus infection in drug users in Slovenia. Zdrav Vestn 2009;78:529-539.
  22. Bedossa P, Poynard T: An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996;24:289-293.
  23. McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, Nyberg LM, Lee WM, Ghalib RH, Schiff ER, Galati JS, Bacon BR, Davis MN, Mukhopadhyay P, Koury K, Noviello S, Pedicone LD, Brass CA, Albrecht JK, Sulkowski MS, IDEAL Study Team: Peginterferon alfa-2a or alfa-2b with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361:580-593.
  24. Bader T, Fazili J, Madhoun M, Aston C, Hughes D, Rizvi S, Seres K, Hasan M: Fluvastatin inhibits hepatitis C replication in humans. Am J Gastroenterol 2008;103:1383-1389.
  25. Sezaki H, Suzuki F, Akuta N, Yatsuji H, Hosaka T, Kobayashi M, Suzuki Y, Arase Y, Ikeda K, Miyakawa Y, Kumada H: An open pilot study exploring the efficacy of fluvastatin, pegylated interferon and ribavirin in patients with hepatitis C virus genotype 1b in high viral loads. Intervirology 2009;52:43-48.
  26. Georgescu EF, Streba L, Teodorescu R, Mateescu G, Tataru Abagiu M: Potential enhancement of both early (EVR) and sustained (SVR) virological response by fluvastatin in chronic hepatitis C treated with standard PEGIFN-RIBAVIRIN therapy. A pilot study. J Hepatol 2011;54:S5-S6.

    External Resources

  27. Kondo C, Atsukawa M, Tsubota A, Itokawa N, Fukuda T, Matsushita Y, Kidokoro H, Kobayashi T, Narahara Y, Nakatsuka K, Kanazawa H, Sakamoto C: An open-label randomized controlled study of pegylated interferon/ribavirin combination therapy for chronic hepatitis C with versus without fluvastatin. J Viral Hepat 2012;19:615-622.
  28. Milazzo L, Caramma I, Mazzali C, Cesari M, Olivetti M, Galli M, Antinori S: Fluvastatin as an adjuvant to pegylated interferon and ribavirin in HIV/hepatitis C genotype 1 co-infected patients: an open-label randomized controlled study. J Antimicrob Chemother 2010;65:735-740.
  29. Jacobson IM, Brown RS Jr, Freilich B, Afdhal N, Kwo PY, Santoro J, Becker S, Wakil AE, Pound D, Godofsky E, Strauss R, Bernstein D, Flamm S, Pauly MP, Mukhopadhyay P, Griffel LH, Brass CA, WIN-R Study Group: Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology 2007;46:971-981.
  30. Thevenot T, Cadranel JF, Di Martino V, Pariente A, Causse X, Renou C, Hagege H, Denis J, Lunel-Fabiani F: A national French survey on the use of growth factors as adjuvant treatment of chronic hepatitis C. Hepatology 2007;45:377-383.
  31. Schaefer M, Capuron L, Friebe A, Diez-Quevedo C, Robaeys G, Neri S, Foster GR, Kautz A, Forton D, Pariante CM: Hepatitis C infection, antiviral treatment and mental health: a European expert consensus statement. J Hepatol 2012;57:1379-1390.
  32. McKenney JM, Davidson MH, Jacobson TA, Guyton JR: Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006;97:89C-94C.
  33. Khorashadi S, Hasson NK, Cheung RC: Incidence of statin hepatotoxicity in patients with hepatitis C. Clin Gastroenterol Hepatol 2006;4:902-907.
  34. Agresti A: Building and applying logistic regression models; in Agresti A (ed): An Introduction to Categorical Data Analysis. Hoboken, John Wiley, 2007, p 138.

    External Resources

  35. Delang L, Paeshuyse J, Vliegen I, Leyssen P, Obeid S, Durantel D, Zoulim F, Op de Beeck A, Neyts J: Statins potentiate the in vitro anti-hepatitis C virus activity of selective hepatitis C virus inhibitors and delay or prevent resistance development. Hepatology 2009;50:6-16.
  36. Burger D, Back D, Buggisch P, Buti M, Craxi A, Foster G, Klinker H, Larrey D, Nikitin I, Pol S, Puoti M, Romero-Gomez M, Wedemeyer H, Zeuzem S: Clinical management of drug-drug interactions in HCV therapy: challenges and solutions. J Hepatol 2012;58:792-800.
  37. Fischer V, Johanson L, Heitz F, Tullman R, Graham E, Baldeck JP, Robinson WT: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin: effect on human cytochrome P-450 and implications for metabolic drug interactions. Drug Metab Dispos 1999;27:410-416.

    External Resources