(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Hepatitis-C--Chronic

The treatment of interferon alfa (IFN-α) and ribavirin for chronic hepatitis C virus (HCV) infection achieves limited sustained virological response (SVR). We conducted a systematic review and meta-analysis to explore the efficacy of adding statins to IFN-α and ribavirin therapy for chronic hepatitis C. Studies with data pertinent to the effect of statins on chronic hepatitis C were reviewed, and randomized controlled trials (RCTs) evaluating the efficacy of the addition of statins to IFN-α and ribavirin were included in meta-analysis. The primary outcome measure was SVR. Secondary outcome measures were rapid virological response (RVR) and early virological response (EVR). The literature was systematically searched through October 2012. After screening of the 1724 non-duplicated entries, 54 potentially relevant studies were fully reviewed. Of those, 18 studies were relevant and 5 RCTs met the inclusion criteria for meta-analysis. In comparison with IFN-α and ribavirin therapy, the addition of statins significantly increased SVR (OR=2.02, 95% CI: 1.38-2.94), RVR (OR=3.51, 95% CI: 1.08-11.42) and EVR (OR=1.89, 95% CI: 1.20-2.98). The SVR increase remained significant for HCV genotype 1 (OR=2.11, 95% CI: 1.40-3.18). There were no significant increases in adverse events and withdrawals with the addition of statins. In conclusion, the addition of statins to IFN-α and ribavirin improves SVR, RVR, and EVR without additional adverse events and thus may be considered as adjuvant to IFN-α and ribavirin for chronic hepatitis C. Statins might also be used for HCV genotypes other than genotype 1, or in patients in whom the use of protease inhibitors is contraindicated or not indicated.

Topics: Adjuvants, Immunologic; Antiviral Agents; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Fluvastatin; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Indoles; Interferon-alpha; Odds Ratio; Randomized Controlled Trials as Topic; Ribavirin; Treatment Outcome; Viral Load

Topics: Antiviral Agents; Cyclosporine; Diterpenes; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Fatty Alcohols; Female; Fluvastatin; Hepatitis C, Chronic; Humans; Indoles; Interferon-alpha; Male; Metformin; Nitro Compounds; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Silybin; Silymarin; Thiazoles

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.. 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.. 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.. 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.

Topics: Adult; Antiviral Agents; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Female; Fluvastatin; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Indoles; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Polyethylene Glycols; Prospective Studies; Recombinant Proteins; Ribavirin; Treatment Outcome

Hepatitis C virus (HCV) utilises cholesterol and lipoprotein metabolism for replication and infectivity. Statins and omega-3 (n-3) polyunsaturated fatty acids (PUFA) have been shown to have antiviral properties in vitro. This open label pilot study evaluated the efficacy of fluvastatin (Lescol(®) 40-80 mg) and n-3 PUFA (Omacor(®) 1 g and 2-4 g) on HCV-RNA and lipoviral particles (LVP) in difficult to treat prior non-responders.. Patients (n = 60) were randomly allocated in a factorial design to: no active drug; low-dose n-3 PUFA; high-dose n-3 PUFA; fluvastatin; low-dose n-3 PUFA + fluvastatin; or high-dose n-3 PUFA + fluvastatin. 50/60 completed study drugs for 12 weeks and followed up to week 24. Comparison was made between fluvastatin (n = 24) vs no fluvastatin (n = 26) and n-3 PUFA high-dose (n = 17) vs low-dose (n = 17) vs none (n = 16). The primary outcomes were change in total HCV-RNA, LVP and ALT at week 12 compared with baseline. Secondary outcome was change in interferon-gamma-inducible protein-10 (IP10) as a measure of interferon activation.. 35% had compensated cirrhosis and 45% were prior null responders. There was no significant change in total HCV RNA, LVP, non-LVP or LVP ratio in patients receiving fluvastatin or n-3 PUFAs. ALT was not significantly different in those treated with fluvastatin or n-3 PUFAs. 12 weeks of low-dose n-3 PUFA decreased median IP10 concentration by -39 pg/ml (-111, 7.0 pg/ml Q1-Q3).. Fluvastatin and n-3 PUFAs have no effect on plasma HCV-RNA or LVP. The effect of low-dose n-3 PUFA on IP10 warrants further prospective evaluation as a supplemental therapy to enhance interferon sensitivity.

Topics: Adult; Alanine Transaminase; Antiviral Agents; Chemokine CXCL10; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Fatty Acids, Omega-3; Female; Fluvastatin; Hepatitis C, Chronic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Middle Aged; Pilot Projects; Viral Load

Neuro-psychiatric and cognitive disorders are frequent in patients with chronic hepatitis C (CHC) virus (HCV) infection which adversely impact quality of life, antiviral treatment adherence and outcome. HCV has neurotrophic properties and affects lipid metabolism, essential for cognitive function. We evaluated the relationship of lipid profiles with depression and anxiety symptoms and the effects of 12-weeks of therapy with fluvastatin and omega-3 ethyl esters (n-3 PUFA) in a randomised pilot study of CHC prior non-responders. Participants (n = 60) had fasting lipid profiles and assessment of depression and anxiety symptoms using the Hospital Anxiety and Depression Scale (HADS) questionnaire at each study visit. At screening 26/60 (43 %) had HADS-A score ≥8 and 13/60 (22 %) had HADS-D scores ≥8. Depressed patients had significantly lower apolipoprotein-E concentrations (30 mg/l vs 39 mg/l, P = 0.029) than those without depression and a tendency toward lower total cholesterol (3.8 vs 4.4 mmol/l, P = 0.053). 3 patients discontinued lipid-modifying treatment because of worsening depression. However, there was a small but significant improvement in anxiety symptoms after 12-weeks of high-dose (2-4 g daily) n-3 PUFA. In conclusion, depression in CHC is associated with plasma apoE deficiency. We postulate that apoE deficiency disrupts blood brain barrier integrity to promote HCV infection of the CNS. High-dose n-PUFAs may alleviate anxiety in some CHC patients but the use of lipid lowering therapy must be balanced against risks of worsening depression.

Topics: Adult; Anxiety; Apolipoproteins E; Cholesterol; Depression; Fatty Acids, Monounsaturated; Female; Fluvastatin; Hepatitis C, Chronic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Middle Aged; Pilot Projects; Treatment Outcome

The addition of fluvastatin significantly improves sustained virological response (SVR) in pegylated interferon and ribavirin (peg-IFN/RBV) combination therapy for patients infected with the hepatitis C virus. However, the add-on effect on telaprevir-based triple combination therapy remains unknown. The aim of this study was to investigate the effect of fluvastatin on telaprevir-based combination therapy by conducting a prospective, open-label, randomized, controlled trial.. Among 124 genotype 1b-infected chronic hepatitis C patients recruited, 116 eligible patients were allocated randomly to two study arms; they received 12 weeks of telaprevir/peg-IFN/RBV, followed by 12 weeks of peg-IFN/RBV with or without 24 weeks of fluvastatin (fluvastatin group and control group, respectively). Treatment outcomes and adverse effects were compared between the two groups.. There were 56 men and 60 women, median age 60 years (range, 28-71 years). Rapid virological response and end of treatment response rates were 87.9% (51/58) and 96.6% (56/58) in the control group and 75.9% (44/58) and 98.3% (57/58) in the fluvastatin group, respectively. SVR rates in the control group and the fluvastatin group were 84.5% (49/58) and 81.0% (47/58), respectively; there was no significant difference (P=0.806). Stratified analysis showed that no factors associated with the SVR rate were found between the two groups. No adverse events were associated with fluvastatin.. In this trial, administration of fluvastatin with telaprevir/peg-IFN/RBV was a safe combination. However, fluvastatin had no add-on effect on 24-week telaprevir-based combination therapy for chronic hepatitis C genotype 1b-infected patients.

Topics: Adult; Aged; Anticholesteremic Agents; Antiviral Agents; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Female; Fluvastatin; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Indoles; Male; Medication Adherence; Middle Aged; Oligopeptides; Prospective Studies; Treatment Outcome

Although the anti-hepatitis C virus (HCV) effect of statins in vitro and clinical efficacy of fluvastatin combined with Pegylated interferon (PEG-IFN)/ribavirin therapy for chronic hepatitis C (CHC) have been reported, the details of clinical presentation are largely unknown. We focused on viral relapse that influences treatment outcome, and performed a post-hoc analysis by using data from a randomized controlled trial.. Thirty-four patients in the fluvastatin group and 33 patients in the non-fluvastatin group who achieved virological response (complete early virological response [cEVR] or late virological response [LVR]) with PEG-IFN/ribavirin therapy were subjected to this analysis. Factors contributing to viral relapse were identified by using multiple logistic regression analysis.. Relapse rate in patients with cEVR was significantly lower in the fluvastatin group (2 of 23, 8.7%) than in the non-fluvastatin group (9 of 26, 34.6%; P = 0.042). The use of fluvastatin decreased relapse rate in patients with LVR (27.3% vs 57.1%), though not significantly. Overall, relapse rate was significantly lower in the fluvastatin group (14.7%; 5 of 34) than in the non-fluvastatin group (39.4%; 13 of 33; P = 0.027). Multivariate analysis identified absence of fluvastatin (P = 0.027, odds ratio [OR] = 3.98, 95% confidence interval [CI] = 1.05-15.11) and low total ribavirin dose (P = 0.002, OR = 2.41, 95% CI = 1.38-4.19) as independent factors contributing to relapse.. The concomitant addition of fluvastatin significantly suppressed viral relapse, resulting in the improvement of sustained virological response rate, in PEG-IFN/ribavirin therapy for CHC patients with HCV genotype 1b and high viral load.

Topics: Adult; Aged; Aged, 80 and over; Antiviral Agents; Confidence Intervals; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Female; Fluvastatin; Hepacivirus; Hepatitis C, Chronic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Interferon alpha-2; Interferon-alpha; Logistic Models; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Polyethylene Glycols; Recombinant Proteins; Recurrence; Ribavirin; RNA, Viral

This study assessed the clinical outcome of fluvastatin in addition to the standard regimen used now for treatment of chronic HCV in Egypt. A total of 80 patients with chronic hepatitis C virus infection fulfilled clinical, laboratory and histo-pathological criteria were ready for interferon therapy. They were divided into two groups: GI (N = 40) received standard treatment for HCV (Pegylated interferon and Ribavirin) and GII (N = 40) received standard treatment plus Fluvastatin (80 mg/daily). Six months before and after treatment liver function tests and HCV-RNA were evaluated. The results showed that addition of Fluvastatin to the standard HCV treatment (Pegylated interferon and Ribavirin) significantly increased sustained virological response (SVR) from (55%-62.5%; P < 0.01) and significantly decreased viral load in relapse patients (P < 0.001). No significant differences and correlations were found between serum levels of LDL-cholesterol and viral load before and after treatment in both groups.

Topics: Adult; Antiviral Agents; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Female; Fluvastatin; Hepacivirus; Hepatitis C, Chronic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Interferon-alpha; Liver; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Ribavirin; RNA, Viral; Viral Load; Virus Replication

Pegylated interferon (PEG-IFN)/ribavirin combination therapy is the standard-of-care (SOC) treatment for chronic hepatitis C patients infected with hepatitis C virus (HCV) genotype 1b and high viral load. The addition of fluvastatin to SOC treatment has been suggested to be effective for better outcome in retrospective pilot analyses. We investigated whether the combination of fluvastatin with PEG-IFN/ribavirin could actually improve sustained viral response (SVR) in patients with HCV genotype 1b and high viral load. A randomized, open-labeled, controlled study was conducted between July 2008 and December 2009 in 101 chronic hepatitis C patients allocated to PEG-IFN/ribavirin combination therapy with or without fluvastatin. SVR rates were calculated in groups, stratifying host and viral factors. We also analyzed predictive factors for SVR among patients on fluvastatin with multivariate regression analysis. Rapid and early virological, and end of treatment response rates in the fluvastatin group were not significantly different from those in the non-fluvastatin group. Notwithstanding, SVR rate was significantly higher in the fluvastatin group than in the non-fluvastatin group (63.0%vs 41.7%, P = 0.0422). Comparison of the two groups stratifying demographic data and HCV characteristics showed significantly higher SVR rates to more than 80% in males, more than two mutations in the interferon sensitivity determining region (ISDR), and a history of relapse among the fluvastatin group than the non-fluvastatin group. Being male and major genotype IL28B single nucleotide polymorphisms (SNPs) were independent predictive factors for SVR among patients on fluvastatin with multivariate analysis. Fluvastatin-combined with PEG-IFN/ribavirin therapy significantly improves SVR rates in patients with HCV genotype 1b and high viral load. Male and major genotype IL28B SNPs were independent predictors for SVR among patients on fluvastatin combination therapy.

Topics: Adult; Aged; Aged, 80 and over; Anticholesteremic Agents; Antiviral Agents; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Female; Fluvastatin; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Indoles; Interferons; Interleukins; Male; Middle Aged; Ribavirin; Sex Factors; Treatment Outcome; Viral Load

Recent reports demonstrated in vitro the efficacy of fluvastatin in inhibiting hepatitis C virus (HCV) replication and a synergistic effect in association with interferon-alpha (IFN-alpha). In vivo the inhibition of HCV replication by statins has not been demonstrated. We evaluated in this open-label, randomized controlled study the efficacy of fluvastatin as adjuvant to pegylated-(PEG)-IFN and ribavirin in HIV/HCV genotype 1 co-infected patients.. Forty-four HIV/HCV co-infected patients were randomized to receive, in addition to PEG-IFN-alpha 2b and ribavirin, 80 mg of fluvastatin once daily or no medication. Primary and secondary endpoints were the achievement of sustained virological response (SVR) and rapid virological response (RVR), respectively.. By intent-to-treat analysis, 25% of the patients achieved an SVR. An SVR was observed in 8/21 patients in the fluvastatin arm and in 3/23 patients in the standard therapy arm (P = 0.08). A significantly higher RVR rate was obtained in the fluvastatin arm compared with the standard therapy [7/21 (33%) and 1/23 (4%), respectively; P = 0.02]. Baseline alanine aminotransferase (ALT) values and fluvastatin treatment arm were the only predictors of RVR at the univariate analysis; however, no predictors were independently associated with RVR or SVR at the multivariate analysis.. Fluvastatin addition to standard therapy did not significantly increase the SVR rate in HIV/HCV genotype 1 co-infected patients; however, it did significantly improve the RVR. Further studies are needed to confirm these promising results and to investigate the mechanisms of action of statins in HCV infection.

Topics: Adult; Antiviral Agents; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Female; Fluvastatin; Genotype; Hepacivirus; Hepatitis C, Chronic; HIV Infections; Humans; Indoles; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Treatment Outcome; Viral Load

Fluvastatin showed anti-hepatitis C virus (HCV) activity in vitro, through the inhibition of geranylgeranylation of cellular proteins, and a synergistic effect with interferon (IFN)-alpha. Nevertheless statins up-regulate low-density lipoprotein (LDL) receptor, required for HCV cell entry, and the closely related scavenger receptors SRBI and CD36; moreover they reduce class II major histocompatibility complex expression on antigen presenting cell, modulating T-cell activation. In vivo LDL levels have been identified as prognostic indicator of sustained viral response to IFN in patients with HCV infection, suggesting that lipid-lowering agents might conversely favour HCV entry into the hepatocytes and translate into higher viral replication. We evaluated the effect of fluvastatin on HCV-RNA levels, CD36 expression and T-cell homeostasis in HCV-RNA positive patients. HCV-RNA was measured at baseline and after 4 weeks in 42 HCV/HIV-1 co-infected patients, randomized to receive either fluvastatin 80 mg qd or no treatment. CD36 expression and markers of T-cell activation were evaluated by means of flow cytometry. Plasma interleukin (IL)-10, IFN-gamma and IL-7 were measured by ELISA. Serum cholesterol and LDL decreased significantly in the treatment group (P = 0.0001 and 0.01, respectively). Surprisingly a significant increase of HCV-RNA levels was seen after 4 weeks of fluvastatin (P = 0.03). The percentages of naive/activated/apoptotic cells and CD36 expression remained unchanged. Fluvastatin did not inhibit HCV-RNA replication in vivo; conversely we observed a significant increase of HCV-RNA levels. CD36 expression on monocytes were not up-regulated by statins as previously reported in vitro. The correlation between HCV infectivity, oxidized-LDL receptor and statins in HCV infection need further evaluation.

Topics: Adult; Antiviral Agents; CD36 Antigens; Cells, Cultured; Cholesterol; Cholesterol, LDL; Enzyme-Linked Immunosorbent Assay; Fatty Acids, Monounsaturated; Female; Fluvastatin; Hepacivirus; Hepatitis C, Chronic; HIV Infections; Humans; Indoles; Interferon-gamma; Interleukin-10; Interleukin-7; Male; Middle Aged; Pilot Projects; RNA, Viral; T-Lymphocytes; Treatment Outcome; Virus Replication

BACKGROUND Hepatitis C viral (HCV) infection is the leading cause of death due to liver disease in the United States. Currently, pegylated interferon and ribavirin produce sustained viral remission in only 50% of patients. Additional agents are needed to increase the cure rate. In vitro experiments show strong antiviral effects of fluvastatin against HCV.. To assess the safety and antiviral effects of fluvastatin in chronic HCV carriers.. 31 veterans with chronic HCV were prospectively given oral doses of fluvastatin, 20 to 320 mg/day, for 2-12 weeks with weekly monitoring of HCV RNA and liver tests. Reductions of viral load (P < 0.01) versus a control group were considered suppressive.. With 80 mg a day or less, 11/22 (50%) patients responded by lowering HCV RNA. The first lowering occurred within 4 weeks (9/11, 82%). The greatest weekly change in HCV RNA level was a 1.75 log(10) reduction. When lowered in responders, the viral load remained relatively constant for 2-5 weeks (7/9, 78%), or on the next test rebounded immediately to a non-significant change from, baseline (n = 2). Continued lowering of virus was seen in 2/19 (22 %) patients when the study ended. We found no evidence of liver tests worsening.. FLV used as monotherapy in vivo showed suppressive effects of HCV clinically that are modest, variable, and often short-lived. These findings support "proof-of-concept" for pilot trials combining fluvastatin with standard therapy. Statins and fluvastatin, in particular, appear to be safe for use in hepatitis C.

Topics: Administration, Oral; Adult; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatty Acids, Monounsaturated; Female; Fluvastatin; Hepatitis C, Chronic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Liver Function Tests; Male; Middle Aged; Prospective Studies; Treatment Outcome; Viral Load

There is a relationship between the life cycle of the hepatitis C virus (HCV) and the synthesis and hemostasis of lipids as well as lipid metabolism and interferon (IFN) regulatory system. This study was aimed to examine the effect of fluvastatin and IFN-ƛ in the expression of mediators involved in lipid metabolism and HCV proliferation in patients with rs12979860 CC polymorphism. Thirteen patients with HCV and five controls with rs1297986CC polymorphism were included in this study. Peripheral blood mononuclear cells (PBMCs) of patients and controls were treated by fluvastatin, IFN-λ or fluvastatin+IFN-λ. Assessment of IL-28B polymorphism, RNA extraction, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was performed. The mRNA expression of sterol regulatory element-binding protein 1 c (SREBP1c), ATP-binding cassette transporter A1 (ABCA1), diacylglycerol acyltransferase 1 (DGAT1), and HCV core as well as measurement of ABCA1 protein level were evaluated before and after treatment. The results indicated that IFN-λ +fluvastatin acted as an inhibitor in mRNA expression of SREBP1c; while acting as an inducer in the expression of ABCA-1. The results of ABCA1 assay showed a significant increase of this protein after treatment with fluvastatin and IFN-λ compared with untreated cells (p=0.02). Moreover, the mRNA expression of HCV core was suppressed in all experimental groups treated with fluvastatin, IFN-λ or their combination which was more significant after treatment with fluvastatin+IFN-λ (p<0.001). The results of this study demonstrated the significant effect of treatment with fluvastatin+IFN-λ in PBMCs of HCV patients with rs12979860 CC polymorphism. According to the drug resistance of viruses and prevention of virus-induced steatosis in patients with HCV, using regulatory agents of lipid mediators in parallel with current medications could be considered as an effective therapeutic strategy.

Topics: Adult; Antiviral Agents; ATP Binding Cassette Transporter 1; Cells, Cultured; Drug Synergism; Female; Fluvastatin; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Interferons; Leukocytes, Mononuclear; Male; Middle Aged; Polymorphism, Genetic

Statins are associated with delayed fibrosis progression and a reduced risk of hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV). Limited data exist regarding the most effective type and dose of statin in this population. We sought to determine the impact of statin type and dose upon fibrosis progression and HCC in patients with HCV. Using the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database, we identified all subjects initiated on HCV antibody (anti-HCV) therapy from 2001 to 2014, and all incident cases of cirrhosis and HCC. Statin use was measured using cumulative defined daily dose (cDDD). Multivariable Cox's proportional hazard regression models were used to examine the relationship between statin use and development of cirrhosis and HCC. Among 9,135 eligible subjects, 1,649 developed cirrhosis and 239 developed incident HCC. Statin use was associated with a 44% reduction in development of cirrhosis (adjusted hazard ratio [HR]: 0.6; 95% confidence interval [CI]: 0.53, 0.68). The adjusted HRs (95% CI) of fibrosis progression with statin cDDD 28-89, 89-180, and >180 were 0.74 (0.59, 0.93), 0.71 (0.59, 0.88), and 0.6 (0.53, 0.68), respectively. Mean change in FIB-4 score with atorvastatin (n = 944) and fluvastatin (n = 34) was -0.17 and -0.13, respectively (P = 0.04), after adjustment for baseline FIB-4 score and established predictors of cirrhosis. Statin use was also associated with a 49% reduction in incident HCC (adjusted HR: 0.51; 95% CI: 0.36, 0.72). A similar dose-response relationship was observed.. In patients with chronic HCV, statin use was associated with a dose-dependent reduction in incident cirrhosis and HCC. Atorvastatin and fluvastatin were associated with the most significant antifibrotic effects, compared with other statins. (Hepatology 2016;64:47-57).

Topics: Atorvastatin; Carcinoma, Hepatocellular; Cohort Studies; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Female; Fibrosis; Fluvastatin; Hepatitis C, Chronic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged

There is currently no consensus treatment for children non-responsive to peginterferon (Peg-IFN) and ribavirin.. Here, we present a Japanese child with chronic hepatitis C with fibrosis, who did not respond to Peg-IFN α-2b but responded to Peg-IFN α-2a with ribavirin, accompanied with fluvastatin. To date, there has been no reported case of re-treatment in children. The early viral response occurred soon after starting treatment using Peg-IFN α-2a/ribavirin plus fluvastatin.. Our result indicates that when treatment by Peg-IFN α-2b/ribavirin combination therapy is not efficient, combination therapy using Peg-IFN α-2a/ribavirin plus fluvastatin should be considered in children with advanced liver change.

Topics: Antiviral Agents; Child; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Fluvastatin; Hepatitis C, Chronic; Humans; Indoles; Interferon alpha-2; Interferon-alpha; Male; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Treatment Outcome

Topics: Antiviral Agents; Fatty Acids, Monounsaturated; Female; Fluvastatin; Hepacivirus; Hepatitis C, Chronic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male

Topics: Fatty Acids, Monounsaturated; Fluvastatin; Hepacivirus; Hepatitis C, Chronic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; RNA, Viral

Response to pegylated (PEG) interferon (IFN) and ribavirin is achieved only in 40-50% of patients infected with hepatitis C virus (HCV) of genotype 1 in high viral loads, which needs to be improved.. In an open-label pilot study, fluvastatin (HMG-CoA reductase inhibitor), 20 mg daily, was given along with PEG-IFN/ribavirin to 21 patients with chronic hepatitis C. They were followed for HCV RNA in serum.. During treatment for 48 weeks, HCV RNA was lost from serum in 93% of the patients. In the 15 patients who received 48-week therapy, a sustained virological response (SVR) with loss of HCV RNA 24 weeks after completion was achieved in 10 (67%), including 7 of the 9 (78%) male and 3 of the 6 (50%) female patients. In the remaining 6 patients who received 72-week therapy, SVR was gained in 4 (67%), including 1 of the 2 male and 3 of the 4 female patients aged 56, 58 and 62 years, respectively.. Fluvastatin could be used safely to increase the response to PEG-IFN and ribavirin, especially in aged women who respond poorly to combined PEG-IFN/ribavirin.

Topics: Adult; Antiviral Agents; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Female; Fluvastatin; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Pilot Projects; Polyethylene Glycols; Recombinant Proteins; Ribavirin; RNA, Viral; Treatment Outcome; Viral Load

With optimal treatment regimens for hepatitis C still under investigation, novel agents that may improve sustained virologic response (SVR) are needed. The targeting of host lipid metabolism, particularly via the cholesterol-lowering 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins, represents a novel approach to hepatitis C therapy and has been proven beneficial in vitro. The study in this issue of the Journal is the first prospective trial that shows benefit, albeit modest, of statin therapy in vivo. While limited by heterogeneous patient population and overall small numbers, this study provides hope that use of statins in combination with standard therapy pegylated interferon and ribavirin may improve SVR.

Topics: Antiviral Agents; Fatty Acids, Monounsaturated; Fluvastatin; Hepacivirus; Hepatitis C, Chronic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Viral Load; Virus Replication

The statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have emerged as the drugs of choice for patients with dyslipidemia and have been shown to reduce major cardiovascular adverse events in large-scale clinical trials for both primary and secondary prevention. Statins are generally safe; however, the results of clinical trials do demonstrate possibilities of significant adverse effects in liver and muscle. Moreover, the numbers from the trials may not reflect the real situation in daily practice because individuals at increased risk for hepatotoxicity are usually deliberately and carefully excluded in clinical trials. We presented an 85-year-old woman who had a marked elevation of ALT (up to 409 U/L) after treatment with fluvastatin 80 mg/day for 6 weeks. Hepatitis C was identified after this episode. The elevation of ALT resolved 10 weeks after discontinuation of fluvastatin. Re-institution of fluvastatin from 40 to 80 mg/day for 2 months only cause mild elevation of ALT. This case suggests that elevation of transaminases during statin therapy may not be solely ascribed to statins. Re-challenge with the same statin at lower doses or with other statins may help to identify the patients who can still be treated with drugs of this category.

Topics: Aged; Aged, 80 and over; Alanine Transaminase; Drug Interactions; Fatty Acids, Monounsaturated; Female; Fluvastatin; Hepatitis C, Chronic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Liver

We recently developed a genome-length hepatitis C virus (HCV) RNA replication system (OR6) with luciferase as a reporter. The OR6 assay system has enabled prompt and precise quantification of HCV RNA replication. Pegylated interferon (IFN) and ribavirin combination therapy is the world standard for chronic hepatitis C, but its effectiveness is limited to about 55% of patients. Newer therapeutic approaches are needed. In the present study, we used the OR6 assay system to evaluate the anti-HCV activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, called statins, and their effects in combination with IFN-alpha. Five types of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) were examined for their anti-HCV activities. Fluvastatin exhibited the strongest anti-HCV activity (IC50: 0.9 micromol/L), whereas atorvastatin and simvastatin showed moderate inhibitory effects. However, lovastatin, reported recently as an inhibitor of HCV replication, was shown to exhibit the weakest anti-HCV activity. The anti-HCV activities of statins were reversed by the addition of mevalonate or geranylgeraniol. Surprisingly, however, pravastatin exhibited no anti-HCV activity, although it worked as an inhibitor for HMG-CoA reductase. The combination of IFN and the statins (except for pravastatin) exhibited strong inhibitory effects on HCV RNA replication. In combination with IFN, fluvastatin also exhibited a synergistic inhibitory effect. In conclusion, statins, especially fluvastatin, could be potentially useful as new anti-HCV reagents in combination with IFN.

Topics: Antiviral Agents; Cells, Cultured; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Fluvastatin; Hepacivirus; Hepatitis C, Chronic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro Techniques; Indoles; Interferon-alpha; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral; Treatment Outcome; Virus Replication