Abstract
Background
We sought to determine the effect of statin therapy on serum AST and ALT levels in a cohort of HCV-infected veterans with well-characterized liver disease.
Study
We examined liver biopsy records of consecutive HCV-infected patients and identified 20 patients who were prescribed statins. We matched them on age, stage of fibrosis, and time between HCV diagnosis and statin start dates with up to four HCV-infected patients who did not use statins. ALT and AST values from up to four time points within 1 year of follow-up were abstracted from the medical record. We compared median ALT and AST levels using Wilcoxon–Mann–Whitney tests and assessed changes in ALT and AST over time between the statin and non-statin groups using a non-parametric repeated measures ANOVA model, adjusting for the matching factors, receipt of HCV treatment, BMI, and diabetes.
Results
Patients prescribed statins had higher median BMIs, were more likely to have diabetes, and had higher total cholesterol levels. Median baseline ALT levels were higher among those prescribed statins (P = 0.04) while median baseline AST levels were lower among statin users (P = 0.03). From baseline to follow-up, the median decreases in both ALT (−13.5 vs. −4.0) and AST (−4.5 vs. −0.5) were significantly larger among statin users compared to non-statin users (P = 0.03 and P = 0.0007, respectively) even after adjustment.
Conclusions
Among HCV-infected patients AST and ALT levels for those prescribed statins decreased over a 6 to 12-month follow-up period compared to patients not taking statins.
Keywords: Hepatitis C virus, Statins, Transaminases, Veterans
Introduction
Coronary heart disease (CHD) is the leading cause of death in the US [1], accounting for one out of every five deaths [2]. The risk factors for CHD include older age, smoking, overweight/obesity, diabetes, as well as high blood cholesterol [2]. A 10% reduction in total cholesterol levels at the population level is estimated to result in a 30% decrease in the incidence of CHD [3]. The most effective cholesterol-lowering drugs are 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, referred to as statins, which act to block the formation of cholesterol in the liver and also generate additional LDL receptors that absorb LDL-cholesterol from the blood [4]. Clinical trials have shown that the use of statins reduces LDL-cholesterol levels by 20–45%, which in turn leads to decreases in CHD and all cause mortality [4–6].
Despite the proven benefits of statins, concern with potential hepatotoxicity of statin drugs in patients with liver disease may have resulted in a reduction of statin use in this subset of the population. A meta-analysis published in 2004 reported that the use of statins increased amino-transferase levels by 0.2 to 2.7% in subjects without liver disease [7]. Although one study reported an increase in risk of mild to moderate hepatotoxicity [8], most studies examining AST or ALT levels among patients with HCV infection found no evidence for increased risk of hepatotoxicity [9, 10]. In 2006, the Liver Expert Panel stated that chronic liver disease is not a contraindication for statin therapy [11].
Recently, an HCV-related beneficial effect of statin use among patients with HCV-related liver disease has been suggested. In vitro studies show that high concentrations of statins disrupt HCV replication via depletion of isoprenoid geranylgeranyl pyrophosphate [12, 13]. Statins may thus have antiviral effects through mechanisms not related to lipid metabolism [14, 15]. A pilot study of 31 HCV-infected veterans who were given fluvastatin 20–320 mg/day for 2–12 weeks with weekly monitoring of HCV RNA and liver tests reported modest reductions of viral load [16]. Furthermore, a pharmacoepidemiologic study found that the use of lovastatin was associated with a 40–50% lower incidence of moderate as well as severe liver injury among patients with preexisting liver disease although baseline severity and cause of liver disease could not be adjusted for [17]. Even though prior individual studies examined important aspects of the association between statin and liver disease in HCV-infected patients, these studies either did not adjust for histological severity of liver disease, had generally short follow-up, or did not use control subjects. Clearly, more information is needed about the possible beneficial effect of statins in HCV-infected patients before these medications are considered for an interventional study.
The purpose of this study was to determine the effect of statin therapy on serum levels of AST and ALT in a cohort of HCV-infected veteran patients with well-characterized liver disease.
Materials and Methods
Study Design
We conducted a retrospective cohort study among consecutive patients with laboratory confirmed HCV-infection who had a liver biopsy between Jan 10, 1994, and Nov 26, 2003, at the Michael E. DeBakey VA Medical Center in Houston, TX. Patients were identified through review of the log of liver biopsy records.
We identified 34 HCV-infected patients with liver biopsy who were prescribed statins (simvastatin or lovastatin). We limited our sample to males who had at least two ALT/AST readings during 1 year of follow-up subsequent to statin start date. We excluded one patient who was HIV positive, seven patients with only one recorded ALT/AST measurement, four patients with statin use before HCV ELISA date, and two patients with statin discontinuation prior to their second ALT/AST measurement. Hence, we included 20 HCV-infected patients with liver biopsy who were prescribed statins. We then matched these patients with up to four HCV-infected patients who did not use statins. Patients were matched on age (±5 years), stage of fibrosis on liver biopsy, and time between HCV diagnosis date (IgG test) date and statin start date. We employed the same exclusion criteria outlined above and identified 64 HCV-infected patients with liver biopsy who were not prescribed statins.
ALT/AST Measurements
For the cohort of 84 HCV-infected patients (20 on statin and 64 not on statin), ALT and AST values from up to four time points within 1 year were abstracted from the medical record. For those prescribed statins, the baseline ALT/AST measurement was the first recorded value prior to the statin start date. In order to have a comparable time frame between HCV diagnosis date and measurement of ALT/AST values for the non-statin group, we computed a time period in which to assess these measurements among the non-statin group. Among those not prescribed statins, the first measurement was taken as the closest reading to the time of the HCV diagnosis date plus the number of days until statin start date for the matched statin user. For both the statin and non-stain groups the second measurement was assessed 4–7 weeks later, the third measurement was taken 8–25 weeks later, and the fourth reading was obtained 6–12 months after the first reading.
Covariates
Covariate information was abstracted from the medical record. Comorbidity data included the presence of diabetes or hypertension. Behavioral information included current and prior alcohol consumption as well as current and prior tobacco use. Patient characteristics included race, ethnicity, and body mass index (BMI) at the time of liver biopsy. Clinical information collected included HCV treatment (within a median of 23 months), HDL-cholesterol, and LDL-cholesterol measurements at baseline.
Statistical Analyses
We compared characteristics of the statin and non-statin groups using Chi-square tests for discrete measures and Wilcoxon–Mann–Whitney tests for continuous measures [18]. To ascertain if differences in transaminase levels in units/liter (U/L) (ALT and AST separately) between the statin and non-statin groups existed at baseline and at 6–12 months, we compared median ALT and AST levels using Wilcoxon–Mann–Whitney tests. Finally, we assessed changes in ALT and AST over time (between baseline and at 6–12 months after baseline) between the statin and non-statin groups using a non-parametric repeated-measures ANOVA model to adjust for the matching factors (age, fibrosis stage on liver biopsy, and time between HCV diagnosis and statin start date), receipt of HCV treatment, BMI, and diabetes. The study was approved by the IRB of Baylor College of Medicine. As a retrospective chart review, individual informed consent was not required.
Results
Characteristics of the HCV-infected cohort by statin use are provided in Table 1. There were no significant differences between 20 HCV-infected patients who received statin therapy and 64 who did not with regard to age, race, ethnicity, HCV genotype, HCV viral load, alcohol consumption, hypertension, tobacco use, fibrosis stage, or receipt of HCV treatment. Of the 20 patients who received statins, most (80%) were prescribed simvastatin, and 15% were prescribed lovastatin. Patients that were prescribed statins had higher median BMIs (30.3 vs. 27.7, P = 0.02), were more likely to have diabetes (45 vs. 16%, P value = 0.02), and had higher total cholesterol levels (201 vs. 180 mg/dl, P = 0.04).
Table 1.
Characteristics of the HCV-infected cohort by statin use
| Characteristic | Prescribed statins n = 20 # (%) |
Not prescribed statins n = 64 (%) # (%) |
P-value |
|---|---|---|---|
| Age (years), median | 52.0 | 50.0 | 0.13 |
| Race | |||
| African-American | 10 (50) | 39 (61) | 0.39 |
| White | 10 (50) | 22 (34) | |
| Other/unknown | 0 (0) | 3 (5) | |
| Ethnicitya | |||
| Hispanic | 1 (5) | 5 (8) | 0.99 |
| Non-Hispanic | 19 (95) | 58 (92) | |
| HCV genotype | |||
| 1 | 16 (80) | 51 (79) | 0.20 |
| 2 | 3 (15) | 3 (5) | |
| 3 | 1 (5) | 0 (0) | |
| 4 | 0 (0) | 1 (2) | |
| Not done | 0 (0) | 9 (14) | |
| RNA viral loadc, median | 534,460 | 553,081 | 0.99 |
| Alcohol use (current) | 13 (65) | 53 (83) | 0.12 |
| BMIa, median | 30.3 | 27.7 | 0.02 |
| Diabetes | 9 (45) | 10 (16) | 0.01 |
| Hypertension | 12 (60) | 41 (64) | 0.79 |
| Tobacco use (current) | 15 (75) | 39 (61) | 0.30 |
| HDL-cholesterolb, median | 35.0 | 46.0 | 0.04 |
| LDL-cholesterolb, median | 123.4 | 109.4 | 0.06 |
| Total-cholesterolb, median | 201.0 | 180.0 | 0.04 |
| Triglycerides, median | 149.0 | 109.0 | 0.10 |
| Liver biopsy fibrosis stage | |||
| 1 | 5 (25) | 11 (17) | 0.95 |
| 2 | 5 (25) | 20 (31) | |
| 3 | 3 (15) | 9 (14) | |
| 4 | 3 (15) | 9 (14) | |
| Unknown | 4 (20) | 15 (23) | |
| Received HCV treatment | 13 (65) | 38 (59) | 0.65 |
Ethnicity missing for one non-statin user; BMI missing for one statin user
HDL missing for seven non-statin users and one statin users; LDL missing for 14 non-statin users and four statin users; Tot Chol missing for five non-statin users and 0 statin users; triglycerides missing for seven non-statin users and one statin user
HCV RNA viral load missing for nine statin users and 30 non-statin users
Since the majority of statin users did not have AST and ALT readings at the second (4–7 weeks) and third (8–25 weeks) time points, the analyses presented in Table 2 focus on the comparison between measurements taken at baseline and the fourth time point (occurring between 6 and 12 months). In comparing the median AST and ALT levels between the statin and non-statin groups, we found that median baseline ALT levels were approximately 1.4 times higher among those prescribed statins (P = 0.04) while median baseline AST levels were approximately one-third lower among statin users (P = 0.03). There were decreases in both ALT and AST from baseline to follow-up that were significantly larger among statin users compared to non-statin users (P = 0.03 and P = 0.0007, respectively). After adjusting for the matching factors, receipt of HCV treatment, BMI, and diabetes, the results were unchanged (data not shown).
Table 2.
Comparison of AST and ALT levels (U/l) by statin use at baseline and at 6–12 month follow-up
| Statin users N = 20 |
Non-statin users N = 64 |
P-value | |
|---|---|---|---|
| Median serum ALT levels (U/l) | |||
| Baseline | 63.5 | 47.0 | 0.04 |
| Follow-up | 52.5 | 44.0 | 0.34 |
| Change from baseline to follow-up | −13.5 | −4.0 | 0.03 |
| Median serum AST levels (U/l) | |||
| Baseline | 41.0 | 63.0 | 0.03 |
| Follow-up | 38.5 | 58.0 | 0.01 |
| Change from baseline to follow-up | −4.5 | −0.5 | 0.0007 |
Among the 20 statin users, 13 (65%) underwent HCV treatment. Of these, ten had HCV treatment before statin use and three had HCV treatment after statin was started. None of these patients had undetectable virus counts.
The disproportionate declines in AST and ALT median values among statin users seemed to be related to a greater proportion of patients having the decline rather than the magnitude of decline. ALT declined for 13/20 (65%) statin users vs. 37/64 (58%) non-statin users. Among statin users, the smallest decrease was 3% and the largest decrease was 63%. For non-statin users, the smallest decrease was 2% and the largest decrease was 67%. Similarly, AST declined for 11/20 (55%) statin users vs. 32/64 (50%) non-statin users. Among statin users, the smallest decrease was 8% and the largest decrease was 63%. For non-statin users, the smallest decrease was 2% and the largest decrease was 87%.
For those who did not show an ALT decrease, there was no association between race and fibrosis stage (P = 0.5). Similarly, for those with no AST decrease, there was no association between race and fibrosis stage (P = 0.6).
Discussion
We found that among HCV-infected patients, patients prescribed a statin medication had larger declines in AST and ALT levels from baseline to follow-up (6–12 months later) compared to those not prescribed statins after matching on age, stage of fibrosis, and time between HCV diagnosis and statin start dates. Further adjustment for receipt of HCV treatment, BMI, and diabetes did not change our findings.
Our results add to the findings of at least five previous studies that examined hepatotoxicity related to statin use among HCV-infected patients (summarized in Table 3). In 2005, Gibson and Rindone [9] reported that the use of statins was not associated with elevations in AST or ALT enzymes in 17 HCV-infected veterans from the Northern Arizona VA Health Care System. A second VA study from the West Palm Beach VA Medical Center evaluated the hepatotoxicity of statins in 146 HCV-infected patients and reported no significant change in ALT levels [10]. These two studies [9, 10] did not use a comparison group of patients not treated with statins so it was unclear how ALT or AST levels among HCV-infected individuals behave in the absence of statins. A subsequent study published in 2006 examined hepatotoxicity from statin use in 166 HCV-infected patients receiving statins compared with two control groups that were matched on age, sex, and BMI—one group consisting of 332 HCV-infected patients not receiving statins and another group comprised of 332 HCV-uninfected patients receiving statins [8]. That study found that compared to HCV-infected patients who were not prescribed statins, HCV-infected patients who were on statin therapy had a decreased risk of severe hepatotoxicity (>10 times ULN, 7 vs. 1%, P = 0.015) but an increased risk of mild to moderate hepatotoxicity (up to 10 times ULN, 13 vs. 23%, P = 0.009). In 2008 Bader et al. [16] published results from a trial in which 31 HCV-infected veterans from Oklahoma City were given oral doses of fluvastatin. Bader et al. reported finding no evidence that ALT worsened during treatment with fluvastatin. Additional adjustment for potential confounding factors as identified by medical chart review would enhance the study designs of all four studies. The last study by Lewis et al. was a randomized controlled trial of pravastatin 80 mg or placebo given to large group of patients with compensated chronic liver disease, 81 of whom were HCV-infected. The subgroup analysis revealed no significant differences in ALT levels before or during statin treatment [19].
Table 3.
Summary of prior studies examining LFT/statin use among HCV-infected patients
| Author, year |
Population | Exposure | Outcome | Result |
|---|---|---|---|---|
| Bader [16] | OK veterans | Baseline to follow-up | Change in ALT | No increase in ALT; non-significant decrease in VL |
| 31 HCV + statin | ||||
| Change in viral load | ||||
| Gibson [9] | AZ veterans | Baseline to follow-up | Change in ALT or AST | Greatest increase in ALT/AST was 1.5× ULN |
| 17 HCV + statin | ||||
| Khorashadi [8] | Palo Alto veterans | Statin versus no statin; HCV+ versus HCV− | Compare hepatotoxicity b/t statin and non-statin groups | Proportion with hepatotoxicity statin versus non-statin HCV + mild/mod: 23 vs. 13%, P = 0.009 |
| 166 HCV + statin | ||||
| 332 HCV + no statin | Mild/moderate: up to 10 times ULN | |||
| 332 HCV-statin | Severe: 1 vs. 7%, P = 0.015 | |||
| Severe: >10× ULN | ||||
| Segarra-Newnham [10] | FL veterans | Baseline to follow-up | Change in LDL | 22% LDL reduction, P < 0.05 No change in ALT |
| 146 HCV + statin | Change in ALT | |||
| Lewis [19] | 81 HCV infected in a trial of 326 patients | Pravastatin (n = 38) or placebo (n = 43) | Change in LDL | Significant LDL reduction |
| Change in ALT | No difference in ALT change |
HCV hepatitis C virus, ALT alanine aminotransferase, AST aspartate aminotransferase, ULN upper limit of normal, P P-value, LDL low density lipoprotein-cholesterol, VL viral load
Interest in a possible beneficial effect of statins has emerged over the last decade as concerns about hepatoxicity are being addressed [19–22]. Statins have been shown in vitro to inhibit hepatic stellate cells proliferation and their production of collagens in a dose-dependent manner [23, 24], with the addition of mevalonic acid (the product of HMG-CoA reductase), reversing the effect [23]. Statins may also have an effect specific to HCV. It has been shown that HCV replication depends in part on geranylgeranylation of a host protein and that HCV RNA replication can be disrupted in vitro by high concentrations of statins. This effect was presumably due to severe depletion of mevalonic acid, which led to low cellular levels of geranylgeranyl pyrophosphates, the substrate for the geranylgeranyl-transferase [12, 25]. However, whether these in vitro effects of statins on HCV have any clinical relevance is not known. Last, it is possible that statins reduce hepatic steatosis, which has been implicated as a risk factor for hepatic fibrosis and cirrhosis. Given our preliminary findings of improved LFTs in statin users, future studies need to measure and adjust for steatosis, fibrosis, and viral levels in order to disentangle the mechanism beneficial effect (if any) of statins.
Our study has to be interpreted within its limitations. Since the study is a retrospective cohort study, patients were not randomly assigned to the statin or non-statin group. While we measured several potential confounders and adjusted for these in our models, it is still possible that other unmeasured factors could account for our results. Additionally, the number of HCV-infected veterans in our study was relatively small. Our study could be improved with additional data such as serial measurements of HCV viral load. While the study was adequately powered to detect differences in the average ASL and ALT levels, the estimates are not very precise due to the relatively limited sample size. Due to the retrospective nature of the study and the small sample size, analyzing additional outcomes such as time to cirrhosis is likely to be inaccurate and considerably underpowered.
In conclusion, we found that among HCV-infected patients AST and ALT levels for those prescribed statins decreased over a 6–12 month follow-up period compared to patients not taking statins. These results add to the growing body of evidence that statin use in patients with HCV infection is likely safe. Larger and prospective studies are needed to more definitively evaluate the possible beneficial impact on HCV-related liver disease.
Acknowledgments
The work was partly supported by NIH K24DK078154-03 for Dr. El-Serag, and Public Health Service Grant DK56338, which funds the Texas Medical Center Digestive Disease Center.
References
- 1.Kung HC, Hoyert DL, Xu JQ, et al. National vital statistics reports. no 10. vol 56. Hyattsville, MD: National Center for Health Statistics; 2008. Deaths: final data for 2005. [PubMed] [Google Scholar]
- 2.Lloyd-Jones D, Adams R, Carnethos M, et al. Heart disease and stroke statistics—2009 update: a report from the American Heart Association statistics committee and stroke statistics subcommittee. Circulation. 2009;119:e1–e161. doi: 10.1161/CIRCULATIONAHA.108.191259. [DOI] [PubMed] [Google Scholar]
- 3.Centers for Disease Control and Prevention (CDC) State-specific cholesterol screening trends: United States, 1991–1999. MMWR. 2000;49:750–755. [PubMed] [Google Scholar]
- 4.Gotto AM. Statins: powerful drugs for lowering cholesterol. Circulation. 2002;105:1514–1516. doi: 10.1161/01.cir.0000014245.25136.d2. [DOI] [PubMed] [Google Scholar]
- 5.Pasternak RC, Smith SC, Bairey-Merz CN, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. JACC. 2002;3:567–572. doi: 10.1016/s0735-1097(02)02030-2. [DOI] [PubMed] [Google Scholar]
- 6.National Cholesterol Education Program (NCEP) Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation. 2002;06:3143–3421. [PubMed] [Google Scholar]
- 7.De Denus S, Spinler SA, Miller K, et al. Statins and liver toxicity: a meta-analysis. Pharmacotherapy. 2004;24:584–591. doi: 10.1592/phco.24.6.584.34738. [DOI] [PubMed] [Google Scholar]
- 8.Khorashadi S, Hasson NK, Cheung RC. Incidence of statin hepatotoxicity in patients with Hepatitis C. Clin Gastroenterol Hepatol. 2006;4(7):902–907. doi: 10.1016/j.cgh.2006.03.014. [DOI] [PubMed] [Google Scholar]
- 9.Gibson K, Rindone JP. Experience with statin use in patients with chronic hepatitis C infection. Am J Cardiol. 2005;96(9):1278–1279. doi: 10.1016/j.amjcard.2005.06.071. [DOI] [PubMed] [Google Scholar]
- 10.Segarra-Newnham M, Parra D, Martin-Cooper EM. Effectiveness and hepatoxicity of statins in men seropositive for hepatitis C virus. Pharmacotherapy. 2007;27(6):845–851. doi: 10.1592/phco.27.6.845. [DOI] [PubMed] [Google Scholar]
- 11.Cohen DE, Anania FA, Chalasani N. An assessment of statin safety by hepatologists. Am J Cardiol. 2006;97(suppl):77C–81C. doi: 10.1016/j.amjcard.2005.12.014. [DOI] [PubMed] [Google Scholar]
- 12.Ye J, Wang C, Sumpter R, Jr, et al. Disruption of hepatitis C virus RNA replication through inhibition of host protein geranylgeranylation. Proc Natl Acad Sci USA. 2003;100(26):15865–15870. doi: 10.1073/pnas.2237238100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Kapadia SB, Chisari FV. HCV RNA replication is regulated by host geranylgeranylation and fatty acids. Proc Natl Acad Sci USA. 2005;7:2561–2566. doi: 10.1073/pnas.0409834102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Ikeda M, Abe K, Yamada M, et al. Different anti-HCV profiles of statins and their potential for combination therapy with interferon. Hepatology. 2006;44(1):117–125. doi: 10.1002/hep.21232. [DOI] [PubMed] [Google Scholar]
- 15.Bader T, Fazili J, Madhoun M, et al. Fluvastatin inhibits hepatitis C replication in humans. Am J Gastroenterol. 2008;103(6):1383–1389. doi: 10.1111/j.1572-0241.2008.01876.x. [DOI] [PubMed] [Google Scholar]
- 16.Avins AL, Manos MM, Ackerson L, et al. Hepatic effects of lovastatin exposure in patients with liver disease: a retrospective cohort study. Drug Saf. 2008;31(4):325–334. doi: 10.2165/00002018-200831040-00006. [DOI] [PubMed] [Google Scholar]
- 17.Wackerly DD, Mendenhall W, III, Scheaffer RL. Mathematical statistics with applications. Belmont, CA: Wadsworth Publishing Company, Duxbury Press; 1996. [Google Scholar]
- 18.Bhardwaj SS, Chalasani N. Lipid-lowering agents that cause drug-induced hepatotoxicity. Clin Liver Dis. 2007;11:597–613. doi: 10.1016/j.cld.2007.06.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Onofrei MD, Butler KL, Fuke DC, et al. Safety of statin therapy in patients with preexisting liver disease. Pharmacotherapy. 2008;28(4):522–529. doi: 10.1592/phco.28.4.522. [DOI] [PubMed] [Google Scholar]
- 20.Chalasani N, Aljadhey, Kesterson J, et al. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology. 2004;126:1287–1292. doi: 10.1053/j.gastro.2004.02.015. [DOI] [PubMed] [Google Scholar]
- 21.Lewis JH, Mortensen ME, Zweig S, et al. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology. 2007;46:1453–1463. doi: 10.1002/hep.21848. [DOI] [PubMed] [Google Scholar]
- 22.Mallat A, Preaux AM, Blazejewski S, et al. Effect of simvastation, an inhibitor of hydroxyl-methylglutaryl coenzyme A reductase, on the growth of human lto cells. Hepatology. 1994;20(6):1589–1594. doi: 10.1002/hep.1840200631. [DOI] [PubMed] [Google Scholar]
- 23.Rombouts K, Kisanga E, Hellemans K, et al. Effect of HMG-CoA reductase inhibitors on proliferation and protein synthesis by rat hepatic stellate cells. J Hepatol. 2003;38:564–572. doi: 10.1016/s0168-8278(03)00051-5. [DOI] [PubMed] [Google Scholar]
- 24.Wang C, Gale M, Keller B, et al. Identification of FBL2 as a geranylgeranylated cellular protein required for hepatitis C virus RNA replication. Mol Cell. 2005;18:425–434. doi: 10.1016/j.molcel.2005.04.004. [DOI] [PubMed] [Google Scholar]
- 25.Lok AS, Everhart JE, Chung RT, et al. Evolution of hepatic steatosis in patients with advanced hepatitis C: results from the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial. Hepatology. 2009;49:1828–1837. doi: 10.1002/hep.22865. [DOI] [PMC free article] [PubMed] [Google Scholar]