Beneficial Effect of Statins on HCV Infection
Posted on May 31, 2015
In a large, national cohort study assessing the impact of statin use upon progression of fibrosis in an unselected group of patients with various stages and genotypes of HCV, controlling for known confounders, statin use was significantly associated with decreased progression of fibrosis independent of having attained an SVR. This is the first study to demonstrate that statin use is significantly associated with increased SVR rates and decreased progression to cirrhosis and hepatocellular carcinoma.
Biologic plausibility can be assigned to the potential benefits of HMG-CoA reductase inhibitors (statins) on virologic response to hepatitis C therapies, fibrosis progression, and incidence of hepatocellular carcinoma, as the host cell lipid metabolism is critical for HCV infectivity and viral replication. However, up until now, antiviral studies of statins in patients with chronic HCV infection have been small and inconclusive. The promising results of a large, national HCV cohort study to further understand the impact of statins upon sustained virologic response, fibrosis progression, development of liver cirrhosis and incidence of hepatocellular carcinoma, have been recently published online in the journal Hepatology (Butt AA et al. Hepatology. 2015 Apr 6. doi: 10.1002/hep.27835. [Epub ahead of print])
- Study participants included persons with HCV infection in the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES). ERCHIVES is a well-established national cohort of HCV infected Veterans and uninfected controls assembled from multiple national databases.
- All HCV infected Veterans seen at any of the Department of Veterans Affairs (VA) facilities were identified based on a positive HCV antibody test between 2002 and 2013.
- Subjects in this study had received at least 14 days of treatment for HCV. Baseline was defined as the date of HCV treatment initiation. If multiple courses of therapy were administered, the most recent course was used for analysis.
- Those with HIV coinfection, positive hepatitis B surface antigen, liver cirrhosis and hepatocellular carcinoma at baseline were excluded from this study.
- Cirrhosis was defined as a FIB-4 score of >3.5. Laboratory data were obtained at yearly intervals and FIB-4 was calculated using these values.
- Sustained virologic response was defined as achieving a negative test for circulating HCV RNA 12 or more weeks after treatment completion.
- Primary outcome measures were 1) progression of liver fibrosis as measured by FIB-4 score; 2) development of cirrhosis defined as FIB-4 score of >3.5; and 3) incident hepatocellular carcinoma based on ICD-9 codes.
Of the evaluable study population (N = 7,248) was divided into two groups, those who received statin therapy (n = 3347, statin group) and those who did not receive any statin therapy (n = 3901, control group).
- Median (IQR) age was 53(49, 56) years (statin group) and 52(48, 56) years (control group, P <0.001).
- 68% (statin group) and 66% (control group) were White (P = 0.01)
- 96% (statin group) and 95% (control group) were male (P = 0.003).
- Baseline HCV RNA levels were similar between groups. Baseline TC, LDL, TG and non-HDL-C were higher and HDL was lower among those who received statins.
In bivariate analysis, those who received statins were more likely to achieve SVR (39.2% vs. 33.3%, P <0.001, decreased cirrhosis development (17.3% vs. 25.2%, P <0.001), and less likely to have incident hepatocellular carcinoma (1.2% vs. 2.6%, P <0.001).
When compared with those subjects who had not received any statin therapy (the control group), subjects who received statin therapy:
- Had minimal or no increase in fibrosis score (FIB-4 score) over time (controls had a gradual progression of fibrosis).
- Had a longer time to diagnosis of cirrhosis.
- Had a longer time to diagnosis of hepatocellular carcinoma.
In multivariate Cox regression analyses adjusted for baseline FIB-4 score:
- Treatment with statins was associated with significantly lower risk of developing cirrhosis (HR 0.56, 95% CI 0.50, 0.63). Factors associated with a higher risk of cirrhosis were increasing age, male sex, higher baseline HCV RNA, infection with HCV genotype 1 (vs. non-1), diabetes mellitus and alcohol use or dependence. Black race and attaining SVR were associated with a lower risk of cirrhosis.
- Treatment with statins was associated with a higher likelihood of achieving SVR (OR 1.44, 95% CI 1.29, 1.61).
- Treatment with statins was also associated with a lower risk of hepatocellular carcinoma (HR 0.51, 95% CI 0.34, 0.76). Factors associated with a higher risk of hepatocellular carcinoma included increasing age, non-white race, development of cirrhosis, diabetes and alcohol abuse or dependence.
Metformin use, which has been associated with a lower risk of hepatocellular carcinoma in some studies, was not associated with developing cirrhosis or hepatocellular carcinoma in this study. Metformin also did not significantly mitigate the effect of statins. The effect of individual statins was not assessed in this study, but the study authors did note that different statins may have varying effects on viral replication and fibrosis progression.
Authors note that in this study, the antifibrotic benefits observed in statin users remained significant even after adjustment not only for SVR, but also for body mass index and the presence of underlying diabetes, suggesting that the protective effect of statins extends beyond modification of the metabolic syndrome and obesity-related inflammation. Despite mounting evidence of the potential benefits of statins on liver disease, the authors make an important observation regarding current utilization of these medications:
“Despite growing evidence of the beneficial effects of statins on liver disease, there remains a likely underutilization of the medications, in particular in patients with advanced liver disease. This was evaluated in a survey of primary care providers in which more than one third underutilized statins and less than half were willing to prescribe them to patients with HCV (Rzouq FS et al. Am J Med Sci 2010 Aug;340(2):89-93). Based on studies demonstrating their safety in liver disease and particularly in HCV, expert recommendations state that statins should not be withheld even in advanced liver disease. HCV in particular is associated with metabolic syndrome that includes insulin resistance, obesity, and dyslipidemia and may be associated with accelerated atherosclerosis, thus increasing the risk of coronary artery disease as well as liver disease progression.”