Southern Medical Journal:
October 2010 - Volume 103 - Issue 10 - pp 1018-1024
CME Topics, Questions, Submission Forms
Andrus, Miranda R. PharmD, BCPS, FCCP; East, Jessica PharmD
From the Department of Pharmacy Practice, Auburn University Harrison School of Pharmacy, Huntsville, AL.
Reprint requests to Miranda R. Andrus, PharmD, BCPS, FCCP, Department of Pharmacy Practice, Auburn University Harrison School of Pharmacy, 301 Governors Drive, Suite 385B, Huntsville, AL 35801. Email: firstname.lastname@example.org
Dr. Andrus and Dr. East have no financial disclosures to declare and no conflicts of interest to report.
Accepted February 12, 2010.
Hepatitis C is a leading cause of liver failure and transplantation in the United States and a major public health issue. Studies have shown that patients with hepatitis C are at an increased risk of cardiovascular disease, which make statins of particular benefit in this patient population. However, the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) lists active or chronic liver disease as an absolute contraindication to statin therapy. The available literature regarding the safety of statins in this patient population is limited, but has not shown clinically significant differences in aminotransferase elevations or evidence of hepatotoxicity in patients with hepatitis C who have received statins versus those who have not. Statins should continue to be avoided in advanced end-stage liver disease, as there is a lack of safety data in these patients and drug metabolism would be severely compromised. Treatment with statins can be used in those with chronic, stable hepatitis C with elevated cardiac risk or a previous cardiac event.
* Patients with chronic hepatitis C often have elevated cardiac risk and could benefit from statin therapy.
* The National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) lists active or chronic liver disease as an absolute contraindication to statins.
* Studies of statins in patients with chronic hepatitis C have not shown a clinically significant risk for hepatotoxicity.
* Statins should be considered in patients with chronic hepatitis C with elevated cardiac risk.
Hepatitis C is a major public health issue and a leading cause of liver failure and transplantation in the United States.1 The most recent data estimate that 1.6% of the United States population (about 4.1 million people) is infected with hepatitis C.2 Of these, over three-fourths (about 3.2 million) have chronic hepatitis C infection.
Two studies have shown that patients with hepatitis C are at an increased risk for cardiovascular disease based on an increased carotid intima-media thickness. In a Japanese study, a higher percentage of patients with persistent hepatitis C infection were found to have carotid plaque (P < 0.0001) and carotid intima-media thickening (P < 0.05) compared to a control group.3 Multivariate logistic regression analysis also showed persistent hepatitis C infection to be an independent predictor of carotid plaque, with an odds ratio of 5.61 (95% confidence interval [CI] 2.06–15.26, P < 0.001). A second study also demonstrated that patients with hepatitis C had greater carotid intima-media thickness compared to control (P < 0.001).4
These increases in markers of early atherosclerosis in chronic hepatitis C may make 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) of particular benefit in this patient population. However, the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) lists active or chronic liver disease as an absolute contraindication to statin therapy.5 The guideline authors state that it is not known if statins worsen outcomes in patients with chronically elevated aminotransferase levels (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) due to hepatitis C. They do recognize that it is unknown if elevated aminotransferase levels due to statin therapy represents true hepatotoxicity, and that progression to liver failure is rare. Clinical trials of statins have generally excluded patients with a history of chronic liver disease, so safety data in this patient population are limited. However, patients with hepatitis C may actually have increased cardiovascular risk, and could greatly benefit from the lipid lowering and pleiotropic effects of statins.
The Liver Expert Panel of the National Lipid Association has affirmed that there is a relationship between statin therapy and elevations in aminotransferase levels.6 However, these experts acknowledge that liver failure associated with statins is extremely rare. Although there are reports of liver failure requiring transplantation, there are no reported deaths due to liver failure associated with statins.6 Elevations in aminotransferase levels of greater than 3 times the upper limit of normal (ULN) have been seen in less than 1% of patients receiving starting or intermediate doses of statins, and up to 2–3% of those receiving maximal doses.7 Most of these elevations are asymptomatic, and usually return to baseline if the statin is discontinued.7 Often, these elevations are transient and resolve spontaneously, even if the statin is continued.7 The elevations also appear to be dose-related, with higher doses of statins more likely to cause enzyme elevations.7–9 Single, unconfirmed enzyme elevations may not be related to statin therapy at all, and these elevations generally do not indicate liver damage or failure.6,7
The exact mechanism by which statins cause increased aminotransferase levels is not clearly understood; however, the mechanism appears to be hepatocellular injury.7 The adverse effect is thought to be more related to the dose and concentration of the statin in tissues, rather than the degree of low density lipoprotein (LDL) reduction.7 Conditions that can increase statin concentrations—and therefore increase the risk of adverse effects—include advanced age, small body frame, declining renal function, infection, untreated hypothyroidism, drugs which inhibit the metabolism of statins, and alcohol abuse.7 The Liver Expert Panel has concluded that all marketed statins can cause elevations in aminotransferase levels, and that no particular statin causes these adverse effects more frequently than the others.6
Several review articles recommend that statins be considered, with careful monitoring, in chronic hepatitis C patients.7–9 The potential benefits of statins in patients with coexisting chronic hepatitis C and elevated cardiovascular risk led us to review the primary literature for specific evidence regarding the safety of statins in this population.
A literature search was conducted using Ovid Medline (1950 to January, Week 1, 2010), combining the medical subject heading search terms “hydroxymethylglutaryl-CoA reductase inhibitors” and “hepatitis C.” References of relevant articles were also reviewed. Studies examining the safety of using statins in patients with hepatitis C are limited to 1 prospective study, 3 retrospective studies in the Veterans Affairs (VA) population (1 of which only included 17 patients), and 1 retrospective study in patients with human immunodeficiency virus (HIV). A summary of these trials is provided in the Table.
A prospective, randomized, double-blind, placebo-controlled, parallel-group trial was designed to determine the efficacy and safety of high-dose pravastatin (80 mg daily) in hypercholesterolemic subjects with well-compensated liver disease.10 The study enrolled 326 patients, of which 62% had nonalcoholic fatty liver (NAFL)/nonalcoholic fatty liver disease (NAFLD), 27% had chronic hepatitis C, and the remainder had other liver diseases.
Inclusion criteria were a LDL cholesterol ≥100 mg/dL after a 4-week lead-in phase of lifestyle modifications, triglycerides <400 mg/dL, age ≥18 years old, and chronic, well-compensated liver disease. Patients were excluded if they were pregnant or breastfeeding, had AST or ALT levels >5 times the upper limit of normal (ULN), total bilirubin level above normal, serum creatinine >1.5 mg/dL, creatinine kinase >3 times the ULN, albumin less than the lower limit of normal, prothrombin time >2 seconds, or platelet count less than the lower limit of normal. Patients were also excluded if they had ascites, jaundice, or cirrhosis with a Child-Pugh score >5, had a disorder affecting serum bilirubin, were taking antiviral therapy for hepatitis B or C, had lipid lowering therapy in the previous 8 weeks or more, had cancer or cancer chemotherapy, or had significant cardiovascular, cerebrovascular, renal or thyroid disease, or uncontrolled diabetes mellitus within 6 months prior to randomization.
The safety objective was to determine the number of patients who had an increase in the ALT ≥2 times the ULN for those with a normal ALT at baseline, or a doubling of the baseline ALT in those who had an elevated ALT at baseline. By these definitions, fewer patients in the pravastatin group experienced ALT elevations compared to the placebo group. The proportion of subjects who had sustained elevations in ALT was comparable, with 8/160 (5%) in the pravastatin group, and 11/160 (7%) in the placebo group. Side effects were experienced in 26.4% of pravastatin patients and 25.2% of placebo patients. Six patients receiving pravastatin and 4 patients receiving placebo experienced treatment-emergent adverse effects associated with aminotransferase elevations, and no clinically apparent hepatotoxicity was experienced in either group. The terminology “treatment-emergent adverse effects” and “clinically apparent hepatotoxicity” was not clearly defined by the study. No patients experienced an acute exacerbation of their underlying liver disease. The study was not specifically powered for the safety endpoint; however, the authors calculated that a sample size of 150 per treatment group would provide approximately 20% power for this endpoint.
A retrospective, multicenter study in the VA population was conducted to determine whether statin therapy increased the risk for developing hepatotoxicity in patients with hepatitis C.11 Eight hundred and thirty patients were divided into 3 cohorts, and the antibody to hepatitis C virus (anti-HCV) was used as a surrogate marker for hepatitis C virus (HCV) infection. Cohort 1 included 166 patients positive for anti-HCV on statin therapy, Cohort 2 included 332 patients anti-HCV positive without statin therapy, and Cohort 3 included 332 patients who were anti-HCV negative and on statin therapy. Patients were excluded from Cohorts 1 and 3 if they did not have liver function tests checked within 1 year before and after initiation of statin therapy. Patients were excluded from Cohort 2 if they did not have liver function tests checked within 1 year before and after hepatitis C diagnosis. The majority of patients were taking simvastatin or lovastatin.
Patients in Cohort 1 (anti-HCV positive + statin) had a lower percentage change in median aminotransferase levels compared with those in Cohort 2 (anti-HCV positive + no statin; AST: 1% versus 5%, respectively, P = 0.032, ALT: 7.3% versus 6.0%, respectively, P < 0.01), and Cohort 3 (anti-HCV negative + statin; AST 5%, P = 0.004; ALT 4.8%, P = 0.002). However, none of the median changes were clinically significant, as all were less than 8%. A higher percentage of patients in Cohort 1 developed mild to moderate increases in aminotransferase levels (defined as AST or ALT ≤10 times the ULN or from baseline) compared to Cohort 2 (22.9% vs. 13.3%, P = 0.009). However, Cohort 2 had a higher percentage of patients with severe increases in liver function tests (defined as serum bilirubin value >3 mg/dL, or AST or ALT >10 times the ULN or baseline) compared to Cohort 1 (6.6% versus 1.2%, P = 0.015). There was no statistically significant difference in the percentage of patients with increased aminotransferase levels who discontinued statin therapy between Cohort 1 (21.6%) and Cohort 3 (9.2%; P = 0.147). The study was not adequately powered to detect idiosyncratic drug reactions.
In another retrospective study conducted in the VA system, 146 males who were seropositive for hepatitis C and received a statin between January 1, 1995, and September 9, 2003 were evaluated.12 Patients were excluded if there were no documented baseline lipid and aminotransferase levels before the start of statin therapy, or no documented follow-up levels. Patients were also excluded if triglyceride levels were ≥400 mg/dL. Hepatotoxicity was defined as an increase in ALT >3 times the ULN.
More than 90% of patients were taking simvastatin (the formulary agent), and statins were taken for a mean of 2.5 years in the study. At baseline, 66% had ALT levels greater than the ULN, and 8% had ALT levels >3 times the ULN. There was no significant increase in ALT at short-term follow up (3–6 months), or long-term follow up (mean 22 months). One patient discontinued statin therapy due to ALT levels >3 times the ULN.
A post hoc analysis did not show a statistically significant increase in the frequency of patients with ALT levels >3 times the ULN at any point in time. When patients who had ALT levels >3 times the ULN at baseline or after statin discontinuation were excluded, only 10 patients had ALT levels >3 times the ULN while receiving statin therapy during the study period. In 3 of these patients, levels later returned to normal. Statin therapy was discontinued in 1 of the 10 patients due to excessive alcohol intake. Of the remaining 6 patients, 3 continued receiving the statin and had subsequent ALT levels between 1 and 3 times the ULN, 1 had subsequent ALT levels 4 to 5 times the ULN, 1 had therapy discontinued, and 1 was lost to follow up.
In another very small retrospective VA study, 17 male patients with a diagnosis of chronic hepatitis C taking statins were reviewed.13 Only 5 patients had elevations of aminotransferase levels while taking statins, and the greatest increase was 1.5 times the ULN.
In a retrospective Italian study reported as a letter to the editor, the safety of statin therapy in patients infected with both HIV and hepatitis C was examined.14 Patients with HIV who had taken statins were divided into 2 groups. Group A included 38 patients with HIV and hepatitis C co-infection who started statin therapy at least 6 months after diagnosis of hepatitis C. Group B included 42 patients with HIV who were hepatitis C and hepatitis B negative who were on statin therapy. Patients were excluded if they had a history of alcohol abuse, concomitant hepatotoxic medications other than antiretrovirals, or were on treatment for hepatitis C. The median age was 45.5 years, and 76.2% of patients were male.
No significant difference was found between the groups in aminotransferase levels. The percentage of patients with an increase of ≥1.5 times the baseline level of AST was 7.9% in Group A and 4.8% in Group B, and for ALT was 7.9% in Group A and 14.3% in Group B. No patients had an increase of aminotransferase levels ≥3 times the ULN, and no patients discontinued a statin due to liver toxicity. About 40% of patients actually experienced a decrease in their aminotransferase levels while on statin therapy. A positive correlation was found between patients who had a decrease in ALT and those who had higher baseline levels of ALT.
All of these studies had weaknesses, limiting their clinical applicability. Almost all patients in the studies were male, and though hepatitis C is more common in males, this may limit the applicability to female patients. Only 1 study was prospective, and it had extensive exclusion criteria, which limits the applicability to the general hepatitis C population (which often has numerous comorbidities). The other 4 studies were retrospective, and therefore not blinded or controlled. Some of the studies used positive anti-HCV as a marker for chronic HCV, which could have included patients without the disease. Other studies did not state how chronic hepatitis C was defined. The safety endpoints and definitions were not consistent between studies, and were not always the most appropriate endpoints. For example, one of the VA studies used the outcome percentage change in aminotransferase levels. If the enzymes were already increased at baseline, a percentage change would not be as significant as it would if the enzymes were normal at baseline. In general, the studies were probably not powered with a large enough sample size to detect a statistically significant difference in safety outcomes.
Potential Benefits of Statins
Interestingly, there is literature to support the theory that statins actually have anti-HCV activity that might be beneficial, in addition to lowering cholesterol. Statins have been identified to have antiviral properties by inhibiting hepatitis C replication.15 Lipid metabolism is part of the life cycle of many viruses, and the resulting metabolites are incorporated into a lipid raft membrane, which is enriched with cholesterols and sphingolipids.16 The hepatitis C virus also forms a replication complex on the lipid raft membrane; therefore, a reduction in cholesterol from the lipid raft structure could theoretically decrease hepatitis C viral replication.15,16 The authors of 1 in vitro study have suggested that the antiviral effect of statins might be useful in treating hepatitis C in combination with interferon alpha.17 In vivo studies have been small and inconclusive at this time.18,19
In summary, the available literature has not shown clinically significant differences in aminotransferase levels or evidence of hepatotoxicity in patients with hepatitis C who have received statins versus those who have not. Statins should continue to be avoided in advanced end-stage liver disease, as there is a lack of safety data in these patients, and drug metabolism would be severely compromised. Treatment with statins should be considered in those with chronic, stable hepatitis C with elevated cardiac risk or a previous cardiac event. If baseline AST or ALT levels are >3 times the ULN statins should be used cautiously, but can be considered if the disease is stable, as the benefit is likely to outweigh the risk of treatment.
When used in patients with hepatitis C, statins should be started at low doses, and the AST and ALT should be monitored more closely than in patients without underlying liver disease, especially at drug initiation. If elevations of >3 times the ULN do occur with statin therapy, these should be repeated and confirmed before discontinuing the drug. After enzymes return to baseline, another statin can be tried if there are no other signs of hepatitis. Alcohol use should be avoided.
We feel that, with careful monitoring of the AST and ALT, statins can be used to reduce cardiovascular risk in patients with chronic, stable hepatitis C.
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