This phase II trial studies how well simvastatin works in preventing liver cancer in patients with liver cirrhosis. Simvastatin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVE:

I. To evaluate the effect of a simvastatin intervention versus placebo on the change in serum AFP-L3% from baseline to 6 months following treatment initiation in patients with liver cirrhosis who have a current model for end-stage liver disease (MELD) =< 20.

SECONDARY OBJECTIVES:

I. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from baseline on the change in:

Ia. Serum AFP; Ib. Serum IL-6; Ic. Serum deoxycholic acid; Id. Liver stiffness; Ie. Fibrosis 4 index (FIB-4) score; If. MELD score.

EXPLORATORY OBJECTIVES:

I. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from baseline on the change in other:

Ia. serum bile acid levels; Ib. serum immune markers.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients receive simvastatin orally (PO) once daily (QD). Patients also undergo collection of blood on study and computed tomography (CT) scans/magnetic resonance imaging (MRI) throughout the trial.

GROUP II: Patients receive placebo PO QD. Patients also undergo collection of blood on study and CT/MRI throughout the trial.

In both groups, treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30, 60, and 90 days.

Inclusion Criteria:

• Confirmed diagnosis of liver cirrhosis assessed by the presence of clinical signs, symptoms, body imaging (ultrasound, computed tomography [CT], or magnetic resonance imaging [MRI]), or liver biopsy
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
• Leukocytes >= 2,500/microliter
• Absolute neutrophil count >= 1,500/microliter
• Platelets >= 50,000/microliter
• Hemoglobin >= 8 g/dL
• Total bilirubin =< 3 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x institutional ULN
• Creatinine =< 1.5 x institutional ULN
• Women who are able to become pregnant must have a confirmed negative pregnancy test result prior to enrollment; women >= 50 years of age who have not had a menstrual period in the past year; and women who have had a hysterectomy, both ovaries removed, or a tubal ligation; will not be required to have a pregnancy test
• The effects of simvastatin on the developing human fetus at the recommended therapeutic dose are unknown; for this reason, women who are able to become pregnant must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
• Ability to understand and the willingness to sign a written informed consent document and medical release
• Willing and able to comply with trial protocol and follow-up
• Have had an abdominal imaging test (CT, MRI, or ultrasound) within the past 18 months

Exclusion Criteria:

• Prior or current use of statin medication
• Current systemic use of medications known to interact with statins and potentially increase toxicity, including gemfibrozil, cyclosporine, danazol, lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine, ranolazine, strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, human immunodeficiency virus [HIV] protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, or cobicistat-containing products), or strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort, bosentan, efavirenz, etravirine, modafinil, nafcillin)
• History of adverse effects, intolerance, or allergic reactions attributed to compounds of similar chemical or biologic composition to simvastatin (i.e., other statin medications)
• Current use of any other investigational agents
• Women who are pregnant or breastfeeding; pregnant women are excluded from this study because simvastatin is a lipid-lowering agent with the potential for teratogenic or abortifacient effects; it is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with simvastatin, breastfeeding should be discontinued if the mother is treated with simvastatin
• Prior liver transplant
• Prior known or suspected hepatocellular carcinoma
• Prior cholangiocarcinoma
• Model for end-stage liver disease (MELD) > 20
• Any lab results that do not meet inclusion criteria after the Screen 1 blood tests
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• History of chronic myopathy
• Prior germ cell cancer
• History of active malignancy within the past 5 years (excluding basal/squamous cell skin cancer or prostate cancer with a Gleason score 6 or less)
• Known active infection with HIV
• Medical contraindications to blood draw (e.g., hemophilia)
• Concurrent illness which in the opinion of the investigators would compromise either the patient or the integrity of the data
• Current excessive alcohol consumption (average alcohol consumption of more than 5 drinks per day)