The cholesterol-lowering medication simvastatin (Zocor) is considered a first line agent for the treatment of a variety of dyslipidemias and for the primary and secondary prevention of cardiovascular events. However, use of simvastatin in HIV-infected patients receiving highly active antiretroviral therapy (HAART) is limited by the potential for this drug to interact with antiretroviral medications, specifically drugs from the protease inhibitor class.  Use of simvastatin with non-nucleoside reverse transcriptase inhibitors (NNRTIs), with the exception of delavirdine (a drug rarely used in routine clinical practice), is generally considered safe.1

The reason why simvastatin use is contraindicated with protease inhibitors is related to the pharmacokinetic properties of both protease inhibitors and simvastatin.  When the two are coadministered, simvastatin concentrations are dramatically elevated.  One key study showed a 3,059% increase in simvastatin exposure when coadministration with the protease inhibitor combo, saquinavir (Invirase) and ritonavir (Norvir).2  The mechanism for the interaction is potent inhibition of the cytochrome P450 3A4 enzyme by all known protease inhibitors.  In particular, CYP450 3A4 is responsible for the vast majority of simvastatin metabolism and plasma clearance.3  Thus, protease inhibitor mediated inhibition of the CYP450 3A4 clearance pathway for simvastatin results in dangerously high concentrations of this statin.  This is important because it is now well known that the toxicities of statins (including simvastatin) are related to the statin dose and/or total drug exposure in the body.4-6  Therefore, patients receiving the combination of a protease inhibitor and simvastatin are at a significant increased risk for developing elevated liver enzymes and rhabdomyolysis (muscle breakdown that can be accompanied by the release of muscle cell contents (as myoglobin and potassium) into the bloodstream resulting in hypovolemia, hyperkalemia and sometimes acute renal failure).4-6

In contrast to protease inhibitors, NNRTIs (specifically the NNRTIs efavirenz (Sustiva), nevirapine (Viramune), and etravirine (Intelence)) are inducers (i.e. they increase the clearance of drugs or other substances) of CYP450 3A4 and thus may lower concentrations of simvastatin.7,8  Indeed, simvastatin exposure was reduced by 58% when coadministered with efavirenz and reduced simvastatin levels are also predicted with etravirine, as described in the product labeling.9,10  While no specific data exist to examine the effect of nevirapine on simvastatin concentrations, no increased statin exposure would be predicted.  

This drug interaction is important for current clinical practice as studies have shown that the inappropriate use of simvastatin with PIs continues to be a problem despite warnings and guidelines.  One study reported that 21% of HIV infected patients were receiving a contraindicated statin with their PI.11  Therefore, the combination of simvastatin and PIs should be avoided and other statin options (such as pravastatin which does not undergo CYP450 metabolism) are preferred.12 Use of simvastatin with nevirapine, efavirenz, or etravirine may be acceptable.

References:

1. Rahman AP, Eaton SE, Nguyen ST et al.  Safety and efficacy of simvastatin for the treatment of dyslipidemia in human immunodeficiency virus-infected patients receiving efavirenz-based highly active antiretroviral therapy.  Pharmacotherapy  2008;28:913-919.
2. Fichtenbaum CJ, Gerber JG, Rosenkranz SL et al.  Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047.  AIDS  2002;16:569-77.
3. Simvastatin (Zocor) product package insert.  Merck & Co, Inc. Whitehouse Station, NJ.  June 2008.  Last accessed on 1-22-2009.
4. Cohen DE, Anania FA, Chalasani N.  An assessment of statin safety by hepatologists.  Am J Cardiol  2006;97:77C-81C.
5. Thompson PD, Clarkson PM, Rosenson RS.  An assessment of statin safety by muscle experts.  Am J Cardiol  2006;97:69C-76C.
6. Cheng CH, Miller C, Lowe C et al.  Rhabdomyolysis due to probable interaction between simvastatin and ritonavir.  Am J Health Syst Pharm  2002;59:728-30.
7. Efavirenz (Sustiva) product package insert.  Bristol-Myers Squibb.  Princeton, NJ.  March 2008.  Last accessed 1-22-2009.
8. Nevirapine (Viramune) product package insert.  Boehringer Ingelheim Pharmaceuticals.  Last accessed on 1-22-2009.
9. Gerber JG, Rosenkranz SL, Fichtenbaum CJ et al.  Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin, and pravastatin: results of AIDS Clinical Trials Group 5108 Study.  J Acquir Immune Defic Syndr  2005;39:307-12.
10. Etravirine (Intelence) product package insert.  Tibotec Therapeutics.  Raritan, NJ.  2008.  Last accessed on 1-22-2009.
11. Hulgan T, Sterling TR, Daugherty J et al.  Prescribing of contraindicated protease inhibitor and statin combinations among HIV-infected persons.  J Acquir Immune Defic Syndr  2005;38:277-82.
12. Pasternak RC, Smith SC Jr, Bairey-Merz CN et al.  ACC AHA NHLBI Clinical advisory on the use and safety of statins.  Circulation  2002;106:1024-8.

Antiretrovirals, Antiretroviral Therapy, HAART, ART, Non-Nucleoside Reverse Transcriptase Inhibitors, NNRTI, Protease Inhibitors, PI, Zocor, Simvastatin, Statin Drug Interactions