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
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
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
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.
- 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.
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.
(Zocor) product package insert. Merck & Co, Inc. Whitehouse
Station, NJ. June 2008. Last accessed on 1-22-2009.
- Cohen DE, Anania FA, Chalasani N. An assessment of statin safety by hepatologists. Am J Cardiol 2006;97:77C-81C.
- Thompson PD, Clarkson PM, Rosenson RS. An assessment of statin safety by muscle experts. Am J Cardiol 2006;97:69C-76C.
CH, Miller C, Lowe C et al. Rhabdomyolysis due to probable interaction
between simvastatin and ritonavir. Am J Health Syst Pharm
- Efavirenz (Sustiva) product package insert. Bristol-Myers Squibb. Princeton, NJ. March 2008. Last accessed 1-22-2009.
- Nevirapine (Viramune) product package insert. Boehringer Ingelheim Pharmaceuticals. Last accessed on 1-22-2009.
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
- Etravirine (Intelence) product package insert. Tibotec Therapeutics. Raritan, NJ. 2008. Last accessed on 1-22-2009.
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.
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.