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Protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) can affect hepatic metabolism of HMG-coenzyme A reductase inhibitors (statins). ARVs generally do not affect the metabolism of other classes of lipid-lowering agents.

PIs

Most PIs inhibit the metabolism of most statins and can significantly increase serum statin levels, thus increasing the risk of toxicity, including myopathy and rhabdomyolysis.

The degree to which statin metabolism is affected by PIs varies according to the statin as well as the specific PI. Unfortunately, many specific interactions have not been studied.

In general, the potential for inhibition of statin metabolism is as follows: simvastatin and lovastatin > atorvastatin and rosuvastatin >> pravastatin.

Interactions of PIs with fluvastatin and pitavastatin have not been studied thoroughly.

NNRTIs

NNRTI effects vary according to the specific NNRTI.

		Efavirenz generally induces statin metabolism, resulting in lower serum statin levels.

		Nevirapine has not been studied well in combination with statins, but its interactions with statins would be expected to be similar to those of efavirenz.

		Etravirine has not been studied thoroughly in combination with statins. Its interactions are expected to depend on the specific statin.

		Rilpivirine has not been studied thoroughly in combination with statins.

		Delavirdine inhibits hepatic cytochrome P450 metabolism. Thus, delavirdine increases statin levels and the risk of statin-related adverse effects.

Medical providers should consult information on drug interactions before prescribing statins for patients taking PIs or NNRTIs, as dosage adjustments are frequently required and some combinations are contraindicated.

Other classes of antiretrovirals (NRTIs, fusion inhibitors, chemokine coreceptor antagonists, and integrase inhibitors) do not have recognized interactions with statins. Other types of lipid-lowering medications are not metabolized by hepatic cytochrome P450 and generally are not affected by ARVs (an exception to this is gemfibrozil, whose levels are decreased by lopinavir/ritonavir, by an unknown mechanism).

Note on cobicistat: The pharmacokinetic enhancer cobicistat is expected to have interactions with statins that are similar to those of ritonavir; however, these have not been well studied.

Color code:

Generally safe to begin treatment with usual starting dosage

Caution; start with low dosage, monitor effects

Coadministration is contraindicated

No data

	Atorvastatin	Fluvastatin	Lovastatin	Pitavastatin	Pravastatin	Rosuvastatin	Simvastatin
Protease Inhibitors
Atazanavir				(unboosted) (ritonavir boosted)		Rosuvastatin AUC ↑ 213% and Cmax ↑ 600%
Darunavir/ ritonavir					Pravastatin AUC ↑ 81%-500%
Fosamprenavir					May need to ↑ pravastatin dosage
Indinavir
Lopinavir/ ritonavir	Atorvastatin AUC ↑ 488%					Rosuvastatin AUC ↑ 108%, Cmax ↑ 466%
Nelfinavir
Ritonavir
Saquinavir					Saquinavir + ritonavir: May need to ↑ pravastatin dosage
Tipranavir	Atorvastatin AUC ↑ 836%
Nonnucleoside Reverse Transcriptase Inhibitors
Efavirenz	May need to ↑ atorvastatin dosage	May need to ↑ fluvastatin dosage	May need to ↑ lovastatin dosage		May need to ↑ pravastatin dosage		May need to ↑ simvastatin dosage
Etravirine	May need to ↑ atorvastatin dosage	May ↑ fluvastatin levels	May need to ↑ lovastatin dosage				May need to ↑ simvastatin dosage
Rilpivirine

Notes:
Nevirapine in combination with statins has not been well studied; its interactions would be expected to be similar to those of efavirenz. Delavirdine's interactions would be expected to be similar to those of PIs. Rilpivirine has been studied only with atorvastatin: atorvastatin C_max is increased modestly.

Other risk factors for elevated rosuvastatin levels include Asian or Pacific Islander heritage, renal insufficiency, and concurrent treatment with gemfibrozil; use with extra caution.

References

Kiser JJ, Gerber JG, Predhomme JA, et al. Drug/drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr. 2008 Apr 15;47(5):570-8. McNicholl I. Database of Antiretroviral Drug Interactions. In: Coffey S, Volberding PA, eds. HIV InSite. San Francisco: UCSF Center for HIV Information; 2008. Available at http://hivinsite.ucsf.edu/insite?page=ar-00-02. Accessed May 2012. Sekar VJ, Spinosa-Guzman S, Marien K, et al. Pharmacokinetic drug-drug interaction between the new HIV protease inhibitor darunavir (TMC114) and the lipid-lowering agent pravastatin. In: Program and abstracts of the 8th International Workshop on Pharmacology of HIV Therapy; April 16-18, 2007; Budapest. Abstract 55. Busse KH, Hadigan C, Chairez C, et al. Gemfibrozil concentrations are significantly decreased in the presence of lopinavir-ritonavir. J Acquir Immune Defic Syndr. 2009 Oct 1;52(2):235-9.