EBM Consult

How does the protease inhibitor, atazanavir (Reyataz) increase the levels of the statin, rosuvastatin (Crestor)?


  • Treatment with highly active antiretroviral therapy (HAART) has significantly improved prognosis for patients infected with HIV.  However, these patients are now at greater risk of CVD due to the metabolic effects of antiretroviral treatment.
  • Atazanavir (Reyataz) is a protease inhibitor (PI) commonly used in the treatment of HIV and is associated with less dyslipidemia and insulin resistance as compared to other PIs.
  • Due to the pharmacokinetic profiles of atorvastatin and simvastatin, the use of rosuvastatin (Crestor) would appear to be an attractive option when a high potency statin is needed to lower LDL-C.
  • Unfortunately, atazanavir (that is typically administered with ritonavir) causes a 3-fold increase in the AUC and a 600% increase in the Cmax of rosuvastatin.  The likely mechanism for this drug interaction is the inhibition of the efflux transporter breast cancer resistance polypeptide (BCRP) and possibly the influx transporter organic anion transport polypeptide (OATP1B1) thereby increasing rosuvastatin's overall bioavailability into systemic circulation.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA

Last Reviewed: February 2018


  • The treatment of human immunodeficiency virus (HIV) infection with highly active antiretroviral therapy (HAART) has dramatically reduced morbidity and mortality related to acquired immunodeficiency syndrome (AIDS).(1,2)  However, these improvements have come with some cost as cardiovascular (CV) complications related to antiretroviral therapy that warrant additional treatment have been revealed.(3,4)  It is now well recognized that antiretrovirals not only cause insulin resistance and dyslipidemia, but also contribute to an increased risk for cardiovascular disease (CVD) in HIV patients.(1,3,4)  Unfortunately, management of antiretroviral-associated metabolic complications will remain a challenge even for the experienced clinician.(5)    This is in part due to the extensive profile of drug interactions associated with HAART.  More specifically,  the use of certain potent lipid lowering agents is limited by these interactions thereby making it more difficult to achieve patient specific lipid goals as recommended by name guidelines.(1)

    One of the first line protease inhibitors (PI) used in clinical practice and recommended by national guidelines is atazanavir (Reyataz) (typically given in combination with ritonavir to enhance the efficacy of atazanavir).(6)  Atazanavir not only works well to control the HIV, but it also causes less glucose abnormalities and dyslipidemia as compared to other protease inhibitors.(7,8)  As such, atazanavir may be used more often in patients with known CV risk factors or existing CVD when a PI is required.  As it relates to potential drug interactions, the product package insert indicates that atazanavir is a metabolism dependent inhibitor of cytochrome P450 (CYP) CYP3A4 and a direct inhibitor of CYP2C8 and UDP-glycosyltransferase (UGT)1A1.(9)  This becomes relevant when deciding which lipid lowering agent to initiate when the patient requires treatment or CV risk reduction.  Due to the greater dependency of atorvastatin, lovastatin, and simvastatin on CYP3A4 for their metabolism, their use is either dose limited (as with atorvastatin) or contraindicated (as with lovastatin and simvastatin).(1,6)  This can be a problem if significant low density lipoprotein (LDL) reductions are needed.  As such, rosuvastatin (Crestor) is the only remaining high potency statin available whose pharmacokinetic profile would not appear to interact with atazanavir coadministration.  The product package insert indicates that rosuvastatin undergoes metabolism by CYP2C9 (10%) with the majority of its excretion being in the feces (90%).(10)  If a clinician were to compare the product package inserts for both atazanavir and rosuvastatin, it would be plausible for them to conclude that no drug-drug interaction is likely to occur.(9,10)  Unfortunately, a single-dose pharmacokinetic study revealed that atazanavir/ritonavir caused a 3-fold increase in the area under the curve after 24 hours (AUC0-24) and 600% increase in the Cmax of rosuvastatin.(11)

    Therefore, the following question remains.   How does atazanavir/ritonavir increase the concentrations of rosuvastatin when there is no apparent pharmacokinetic interaction based on their product inserts?
    Without direct evidence, it would appear that this drug interaction is being mediated outside of the CYP450 system.  There are data that show rosuvastatin to be a substrate for the efflux pump, breast cancer resistance protein (BCRP).(12)  While BCRP transporters are found on breast cancer cells, they are also found in many other places including the apical surfaces of the enterocytes and the bile canalicular membrane of hepatocytes where they can influence the bioavailability and efflux of drugs out of the body.(13)  In addition, it is now known that atazanavir is an inhibitor of BCRP.(14)  Therefore, it is plausible that atazanavir inhibits BCRP-mediated enteric and/or biliary efflux of rosuvastatin thereby allowing for a greater extent of absorption and/or decrease in biliary excretion of rosuvastatin.(11)

    Another potential mechanism for a reduction in rosuvastatin excretion might be the inhibition of hepatic uptake of rosuvastatin via the influx transporter organic anion transporter polypeptide (OATP1B1) in the liver by atazanavir.  While the specific inhibition of OATP1B1 in humans by atazanavir is not known, there is data in rats that demonstrates that atazanavir is an inhibitor of OATP (subtypes of OATP not specified).15  This is consistent with the PI, indinavir which has similar pharmacologic properties to atazanavir.(16)  In addition, a previous drug interaction study between rosuvastatin and gemfibrozil (a known inhibitor of OAT1B1) showed similar increases in pharmacokinetic parameters as in the drug interaction study between atazanavir and rosuvastatin.(17)  The last factor involved in atazanavir's ability to increase rosuvastatin concentrations could be in atazanavir's inhibition of UGT1A1 in the enterocyte and hepatocyte which is another pathway of metabolism for rosuvastatin.(9,11)

    It is very apparent that the drug interaction between atazanavir and rosuvastatin cannot be predicted by only evaluating the approved product labeling and thus highlights the need for a greater understanding of the various mechanisms for drug interactions.  Due to the 3-fold increase in rosuvastatin concentrations when coadministered with atazanavir based HAART, the dose of rosuvastatin should probably be limited to no more than 10 mg a day, similar to atorvastatin.(11)  This is clinically relevant since increased levels (regardless of the cause) of any statin are known to increase the risk of both hepatotoxicity and myositis (including rhabdomyolysis).(18-20)


    1. Dube MP, Stein JH, Aberg JA et al.  Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group.  Clin Infect Dis  2003;37:613-27.       
    2. Palella FJ Jr, Delaney KM, Moorman AC et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection.  HIV Outpatient Study Investigators.  N Engl J Med  1998;338:853-60.
    3. DAD Study Group, Friis-Moller N, Reiss P et al.  Class of antiretroviral drugs and risk of myocardial infarction.  N Engl J Med  2007;356:1723-35.
    4. Triant VA, Lee H, Hadigan C et al.  Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease.  J Clin Endocrinol Metab  2007;92:2506-12.
    5. Bain AM, White EA, Rutherford WS et al.  A multimodal, evidence-based approach to achieve lipid targets in the treatment of antiretroviral-associated dyslipidemia: case report and review of the literature.  Pharmacotherapy  2008;28:932-8.
    6. Panel n Antiretroviral Guidelines for Adults and Adolescents.  Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.  Department of Health and Human Services.  November 3, 2008:1-139.
    7. Busti AJ, Bedimo R, Margolis DM et al.  Improvements in insulin sensitivity and dyslipidemia in protease inhibitor-treated adult male patients after switch to atazanavir/ritonavir switch.  J Investig Med  2008;56:539-44.        
    8. Busti AJ, Hall RG, Margolis DM.  Atazanavir for the treatment of human immunodeficiency virus infection.  Pharmacotherapy  2004;24:1732-47.
    9. Atazanavir sulfate (Reyataz®) product package insert.  Bristol-Meyers Squibb; Princeton, NJ.  April 2009.
    10. Rosuvastatin (Crestor®) product package insert.  AstraZeneca; Wilmington, DE.  February 2009.
    11. Busti AJ, Bain AM, Hall RG 2nd et al.  Effects of atazanavir/ritonavir or fosamprenavir on the pharmacokinetics of rosuvastatin.  J Cardiovasc Pharmacol  2008;51:605-10.
    12. Huang L, Wang Y, Grimm S.  ATP-dependent transport of rosuvastatin in membrane vesicles expressing breast cancer resistance protein.  Drug Metab Dispos  2006;34:738-42.
    13. Mao Q, Unadkat JD.  Role of the breast cancer resistance protein (ABCG2) in drug transport.  AAPS J  2005;7:E118-33.
    14. Weiss J, Rose J, Storch CH et al.  Modulation of human BCRP (ABCG2) activity by anti-HIV drugs.  J Antimicrob Chemother  2007;59:238-45.
    15. Ye ZW, Augustijns P, Annaert P.  Cellular accumulation of cholyl-glycylamido-fluorescein in sandwich-cultured rat hepatocytes: kinetic characterization, transport mechanisms, and effect of human immunodeficiency virus protease.  Drug Metab Dispos  2008;36:1315-21.
    16. Campbell Sd, de Morais SM, Xu JJ.  Inhibition of human organic anion transporting polypeptide OATP1B1 as a mechanism of drug-induced hyperbilirubinemia.  Chem Biol Interact  2004;150:179-87.
    17. Schneck DW, Birminghalm BK, Zalikoski JA et al.  The effect of gemfibrozil on the pharmacokinetics of rosuvastatin.  Clin Pharmacol Ther  2004;75:455-63.
    18. Cohen DE, Anania FA, Chalasani N.  As assessment of statin safety by hepatologists.  Am J Cardiol  2006;97:77C-81C.
    19. Thompson PD, Clarkson PM, Rosenson RS.  As assessment of statin safety by muscle experts.  Am J Cardiol  2006;97:69C-76C.
    20. Omar MA, Wilson JP.  FDA adverse event reports on statin-associated rhabdomyolysis.  Ann Pharmacother  2002;36:288-95.


  • HIV, Atazanavir, Reyataz, Rosuvastatin, Crestor, Atazanavir Crestor Interaction