Abstract
More than 50 % of women living with HIV in low- and middle-income countries are of reproductive age, but there are limitations to the administration of oral contraception for HIV-infected women receiving antiretroviral therapy due to drug–drug interactions caused by metabolism via the cytochrome P450 isoenzymes and glucuronidation. However, with the development of newer antiretrovirals that use alternative metabolic pathways, options for contraception in HIV-positive women are increasing. This paper aims to review the literature on the pharmacokinetics and pharmacodynamics of oral hormonal contraceptives when given with antiretroviral agents, including those currently used in developed countries, older ones that might still be used in salvage regimens, or those used in resource-limited settings, as well as newer drugs. Nucleos(t)ide reverse transcriptase inhibitors (NRTIs), the usual backbone to most combined antiretroviral treatments (cARTs) are characterised by a low potential for drug–drug interactions with oral contraceptives. On the other hand non-NRTIs (NNRTIs) and protease inhibitors (PIs) may interact with oral contraceptives. Of the NNRTIs, efavirenz and nevirapine have been demonstrated to cause drug–drug interactions; however, etravirine and rilpivirine appear safe to use without dose adjustment. PIs boosted with ritonavir are not recommended to be used with oral contraceptives, with the exception of boosted atazanavir which should be used with doses of at least 35 µg of estrogen. Maraviroc, an entry inhibitor, is safe for co-administration with oral contraceptives, as are the integrase inhibitors (INIs) raltegravir and dolutegravir. However, the INI elvitegravir, which is given in combination with cobicistat, requires a dose of estrogen of at least 30 µg. Despite the growing evidence in this field, data are still lacking in terms of large cohort studies, randomised trials and correlations to real clinical outcomes, such as pregnancy rates, in women on antiretrovirals and hormonal contraception.
Similar content being viewed by others
References
UNAIDS report on the global AIDS epidemic 2013. UNAIDS/JC2502/1/E. http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2013/gr2013/UNAIDS_Global_Report_2013_en.pdf. Accessed 26 Jul 2014.
UNAIDS. Women out loud: how women living with HIV will help the world end AIDS. 2012. UNAIDS/JC2416E. http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2012/20121211_Women_Out_Loud_en.pdf. Accessed 26 Jul 2014.
Alkema L, Kantorova V, Menozzi C, et al. National, regional and global rates and trends in contraceptive prevalence and unmet need for family planning between 1990 and 2015: a systematic and comprehensive analysis. Lancet. 2013;381(9878):1642–52.
Writing Group, Williams I, Churchill D, et al. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012 (Updated November 2013. All changed text is cast in yellow highlight.). HIV Med. 2014;15(Suppl 1):1–85.
Günthard HJ, Aberg JA, Eron JJ, et al. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society—USA Panel. JAMA. 2014;312(4):410–25.
EACS treatment guidelines, version 7.02. European AIDS Clinical Society. 2014. http://eacsociety.org/Portals/0/140601_EACS%20EN7.02.pdf. Accessed 1 Aug 2014.
Watkins PB. Drug metabolism by cytochromes P450 in the liver and small bowel. Gastroenterol Clin North Am. 1992;21:511–26.
Spatzenegger M, Jaeger W. Clinical importance of hepatic cytochrome P450 in drug metabolism. Drug Metab Rev. 1995;27:397–417.
Wang B, Sanchez RJ, Franklin RB, et al. The involvement of CYP3A4 and CYP2C9 in the metabolism of 17 alpha-ethinyl estradiol. Drug Metab Dispos. 2004;32(11):1209–12.
Zhang H, Cui D, Wang B, et al. Pharmacological drug interactions involving 17 alpha-ethinyl estradiol: a new look at an old drug. Clin Pharmacokinet. 2007;46:133–57.
Elliman A. Interactions with hormonal contraception. J Fam Plann Reprod Health Care. 2000;26:109–11.
Edelman AB, Cherala G, Stancyzk FZ. Metabolism and pharmacokinetics of contraceptive steroids in obese women a review. Contraception. 2010;82(4):314–23.
Faculty of Sexual and Reproductive Healthcare clinical guidance. Drug interactions with hormonal contraception. January 2011 (updated Jan 2012). http://www.fsrh.org/pdfs/CEUGuidanceDrugInteractionsHormonal.pdf. Accessed 26 Jul 2014.
Retrovir (zidovudine) product information. Research Triangle Park: GlaxoSmithKline; 1998.
Zerit (stavudine) product information. Princeton: Bristol-Meyers Squibb; 1999.
Epivir (lamivudine) product information. Research Triangle Park: GlaxoSmithKline; 1999.
Ziagen (abacavir) product information. Research Triangle Park: GlaxoSmithKline; 2001.
Videx (didanosine) product information. Princeton: Bristol-Meyers Squibb; 2000.
Hivid (zalcitabine) product information. Nutley: Roche Pharmaceuticals; 2000.
Kim RB, Fromm MF, Wandel C, et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest. 1998;101:289–94.
Eagling VE, Back DJ, Barry MG. Differential inhibition of cytochrome P450 isoforms by the protease inhibitors ritonavir, saquinavir and indinavir. Br J Clin Pharmacol. 1997;44:190–4.
Washington CB, Duran GE, Man MC, et al. Interaction of anti-HIV protease inhibitors with the multidrug transporter P-glycoprotein (P-gp) in human cultured cells. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;19:203–9.
Drewe J, Gutmann H, Fricker G, et al. HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833. Biochem Pharmacol. 1999;57:1147–52.
Foisy M, Yakiwchuk E, Hughes C. Induction effects of ritonavir: implications for drug interactions. Ann Pharmacother. 2008;42:1048–59.
Canada Abbott Laboratories Ltd. Norvir (ritonavir) prescribing information. Saint-Laurent: AbbVie Corporation; 2011.
Wang H, Tompkins L. CYP2B6: new insights into a historically overlooked cytochrome P450 isozyme. Curr Drug Metab. 2008;9(7):598–610.
Gilead Science. Viread® (tenofovir) summary of product characteristics. Foster City: Gilead Sciences Ltd; 2011.
Hyland R, Dickins M, Collins C, et al. Maraviroc: in vitro assessment of drug–drug interaction potential. Br J Clin Pharmacol. 2008;66(4):498–507.
HIV drug interactions (University of Liverpool). http://www.hiv-druginteractions.org/. Accessed 23 Sep 2014.
Aweeka F, Rosenkranz S, Yoninah S, et al. The impact of sex and contraceptive therapy on the plasma and intracellular pharmacokinetics of zidovudine. AIDS. 2006;20:1833–41.
Kearney BP, Mathias A. Lack of effect of tenofovir disoproxil fumarate on pharmacokinetics of hormonal contraceptives. Pharmacotherapy. 2009;29(8):924–9.
Mildvan D, Yarrish R, Marshak A, et al. Pharmacokinetic interaction between nevirapine and ethinyl estradiol/norethindrone when administered concurrently to HIV-infected women. J Acquir Immune Defic Syndr. 2002;29:471–7.
Boehringer Ingelheim International. Viramune summary of product characteristics. Ingelheim am Rhein: Boehringer Ingelheim International GmbH; 2001.
Landolt N, Phanuphak N, Ubolyam S, et al. Efavirenz, in contrast to nevirapine, is associated with unfavorable progesterone and antiretroviral levels when coadministered with combined oral contraceptives. J Acquir Immune Defic Syndr. 2013;62:534–9.
Stuart G, Moses A, Corbett A, et al. Combined oral contraceptives and antiretroviral PK/PD in Malawian women: pharmacokinetics and pharmacodynamics of a combined oral contraceptive and a generic combined formulation antiretroviral in Malawi. J Acquir Immune Defic Syndr. 2011;58(2):40–3.
Nanda K, Delany-Moretlwe S, Dubé K, et al. Nevirapine-based antiretroviral therapy does not reduce oral contraceptive effectiveness. AIDS. 2013;27:S17–25.
Joshi AS, Fiske WD, Benedek IH, et al. Lack of a pharmacokinetic interaction between efavirenz (DMP 266) and ethinyl estradiol in healthy female volunteers [abstract no. 348]. 5th Conference on Retroviruses and Opportunistic Infections; 1–5 Feb 1998; Chicago.
Sinicco A, Raiteri R, Rossati A, et al. Efavirenz interference in estradiol ELISA assay. Clin Chem. 2000;46:734–5.
Sevinsky H, Eley T, Persson A, et al. The effect of efavirenz on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy HIV-negative women. Antivir Ther. 2011;16:149–56.
Schöller-Gyüre M, Kakuda T, Woodfall B, et al. Effect of steady-state etravirine on the pharmacokinetics and pharmacodynamics of ethinyl estradiol and norethindrone. Contraception. 2009;80:44–52.
Crauwels HM, van Heeswijk RP, Buelens A, et al. Lack of an effect of rilpivirine on the pharmacokinetics of ethinyl estradiol and norethindrone in healthy volunteers. Int J Clin Pharmacol Ther. 2014;52:118–28.
Winston A, Boffito M. The management of HIV-1 protease inhibitor pharmacokinetic interactions. J Antimicrob Chemother. 2005;56:1–5.
Ouellet D, Hsu A, Qian J, et al. Effect of ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers. Br J Clin Pharmacol. 1998;46:111–6.
Tackett D, Child M, Agarwala S, et al. Atazanavir: a summary of two pharmacokinetic drug interaction studies in healthy subjects [abstract no. 543]. 10th Conference on Retrovirus and Opportunistic Infections; 10–14 Feb 2003; Boston.
Zhang J, Chung E, Yones C, et al. The effect of atazanavir/ritonavir on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy women. Antivir Ther. 2011;16:157–64.
Atrio J, Stanczyk FZ, Neely M, et al. Effect of protease inhibitors on steady-state pharmacokinetics of oral norethindrone contraception in HIV-infected women. J Acquir Immune Defic Syndr. 2014;65:72–7.
Sekar VJ, Lefebvre E, Guzman SS, et al. Pharmacokinetic interaction between ethinyl estradiol, norethindrone and darunavir with low-dose ritonavir in healthy women. Antivir Ther. 2008;134:563–9.
Vogler MA, Patterson K, Kamemoto L, et al. Contraceptive efficacy of oral and transdermal hormones when co-administered with protease inhibitors in HIV-1-infected women: pharmacokinetic results of ACTG trial A5188. J Acquir Immune Defic Syndr. 2010;55:473–82.
Abel S, Russell D, Whitlock LA, et al. Effect of maraviroc on the pharmacokinetics of midazolam, lamivudine/zidovudine, and ethinyl estradiol/levonorgestrel in healthy volunteers. Br J Clin Pharmacol. 2008;65(Suppl 1):19–26.
Anderson MS, Hanley WD, Moreau AR, et al. Effect of raltegravir on estradiol and norgestimate plasma pharmacokinetics following oral contraceptive administration in healthy women. Br J Clin Pharmacol. 2011;71:616–20.
German P, Wang M, Warren D, Kearney PB. Pharmacokinetic interaction between norgestimate/ethinyl estradiol and EVG/COB/FTC/TDF single tablet regimen [abstract no. 17]. 12th International Workshop on Clinical Pharmacology of HIV therapy; 13–15 Apr 2011; Miami.
Song I, Mark S, Borlan J, et al. Dolutegravir has no effect on the pharmacokinetics of methadone or oral contraceptives with norgestimate and ethinyl estradiol. 20th Conference on Retroviruses and Opportunistic Infections; 3–6 Mar 2013; Atlanta.
Marions L, Hultenby K, Sun X, et al. Emergency contraception with mifepristone and levonorgestrel: mechanism of action. Obstet Gynecol. 2002;100:65–71.
Croxatto HB, Brache V, Pavez M, et al. Pituitary-ovarian function following the standard levonorgestrel emergency contraceptive dose or a single 0.75-mg dose given on the days preceding ovulation. Contraception. 2004;70:442–50.
Hapangama D, Glasier AF, Baird DT. The effects of peri-ovulatory administration of levonorgestrel on the menstrual cycle. Contraception. 2001;63:123–9.
Durand M, del Carmen Cravioto M, Raymond EG, et al. On the mechanisms of short-term levonorgestrel administration in emergency contraception. Contraception. 2001;64:227–34.
Marions L, Cekan SZ, Bygdeman M, Gemzell-Danielsson K. Effect of emergency contraception with levonorgestrel or mifepristone on ovarian function. Contraception. 2004;69:373–7.
Okewole IA, Arowojolu AO, Odusoga OL, et al. Effect of a single administration of levonorgestrel on the menstrual cycle. Contraception. 2007;75:372–7.
Stratton P, Hartog B, Hajizadeh N, et al. A single mid-follicular dose of CDB-2914, a new antiprogestin, inhibits folliculogenesis and endometrial differentiation in normally cycling women. Hum Reprod. 2000;15:1092–9.
Croxatto HB, Brache V, Cochon L, et al. The effects of immediate pre-ovulatory administration of 30 mg ulipristal acetate on follicular rupture [abstract]. 8th Congress of the European Society of Gynecology; 10–13 Sep 2009; Rome.
Stratton P, Levens ED, Hartog B, et al. Endometrial effects of a single early luteal dose of the selective progesterone receptor modulator CDB-2914. Fertil Steril. 2010;93(6):2035–41.
Carten ML, Kiser JJ, Kwara A, et al. Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel (Plan B), and efavirenz. Infect Dis Obstet Gynecol. 2012;2012:137192. doi:10.1155/2012/137192.
Ella One (ulipristal) product information. Paris: HRA Pharma; 2009.
Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach. World Health Organization. 2013. http://www.who.int/hiv/pub/guidelines/arv2013/download/en. Accessed 4 Aug 2014.
Merck. Cerazette: summary of product characteristics. Hoddesdon: Merck; 2007.
Desogen (desogestrel/ethinyl estradiol) prescribing information. Whitehouse Station: Merck; 2012.
Bachmann G, Kopacz S. Drospirenone/ethinyl estradiol 3 mg/20 μg (24/4 day regimen): hormonal contraceptive choices—use of a fourth-generation progestin. Patient Prefer Adherence. 2009;3:259–64.
Yasmin (drospirenone/ethinyl estradiol) tablets prescribing information. Wayne: Bayer HealthCare Pharmaceuticals Inc.; 2012.
Yaz (drospirenone/ethinyl estradiol) tablets prescribing information. Wayne: Bayer HealthCare Pharmaceuticals Inc.; 2012.
Nexplanon. Summary of product characteristics. Hoddesdon: Merck; 1999.
Maddox D, Rahman Z. Etonogestrel (Implanon), another treatment option for contraception. Pharm Ther. 2008;33(6):337–47.
Wenzl R, van Beek A, Schnabel P, Huber J. Pharmacokinetics of etonogestrel released from the contraceptive implant Implanon. Contraception. 1998;58(5):283–8.
Guengerich FP. Mechanism-based inactivation of human liver microsomal cytochrome P-450 IIIA4 by gestodene. Chem Res Toxicol. 1990;3:363–71.
Back DJ, Houlgrave R, Tjia JF, et al. Effect of the progestogens, gestodene, 3-keto desogestrel, levonorgestrel, norethisterone and norgestimate on the oxidation of ethinyl estradiol and other substrates by human liver microsomes. J Steroid Biochem Mol Biol. 1991;38:219–25.
Femodene: summary of product characteristics. Newbury: Bayer Pharmaceuticals; 2008.
Levonelle: summary of product characteristics. Newbury: Bayer Pharmaceuticals;. 2004.
Norethisterone: summary of product characteristics. Wrexham: Wockhardt; 2008.
Back D, Beckenridge A, Crawford F, MacIver M, Orme M, Rowe P, Smith E. Pharmacokinetics or norethindrone in women. Clin Pharmacol Ther. 1978;24:447–54.
Cilest: summary of product characteristics. High Wycombe: Janssen; 1995.
Weiss J, Rose J, Storch CH, et al. Modulation of human BCRP (ABCG2) activity by anti-HIV drugs. J Antimicrob Chemother. 2007;59(2):238–45.
Weiss J, Theile D, Ketabi-Kiyanvash N, et al. Inhibition of MRP1/ABCC1, MRP2/ABCC2 and MRP3/ABCC3 by nucleoside, nucleotide and non-nucleoside reverse transcriptase inhibitors. Drug Metab Dispos. 2007;35(3):340–4.
Shaik N, Giri N, Pan G, Elmquist WF. P-glycoprotein-mediated active efflux of the anti-HIV1 nucleoside abacavir limits cellular accumulation and brain distribution. Drug Metab Dispos. 2007;35(11):2076–85.
Pan G, Giri N, Elmquist W. Abcg2/Bcrp1 mediates the polarized transport of antiretroviral nucleosides abacavir and zidovudine. Drug Metab Dispos. 2007;35(7):1165–73.
Nakatani-Freshwater T, Taft DR. Renal excretion of emtricitabine I: effects of organic anion, organic cation, and nucleoside transport inhibitors on emtricitabine excretion. J Pharm Sci. 2008;97(12):5401–10.
Turriziani O, Schuetz JD, Focher F, et al. Impaired 2′,3′-dideoxy-3′-thiacytidine accumulation in T-lymphoblastoid cells as a mechanism of acquired resistance independent of multidrug resistant protein 4 with a possible role for ATP-binding cassette C11. Biochem J. 2002;368(Pt 1):325–32.
FDA. Rilpivirine clinical pharmacology and biopharmaceutics review (NDA202-022). http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202022Orig1s000TOC.cfm. Accessed 23 Sep 2014.
Tirona R, Leake B, Wolkoff AW, Kim RB. Human organic anion transporting polypeptide-C (SLC21A6) is a major determinant of rifampicin mediated pregnane X receptor activation. J Pharmacol Exp Ther. 2003;304(1):223–8.
Gupta A, Zhang Y, Unadkat JD, Mao Q. HIV protease inhibitors are inhibitors but not substrates of the human breast cancer resistance protein (BCRP/ABCG2). J Pharmacol Exp Ther. 2004;310(1):334–41.
Thomas S. Drug transporters relevant to HIV therapy. J HIV Ther. 2004;9(4):92–6.
Srinivas R, Middlemas D, Flynn P, Fridland A. Human immunodeficiency virus protease inhibitors serve as substrates for multidrug transporter proteins MDR1 and MRP1 but retain antiviral efficacy in cell lines expressing these transporters. Antimicrob Agents Chemother. 1998;42(12):3157–62.
Bousquet L, Roucairol C. Comparison of ABC transporter modulation by atazanavir in lymphocytes and human brain endothelial cells: ABC transporters are involved in the atazanavir-limited passage across an in vitro human model of the blood–brain barrier. AIDS Res Hum Retroviruses. 2008;24(9):1147–54.
Lucia MB, Golotta C, Rutella S, et al. Atazanavir inhibits P-glycoprotein and multi-drug resistance-associated protein efflux activity. J Acquir Immune Defic Syndr. 2005;39(5):635–7.
Ye Z, 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 inhibitors. Drug Metab Dispos. 2008;36(7):1315–21.
Rittweger M, Arasteh K. Clinical pharmacokinetics of darunavir. Clin Pharmacokinet. 2007;46(9):739–56.
Janneh O, Hartkoorn RC, Jones E, et al. Cultured CD4 T cells and primary human lymphocytes express hOATPs: intracellular accumulation of saquinavir and lopinavir. Br J Pharmacol. 2008;155(6):875–83.
Acknowledgments
No sources of funding were used to assist in the preparation of this review. Marta Boffito has received travel and research grants from and has been an adviser for Janssen, Roche, Pfizer, ViiV, Bristol-Myers Squibb, Merck Sharp and Dohme, Boehringer Ingelheim, AbbieVie and Gilead. Lauren Bull has received sponsorship from Gilead to attend the BASHH (British Association for Sexual Health and HIV) conference in 2012 and BHIVA (British HIV Association) 2013, and received sponsorship from Janssen to attend the BASHH conference in 2013. Victoria Tittle has received payment by Gilead for organising an educational evening for junior doctors, and sponsorship from Gilead to attend BHIVA 2012 and EACS (European AIDS Clinical Society) 2011. Nneka Nwokolo has no conflicts of interest to declare.
Author information
Authors and Affiliations
Corresponding author
Additional information
V. Tittle and L. Bull are joint first author.
Rights and permissions
About this article
Cite this article
Tittle, V., Bull, L., Boffito, M. et al. Pharmacokinetic and Pharmacodynamic Drug Interactions Between Antiretrovirals and Oral Contraceptives. Clin Pharmacokinet 54, 23–34 (2015). https://doi.org/10.1007/s40262-014-0204-8
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40262-014-0204-8