{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T16:52:05Z","timestamp":1778691125752,"version":"3.51.4"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>In AIDS Clinical Trials Group study A5316, efavirenz lowered plasma concentrations of etonogestrel and ethinyl estradiol, given as a vaginal ring, while atazanavir\/ritonavir increased etonogestrel and lowered ethinyl estradiol concentrations. We characterized the pharmacogenetics of these interactions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In A5316, women with HIV enrolled into control (no antiretrovirals), efavirenz [600\u2009mg daily with nucleoside\/nucleotide reverse transcriptase inhibitors (NRTIs)], and atazanavir\/ritonavir (300\/100\u2009mg daily with NRTIs) groups. On day 0, a vaginal ring was inserted, releasing etonogestrel\/ethinyl estradiol 120\/15 \u03bcg\/day. Intensive plasma sampling for antiretrovirals was obtained on days 0 and 21, and single samples for etonogestrel and ethinyl estradiol on days 7, 14, and 21. Seventeen genetic polymorphisms were analyzed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The 72 participants in this analysis included 25, 24 and 23 in the control, efavirenz, and atazanavir\/ritonavir groups, respectively. At day 21 in the efavirenz group,\n                      <jats:italic toggle=\"yes\">CYP2B6<\/jats:italic>\n                      genotype was associated with increased plasma efavirenz exposure (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009=\u20093.2 \u00d7 10\n                      <jats:sup>\u22123<\/jats:sup>\n                      ), decreased plasma concentrations of etonogestrel (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009=\u20091.7 \u00d7 10\n                      <jats:sup>\u22123<\/jats:sup>\n                      ), and decreased ethinyl estradiol (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009=\u20096.7 \u00d7 10\n                      <jats:sup>\u22124<\/jats:sup>\n                      ). Compared to controls, efavirenz reduced median etonogestrel concentrations by at least 93% in\n                      <jats:italic toggle=\"yes\">CYP2B6<\/jats:italic>\n                      slow metabolizers versus approximately 75% in normal and intermediate metabolizers. Efavirenz reduced median ethinyl estradiol concentrations by 75% in\n                      <jats:italic toggle=\"yes\">CYP2B6<\/jats:italic>\n                      slow metabolizers versus approximately 41% in normal and intermediate metabolizers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">CYP2B6<\/jats:italic>\n                      slow metabolizer genotype worsens the pharmacokinetic interaction of efavirenz with hormonal contraceptives administered by vaginal ring. Efavirenz dose reduction in\n                      <jats:italic toggle=\"yes\">CYP2B6<\/jats:italic>\n                      slow metabolizers may reduce, but will likely not eliminate, this interaction.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1097\/fpc.0000000000000396","type":"journal-article","created":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T12:22:45Z","timestamp":1582806165000},"page":"45-53","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":11,"title":["Pharmacogenetic interactions between antiretroviral drugs and vaginally administered hormonal contraceptives"],"prefix":"10.1097","volume":"30","author":[{"given":"David W.","family":"Haas","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee"},{"name":"Department of Internal Medicine, Meharry Medical College, Nashville, Tennessee"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoninah S.","family":"Cramer","sequence":"additional","affiliation":[{"name":"Harvard TH Chan School of Public Health, Boston, Massachusetts"},{"name":"Frontier Science Foundation, Brookline, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"Godfrey","sequence":"additional","affiliation":[{"name":"Division of AIDS, National Institutions of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan L.","family":"Rosenkranz","sequence":"additional","affiliation":[{"name":"Harvard TH Chan School of Public Health, Boston, Massachusetts"},{"name":"Frontier Science Foundation, Brookline, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Aweeka","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, University of California San Francisco, San Francisco, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baiba","family":"Berzins","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Northwestern University, Chicago, Illinois"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Coombs","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Laboratory Medicine, University of Washington, Seattle, Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristine","family":"Coughlin","sequence":"additional","affiliation":[{"name":"Frontier Science & Technology Research Foundation, Inc, Amherst, New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura E.","family":"Moran","sequence":"additional","affiliation":[{"name":"Social & Scientific Systems, Silver Spring, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Gingrich","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, University of California San Francisco, San Francisco, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen D.","family":"Zorrilla","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Puerto Rico School of Medicine, San Juan, Puerto Rico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paxton","family":"Baker","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan E.","family":"Cohn","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Northwestern University, Chicago, Illinois"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly K.","family":"Scarsi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"R1-20251204","doi-asserted-by":"crossref","first-page":"137192","DOI":"10.1155\/2012\/137192","article-title":"Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel (plan B), and efavirenz.","volume":"2012","author":"Carten","year":"2012","journal-title":"Infect Dis Obstet Gynecol"},{"key":"R2-20251204","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1097\/QAD.0000000000001591","article-title":"Efavirenz decreases etonogestrel exposure: a pharmacokinetic evaluation of implantable contraception with antiretroviral therapy.","volume":"31","author":"Chappell","year":"2017","journal-title":"AIDS"},{"key":"R3-20251204","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1093\/cid\/civ1001","article-title":"Unintended pregnancies observed with combined use of the levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: a three-arm pharmacokinetic evaluation over 48 weeks.","volume":"62","author":"Scarsi","year":"2016","journal-title":"Clin Infect Dis"},{"key":"R4-20251204","doi-asserted-by":"crossref","first-page":"149","DOI":"10.3851\/IMP1725","article-title":"The effect of efavirenz on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy HIV-negative women.","volume":"16","author":"Sevinsky","year":"2011","journal-title":"Antivir Ther"},{"key":"R5-20251204","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1097\/QAI.0000000000000189","article-title":"Effect of antiretroviral therapy including lopinavir\/ritonavir or efavirenz on etonogestrel-releasing implant pharmacokinetics in HIV-positive women.","volume":"66","author":"Vieira","year":"2014","journal-title":"J Acquir Immune Defic Syndr"},{"key":"R7-20251204","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1097\/QAD.0000000000001392","article-title":"Drug interactions between hormonal contraceptives and antiretrovirals.","volume":"31","author":"Nanda","year":"2017","journal-title":"AIDS"},{"key":"R8-20251204","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1007\/s40264-016-0452-7","article-title":"Drug-drug interactions, effectiveness, and safety of hormonal contraceptives in women living with HIV.","volume":"39","author":"Scarsi","year":"2016","journal-title":"Drug Saf"},{"key":"R9-20251204","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/0960-0760(91)90129-S","article-title":"Effect of the progestogens, gestodene, 3-keto desogestrel, levonorgestrel, norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes.","volume":"38","author":"Back","year":"1991","journal-title":"J Steroid Biochem Mol Biol"},{"key":"R10-20251204","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/S0009-9236(03)00202-9","article-title":"Inhibition of cytochrome P450 2B6 activity by hormone replacement therapy and oral contraceptive as measured by bupropion hydroxylation.","volume":"74","author":"Palovaara","year":"2003","journal-title":"Clin Pharmacol Ther"},{"key":"R11-20251204","doi-asserted-by":"crossref","first-page":"e601","DOI":"10.1016\/S2352-3018(19)30155-9","article-title":"Antiretroviral therapy and vaginally administered contraceptive hormones: a three-arm, pharmacokinetic study.","volume":"6","author":"Scarsi","year":"2019","journal-title":"Lancet HIV"},{"key":"R12-20251204","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1002\/cpt.1477","article-title":"Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2B6 and efavirenz-containing antiretroviral therapy.","volume":"106","author":"Desta","year":"2019","journal-title":"Clin Pharmacol Ther"},{"key":"R13-20251204","first-page":"2391","article-title":"Pharmacogenetics of efavirenz and central nervous system side effects: an adult AIDS clinical trials group study.","volume":"18","author":"Haas","year":"2004","journal-title":"AIDS"},{"key":"R14-20251204","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1016\/j.bbrc.2004.05.116","article-title":"Homozygous CYP2B6 *6 (Q172H and K262R) correlates with high plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-containing regimens.","volume":"319","author":"Tsuchiya","year":"2004","journal-title":"Biochem Biophys Res Commun"},{"key":"R15-20251204","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/01213011-200501000-00001","article-title":"Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients.","volume":"15","author":"Rotger","year":"2005","journal-title":"Pharmacogenet Genomics"},{"key":"R16-20251204","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1086\/429327","article-title":"Influence of 516G>T polymorphisms at the gene encoding the CYP450-2B6 isoenzyme on efavirenz plasma concentrations in HIV-infected subjects.","volume":"40","author":"Rodriguez-Novoa","year":"2005","journal-title":"Clin Infect Dis"},{"key":"R17-20251204","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1097\/FPC.0b013e32835a450b","article-title":"Genome-wide association study of plasma efavirenz pharmacokinetics in AIDS clinical trials group protocols implicates several CYP2B6 variants.","volume":"22","author":"Holzinger","year":"2012","journal-title":"Pharmacogenet Genomics"},{"key":"R18-20251204","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1093\/jac\/dkn029","article-title":"Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV-infected patients.","volume":"61","author":"Wyen","year":"2008","journal-title":"J Antimicrob Chemother"},{"key":"R19-20251204","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1097\/01.fpc.0000189797.03845.90","article-title":"Identification of a novel specific CYP2B6 allele in Africans causing impaired metabolism of the HIV drug efavirenz.","volume":"16","author":"Wang","year":"2006","journal-title":"Pharmacogenet Genomics"},{"key":"R20-20251204","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1086\/655470","article-title":"Effect of CYP2B6, ABCB1, and CYP3A5 polymorphisms on efavirenz pharmacokinetics and treatment response: an AIDS clinical trials group study.","volume":"202","author":"Ribaudo","year":"2010","journal-title":"J Infect Dis"},{"key":"R21-20251204","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1097\/FPC.0b013e328328d577","article-title":"In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function.","volume":"19","author":"di Iulio","year":"2009","journal-title":"Pharmacogenet Genomics"},{"key":"R22-20251204","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1111\/j.1365-2125.2009.03368.x","article-title":"CYP2B6 (c.516G\u2013>T) and CYP2A6 (*9B and\/or *17) polymorphisms are independent predictors of efavirenz plasma concentrations in HIV-infected patients.","volume":"67","author":"Kwara","year":"2009","journal-title":"Br J Clin Pharmacol"},{"key":"R23-20251204","doi-asserted-by":"crossref","first-page":"2101","DOI":"10.1097\/QAD.0b013e3283319908","article-title":"CYP2B6, CYP2A6 and UGT2B7 genetic polymorphisms are predictors of efavirenz mid-dose concentration in HIV-infected patients.","volume":"23","author":"Kwara","year":"2009","journal-title":"AIDS"},{"key":"R24-20251204","doi-asserted-by":"crossref","first-page":"2175","DOI":"10.1093\/jac\/dku110","article-title":"Secondary metabolism pathway polymorphisms and plasma efavirenz concentrations in HIV-infected adults with CYP2B6 slow metabolizer genotypes.","volume":"69","author":"Haas","year":"2014","journal-title":"J Antimicrob Chemother"},{"key":"R25-20251204","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1097\/QAI.0b013e318158a44f","article-title":"Optimizing measurement of self-reported adherence with the ACTG adherence questionnaire: a cross-protocol analysis.","volume":"46","author":"Reynolds","year":"2007","journal-title":"J Acquir Immune Defic Syndr"},{"key":"R26-20251204","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1086\/514010","article-title":"JC virus (JCV) genotypes in brain tissue from patients with progressive multifocal leukoencephalopathy (PML) and in urine from controls without PML: increased frequency of JCV type 2 in PML.","volume":"176","author":"Agostini","year":"1997","journal-title":"J Infect Dis"},{"key":"R27-20251204","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1097\/FPC.0000000000000034","article-title":"Genomewide association study of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS clinical trials group protocol A5202.","volume":"24","author":"Johnson","year":"2014","journal-title":"Pharmacogenet Genomics"},{"key":"R28-20251204","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1210\/me.2012-1397","article-title":"TSPYL5 SNPs: association with plasma estradiol concentrations and aromatase expression.","volume":"27","author":"Liu","year":"2013","journal-title":"Mol Endocrinol"},{"key":"R29-20251204","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1136\/jmedgenet-2013-101705","article-title":"Genome-wide association study of sex hormones, gonadotropins and sex hormone-binding protein in Chinese men.","volume":"50","author":"Chen","year":"2013","journal-title":"J Med Genet"},{"key":"R30-20251204","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/ejhg.2015.102","article-title":"Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes.","volume":"24","author":"Ruth","year":"2016","journal-title":"Eur J Hum Genet"},{"key":"R31-20251204","doi-asserted-by":"crossref","first-page":"e37815","DOI":"10.1371\/journal.pone.0037815","article-title":"Genome-wide association study of circulating estradiol, testosterone, and sex hormone-binding globulin in postmenopausal women.","volume":"7","author":"Prescott","year":"2012","journal-title":"PLoS One"},{"key":"R32-20251204","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/nature10354","article-title":"Human metabolic individuality in biomedical and pharmaceutical research.","volume":"477","author":"Suhre","year":"2011","journal-title":"Nature"},{"key":"R33-20251204","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1093\/eurheartj\/ehv116","article-title":"Effect of genetic variations on ticagrelor plasma levels and clinical outcomes.","volume":"36","author":"Varenhorst","year":"2015","journal-title":"Eur Heart J"},{"key":"R35-20251204","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/ejhg.2015.85","article-title":"Genomics and metabolomics of muscular mass in a community-based sample of UK females.","volume":"24","author":"Korostishevsky","year":"2016","journal-title":"Eur J Hum Genet"},{"key":"R36-20251204","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1038\/mp.2011.101","article-title":"Genome-wide association analysis of coffee drinking suggests association with CYP1A1\/CYP1A2 and NRCAM.","volume":"17","author":"Amin","year":"2012","journal-title":"Mol Psychiatry"},{"key":"R37-20251204","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1093\/hmg\/ddr086","article-title":"Sequence variants at CYP1A1-CYP1A2 and AHR associate with coffee consumption.","volume":"20","author":"Sulem","year":"2011","journal-title":"Hum Mol Genet"},{"key":"R38-20251204","doi-asserted-by":"crossref","first-page":"e1002033","DOI":"10.1371\/journal.pgen.1002033","article-title":"Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of habitual caffeine consumption.","volume":"7","author":"Cornelis","year":"2011","journal-title":"Plos Genet"},{"key":"R39-20251204","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses.","volume":"81","author":"Purcell","year":"2007","journal-title":"Am J Hum Genet"},{"key":"R40-20251204","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1002\/cpt.667","article-title":"The effect of gene variants on levonorgestrel pharmacokinetics when combined with antiretroviral therapy containing efavirenz or nevirapine.","volume":"102","author":"Neary","year":"2017","journal-title":"Clin Pharmacol Ther"},{"key":"R41-20251204","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1093\/jac\/dkx515","article-title":"Physiologically based pharmacokinetic modelling prediction of the effects of dose adjustment in drug-drug interactions between levonorgestrel contraceptive implants and efavirenz-based ART.","volume":"73","author":"Roberts","year":"2018","journal-title":"J Antimicrob Chemother"},{"key":"R42-20251204","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.1093\/jac\/dkz298","article-title":"Effect of patient genetics on etonogestrel pharmacokinetics when combined with efavirenz or nevirapine ART.","volume":"74","author":"Neary","year":"2019","journal-title":"J Antimicrob Chemother"},{"key":"R44-20251204","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1002\/cpt.156","article-title":"Pharmacokinetic and pharmacodynamic comparison of once-daily efavirenz (400\u2009mg vs. 600\u2009mg) in treatment-na\u00efve HIV-infected patients: results of the ENCORE1 study.","volume":"98","author":"Dickinson","year":"2015","journal-title":"Clin Pharmacol Ther"},{"key":"R45-20251204","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1080\/17512433.2016.1235972","article-title":"Therapeutic drug monitoring of antiretroviral drugs in HIV-infected patients.","volume":"9","author":"Punyawudho","year":"2016","journal-title":"Expert Rev Clin Pharmacol"}],"container-title":["Pharmacogenetics and Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.lww.com\/10.1097\/FPC.0000000000000396","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T13:00:46Z","timestamp":1764853246000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1097\/FPC.0000000000000396"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4]]},"references-count":42,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2020]]}},"URL":"https:\/\/doi.org\/10.1097\/fpc.0000000000000396","relation":{},"ISSN":["1744-6872"],"issn-type":[{"value":"1744-6872","type":"print"}],"subject":[],"published":{"date-parts":[[2020,4]]}}}