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.
abstract: BACKGROUND
  Levonorgestrel subdermal implants are preferred contraceptives with an expected failure rate of <1% over 5 years. We assessed the effect of efavirenz- or nevirapine-based antiretroviral therapy (ART) coadministration on levonorgestrel pharmacokinetics.
  
  
  METHODS
  This nonrandomized, parallel group, pharmacokinetic evaluation was conducted in three groups of human immunodeficiency virus-infected Ugandan women: ART-naive (n = 17), efavirenz-based ART (n = 20), and nevirapine-based ART (n = 20). Levonorgestrel implants were inserted at baseline in all women. Blood was collected at 1, 4, 12, 24, 36, and 48 weeks. The primary endpoint was week 24 levonorgestrel concentrations, compared between the ART-naive group and each ART group by geometric mean ratio (GMR) with 90% confidence interval (CI). Secondary endpoints included week 48 levonorgestrel concentrations and unintended pregnancies.
  
  
  RESULTS
  Week 24 geometric mean levonorgestrel concentrations were 528, 280, and 710 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively (efavirenz: ART-naive GMR, 0.53; 90% CI, .50, .55 and nevirapine: ART-naive GMR, 1.35; 90% CI, 1.29, 1.43). Week 48 levonorgestrel concentrations were 580, 247, and 664 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively (efavirenz: ART-naive GMR, 0.43; 90% CI, .42, .44 and nevirapine: ART-naive GMR, 1.14; 90% CI, 1.14, 1.16). Three pregnancies (3/20, 15%) occurred in the efavirenz group between weeks 36 and 48. No pregnancies occurred in the ART-naive or nevirapine groups.
  
  
  CONCLUSIONS
  Within 1 year of combined use, levonorgestrel exposure was markedly reduced in participants who received efavirenz-based ART, accompanied by contraceptive failures. In contrast, nevirapine-based ART did not adversely affect levonorgestrel exposure or efficacy.
  
  
  BACKGROUND
  NCT01789879.
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha.
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Scarsi
authors.affiliation: Center for Global Health.|Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Darin
authors.affiliation: Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Shadia
authors.initials: S
authors.lastname: Nakalema
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Back
authors.affiliation: Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Pauline
authors.initials: P
authors.lastname: Byakika-Kibwika
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Else
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.
authors.forename: Sujan
authors.initials: S
authors.lastname: Dilly Penchala
authors.affiliation: Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Allan
authors.initials: A
authors.lastname: Buzibye
authors.affiliation: Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Cohn
authors.affiliation: Center for Global Health.|Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda.|Department of Medicine, Trinity College Dublin, Ireland.
authors.forename: Concepta
authors.initials: C
authors.lastname: Merry
authors.affiliation: Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Lamorde
mesh_terms: D000293:Adolescent; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D048588:Benzoxazines / Q000627:therapeutic use*; D003271:Contraceptive Agents, Female / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D003521:Cyclopropanes; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000208:ethnology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D016912:Levonorgestrel / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019829:Nevirapine / Q000627:therapeutic use; D011247:Pregnancy; D049168:Pregnancy, Unplanned; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D013997:Time Factors; D014454:Uganda
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003271:Contraceptive Agents, Female; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D016912:Levonorgestrel; D019829:Nevirapine; C098320:efavirenz
keywords: contraceptive implant; efavirenz; levonorgestrel; nevirapine; unintended pregnancy