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Clinical Pharmacokinetics and Pharmacodynamics of Etravirine: An Updated Review

  • Joshua P. HavensEmail author
  • Anthony T. Podany
  • Kimberly K. Scarsi
  • Courtney V. Fletcher
Review Article
  • 39 Downloads

Abstract

Etravirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of human immunodeficiency virus type 1 infection. It is a potent inhibitor of HIV reverse transcriptase and retains activity against wild-type and most NNRTI-resistant HIV. The pharmacokinetic profile of etravirine and clinical data support twice-daily dosing, although once-daily dosing has been investigated in treatment-naïve and treatment-experienced persons. Despite similar pharmacokinetic and pharmacodynamic results compared with twice-daily dosing, larger studies are needed to fully support once-daily etravirine dosing in treatment-naïve individuals. Etravirine is reserved for use in third- or fourth-line antiretroviral treatment regimens, as recommended, for example, in treatment guidelines by the US Department of Health and Human Services—Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Etravirine exhibits the potential for bi-directional drug–drug interactions with other antiretrovirals and concomitant medications through its interactions with cytochrome P450 (CYP) isozymes: CYP3A4, CYP2C9, and CYP2C19. This review summarizes the pharmacokinetic and pharmacodynamic parameters of etravirine, with particular attention to information on drug–drug interactions and use in special patient populations, including children/adolescents, women, persons with organ dysfunction, and during pregnancy.

Notes

Compliance with ethical standards

Funding

The authors acknowledge support from the following grants from the National Institutes of Health: 1K23AI134307 (to Anthony T. Podany), 1R01HD085887-01A1 (to Kimberly K. Scarsi), and RO1 AI124965-04 and UM1AI06701 (to Courtney V. Fletcher).

Conflict of interest

Joshua P. Havens reports receiving grants from Gilead Sciences that are paid directly to the University of Nebraska Medical Center. Anthony T. Podany, Kimberly K. Scarsi and Courtney V. Fletcher report no conflicts of interest that are directly relevant to the content of this review.

References

  1. 1.
    Vingerhoets J, Tambuyzer L, Azijn H, Hoogstoel A, Nijs S, Peeters M, et al. Resistance profile of etravirine: combined analysis of baseline genotypic and phenotypic data from the randomized, controlled Phase III clinical studies. AIDS. 2010;24(4):503–14.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Andries K, Azijn H, Thielemans T, Ludovici D, Kukla M, Heeres J, et al. TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother. 2004;48(12):4680–6.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Wensing AM, Calvez V, Gunthard HF, Johnson VA, Paredes R, Pillay D, et al. 2017 update of the drug resistance mutations in HIV-1. Top Antivir Med. 2017;24(4):132–3.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Scherrer AU, Hasse B, von Wyl V, Yerly S, Boni J, Burgisser P, et al. Prevalence of etravirine mutations and impact on response to treatment in routine clinical care: the Swiss HIV Cohort Study (SHCS). HIV Med. 2009;10(10):647–56.PubMedCrossRefGoogle Scholar
  5. 5.
    Tambuyzer L, Thys K, Hoogstoel A, Nijs S, Tomaka F, Opsomer M, et al. Assessment of etravirine resistance in HIV-1-infected paediatric patients using population and deep sequencing: final results of the PIANO study. Antivir Ther. 2016;21(4):317–27.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Tudor-Williams G, Cahn P, Chokephaibulkit K, Fourie J, Karatzios C, Dincq S, et al. Etravirine in treatment-experienced, HIV-1-infected children and adolescents: 48-week safety, efficacy and resistance analysis of the phase II PIANO study. HIV Med. 2014;15(9):513–24.PubMedCrossRefGoogle Scholar
  7. 7.
    Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 6 Jun 2019.
  8. 8.
    European AIDS Clinical Society Guidelines version 9.1, October 2018.Google Scholar
  9. 9.
    Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. 2nd Edition. Geneva: World Health Organization. 2016. http://www.who.int/hiv/pub/guidelines/hiv-testing-services/en/. Accessed 14 Jun 2019.
  10. 10.
    Konigs C, Feiterna-Sperling C, Esposito S, Viscoli C, Rosso R, Kakuda TN, et al. Pharmacokinetics and short-term safety and tolerability of etravirine in treatment-experienced HIV-1-infected children and adolescents. AIDS. 2012;26(4):447–55.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Scholler-Gyure M, Kakuda TN, Raoof A, De Smedt G, Hoetelmans RM. Clinical pharmacokinetics and pharmacodynamics of etravirine. Clin Pharmacokinet. 2009;48(9):561–74.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Kakuda TN, Wade JR, Snoeck E, Vis P, Scholler-Gyure M, Peeters MP, et al. Pharmacokinetics and pharmacodynamics of the non-nucleoside reverse-transcriptase inhibitor etravirine in treatment-experienced HIV-1-infected patients. Clin Pharmacol Ther. 2010;88(5):695–703.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Scholler M, Hoetelmans R, Beets G, et al. Substantial improvement of oral bioavailability of TMC125 using new tablet formulations in healthy volunteers [abstract no. 82]. In: 6th International Workshop of Clinical Pharmacology of HIV Therapy; 28–30 Apr 2005; Quebec.Google Scholar
  14. 14.
    Scholler-Gyure M, Kakuda TN, De Smedt G, et al. Pharmacokinetics of TMC125 in once- and twice-daily regimens in HIV-1 negative volunteers [abstract no. A-1427]. In: 47th Interscience Conference Agents and Chemotherapy; 17–20 Sep 2007; Chicago.Google Scholar
  15. 15.
    Kakuda TN, Scholler-Gyure M, Workman C, Arasteh K, Pozniak AL, De Smedt G, et al. Single- and multiple-dose pharmacokinetics of etravirine administered as two different formulations in HIV-1-infected patients. Antivir Ther. 2008;13(5):655–61.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Annaert P. Determination of the in vitro transport characteristics of TMC125, evaluation of the possible role of p-glycoprotein in TMC125 transport and assessment of possible inhibition of p-glycoprotein activity by TMC125: a study in Caco-2 monolayers. Nonclinical pharmacokinetics report, study no. TMC125-NC183 (FK4784). Beerse: Johnson & Johnson Pharmaceutical Research & Development; 2004 (data on file).Google Scholar
  17. 17.
    Scholler-Gyure M, Boffito M, Pozniak AL, Leemans R, Kakuda TN, Woodfall B, et al. Effects of different meal compositions and fasted state on the oral bioavailability of etravirine. Pharmacotherapy. 2008;28(10):1215–22.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Etravirine [prescribing information]. Titusville. NJ: Janssen Therapeutics; 2013.Google Scholar
  19. 19.
    Scholler-Gyure M, Kakuda TN, De Smedt G, Vanaken H, Bouche MP, Peeters M, et al. A pharmacokinetic study of etravirine (TMC125) co-administered with ranitidine and omeprazole in HIV-negative volunteers. Br J Clin Pharmacol. 2008;66(4):508–16.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Kakuda TN, Berckmans C, De Smedt G, Leemans R, Leopold L, Peeters M, et al. Single-dose pharmacokinetics of pediatric and adult formulations of etravirine and swallowability of the 200-mg tablet: results from three Phase 1 studies. Int J Clin Pharmacol Ther. 2013;51(9):725–37.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Sandkovsky U, Swindells S, Moore R, Acosta EP, Fletcher CV. Acceptable plasma concentrations of raltegravir and etravirine when administered by gastrostomy tube in a patient with advanced multidrug-resistant human immunodeficiency virus infection. Pharmacotherapy. 2012;32(2):142–7.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Mamidi RNVS. The plasma protein binding and blood distribution of TMC125 in animals and man. Nonclinical pharmacokinetics report, study no. TMC125-NC143 (FK5135). Beerse: Johnson & Johnson Pharmaceutical Research & Development; 2004 (data on file).Google Scholar
  23. 23.
    John J, John M, Wu L, Hsiao C, Abobo CV, Liang D. Effects of etravirine on the pharmacokinetics and pharmacodynamics of warfarin in rats. Br J Pharmacol. 2013;168(8):1851–8.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Kakuda TN, Scholler-Gyure M, Peeters M, et al. Pharmacokinetics of etravirine are not affected by sex, age, race, use of enfuvirtide or treatment duration in HIV-1 infected patients [abstract no. P34]. In: 9th International Workshop of Clinical Pharmacology of HIV Therapy; 7–9 Apr 2008; New Orleans.Google Scholar
  25. 25.
    Nguyen A, Rossi S, Croteau D, Best BM, Clifford D, Collier AC, et al. Etravirine in CSF is highly protein bound. J Antimicrob Chemother. 2013;68(5):1161–8.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Tiraboschi JM, Niubo J, Vila A, Perez-Pujol S, Podzamczer D. Etravirine concentrations in CSF in HIV-infected patients. J Antimicrob Chemother. 2012;67(6):1446–8.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Patterson K, Jennings S, Falcon R, Mrus J, Kashuba A. Darunavir, ritonavir, and etravirine pharmacokinetics in the cervicovaginal fluid and blood plasma of HIV-infected women. Antimicrob Agents Chemother. 2011;55(3):1120–2.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Clavel C, Peytavin G, Tubiana R, Soulié C, Courbon E, Crenn-Hebert C, et al. Etravirine concentrations in the cervicovaginal compartment in HIV-1-infected women receiving etravirine-containing antiretroviral therapy: DIVA 02 study. Antimicrob Agents Chemother. 2012;56(7):4018–20.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Brown KC, Patterson KB, Jennings SH, Malone SA, Shaheen NJ, Asher Prince HM, et al. Single- and multiple-dose pharmacokinetics of darunavir plus ritonavir and etravirine in semen and rectal tissue of HIV-negative men. J Acquir Immune Defic Syndr. 2012;61(2):138–44.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Raoof A, Mannens G, Mamidi R, et al. In vivo metabolism and mass balance of the anti-HIV compound TMC125 in laboratory animals and healthy volunteers [abstract no. M1342]. In: American Association of Pharmaceutical Scientists Annual Meeting and Exposition; 28 Oct–2 Nov 2006; San Antonio.Google Scholar
  31. 31.
    Scholler-Gyure M, Raoof A, Mannens G, et al. Mass-balance of 14C-labelled TMC125 in healthy volunteers [abstract no. 78]. In: 8th International Workshop of Clinical Pharmacology of HIV Therapy; 16–18 Apr 2007; Budapest.Google Scholar
  32. 32.
    Smeulders L. Overview of the antiviral activities of TMC125 metabolites on a panel of NNRTI viruses. Tibotec research report no. CB-SR-2004-00052-AVE-NNRTI. Mechelen: Tibotec; Feb 2005 (data on file).Google Scholar
  33. 33.
    Scholler-Gyure M, Kakuda TN, De Smedt G, Woodfall B, Berckmans C, Peeters M, et al. Effects of hepatic impairment on the steady-state pharmacokinetics of etravirine 200 mg BID: an open-label, multiple-dose, controlled Phase I study in adults. Clin Ther. 2010;32(2):328–37.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Kakuda TN, Brochot A, Green B, Nijs S, Vis P, Opsomer M, et al. Pharmacokinetics and pharmacokinetic/pharmacodynamic relationships of etravirine in HIV-1-infected, treatment-experienced children and adolescents in PIANO. J Clin Pharmacol. 2016;56(11):1395–405.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Lubomirov R, Arab-Alameddine M, Rotger M, Fayet-Mello A, Martinez R, Guidi M, et al. Pharmacogenetics-based population pharmacokinetic analysis of etravirine in HIV-1 infected individuals. Pharmacogenet Genomics. 2013;23(1):9–18.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Ter Heine R, Mulder JW, van Gorp EC, Wagenaar JF, Beijnen JH, Huitema AD. Intracellular and plasma steady-state pharmacokinetics of raltegravir, darunavir, etravirine and ritonavir in heavily pre-treated HIV-infected patients. Br J Clin Pharmacol. 2010;69(5):475–83.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Scholler-Gyure M, Kakuda TN, De Smedt G, et al. Pharmacokinetics of TMC125 in HIV-negative volunteers with mild or moderate hepatic impairment [abstract no. A-1428]. In: 47th Interscience Conferrence on Antimicrobial Agents and Chemotherapy; 17–20 Sep 2007; Chicago.Google Scholar
  38. 38.
    Mulligan N, Schalkwijk S, Best BM, Colbers A, Wang J, Capparelli EV, et al. Etravirine pharmacokinetics in HIV-infected pregnant women. Front Pharmacol. 2016;7:239.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    US FDA. Clinical and cross-discipline team leader review/addendum. NDA#22187/Supplement 024. 2018. https://www.fda.gov/media/115201/download. Accessed 27 Jun 2019.
  40. 40.
    MacBrayne CE, Rutstein R, Yogev R, et al. Etravirine pharmacokinetics in treatment-experienced children ages 1–< 6 years [abstract no. 465]. In: The Conference on Retroviruses and Opportunistic Infections; 4–7 Mar 2018; Boston.Google Scholar
  41. 41.
    Kakuda TN, Scholler-Gyure M, Hoetelmans RM. Pharmacokinetic interactions between etravirine and non-antiretroviral drugs. Clin Pharmacokinet. 2011;50(1):25–39.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Zembruski NC, Haefeli WE, Weiss J. Interaction potential of etravirine with drug transporters assessed in vitro. Antimicrob Agents Chemother. 2011;55(3):1282–4.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Kakuda TN, Van Solingen-Ristea RM, Onkelinx J, Stevens T, Aharchi F, De Smedt G, et al. The effect of single- and multiple-dose etravirine on a drug cocktail of representative cytochrome P450 probes and digoxin in healthy subjects. J Clin Pharmacol. 2014;54(4):422–31.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Kakuda TN, Scholler-Gyure M, Hoetelmans RM. Clinical perspective on antiretroviral drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor etravirine. Antivir Ther. 2010;15(6):817–29.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Kakuda TN, Abel S, Davis J, Hamlin J, Scholler-Gyure M, Mack R, et al. Pharmacokinetic interactions of maraviroc with darunavir-ritonavir, etravirine, and etravirine-darunavir-ritonavir in healthy volunteers: results of two drug interaction trials. Antimicrob Agents Chemother. 2011;55(5):2290–6.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Fostemsavir Drug Information. AIDSinfo Health Professional. https://aidsinfo.nih.gov/drugs/508/fostemsavir/0/professional. Accessed 3 Sep 2019.
  47. 47.
    Savant Landry I, Tao X, Anderson J, Hesney M, Stonier M, Lubin S, Wang J, Hanna GJ, Boulton DW. HIV-1 Attachment Inhibitor Prodrug BMS-663068: Interactions with DRV/r and/or ETR [abstract no. 523]. In: The Conference on Retroviruses and Opportunistic Infections; 23–26 Feb 2015; Seattle.Google Scholar
  48. 48.
    Anderson MS, Kakuda TN, Hanley W, Miller J, Kost JT, Stoltz R, et al. Minimal pharmacokinetic interaction between the human immunodeficiency virus nonnucleoside reverse transcriptase inhibitor etravirine and the integrase inhibitor raltegravir in healthy subjects. Antimicrob Agents Chemother. 2008;52(12):4228–32.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Song I, Borland J, Min S, Lou Y, Chen S, Patel P, et al. Effects of etravirine alone and with ritonavir-boosted protease inhibitors on the pharmacokinetics of dolutegravir. Antimicrob Agents Chemother. 2011;55(7):3517–21.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Kakuda TN, Scholler-Gyure M, De Smedt G, Beets G, Aharchi F, Peeters MP, et al. Assessment of the steady-state pharmacokinetic interaction between etravirine administered as two different formulations and tenofovir disoproxil fumarate in healthy volunteers. HIV Med. 2009;10(3):173–81.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Molto J, Curran A, Miranda C, Challenger E, Santos JR, Ribera E, et al. Pharmacokinetics of darunavir/cobicistat and etravirine alone and co-administered in HIV-infected patients. J Antimicrob Chemother. 2018;73(3):732–7.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Orrell C, Felizarta F, Nell A, Kakuda TN, Lavreys L, Nijs S, et al. Pharmacokinetics of etravirine combined with atazanavir/ritonavir and a nucleoside reverse transcriptase inhibitor in antiretroviral treatment-experienced, HIV-1-infected patients. AIDS Res Treat. 2015;2015:938628.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Belkhir L, Elens L, Zech F, Panin N, Vincent A, Yombi JC, et al. Interaction between darunavir and etravirine is partly mediated by CYP3A5 polymorphism. PLoS One. 2016;11(10):e0165631.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Green B, Crauwels H, Kakuda TN, Vanveggel S, Brochot A. Evaluation of concomitant antiretrovirals and CYP2C9/CYP2C19 polymorphisms on the pharmacokinetics of etravirine. Clin Pharmacokinet. 2017;56(5):525–36.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Vingerhoets J, Azijn H, Fransen E, De Baere I, Smeulders L, Jochmans D, et al. TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. J Virol. 2005;79(20):12773–82.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Haddad M, Stawiski E, Benhamida J, Coakley E. Improved genotypic algorithm for predicting etravirine susceptibility: comprehensive list of mutations identified through correlation with matched phenotype. In: Poster presented at: 17th Conference on Retroviruses and Opportunistic Infections (CROI); 16–19 Feb 2010; San Francisco.Google Scholar
  57. 57.
    Girard PM, Campbell TB, Grinsztejn B, Hartikainen J, Rachline A, Nijs S, et al. Pooled week 96 results of the phase III DUET-1 and DUET-2 trials of etravirine: further analysis of adverse events and laboratory abnormalities of special interest. HIV Med. 2012;13(7):427–35.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Panel on Antiretroviral Guidelines for Pediatrics. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Department of Health and Human Services. https://aidsinfo.nih.gov/guidelines/html/2/pediatric-arv/0. Accessed 6 Jun 2019.
  59. 59.
    Katlama C, Haubrich R, Lalezari J, Lazzarin A, Madruga JV, Molina JM, et al. Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials. AIDS. 2009;23(17):2289–300.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Lazzarin A, Campbell T, Clotet B, Johnson M, Katlama C, Moll A, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370(9581):39–48.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Madruga JV, Cahn P, Grinsztejn B, Haubrich R, Lalezari J, Mills A, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370(9581):29–38.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Katlama C, Clotet B, Mills A, Trottier B, Molina JM, Grinsztejn B, et al. Efficacy and safety of etravirine at week 96 in treatment-experienced HIV type-1-infected patients in the DUET-1 and DUET-2 trials. Antivir Ther. 2010;15(7):1045–52.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Clumeck N, Cahn P, Molina JM, Mills A, Nijs S, Vingerhoets J, et al. Virological response with fully active etravirine: pooled results from the DUET-1 and DUET-2 trials. Int J STD AIDS. 2010;21(11):738–40.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Trottier B, Di Perri G, Madruga JV, Peeters M, Vingerhoets J, Picchio G, et al. Impact of the background regimen on virologic response to etravirine: pooled 48-week analysis of DUET-1 and -2. HIV Clin Trials. 2010;11(4):175–85.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Schneider L, Ktorza N, Fourati S, Assoumou L, Courbon E, Caby F, et al. Switch from etravirine twice daily to once daily in non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-infected patients with suppressed viremia: the Monetra study. HIV Clin Trials. 2012;13(5):284–8.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Echeverria P, Bonjoch A, Puig J, Molto J, Paredes R, Sirera G, et al. Randomised study to assess the efficacy and safety of once-daily etravirine-based regimen as a switching strategy in HIV-infected patients receiving a protease inhibitor-containing regimen. Etraswitch study. PLoS One. 2014;9(2):e84676.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Yazdanpanah Y, Fagard C, Descamps D, Taburet AM, Colin C, Roquebert B, et al. High rate of virologic suppression with raltegravir plus etravirine and darunavir/ritonavir among treatment-experienced patients infected with multidrug-resistant HIV: results of the ANRS 139 TRIO trial. Clin Infect Dis. 2009;49(9):1441–9.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Ruane PJ, Brinson C, Ramgopal M, Ryan R, Coate B, Cho M, et al. The Intelence aNd pRezista Once A Day Study (INROADS): a multicentre, single-arm, open-label study of etravirine and darunavir/ritonavir as dual therapy in HIV-1-infected early treatment-experienced subjects. HIV Med. 2015;16(5):288–96.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Katlama C, Assoumou L, Valantin MA, Soulie C, Martinez E, Beniguel L, et al. Dual therapy combining raltegravir with etravirine maintains a high level of viral suppression over 96 weeks in long-term experienced HIV-infected individuals over 45 years on a PI-based regimen: results from the phase II ANRS 163 ETRAL study. J Antimicrob Chemother. 2019;74(9):2742–51.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Floris-Moore MA, Mollan K, Wilkin AM, Johnson MA, Kashuba AD, Wohl DA, et al. Antiretroviral activity and safety of once-daily etravirine in treatment-naive HIV-infected adults: 48-week results. Antivir Ther. 2016;21(1):55–64.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Gazzard B, Duvivier C, Zagler C, Castagna A, Hill A, van Delft Y, et al. Phase 2 double-blind, randomized trial of etravirine versus efavirenz in treatment-naive patients: 48-week results. AIDS. 2011;25(18):2249–58.PubMedCrossRefGoogle Scholar
  72. 72.
    Clotet B, Feinberg J, van Lunzen J, Khuong-Josses MA, Antinori A, Dumitru I, et al. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet. 2014;383(9936):2222–31.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Gallant J, Lazzarin A, Mills A, Orkin C, Podzamczer D, Tebas P, et al. Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial. Lancet. 2017;390(10107):2063–72.PubMedCrossRefGoogle Scholar
  74. 74.
    Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009;374(9692):796–806.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Orrell C, Hagins DP, Belonosova E, Porteiro N, Walmsley S, Falco V, et al. Fixed-dose combination dolutegravir, abacavir, and lamivudine versus ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate and emtricitabine in previously untreated women with HIV-1 infection (ARIA): week 48 results from a randomised, open-label, non-inferiority, phase 3b study. Lancet HIV. 2017;4(12):e536–46.PubMedCrossRefGoogle Scholar
  76. 76.
    Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutierrez F, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369(19):1807–18.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Ramgopal M, Osiyemi O, Zorrilla C, Crauwels HM, Ryan R, Brown K, et al. Pharmacokinetics of total and unbound etravirine in HIV-1-infected pregnant women. J Acquir Immune Defic Syndr. 2016;73(3):268–74.PubMedCrossRefGoogle Scholar
  78. 78.
    Fatkenheuer G, Duvivier C, Rieger A, Durant J, Rey D, Schmidt W, et al. Lipid profiles for etravirine versus efavirenz in treatment-naive patients in the randomized, double-blind SENSE trial. J Antimicrob Chemother. 2012;67(3):685–90.PubMedCrossRefGoogle Scholar
  79. 79.
    Calcagno A, Marinaro L, Nozza S, Aldieri C, Carbone A, Ghisetti V, et al. Etravirine plasma exposure is associated with virological efficacy in treatment-experienced HIV-positive patients. Antiviral Res. 2014;108:44–7.PubMedCrossRefGoogle Scholar
  80. 80.
    Kakuda TN, DeMasi R, van Delft Y, Mohammed P. Pharmacokinetic interaction between etravirine or darunavir/ritonavir and artemether/lumefantrine in healthy volunteers: a two-panel, two-way, two-period, randomized trial. HIV Med. 2013;14(7):421–9.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Ford SL, Gould E, Chen S, Lou Y, Dumont E, Spreen W, et al. Effects of etravirine on the pharmacokinetics of the integrase inhibitor S/GSK1265744. Antimicrob Agents Chemother. 2013;57(1):277–80.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Gutierrez-Valencia A, Martin-Pena R, Torres-Cornejo A, Ruiz-Valderas R, Castillo-Ferrando JR, Lopez-Cortes LF. Intracellular and plasma pharmacokinetics of 400 mg of etravirine once daily versus 200 mg of etravirine twice daily in HIV-infected patients. J Antimicrob Chemother. 2012;67(3):681–4.PubMedCrossRefPubMedCentralGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of Infectious Diseases, Department of Internal Medicine, College of MedicineUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Antiviral Pharmacology Laboratory, Department of Pharmacy Practice and Science, College of PharmacyUniversity of Nebraska Medical CenterOmahaUSA

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