Etravirine: The renaissance of non-nucleoside reverse transcriptase inhibitors

Expert Opinion on Pharmacotherapy

Volumn 9, Issue 17, 2008, Pages 3083-3094

  Jayaweera, Dushyantha T ^a   Espinoza, Luis ^a   Castro, Jose ^a  

^a UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

Author keywords

AIDS; Etravirine; HIV; NNRTI; TMC 125

Indexed keywords

CYTOCHROME P450; CYTOCHROME P450 1A1; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; ETRAVIRINE; PLACEBO; RNA DIRECTED DNA POLYMERASE INHIBITOR;

CAUCASIAN; CLINICAL TRIAL; DIARRHEA; DRUG EFFICACY; DRUG INDUCED HEADACHE; DRUG MECHANISM; DRUG RESISTANCE; DRUG SAFETY; DRUG STRUCTURE; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; IN VITRO STUDY; NAUSEA; PHARMACODYNAMICS; RASH; REVERSE TRANSCRIPTION; REVIEW; VIRUS MUTATION; WILD TYPE;

ANTI-HIV AGENTS; CLINICAL TRIALS AS TOPIC; DRUG RESISTANCE, VIRAL; HIV INFECTIONS; HUMANS; PYRIDAZINES; REVERSE TRANSCRIPTASE INHIBITORS;

EID: 57549085009     PISSN: 14656566     EISSN: None     Source Type: Journal    
DOI: 10.1517/14656560802489569     Document Type: Review

References (60)

1. Fauci Anthony. Opinion Assay 26 Years of HIV. Nature 2008;453:289-90
2. Mocroft A, Ledergerber B, Katlama C, et al. Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet 2003;362:22-9
3. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338:853-60
4. Gazzard B. on behalf of the BHIVA Writing Committee. British HIV Association (BHIVA) guidelines for the treatment of HIV infected adults with antiretroviral therapy (2006). HIV Med 2006;7:487-503
5. Hammer SM, Saag MS, Schechter M, et al. Treatment for Adult HIV infection: 2006 recommendations of the International Aids Society-USA panel. JAMA 2006;296:827-43
6. Guidelines for the use of antiretroviral agents in HIV-1-Infected adults and adolescents January 29th 2008. Available from: http://AIDSinfo.nih.gov on June 1st 2008
7. Riddler SA, Haubrich R, Di Rienzo G, et al. A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection: ACTG 5142. XVI International AIDS Conference [abstract THLB0204]. Toronto, Canada; 2006
8. Bacheler L, Jeffrey S, Hanna G, et al. Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing non-nucleoside reverse transcriptase inhibitor therapy. J Virol 2001;75:4999-5008
9. Delaugerre C, Rohban R, Simon A, et al. Resistance profile and cross-resistance of HIV-1 among patients failing a non-nucleoside reverse transcriptase inhibitor-containing regimen. J Med Virol 2001;65:445-4814
10. Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 1999;341:1865-73
11. Tashima K, Staszewski S, Nelson M, et al. Durable viral suppression on EFV-based HAART: 168 weeks of follow-up. XV International AIDS Conference [abstract TuPeB4547]. Bangkok, Thailand; 2004
12. Van Leth F, Phanuphak P, Ruxungtham K, et al. 2NN Study Team. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomized open-label trial, the 2NN Study. Lancet 2004;363:1253-63
13. DeJesus E, Young B, Fisher A, et al. Virologic suppression is maintained after change to efavirenz/emtricitabine/tenofovir disoproxil fumarate single tablet regimen (EFV/FTC/TDF) vs. continuation of current antiretroviral therapy: Study 073 -Results of 24-week interim efficacy analyses. 11th European AIDS Conference (EACS) [abstract (late-breaker) PS7/6]. October 24-27; Madrid, Spain; 2007
14. Andries K, Azijn H, Thielemans T, et al. TMC125, a novel next-generation non-nucleoside reverse transcriptase inhibitor active against non-nucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 2004;48(12):4680-6
15. Tantillo C, Ding J, Jacobo-Molina A, et al. Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Implications for mechanisms of drug inhibition and resistance. J Mol Biol 1994;243(3):369-87
16. Ding J, Das K, Moereels H, et al. Structure of HIV-1 RT/TIBO R 86183 complex reveals similarity in the binding of diverse non-nucleoside inhibitors. Nat Struct Biol 1995;2(5):407-15
17. Bacheler LT. Resistance to non-nucleoside inhibitors of HIV-1 reverse transcriptase. Drug Resist Updat 1999;2(1):56-67
18. Das K, Clark AD Jr, Lewi PJ, et al. Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. J Med Chem 2004;47(10):2550-60
19. Hsiou Y, Ding J, Das K, et al. Structure of unliganded HIV-1 reverse transcriptase at 2.7 a resolution: implications of conformational changes for polymerization and inhibition mechanisms. Structure 1996;4(7):853-60
20. Das K, Lewi PJ, Hughes SH, Arnold E. Crystallography and the design of anti-AIDS drugs: conformational flexibility and positional adaptability are important in the design of nonnucleosideHIV-1 reverse transcriptase inhibitors. Prog Biophys Mol Biol 2005;88(2):209-31
21. Knoll MB, Vento S, Temesgen Z. Etravirine. Drugs Today 2008;44(1):23-33
22. Schöller M, Hoetelmanns R, Beets G, et al. Substantial improvement of oral bioavailability of TCM125 using new tablet formulations in healthy volunteers. Program and abstracts of the 3rd IAS Conference on HIV Pathogenesis and Treatment [abstractTuPe3.1B11]. July 24-27; Rio de Janeiro, Brazil; 2005
23. Schöller-Gyure M, Leemans R, Beets G, et al. Effect of food on the oral bioavailability of the phase III formulation of TMC125. Program and abstracts of the 7th International Workshop on Clinical Pharmacology of HIV Therapy [abstract 80]. Lisbon, Portugal; 2006
24. Gruzdev B, Rakhmanova A, Doubovskaya E, et al. A randomized, double-blind, placebo controlled trial of TMC125 as 7-day monotherapy in antiretroviral naive, HIV-1 infected subjects. AIDS 2003;17(17):487-94
25. Etravirine, prescribing information distributed by Tibotec Therapeutics, Division of Ortho Biotech Products, L.P. Raritan, NJ. January 2008. Available from: http://www.ttmedicalinformation.comttmedicalinformation/ assets/INTELENCE_PI.pdf
26. Gazzard BG, Pozniak AL, Rosenbaum W, et al. An open-label assessment of TMC125, a new, next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance. AIDS 2003;17(18):F49-54
27. Schöller-Gyüre M, Kakuda TN, De Smedt G, et al. Pharmacokinetics of TMC125 in once- and twice-daily regimens in HIV-1-negative volunteers. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy [Poster # A-1427]. September 17-20; Chicago, IL, USA; 2007
28. Kakuda TN, Wade JR, Snoeck E, et al. Pharmacokinetics and pharmacodynamics of the NNRTI etravirine (ETR; TMC125) in treatment-experienced HIV-1-infected patients: pooled 24 - week results of DUET-1 and DUET-2. Poster presented at the 15th Conference on Retroviruses and Opportunistic Infections (CROI) [abstract 762]. February 3-6; Boston, MA; 2008
29. Baede P, Piscitelli S, Graham N, et al. Drug interactions with TMC125, a potent next generation NNRTI. Program and abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy [abstract A-1827]. September 27-30; San Diego, California; 2002
30. Kakuda TN, Scholler-Gyure M, Peeters M, et al. Pharmacokinetics of etravirine (ETR; TMC125) are not affected by sex, age, race, use of enfuvirtide (ENF) or treatment duration in HIV-1-infected subjects. Poster presented at the 9th International Workshop on Clinical Pharmacology of HIV Therapy (IWCPHIV) [abstract 34]. April 7-9; New Orleans, LA; 2008
31. De Bethune MP, Hertogs K, Azijn H, et al. TMC 125, a third generation non nucleoside reverse transcriptase inhibitor, inhibits 98% of more than 2,000 recombinant HIV clinical isolates at 100 nM. Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy [abstract 219]. September 17-20; Toronto, Canada; 2000
32. Harris M, Zala C, Ramirez S, et al. Pharmacokinetics and safety of adding TMC125 to stable regimens of saquinavir, lopinavir, ritonavir, and NRTI in HIV + adults. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections [abstract 575b]. Denver, Colorado; 2006
33. Woodfall B, Vingerhoets J, Peeters M, et al. Impact of NNRTI and NRTI resistance on the response to the regimen of TMC125 plus two NRTIs in Study TMC125-C227. 8th International Congress on Drug Therapy in HIV Infection. November 12-16; Glasgow; 2006. Oral presentation PL5.6
34. Montaner J, Domingo P, Junod P, et al. Safety and tolerability of TMC125 in 3-class experienced HIV-infected patients: 24-week primary analysis of trial TMC125-C203. Program and abstracts of the European AIDS Clinical Society 10th European AIDS Conference [abstract LBPS3/7B]. November 17-20; Dublin, Ireland; 2005
35. Lazzarin A, Arribas J, Pozniak A, et al. Sustained antiviral activity of TMC125 plus optimized antiretroviral therapy in highly treatment-experienced patients. Program and abstracts of the 7th International Congress on Drug Therapy in HIV Infection [abstract 316]. November 14-18; Glasgow, Scotland; 2004
36. Writing Group TMC125-C223, Nadler JP, Berger DS, Blick G, et al. Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1: primary 24-week analysis. AIDS 2007;21(6):F1-10
37. Cohen C, Steinhart C, Ward D, et al. Efficacy and safety results at 48 weeks with the novel NNRTI, TMC125, and impact of baseline resistance on the virologic response in study TMC125-C223. Program and abstracts of the XVI International AIDS Conference [abstract TUPE0061]. August 13-18; Toronto, Canada; 2006
38. Madruga JV, Cahn P, Grinsztejn B, et al. DUET-1 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomized, double-blind, placebo-controlled trial. Lancet 2007;370(9581):29-38
39. Lazzarin A, Campbell T, Clotet B, et al. DUET-2 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomized, double-blind, placebo-controlled trial. Lancet 2007;370(9581):39-48
40. Trottier B, Johnson M, Katlama C, et al. Pooled 48-Week analysis of DUET-1 and DUET-2: durable efficacy and safety results of etravirine (ETR; TMC125) in treatment-experienced HIV-infected patients. 17th Annual Canadian Conference on HIV/AIDS Research (CAHR) [abstract 167]. April 24-27; Montréal, Canada; 2008
41. Johnson M, Campbell T, Clotet B, et al. DUET-2: Week 48 results of a Phase III randomized double-blind trial to evaluate the efficacy and safety of etravirine (ETR; TMC125) versus placebo in 591 treatment-experienced HIV-1-infected patients. 15th Conference on Retroviruses and Opportunistic Infections (CROI) [abstract 791]. February 3-6; Boston, MA; 2008
42. Gatell J, Beatty G, Johnson M, et al. Impact of TMC125, a Next-generation NNRTI, on Clinical Outcomes (AIDS-defining Illnesses and Deaths): 24-week Findings from a Planned Pooled Analysis of the DUET Studies [abstract P7.3/18]. 11th EACS 2007
43. Hirschel B, Pernege T, Editorial Comment. No patient left behind-better treatments for resistant HIV infection. Available from: www.thelancet.com, 2007;370:3-5
44. Peeters M, Nijs S, Vingerhoets J, et al. Determination of phenotypic clinical cut-offs for etravirine (ETR): pooled Week 24 results of the DUET-1 and DUET-2 trials 11th European AIDS Conference (EACS) [abstract 121]. October 24-27; Madrid, Spain; 2007
45. Vingerhoets J, Azijn H, Fransen E, 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
46. Bacheler LT. Resistance to non-nucleoside inhibitors of HIV-1 reverse transcriptase. Drug Resist Updat 1999;2(1):56-67
47. Udier-Blagovic M, Tirado-Rives J, Jorgensen WL. Validation of a model for the complex of HIV-1 reverse transcriptase with non-nucleoside inhibitor TMC125. J Am Chem Soc 2003;125(20):6016-7
48. Vingerhoets J, Clotet B, Peeters M, et al. Impact of baseline NNRTI mutations on the virologic response to TMC125 (etravirine, ETR) in the DUET-1 and DUET-2 Phase III clinical trials. 11th European AIDS Clinical Society (EACS) Conference [abstract P7.3/05]. October 24-27; Madrid, Spain; 2007
49. Vingerhoets J, Peeters M, Azijn H, et al. An update of the list of NNRTI mutations associated with decreased virologic response to etravirine (ETR): multivariate analyses on the pooled DUET-1 and DUET-2 clinical trial data. XVIIth International Drug Resistance Workshop [abstract # 24]. June 10-14; Sitges, Spain; 2008
50. Winters B, Villacian J, Van Craenenbroeck E, et al. Development of Virco TYPE HIV-1 resistance analysis, including clinical cutoffs for TMC125 (etravirine, ETR), a new NNRTI. 15th Conference on Retroviruses and Opportunistic Infections (CROI) [abstract 873]. February 3-6; Boston, MA; 2008
51. Picchio G, Vingerhoets J, Staes M, et al. Prevalence of etravirine (ETR, TMC125) resistance-associated mutations in a large panel of clinical isolates. 15th Conference on Retroviruses and Opportunistic Infections [abstract 866]. February 3-6; Boston, MA; 2008
52. Lapadula G, Ilzzo i, Gargiulo F, et al. Updated Prevalence of Genotypic Resistance Among HIV-1 Positive Patients Naive to Antiretroviral Therapy: A Single Center Analysis. J Med Virol 2008;80:747-53
53. Picchio G, Vingerhoets J, Parkin N. Nucleoside-associated mutations cause hypersusceptibility to etravirine (ETR). XVIIth International Drug Resistance Workshop [abstract 23]. June 10-14; Sitges, Spain; 2008
54. Janssen PA, Lewi PJ, Arnold E, Daeyaert F, et al. In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4- 4-4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino] benzonitrile (R278474, rilpivirine). J Med Chem 2005;48(6):1901-9
55. Pozniak A, Morales-Ramirez J, Mohapi, et al. 48-Week Primary Analysis of Trial TMC278-C204: TMC278 Demonstrates Potent and Sustained Efficacy in ART-naïve Patients. 15th Conference on Retroviruses and Opportunistic Infections (CROI 2008) [abstract 134]. February 3-6; Boston, MA; 2008. Boston, MA. February 3-6, 2008. Abstract 144 LB
56. van't Klooster G, Verloes R, Baert L, et al. Long-acting TMC278, a Parenteral Depot Formulation Delivering Therapeutic NNRTI Concentrations in Preclinical and Clinical Settings. Long-acting TMC278, the Parenteral Formulation Depot Delivering Therapeutic NNRTI Concentrations in Preclinical and Clinical Settings. 15th Conference on Retroviruses and Opportunistic Infections (CROI 2008). 15th Conference on Retroviruses and Opportunistic Infections (CROI 2008) [abstract 134]. February 3-6; Boston, MA; 2008
57. Goebel F, Yakovlev A, Pozniak AL, et al. Short-term antiviral activity of TMC278 - a novel NNRTI - in treatment-naive HIV-1-infected subjects. AIDS 2006;20(13):1721-6
58. David Cooper, Gatell J, Rockstroh J, at el. Results of BENCHMRK-1, a Phase III Study Evaluating the Efficacy and Safety of MK-0518, a Novel HIV-1 Integrase Inhibitor, in Patients with Triple-class Resistant Virus. 14th Conference on Retroviruses and Opportunistic Infections [abstract 788]. Los Angeles, CA; 2007
59. Nelson M, Fatkenheuer G, Konourina I, et al. Efficacy and Safety of Maraviroc plus Optimized Background Therapy in Viremic, ART-experienced Patients Infected with CCR5-tropic HIV-1 in Europe, Australia, and North America 24-Week Results. 14th Conference on Retroviruses and Opportunistic Infections [abstract 104aLB]. Los Angeles, CA; 2007
60. Lalezari J, Goodrich J, DeJesus E, et al. Efficacy and Safety of Maraviroc plus Optimized Background Therapy in Viremic ART-experienced Patients Infected with CCR5-tropic HIV-1: 24-Week Results of a Phase 2b/ 3 Study in the US and Canada. 14th Conference on Retroviruses and Opportunistic Infections [abstract 104bLB]. Los Angeles, CA; 2007