title: TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
abstract: Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
authors.affiliation: Tibotec-Virco BVBA, Generaal de Wittelaan L11 B3, B-2800 Mechelen, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Azijn
authors.forename: Ilse
authors.initials: I
authors.lastname: Tirry
authors.forename: Johan
authors.initials: J
authors.lastname: Vingerhoets
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: de Béthune
authors.forename: Guenter
authors.initials: G
authors.lastname: Kraus
authors.forename: Katia
authors.initials: K
authors.lastname: Boven
authors.forename: Dirk
authors.initials: D
authors.lastname: Jochmans
authors.forename: Elke
authors.initials: E
authors.lastname: Van Craenenbroeck
authors.forename: Gaston
authors.initials: G
authors.lastname: Picchio
authors.forename: Laurence T
authors.initials: LT
authors.lastname: Rimsky
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D002478:Cells, Cultured; D003521:Cyclopropanes; D024882:Drug Resistance, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D015394:Molecular Structure; D019829:Nevirapine / Q000494:pharmacology / Q000627:therapeutic use; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D011724:Pyridazines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D000068696:Rilpivirine
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; C451734:etravirine; D019829:Nevirapine; D000068696:Rilpivirine; C098320:efavirenz