TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1

Antimicrob Agents Chemother. 2010 Feb;54(2):718-27. doi: 10.1128/AAC.00986-09. Epub 2009 Nov 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkynes
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Anti-HIV Agents / therapeutic use*
  • Benzoxazines / pharmacology
  • Benzoxazines / therapeutic use
  • Cell Line
  • Cells, Cultured
  • Cyclopropanes
  • Drug Resistance, Viral / genetics
  • HIV Infections / drug therapy
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • Humans
  • Molecular Structure
  • Nevirapine / pharmacology
  • Nevirapine / therapeutic use
  • Nitriles / chemistry
  • Nitriles / pharmacology*
  • Nitriles / therapeutic use*
  • Pyridazines / pharmacology
  • Pyridazines / therapeutic use
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use*
  • Rilpivirine

Substances

  • Alkynes
  • Anti-HIV Agents
  • Benzoxazines
  • Cyclopropanes
  • Nitriles
  • Pyridazines
  • Pyrimidines
  • etravirine
  • Nevirapine
  • Rilpivirine
  • efavirenz