TMC278, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), Active against Wild-Type and NNRTI-Resistant HIV-1

Interaction of Reverse Transcriptase (RT) Mutations Conferring Resistance to Lamivudine and Etravirine: Effects on Fitness and RT Activity of Human Immunodeficiency Virus Type 1

“…Because we were unable to obtain RPV, we used ETV as a surrogate. As the E138K mutation confers similar levels of resistance to both drugs (3,22), it is likely that similar results would be obtained if the experiments reported here were conducted with RPV. The salutary effect of E138K on the fitness of HIV-1 carrying M184V raises the question of why E138K does not appear to arise as a compensatory mutation under the selective pressure of 3TC or FTC in the absence of ETV or RPV.…”

“…The E138K mutation, which emerges both in vitro and in vivo, confers resistance to ETV and RPV (2,3,22,23). Although in vitro passage experiments suggested that resistance to ETV and RPV emerges more slowly than resistance to first-generation NNRTIs (e.g., nevirapine [NVP] or EFV) (3,25), this finding has not been confirmed in clinical trials, which show the emergence of ETV and RPV resistance at the time of virologic failure in most patients treated with these drugs (17,18).…”

“…Etravirine (ETV; formerly TMC125) and rilpivirine (RPV; formerly TMC278) are potent next-generation NNRTIs that retain activity against efavirenz (EFV)-resistant viruses carrying the K103N mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) (1,3); both are diarylpyrimidine (DAPY) compounds. The E138K mutation, which emerges both in vitro and in vivo, confers resistance to ETV and RPV (2,3,22,23).…”

“…Etravirine (ETV; formerly TMC125) and rilpivirine (RPV; formerly TMC278) are potent next-generation NNRTIs that retain activity against efavirenz (EFV)-resistant viruses carrying the K103N mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) (1, 3); both are diarylpyrimidine (DAPY) compounds. The E138K mutation, which emerges both in vitro and in vivo, confers resistance to ETV and RPV (2,3,22,23). Although in vitro passage experiments suggested that resistance to ETV and RPV emerges more slowly than resistance to first-generation NNRTIs (e.g., nevirapine [NVP] or EFV) (3, 25), this finding has not been confirmed in clinical trials, which show the emergence of ETV and RPV resistance at the time of virologic failure in most patients treated with these drugs (17, 18).…”

Future Perspectives in NNRTI-Based Therapy: Bases for Understanding Their Toxicity

“…In fact, studies are underway to develop a new once-daily fixed-dose antiretroviral regimen containing Emtricitabine, Tenofovir disoproxil fumarate and Rilpivirine hydrochloride (de Béthune, 2010). Rilpivirine has an in vitro resistance profile comparable to that of ETR (Azijn, 2010), and results from week 96 of a Phase IIB trial (TMC278-C204) in naïve patients have demonstrated a potent and sustained efficacy similar to that of EFV, while it seems to produce fewer adverse events. Indeed, rilpivirine is associated with fewer incidences of neuropsychiatric events and rash, and a smaller rise in lipid levels than EFV (Pozniak, 2010).…”