An open-label assessment of TMC 125--a new, next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance.
The development of resistance to any of the currently licensed non-nucleoside reverse transcriptase inhibitors (NNRTI) invariably leads to cross-resistance to the drugs in that class. New NNRTI, that have the promise of being active even when such 'signature' mutations are present, are in development. Such novel therapies could be effective after current NNRTI failure as there would probably be no cross-resistance. We assessed the short-term efficacy and safety of a next generation NNRTI, TMC 125, a diarylpyrimidine derivative that has in vitro activity against NNRTI resistant HIV-1. TMC 125 was studied in HIV-1 infected patients with high-level phenotypic NNRTI resistance in an open-label phase IIa trial.


METHODS
Sixteen individuals receiving an NNRTI-containing antiretroviral regimen (efavirenz or nevirapine) with an HIV-1 RNA viral load of > 2000 copies/ml and phenotypic resistance to NNRTI, received TMC 125 for 7 days, as a substitute for their current NNRTI in their failing therapy. Full pharmacokinetic profiles were investigated.


RESULTS
The primary end point--viral load decay rate per day--was 0.13 log10 RNA copies/ml per day. Over 7 days, we observed a median 0.89 log10 decrease in HIV-1 viral load; seven individuals (44%) had a decrease of > 1 log10. The most significant adverse effects were grade I diarrhoea (31%) and a mild headache (25%). Steady-state drug levels were achieved by day 6.


CONCLUSIONS
TMC 125, a next generation NNRTI, is well tolerated and demonstrates significant and rapid antiviral activity in patients with high levels of phenotypic NNRTI resistance to current NNRTI.
Gazzard
Brian G
BG
St Stephen's Centre, Chelsea and Westminster Hospital, London, UK.
Pozniak
Anton L
AL
Rosenbaum
Willy
W
Yeni
G Patrick
GP
Staszewski
Schlomo
S
Arasteh
Keikawus
K
De Dier
Karin
K
Peeters
Monika
M
Woodfall
Brian
B
Stebbing
Justin
J
vant' Klooster
Gerben A
GA
D000328:Adult; D024882:Drug Resistance, Viral; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009570:Nitriles; D010641:Phenotype; D011724:Pyridazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines; D012367:RNA, Viral / Q000032:analysis; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load
D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine