Impact of reverse transcriptase resistance on the efficacy of TMC125 (etravirine) with two nucleoside reverse transcriptase inhibitors in protease inhibitor-naïve, nonnucleoside reverse transcriptase inhibitor-experienced patients: study TMC125-C227.
OBJECTIVE
TMC125-C227, an exploratory phase II, randomized, controlled, open-label trial, compared the efficacy and safety of TMC125 (etravirine) with an investigator-selected protease inhibitor (PI) in nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant, protease inhibitor-naïve, HIV-1-infected patients.


METHODS
Patients were randomized to TMC125 800 mg twice a day (bid) (phase II formulation; n=59) or the control PI (n=57), plus two nucleoside reverse transcriptase inhibitors (NRTIs).


RESULTS
In an unplanned interim analysis, patients receiving TMC125 demonstrated suboptimal virological responses relative to the control PI. Therefore, trial enrolment was stopped prematurely and TMC125 treatment discontinued after a median of 14.3 weeks. In this first-line NNRTI-failure population, baseline NRTI and NNRTI resistance was high and reduced virological responses were observed relative to the control PI. No statistically significant relationship was observed between TMC125 exposure and virological response at week 12. TMC125 was better tolerated than a boosted PI for gastrointestinal-, lipid- and liver-related events.


CONCLUSIONS
In a PI-naïve population, with baseline NRTI and NNRTI resistance and NRTI recycling, TMC125 was not as effective as first use of a PI. Therefore the use of TMC125 plus NRTIs alone may not be optimal in PI-naïve patients with first-line virological failure on an NNRTI-based regimen. Baseline two-class resistance, rather than pharmacokinetics or other factors, was the most likely reason for suboptimal responses.
Ruxrungtham
K
K
HIV-NAT, Thai Red Cross AIDS Research Center and Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. kiat.r@chula.ac.th
Pedro
R J
RJ
Latiff
G H
GH
Conradie
F
F
Domingo
P
P
Lupo
S
S
Pumpradit
W
W
Vingerhoets
J H
JH
Peeters
M
M
Peeters
I
I
Kakuda
T N
TN
De Smedt
G
G
Woodfall
B
B
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D018791:CD4 Lymphocyte Count; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral / Q000187:drug effects; D004812:Epidemiologic Methods; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D011724:Pyridazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019562:Viral Load; D055815:Young Adult
D017320:HIV Protease Inhibitors; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine