Short-term randomized proof-of-principle trial of TMC278 in patients with HIV type-1 who have previously failed antiretroviral therapy.
BACKGROUND
In vitro, TMC278, an investigational next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), has shown activity against wild-type and NNRTI-resistant HIV type-1 (HIV-1) and a higher genetic barrier to the development of resistance than efavirenz or nevirapine. This Phase II open-label trial evaluated the short-term (7-day) antiviral activity of TMC278 administered at three different doses replacing either the protease inhibitor (PI) or NNRTI of an ongoing failing treatment regimen in HIV-1-infected patients.


METHODS
A total of 36 patients on failing antiretroviral therapy containing either an NNRTI or a PI (with evidence of > or =1 NNRTI resistance-associated mutation at screening for the PI group) and plasma viral load (VL)>1,000 copies/ml were randomized to one of three once-daily TMC278 doses (25 mg, 50 mg or 150 mg) for 7 days, while continuing NRTIs used at screening. The primary efficacy parameter was the change on day 8 in log(10) plasma VL from baseline.


RESULTS
On day 8, median (min, max) changes from baseline in plasma VL were -0.87 (-2.3, 0.0), -0.95 (-1.8, 0.4) and -0.66 (-1.3, -0.2) log(10) copies/ml for the 25 mg, 50 mg and 150 mg once-daily TMC278 groups, respectively (P<0.001-<0.01). Overall, the median change from baseline was -1.19 log(10) copies/ml in the PI-substituted therapy group and -0.71 log(10) copies/ml in the NNRTI-substituted therapy group. TMC278 was generally safe and well tolerated with no apparent differences in safety among the three dose groups.


CONCLUSIONS
Once-daily TMC278 showed significant antiviral activity against HIV-1 in treatment-experienced patients with NNRTI failure and/or resistance, and was generally safe and well tolerated.
Arastéh
Keikawus
K
EPIMED GmbH, c/o Klinik für Innere Medizin-Infektiologie/Gastroenterologie, Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany. keikawus.arasteh@vivantes.de
Rieger
Armin
A
Yeni
Patrick
P
Pozniak
Anton
A
Boogaerts
Griet
G
van Heeswijk
Rolf
R
de Béthune
Marie-Pierre
MP
Peeters
Monika
M
Woodfall
Brian
B
D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D009570:Nitriles / Q000008:administration & dosage / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D000068696:Rilpivirine; D013997:Time Factors; D017211:Treatment Failure; D016896:Treatment Outcome; D019562:Viral Load
D019380:Anti-HIV Agents; D009570:Nitriles; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D000068696:Rilpivirine