Tipranavir: a ritonavir-boosted protease inhibitor.
Tipranavir is a non-peptidic HIV-1 protease inhibitor. It binds strongly and selectively, has a favourable resistance profile, and is administered orally twice daily with a subtherapeutic dosage of ritonavir in a 'boosted' regimen (TPV/r) in order to increase its bioavailability. Analysis of clinical isolates from treatment-experienced patients identified the following tipranavir resistance-associated HIV protease mutations: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D, I84V. In two large, well designed phase III trials in protease inhibitor-experienced, HIV-infected patients, the RESIST (Randomised Evaluation of Strategic Intervention in multidrug reSistant patients with Tipranavir)-1 and -2 studies, oral TPV/r 500mg/200mg twice daily achieved a significantly better virological response after 24 weeks than standard ritonavir-boosted protease inhibitors. This held true for the proportion of patients achieving a >or=1 log(10) decrease in plasma HIV-RNA levels (viral load) [42% and 41% vs 22% and 15%; both p < 0.0001; primary endpoint] and other virological parameters (the proportion of patients with undetectable viral load and total viral load reduction). In addition, a significantly larger increase in CD4+ cell count was achieved with TPV/r than comparator regimens in these trials. The most common adverse events in clinical trials of tipranavir were gastrointestinal. The incidence of treatment discontinuation because of adverse events in the RESIST trials was 8% (pooled data).
Croom
Katherine F
KF
Adis International Limited, Auckland, New Zealand. demail@adis.co.nz
Keam
Susan J
SJ
D017326:Clinical Trials, Phase III as Topic; D004334:Drug Administration Schedule; D004338:Drug Combinations; D024882:Drug Resistance, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy*; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015497:HIV-1 / Q000201:enzymology / Q000302:isolation & purification; D006801:Humans; D009154:Mutation; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011753:Pyrones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013449:Sulfonamides; D019562:Viral Load
D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D016333:HIV Protease; D019438:Ritonavir; C107201:tipranavir