title: Pharmacokinetics, safety, and efficacy of tipranavir boosted with ritonavir alone or in combination with other boosted protease inhibitors as part of optimized combination antiretroviral therapy in highly treatment-experienced patients (BI Study 1182.51).
abstract: BACKGROUND
  Given the limited treatment options for patients with high-level resistance, antiretroviral (ARV) regimens based on concomitant use of 2 ritonavir (RTV)-boosted protease inhibitors (PIs) were considered a therapeutic option.
  
  
  METHODS
  Boehringer Ingelheim (BI) study 1182.51 examined the pharmacokinetic profile, safety, and efficacy of RTV-boosted tipranavir (TPV/r), alone and in combination with comparator PIs (CPIs) in 315 triple-class-experienced, HIV-infected patients.
  
  
  RESULTS
  Two weeks after single PI therapy, the addition of TPV/r reduced plasma trough levels 52%, 80%, and 56% for lopinavir (LPV), saquinavir (SQV), and amprenavir (APV) recipients, respectively. After 2 weeks, a TPV/r-only regimen reduced HIV viral load (VL) by a median of 1.06 log(10) copies/mL. VL reductions at 2 weeks between single-boosted CPIs were difficult to compare, because the numbers of patients maintaining their previous failing PI after randomization were different. At week 4, patients initiating treatment with TPV-containing regimens sustained VL reduction (median decrease of 1.27 log(10) copies/mL). Patients adding TPV to regimens at week 2 achieved median reductions from a baseline of 1.19 log(10), 0.96 log(10), and 1.12 log(10) copies/mL at week 4 in dual-boosted LPV, SQV, and APV groups, respectively. At 24 weeks, VL reductions (median: -0.24 to -0.47 log(10) copies/mL) were comparable between treatment groups.
  
  
  CONCLUSIONS
  The efficacy of a dual PI regimen depended on the presence of TPV, with additional recycled CPIs having limited activity, even in drug-resistant patient populations with plasma trough concentrations regarded as likely to be adequate in this study. No clear guidelines exist about ARV plasma trough concentrations in treatment-experienced patients, however.
authors.affiliation: Division of Clinical Investigation and Human Physiology, University of Toronto, Toronto, ON, Canada. sharon.walmsley@uhn.on.ca
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Walmsley
authors.forename: Christine
authors.initials: C
authors.lastname: Katlama
authors.forename: Adriano
authors.initials: A
authors.lastname: Lazzarin
authors.forename: Keikawus
authors.initials: K
authors.lastname: Arestéh
authors.forename: Gerald
authors.initials: G
authors.lastname: Pierone
authors.forename: Gary
authors.initials: G
authors.lastname: Blick
authors.forename: Margaret
authors.initials: M
authors.lastname: Johnson
authors.forename: Ulrich
authors.initials: U
authors.lastname: Meier
authors.forename: Thomas R
authors.initials: TR
authors.lastname: MacGregor
authors.forename: Johnathan G
authors.initials: JG
authors.lastname: Leith
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D003967:Diarrhea / Q000139:chemically induced; D004359:Drug Therapy, Combination; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011753:Pyrones / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019438:Ritonavir / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013449:Sulfonamides; D016896:Treatment Outcome
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D019438:Ritonavir; C107201:tipranavir