Efficacy and safety of three doses of tipranavir boosted with ritonavir in treatment-experienced HIV type-1 infected patients.
The efficacy, safety, and pharmacokinetics of three doses of tipranavir/ritonavir (TPV/r) in highly treatment-experienced human immunodeficiency virus (HIV)-1-infected patients with protease inhibitor (PI)-resistant isolates were evaluated. A 24-week multicenter, double-blind, randomized, dose-finding trial was conducted. All patients were three-drug class experienced and had taken at least two PI-based regimens. All had at least one primary PI mutation and had plasma HIV-RNA > 1000 copies/ml. Patients remained on their background non-PI antiretroviral medications for the first 14 days. After this 14-day period of functional TPV/r monotherapy, the background antiretroviral medications were optimized based on treatment history and the screening genotype. A total of 216 patients were randomized. All groups [TPV/r 500 mg/100 mg (n = 73), 500 mg/200 mg (n = 72), and 750 mg/200 mg (n = 71) twice daily] achieved an approximate 1 log10 reduction in the median HIV-RNA at week 2. A significant reduction was sustained through 24 weeks in the TPV/r 500 mg/200 mg and 750 mg/200 mg groups. The 500 mg/200 mg dose achieved optimal median TPV trough concentrations and lower interpatient variability. The most frequently reported adverse events (AEs) were diarrhea, nausea, vomiting, fatigue, and headache. The TPV/r 750 mg/200 mg group had the highest rate of grade 3 or 4 laboratory abnormalities and study discontinuations due to AEs. All doses of TPV/r tested in this study were associated with HIV-1 viral load reductions through 24 weeks. The 500 mg/200 mg dose achieved the best efficacy, safety, and pharmacokinetic profile in this highly treatment-experienced population and was selected for the pivotal phase 3 studies.
Gathe
Joseph C
JC
Therapeutic Concepts, 4900 Fannin Street, Houston, TX 77004, USA. drgathe@josephgathe.com
Pierone
Gerald
G
Piliero
Peter
P
Arasteh
Keikawus
K
Rubio
Rafael
R
Lalonde
Richard G
RG
Cooper
David
D
Lazzarin
Adriano
A
Kohlbrenner
Veronika M
VM
Dohnanyi
Catherine
C
Sabo
John
J
Mayers
Douglas
D
D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D024921:Drug Resistance, Multiple, Viral / Q000187:drug effects*; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008297:Male; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D011753:Pyrones / Q000008:administration & dosage* / Q000009:adverse effects; D019438:Ritonavir / Q000008:administration & dosage* / Q000009:adverse effects; D013449:Sulfonamides; D016896:Treatment Outcome
D019380:Anti-HIV Agents; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D019438:Ritonavir; C107201:tipranavir