tipranavir and Diarrhea

Topics: Animals; Anti-HIV Agents; Clinical Trials as Topic; Darunavir; Diarrhea; Dizziness; Drug Evaluation, Preclinical; Drug Therapy, Combination; Headache; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Pyridines; Pyrones; Sulfonamides; Treatment Outcome

To evaluate the efficacy, safety and tolerability of ritonavir-boosted tipranavir (TPV/r) in HIV-1-infected pediatric patients.. Open-label randomized pediatric trial (1182.14/PACTG1051) comparing TPV/r at two doses including an optimized background regimen.. HIV-1-infected patients (2-18 years) with plasma viral load 1500 copies/ml or more were randomized to TPV/r 290/115 or 375/150 mg/m twice-daily oral solution and optimized background regimen. Week 48 efficacy, safety and tolerability results were evaluated.. Children (n = 115; 97% treatment experienced) were randomized to low or high dose therapy. Eighty-eight remained on-treatment through 48 weeks. Baseline characteristics were similar between dose groups. At study entry, half of the HIV-1 isolates were resistant to all protease inhibitors. At 48 weeks, 39.7% low-dose and 45.6% high-dose TPV/r recipients had viral load less than 400 copies/ml and 34.5 and 35.1%, respectively, achieved viral load less than 50 copies/ml. Vomiting, cough and diarrhea were the most frequent adverse events. Grade 3 alanine aminotransferase elevations were observed in 6.3% of patients. No grade 4 alanine aminotransferase or grade 3/4 aspartate aminotransferase elevations were reported.. TPV/r achieved a sustained virologic response, showed a good safety profile and was well tolerated at either dose. In pediatric patients with high baseline resistance profiles, high-dose TPV/r tended to demonstrate a better sustained response.

Topics: Adolescent; Alanine Transaminase; Anti-HIV Agents; Biomarkers; Blood Coagulation Disorders; Child; Child, Preschool; Diarrhea; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Logistic Models; Male; Pyridines; Pyrones; Ritonavir; Sulfonamides; Treatment Outcome; Viral Load; Vomiting

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.. 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.. 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.. 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.

Topics: Adolescent; Adult; Anti-HIV Agents; Area Under Curve; Diarrhea; Drug Therapy, Combination; Fatigue; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Metabolic Clearance Rate; Middle Aged; Nausea; Pyridines; Pyrones; Ritonavir; Sulfonamides; Treatment Outcome