Tipranavir/Ritonavir Superior to Comparator PI/Ritonavir at Week 48 in Multiclass-Experienced Patients Slideset on: Hicks CB, Cahn P, Cooper DA, et al. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multidrug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet. 2006;368:

clinicaloptions.com/hiv Tipranavir/Ritonavir Superior to Comparator PI/Ritonavir at Week 48 in Multiclass-Experienced Patients Hicks CB, et al. Lancet. 2006;368: Background and Rationale  Tipranavir a novel nonpeptidic PI with potent activity against PI-resistant HIV-1 both in vitro and in vivo –Approved in United States and Europe for use in PI- experienced patients in combination with ritonavir  Current study reported pooled analysis of 48-week efficacy and safety data from RESIST 1 and 2 in which tipranavir plus OBR compared with ritonavir-boosted comparator PI (CPI) plus optimized background regimen (OBR)

clinicaloptions.com/hiv Tipranavir/Ritonavir Superior to Comparator PI/Ritonavir at Week 48 in Multiclass-Experienced Patients Hicks CB, et al. Lancet. 2006;368: Schematic of Study Design Patients failing PI-containing HAART (N = 1483) Baseline genotypic resistance testing Preselection of CPI plus OBR by investigator Tipranavir/ritonavir n = 746 CPI Arm Lopinavir/ritonavir Indinavir/ritonavir Saquinavir/ritonavir Amprenavir/ritonavir n = 737 Week 48

clinicaloptions.com/hiv Tipranavir/Ritonavir Superior to Comparator PI/Ritonavir at Week 48 in Multiclass-Experienced Patients Hicks CB, et al. Lancet. 2006;368:  Inclusion criteria –≥ 18 years of age –NRTI, NNRTI, and PI experience for ≥ 3 consecutive months –≥ 2 PI-based regimens for ≥ 3 months –On PI-based regimen at enrollment –HIV-1 RNA ≥ 1000 copies/mL –≥ 1 documented primary PI mutation (30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, 90M) –≤ 2 mutations at codons 33, 82, 84, and 90 –No restrictions on CD4+ cell count or prior enfuvirtide use Inclusion Criteria

clinicaloptions.com/hiv Tipranavir/Ritonavir Superior to Comparator PI/Ritonavir at Week 48 in Multiclass-Experienced Patients Hicks CB, et al. Lancet. 2006;368: Description of Current Analysis  Data for RESIST 1 and 2 pooled in current analysis, given similar study design and patient demographics  Patients assessed at Weeks 2, 4, 8, 16, 24, 32, 40, and 48 for clinical and laboratory evaluations  Primary endpoints –Treatment response, defined as confirmed reduction in HIV-1 RNA ≥ 1 log10 copies/mL at Week 48 –Time to treatment failure  Safety assessed via adverse-event monitoring –Adverse events and laboratory abnormalities graded according to Division of AIDS grading scale –Total cholesterol abnormalities graded according to Common Toxicity Criteria Scale  Intent-to-treat analyses using noncompletion-equals-failure and last-observation-carried- forward methods

clinicaloptions.com/hiv Tipranavir/Ritonavir Superior to Comparator PI/Ritonavir at Week 48 in Multiclass-Experienced Patients Hicks CB, et al. Lancet. 2006;368: Outcome at Week 48 Tipranavir/Ritonavir (n = 746) CPI/Ritonavir (n = 737) P Value Treatment response, % <.0001  In patients using ENF <.0001*  In patients using first-time ENF <.0001 Median time to treatment failure, days (IQR) 113 (0-> 494)0 (0-119)<.0001  In patients using ENF 337 (0-> 475)0 (0-232)<.0001 HIV-1 RNA < 400 copies/mL, % <.0001  In patients using ENF <.0001* HIV-1 RNA < 50 copies/mL, % <.0001  In patients using ENF <.0001* Mean HIV-1 RNA reduction, log 10 copies/mL (SD) 1.14 (1.30)0.54 (1.02)<.0001 Mean CD4+ cell count increase, cells/mm 3 (SD) 45 (104)21 (89)<.0001 ENF, enfuvirtide; IQR, interquartile range. *Comparison between use and nonuse of enfuvirtide within treatment arm. Main Findings

clinicaloptions.com/hiv Tipranavir/Ritonavir Superior to Comparator PI/Ritonavir at Week 48 in Multiclass-Experienced Patients Hicks CB, et al. Lancet. 2006;368:  Several factors significantly and independently associated with treatment response to tipranavir/ritonavir in logistic regression analysis –ENF use: Odds Ratio (95% CI), 4.07 ( ); P <.0001 –Higher tipranavir trough concentration (40-80 µmol/L vs µmol/L): Odds Ratio (95% CI), 2.16 ( ); P <.05 –Fewer baseline tipranavir mutations (0-2 vs 5-6): Odds Ratio (95% CI), 0.14 ( ); P <.0001  Other factors associated with treatment response to tipranavir/ritonavir vs CPI/ritonavir –≤ 2 primary PI mutations at baseline: 40.8% vs 31.5% (P =.03) –Prior treatment with ≤ 3 PIs: 40.9% vs 30.5% (P =.007) Patient Outcomes

clinicaloptions.com/hiv Tipranavir/Ritonavir Superior to Comparator PI/Ritonavir at Week 48 in Multiclass-Experienced Patients Hicks CB, et al. Lancet. 2006;368:  Incidence of exposure-adjusted adverse events similar between arms  Significantly higher triglycerides, ALT/AST, and cholesterol in the tipranavir/ritonavir arm Other Outcomes Adverse Events and Grade 3/4 Laboratory Abnormalities, n (Rate per 100 Patient- Years) Tipranavir/Ritonavir (n = 749) CPI/Ritonavir (n = 737) P Value Any death18 (2.4)13 (2.8)-- Any adverse event680 (519.9)604 (525.9)-- Any adverse event leading to study discontinuation 90 (12.4)48 (10.6)-- Triglycerides184 (30.8)94 (23.1)<.0001 ALT71 (10.1)15 (3.3)<.0001 AST45 (6.3)13 (2.9).002 Cholesterol31 (4.3)3 (0.7)<.0001 ALT, alanine aminotransferase; AST, aspartate aminotransferase.

clinicaloptions.com/hiv Tipranavir/Ritonavir Superior to Comparator PI/Ritonavir at Week 48 in Multiclass-Experienced Patients Hicks CB, et al. Lancet. 2006;368:  Tipranavir/ritonavir plus OBR associated with significantly superior treatment outcomes vs use of ritonavir-boosted CPI plus OBR in highly treatment-experienced patients through 48 weeks of treatment –Treatment response rate significantly higher with tipranavir/ritonavir –Significantly longer time to treatment failure with tipranavir/ritonavir  Inclusion of enfuvirtide in OBR increased likelihood of effective treatment outcomes  Safety profile of tipranavir/ritonavir similar to that of other ritonavir-boosted PIs Key Conclusions