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1	Tipranavir Resistance Lisa K. Naeger, Ph.D. Kimberly Struble, Pharm.D. Division of Antiviral Drug Products Food and Drug Administration
2	TPV In Vitro Resistance Profile
3	Cross-Resistance In Vitro TPV showed <4-fold decreased susceptibility against 90% (94/105) of HIV-1 isolates resistant to APV, ATV, IDV, LPV, NFV, RTV, or SQV. TPV-resistant viral molecular clones showed decreased susceptibility to all currently available protease inhibitors except SQV.
4	Clinical Resistance Baseline genotype/phenotype and virologic outcome analyses Development of resistance on TPV treatment
5	Clinical Resistance Baseline genotype/phenotype and virologic outcome analyses Development of resistance on TPV treatment
6	Baseline Genotype/Phenotype and Virologic Outcome Analyses
7	Endpoints Proportion of Responders (confirmed 1 log₁₀ decrease) Median DAVG24 Median change in HIV RNA from Baseline at Week 2, 4, 8, 16, 24
8	FDA Reasons for Censoring Primary Endpoint Dataset
9	FDA Reasons for Censoring DAVG24 Dataset
10	Baseline Outcome Analyses Number of Baseline PI Mutations Type of Baseline PI Mutation Baseline TPV Phenotype
11	Response by Number of Baseline PI Mutations
12	Response by #Baseline PI Mutations Median Change from Baseline: Overall
13	Response by #Baseline PI Mutations Median Change from Baseline: No T20
14	Response by #Baseline PI Mutations Median Change from Baseline: +T20 Use
15	Baseline Outcome Analyses Number of Baseline PI Mutations Type of Baseline PI Mutation Baseline TPV Phenotype
16	Effect of Type of Baseline PI Mutation on the Primary Endpoint
17	Effect of Type of Baseline PI Mutation on the Primary Endpoint
18	Baseline Outcome Analyses Number of Baseline PI Mutations Type of Baseline PI Mutation Baseline TPV Phenotype
19	Proportion of Responders by Baseline TPV Phenotype
20	Baseline TPV Phenotype: DAVG24
21	Mutations Developing on TPV Treatment
22	Mutations that Developed on TPV: RESIST 1 and 2
23	Resistance Summary TPV is a protease inhibitor with antiviral activity against multi PI-resistant clinical HIV-1 isolates. The most common protease mutations that developed in >20% of isolates from treatment-experience subjects who failed on TPV/r treatment were L10I/V/S, I13V, L33V/I/F, M36V/I/L, V82T or L, and I84V. The resistance profile in treatment-naive subjects has not yet been characterized.
24	Resistance Summary Virologic response rates in TPV/r-treated subjects were reduced when: isolates with substitutions at positions I13, V32, M36, I47, Q58, D60 or I84 and substitutions V82S/F/I/L were present at baseline. the number of baseline PI mutations was 5 or more. Subjects taking T20 with TPV/r were able to achieve >1.5 log₁₀ reductions in viral load through 24 weeks the baseline phenotype for TPV was >3. Consistent observations were made in each of the analyses conducted by multiple endpoints. 20% more responders in the TPV/r arm compared to CPI/r Greater reductions in viral load in TPV/r arm vs. CPI/r arm