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Effect of Baseline Genotype on Response to Tipranavir/ritonavir (TPV/r) Compared with Standard-of-care Comparator (CPI/r) in Treatment-experienced Patients: The Phase 3 RESIST-1 and -2 Trials
J Schapiro*1, P Cahn2, B Trottier3, F Antunes4, D Jayaweera5, J Gerstoft6, D Norris7, D Cooper8, C Hicks9, S McCallister10, D Hall10, H Valdez10, D Neubacher10, V Kohlbrenner10, and D Mayers10
1Ctr for AIDS Res, Stanford Univ Med Sch, CA, USA; 2Fndn Huésped, Buenos Aires, Argentina; 3Clin Med l' Actuel, Montreal, Canada; 4Hosp Santa Maria, Lisbon, Portugal; 5Jackson Med Ctr, Miami, FL, USA; 6Natl Univ Hosp, Rigshospitalet, Copenhagen, Denmark; 7Ctr for Quality Care, Tampa, FL, USA; 8St Vincent's Hosp, Univ of New South Wales, Sydney, Australia; 9Duke Univ Med Ctr, Durham, NC, USA; and 10Boehringer Ingelheim Pharma Inc, Ridgefield, CT, USA
Background: Tipranavir (TPV) is
a non-peptidic protease inhibitor (PI) that has
demonstrated potent activity in treatment-experienced patients with resistance
to available PI. The phase
3, multi-center, randomized, open-label RESIST-1 and
-2 trials demonstrated superiority of TPV/ritonavir (r)
over comparator/r (CPI/r). The objective of this analysis was to further
evaluate the genotypic resistance profile of TPV/r relative to CPI/r.
Methods: Patients with ≥
3-class
antiretroviral (ARV) experience including ≥ 2 PI-based ARV regimens, ≥ 1 primary PI mutation (30N, 46I/L,
48V, 50V, 82A/F/L/T, 84V, or 90M) and as
many as 2 key mutations at amino acids 33, 82, 84, 90, and viral load ≥ 1000 copies/mL
were eligible. Before randomization, an optimized CPI/r regimen was selected from among LPV, IDV, SQV,
or APV. Patients were then randomized to TPV/r (500 mg/200 mg twice daily) or CPI/r. Resistance was determined from genotypic
interpretation of TruGene or VirtualPhenotype assays. Protease
mutations were defined as deviations from the N American Consensus Sequence B.
This planned interim analysis compared the effect of baseline genotype on the
efficacy of TPV/r and CPI/r. The
primary endpoint (treatment response) was defined as a confirmed ≥ 1 log
decrease in viral load from baseline without prior treatment changes.
Results: We
randomized and treated 1483 patients in the 2 trials, of which 1159 were
available for analysis at 24 weeks.
Patients had previously received a median 6 nucleoside reverse transcriptase
inhibitors (NRTI), 1 non-NRTI (NNRTI), and 4 PI; 11.8% had previously taken enfuvirtide. At 24 weeks, TPV/r had a superior treatment
response to CPI/r in all genotype
strata (ITT-NCF); 50.4% vs 29.8% with ≤ 12 protease gene mutations, 39.4% vs 26.3% with 13 to 15, 43.6% vs
13.0% with 16 to 18, and 31.7% vs 7.7% with ≥
19.Similarly,
treatment response to TPV/r was not affected by the number of primary PI
mutations, with > 40% of patients whose virus had up to 6 primary PI
mutations achieving treatment response. This compared with 28% of CPI/r patients with 1 to 2 of these mutations,
13.6% with 3 to 4, and 16.7% with 5 to 6. There was no difference in treatment
response in the presence of 0 key mutations. However, with 1 to 2 key
mutations, 44.2% vs 25% and 40.9% vs
15.3% had treatment response in the TPV/r and CPI/r
groups respectively.
Conclusions: These
results indicate that the efficacy of TPV/r-based therapy was consistently
superior to CPI/r in this cohort of treatment-experienced HIV+
patients regardless of the number of total baseline protease mutations, primary
PI mutations, or key mutations.
Keywords: Tipranavir; Protease Inhibitor ; Genotype
