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Baseline Genotype and Phenotype Do Not Predict Response to ABT-378/Ritonavir in PI-Experienced Patients at 24 and 48 Weeks D. KEMPF*1, Y. XU1, S. BRUN1, M. KING1, H. MO1, K. REAL1, B. BERNSTEIN1, K. HERTOGS2, B. LARDER3, A. MOLLA1, A. JAPOUR1, E. SUN1, and the M97-765 Study Team.
1Abbott Labs., Chicago, IL; 2VIRCO, Mechelen, Belgium, and 3Cambridge, UK Background: ABT-378 is an advanced generation PI that, co-formulated with a low dose of ritonavir (r), maintains mean plasma levels >30-fold higher than its EC50 for wt HIV. Treatment of patients failing current PI therapy with ABT-378/r plus NVP and two NRTIs produced a decline to <400 copies/mL in 84% of patients on study at Week 48 (Study M97-765).
Objective: To analyze the virologic response in Study M97-765 after 24 and 48 weeks with respect to baseline viral phenotype and genotype.
Methods: Baseline phenotype was measured by the AntivirogramŽ method. Baseline genotype was determined by population sequencing. Virologic response was analyzed using logistic regression.
Results: Baseline genotype and/or phenotype data were available for 61/70 patients. The incidence of greater than or equal to a 4-fold change in EC50 to 1, 2 or all 3 drugs in their existing regimen was 36%, 43% and 17%, respectively. The fold change in EC50 to ABT-378 ranged from 0.7 to 26-fold, with 19% of patients displaying a greater than or equal to a 4-fold change. The number of analyzed patients that experienced virologic failure (confirmed increase in HIV RNA to >400 copies/mL) at weeks 24 and 48 was 6/58 and 10/55, respectively. In both univariate and multivariate analyses, neither the presence of PI-associated mutations (p>0.2) nor a greater than or equal to a 4-fold change in EC50 to ABT-378 (p>0.6) correlated with virologic response. Instead, baseline HIV RNA was significantly associated with Week 24 (p<0.05) and Week 48 (p<0.10) response.
Conclusion: Statistical models utilizing protease genotype and a >4-fold cutoff in phenotype do not adequately describe the activity of ABT-378/r in patients failing an initial PI-based regimen. These findings and the high response rate are consistent with the high, sustained plasma concentrations of ABT-378 observed in this study.
Key Words: ABT-378, Genotype/phenotype, Salvage therapy
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