452   Patterns of Protease Inhibitor Cross-Resistance in Viral Isolates with Reduced Susceptibility to ABT-378.

S. Brun*¹, D. Kempf¹, J. Isaacson¹, A. Molla¹, H. Mo¹, C. Benson², and E. Sun¹for the M97-765 and M98-957 Study Groups.
¹Abbott Labs and²Univ. of Colorado.

Background:Kaletra (ABT-378/r) is a novel HIV protease inhibitor (PI) with a high inhibitory quotient (IQ,^Ctrough/EC₅₀) that theoretically provides a pharmacologic barrier to the emergence of resistance from wild-type virus. To date, the selection of resistance to ABT-378 has not been identified among 470 antiretroviral-naïve patients treated for >48 weeks. In the absence of data from primary treatment failures, analysis of cross- resistance patterns from viral isolates with reduced ABT-378 susceptibility can provide insight into potential treatment options following failures associated with ABT-378 resistance.

Methods:Susceptibility of 56 viral isolates from multiple PI-experienced patients to PIs was compared by linear regression. Cross-resistance of 5 rebound isolates from PI-experienced patients failing Kaletra therapy was also measured.

Results:Phenotypic susceptibility (log fold EC₅₀) to ABT-378 correlated closely with the susceptibility to ritonavir (RTV) and indinavir (R²= 0.82 and 0.67, respectively) but poorly with the susceptibility to amprenavir (APV) and saquinavir (SQV) (R²= 0.27 and 0.21) in isolates with reduced susceptibility to at least one agent. Viral isolates with 8 or more protease mutations associated with ABT-378 resistance displayed a median of 44- fold reduced susceptibility to ABT-378 relative to wild-type virus, compared to 6-fold for APV. In rebound isolates from PI-experienced patients failing Kaletra that displayed 9- to 99-fold reduced susceptibility to ABT- 378, the corresponding reduced susceptibility to APV was 1- to 8.5-fold. Isolates from 3 SQV-naïve patients maintained wild-type sensitivity to SQV. Clinical data is available from a patient who developed 25-fold reduced susceptibility to ABT-378 but remained susceptible (1.0-fold) to APV after viral rebound during Kaletra therapy. Subsequent treatment with a RTV/APV-based regimen suppressed plasma HIV RNA to <400 c/mL through 12 weeks of follow-up to date.

Conclusion:Based on cross-resistance patterns, APV with RTV PK enhancement should be studied in patients who fail Kaletra therapy with virus resistant to ABT-378. Further clinical investigation is underway.