592-T. Alternative Phenotypic Sensitivity Scores and Outcome Measures Increase Detection of the Impact of Drug Resistance on Response to Salvage Therapy -- Results from ACTG 359

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Session 77 Poster Session
Resistance Testing in Drug Selection
Session Time: 4:30-6:30 pm
Room 4E-F

592-T.

Alternative Phenotypic Sensitivity Scores and Outcome Measures Increase Detection of the Impact of Drug Resistance on Response to Salvage Therapy -- Results from ACTG 359
R. Swanstrom*¹, H. Cheng², N. S. Hellmann³, D. Katzenstein⁴, R. J. Bosch², S. A. Fiscus¹, R. Haubrich⁵, and R. Gulick⁶
¹Univ. of North Carolina, Chapel Hill; ² Harvard Sch. of Publ. Health, Boston, MA; ³ViroLogic, Inc., South San Francisco, CA; ⁴Stanford Univ. Med. Ctr., Palo Alto, CA; ⁵Univ. of California, San Diego; and ⁶Weill Med. Coll. of Cornell Univ., New York, NY

Background: ACTG 359 was a study to determine the efficacy of saquinavir SGC + either ritonavir (RTV) or nelfinavir + delavirdine, adefovir (ADV), or both as salvage therapy. At entry, patients had taken an indinavir-containing regimen for >6 months, were naļve to study drugs, and had median baseline virus load (VL) = 31,746 copies/mL. Overall, 31% of subjects achieved HIV RNA <500 copies/mL at week 16.
Methods: Phenotypic drug susceptibility (IC50) was determined for all study drugs from 142 baseline plasma HIV-1 RNA samples using the ViroLogic Phenosense assay. Regression methods were used to investigate the relationship between baseline IC50 and week 16 virologic outcome using different models.
Results: Initially, dichotomous scores of 0 (resistant) or 1 (sensitive) were assigned using IC50 cut-offs of <2.5-, <4-, or <10-fold higher than the drug-sensitive control IC50. The phenotypic sensitivity score (PSS) was the sum of the scores for each drug in a subject’s regimen. Regression models were constructed from the baseline log₁₀ HIV RNA, CD4 cell count, and PSS to investigate the relationship with VL <500 copies/mL at week 16. Baseline VL was significantly associated with outcome, but CD4 cell count and dichotomous PSS scores at any of the cut-off values were not. To enhance the sensitivity, alternative PSS were devised: dichotomous PSS with weighting of score based on expected relative drug potency (ADV= 0.3, RTV=0.5 [reduced, pharmacokinetic-enhancing dose], others=1); and continuous PSS with intermediate scores between 1 and 0 for fold-change in IC50 values between 2.5 and 10 and weighting by relative drug potency. After adjusting for baseline VL, the continuous/ weighted PSS was significantly associated with week 16 VL (p=0.05), and the dichotomous/ weighted PSS showed a trend toward significance (p=0.08). The nadir VL between weeks 4 and 16 showed a highly significant association with the dichotomous/weighted PSS (p= 0.0006) and the continuous/weighted PSS (p=0.0029).
Conclusions: These results show that weighting PSS by relative drug potency and using a continuous scale to score moderate drug resistance (2.5-10 fold) improves the predictive value of baseline IC50 on virologic outcome. Baseline IC50 appears to be more strongly associated with nadir VL than achieving HIV RNA <500 copies/ml, suggesting that the latter is dependent on the baseline VL and relative drug potencies and susceptibilities.