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Session 13 Oral Abstract Session Antiretroviral Chemotherapy: Combination Therapy, Drug Resistance, and Treatment Interruption Session Time: Tuesday, 10 am - 12:30 pm Room 4B

11:00   45. Efavirenz Hypersusceptibility Improves Virologic Response to Multidrug Salvage Regimens in ACTG 398 J. Mellors*1, F. Vaida2, K. Bennett2, N. S. Hellmann3, V. DeGruttola2, and S. Hammer4 for the ACTG 398 Study Team 1Univ. of Pittsburgh, PA; 2Harvard Sch. of Publ. Hlth., Boston, MA; 3ViroLogic, San Francisco, CA; and 4Columbia Univ., New York, NY Background and Methods: ACTG 398 assessed whether a second protease inhibitor (PI), combined with amprenavir (APV 1200 mg BID), abacavir (ABC 300 mg BID), efavirenz (EFV 600 qd), and adefovir (ADV 60 mg qd), would improve virologic response in PI-experienced patients with HIV RNA >1000 copies/mL. 481 patients were selectively randomized, based on prior PI experienced, to 1 of 4 arms: saquinavir soft-gel (SQVsgc) 1600 mg BID; indinavir (IDV) 1200 mg BID; nelfinavir (NFV) 1250 mg BID; or second PI placebo. Analyses were ITT with missing HIV RNA = failure. Results: At baseline: 87% were men; 58% white, 23% African American, 15% Hispanic; 44% NNRTI experienced; median age 39 years, CD4 count 212/mm3 and HIV RNA 51,025 copies/mL. At 24 and 48 weeks, the off-study rates were 6% and 12% and off-treatment rates for toxicity were 30% and 42%, respectively. The proportion reaching the primary study endpoint of virologic failure (confirmed HIV RNA > 200 copies/mL) at 24 and 48 weeks were 69% and 79%, respectively. Virologic failure was significantly less frequent in the 3 dual-PI arms combined compared with the placebo arm at week 24 (66% vs 75%, p=0.03) but not at week 48 (77% vs 82%, p=0.17). Virologic failure at wks 24 and 48 was strongly associated with NNRTI experience (p <0.001). Phenotypic drug susceptibility was determined (ViroLogic) in 139 randomly selected patients at baseline and in 64 patients with virologic failure by week 24. Baseline EFV resistance (>10-fold) predicted virologic failure at weeks 24 (OR 3.22; p = 0.03) and 48 (OR 4.04; p = 0.02). In contrast, baseline EFV hypersusceptibility (<0.4-fold) protected against virologic failure at weeks 24 (OR 0.27; p< 0.001) and 48 (OR 0.16, p< 0.001). Among virologic failures by week 24, resistance developed to EFV (mean 30.2-fold increase in IC50; p< 0.001) but not to other study drugs. Conclusions: HIV RNA suppression to <200 copies/mL at 48 weeks was achieved in only 21% of patients despite 4-5 new agents. NNRTI experienced, baseline EFV resistance, and development of EFV resistance were associated with virologic failure. Baseline EFV hypersusceptibility was strongly associated with better virologic response.

©2002 9th Conference on Retroviruses and Opportunistic Infections