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Relationship of Baseline Viral Phenotype and Genotype to RNA Response after Switching from Long-Term Saquinavir (SQVhc) to Indinavir (IDV) or Saquinavir Soft-Gelatin Capsule (SQVsgc) in ACTG 333 M. F. PARA*1, D. GLIDDEN2, R. COOMBS3, A. COLLIER3, J. CONDRA4, C. CRAIG5, R. BASSETT6, C. BOUCHER7, and S. SNYDER8 for the ACTG 333 Study Team.
1Ohio State Univ., Columbus; 2Univ. of California, San Francisco; 3Univ. of Washington, Seattle; 4Merck & Co., West Point, PA; 5Roche Discovery, Welwyn, Herts, UK; 6Harvard Univ., Cambridge MA; 7Univ. Hosp. Utrecht, The Netherlands; and 8AACTG Operations Ctr., Rockville, MD, and the NIAID sponsored ACTG, Bethesda, MD Objective: To determine if after >1yr SQVhc use, drug susceptibility and genotype of baseline viral isolates predicted antiviral response after single drug switch to IDV or SQVsgc.
Method: 89 subjects were randomized to receive IDV (2.4 g/d), SQVsgc (3.6 g/d) or remain on SQVhc (1.8 g/d) and stay on unchanged non-protease antivirals for the first 8 wks. At wk 8, subjects receiving SQVhc switched to IDV. Short term viral response was defined as change in log RNA from baseline to the mean from weeks 4, 6, and 8. Drug susceptibility by recombinant virus assay was tested in 76 baseline isolates, and 81 had protease (Pr) gene sequencing using ABI automated sequencer. 12 amino acid positions related to IDV and SQV resistance in the Pr were evaluated.
Findings: Median prior SQVhc use = 105 wks, median baseline RNA = 4.10 log10 copies/mL, median CD4 = 240 cell/mm3. 25% of subjects had no Pr substitutions. L90M was the most common substitution (59% subjects), 10% had G48V. The most common combination of substitutions was 90+71+10. Number of substitutions correlated with baseline CD4, HIV-RNA, and SQV experience. Substitution at codon 10 was most associated with blunted RNA response but codon 10 substitution occurred only in isolates with 2 or more Pr substitutions. Drug susceptibility correlated to number of Pr substitutions. Higher SQV IC50 correlated with higher baseline RNA. Viral drug susceptibility to IDV correlated with HIV RNA response following switch to IDV. However, IDV IC50 added little predictive power once the genotype was considered.
Conclusion: A majority of patients with prior extensive SQV had Pr mutations at baseline. The number of Pr substitutions predicted virologic response. Drug susceptibility was predictive of response but added no prognostic information once genotype was known.
Key Words: genotype, phenotype, protease
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