1st International Workshop on HIV Drug Resistance & Treatment Strategies 25-28 June 1997, St. Petersburg, Florida, USA

GENOTYPIC AND PHENOTYPIC ANALYSES OF HIV-1 VARIANTS ISOLATED FROM PATIENTS TREATED WITH NELFINAVIR AND OTHER HIV-1 PROTEASE INHIBITORS

Antiviral Therapy 1997;2 (Suppl 5):12 (abstract no. 18)

AK Patick¹, D Kuritzkes², VA Johnson³, D Shugarts², M Bakhtiari², KE Potts¹, A Farnsworth¹, R Anderson¹, JL Koel³, JD Hazelwood³, CD Nail³, M Duran⁴, M Markowitz⁴, D Ho⁴ and D Richman^5
1Agouron Pharmaceuticals, San Diego, California; ²University of Colorado, Health Sciences Center, Denver, Colorado; ³University of Alabama at Birmingham School of Medicine, Birmingham, Alabama; ⁴Aaron Diamond AIDS Research Center, New York, New York; and ⁵University of California, San Diego, California, USA

Nelfinavir mesylate is an inhibitor of HIV protease discovered using protein structure-based drug design. DNA sequence analysis of protease genes obtained from 170 patients treated with nelfinavir for periods up to 52 weeks identified a unique aspartic acid (D) to asparagine (N) substitution at residue 30 (D30N). Clinically relevant mutations described for other protease inhibitors were either never (G48V, V82F/T, I84V) or only rarely (L90M) observed. A significant degree of polymorphism was observed in protease gene sequences derived from patients prior to their initiation of nelfinavir therapy with predominant substitutions occurring at amino acid residues 10, 12, 13, 15, 35, 36, 37, 41, 62, 63, 64, 72, 77 and 93. Statistical analyses indicated that protease inhibitor-naïve patients whose protease genes contained these polymorphisms were no more likely to acquire the D30N substitution following nelfinavir therapy than those patients whose protease genes did not contain these polymorphisms. These results indicate that baseline polymorphisms are not associated with an increased risk of developing genotypic resistance to nelfinavir. In phenotypic assays, HIV clinical isolates with high-level resistance to nelfinavir were fully susceptible to indinavir, saquinavir, ritonavir, and 141W94. Similar results were observed in phenotypic assays utilizing recombinant virus strains which contained the D30N substitution alone or with other compensatory substitutions (A71V, N88D). To study the susceptibility to nelfinavir of HIV variants which exhibit resistance to other protease inhibitors, 29 HIV isolates were obtained from patients who had failed on treatment regimens involving indinavir, saquinavir and/or ritonavir. Results indicate that 17 of the 29 (59%) isolates examined retained sensitivity to nelfinavir. Genotypic analysis of protease genes from these variants is currently underway.

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1997-06-25
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