4th Conference on Retroviruses and Opportunistic Infections
Washington, DC - January 22-26, 1997
Genotypic analysis of HIV-1 variants isolated from patients treated with the protease inhibitor nelfinavir, alone or in combination with d4T or AZT and 3TC.
Patick AK, Duran M, Cao Y, Ho T, Zhou P, Keller MR, Chapman S, Anderson R, Kuritzkes D, Shugarts D, Ho D, Markowitz M; Agouron Pharmaceuticals, Inc., La Jolla, CA.
Nelfinavir (formerly AG1343) is a selective, nonpeptidic inhibitor of HIV protease discovered using protein structure-based drug design methodologies. Sequence analysis of protease genes obtained by RT-PCR from plasma vRNA from patients from Pilot Phase II monotherapy, dose range-finding studies identified as the predominant mutation, a previously undescribed change from an aspartic acid (D) to an asparagine (N) at position 30. Protease genes from patient isolates containing the D30N change were further analyzed for additional mutations occurring over time. Results indicate that the D30N mutation was stably maintained up to 44 weeks of study. The appearance of D30N was occasionally associated with concurrent or sequential emergence of other changes including M36I, M46I, A71T, V and N88D,S. Mutations described for other protease inhibitors were never observed (G48V, V82F/T, I84V) or only rarely observed (L90M) in all patients studied (n=55). Sequence analysis of protease genes isolated from patients treated with nelfinavir in combination with d4T also revealed the occurrence of D30N. In phenotype assays, clinical isolates which exhibited a reduction in susceptibility to nelfinavir contained the D30N change while isolates which lacked this mutation were susceptible to nelfinavir. Moreover, HIV variants with high-level resistance to nelfinavir were fully susceptible to indinavir, saquinavir, ritonavir, and VX-478. This data suggests the pathway to resistance to nelfinavir is unique and mediated through D30N and that subsequent treatment with other protease inhibitors may be effective. Sequence analysis of protease genes from patients from ongoing Phase III clinical trials of nelfinavir alone or in combination with AZT and 3TC is currently underway.
Keywords: AEGIS, Nelfinavir, Zidovudine, Lamivudine, Stavudine, HIV-1, Protease Inhibitors, HIV Protease, HIV Protease Inhibitors, Saquinavir, Indinavir, Anti-HIV Agents, Reverse Transcriptase Inhibitors, HIV Infections, HIV, Ritonavir, Human, AIDS
