Second International Congress Drug Therapy in HIV Infection 18-22 November 1994 Glasgow, UK

CLINICAL DEVELOPMENT OF HIV-1 RESISTANCE TO THE VIRAL PROTEASE INHIBITOR L-735,524

EA Emini, P Deutsch, WA Schleif, JH Condra
Merck Research Laboratories, West Point, PA 19486, USA

Int Cong Drug Therapy HIV 1994 Nov 18-22;2:Abstract No. 11.5
AIDS 1994, Vol. 8 (Suppl. 4);S10

L-735,524 is a potent and selective inhibitor of the HIV-1 protease. Phase I studies demonstrated that the compound is orally available, has an acceptable safety profile and demonstrates a noted antiviral effect. This effect is associated, in a number of patients, with a persistent recovery of the CD4 cell count. However, many treated patients also yield resistant viral variants. Selection of these variants appears to coincide with loss of the antiviral effect. We have identified multiple amino acid substitutions in the protease of. these variants. Because the patterns of appearance of these mutations are complex and variable, it has not been possible to discern the minimal requirements for resistance by sequence analyses of clinical viral isolates. Accordingly, we have introduced many of the substitutions, alone and in combination, into an HIV-1 proviral plasmid and recovered mutant viruses. Phenotypic resistance to L-735,524 correlated with substitutions of valine 82 to either alanine, phenylalanine or threonine. These mutations alone, however, were insufficient for resistance and required complex interactions with other amino acid substitutions that occur during therapy. Following prolonged treatment with L-735,524, viral variants were isolated that exhibited cross-resistance to a panel of structurally diverse protease inhibitors.

Presenting author: EA Emini

1994-11-18
11.5

Originally published in AIDS Volume 8, Supplement 4 and hosted with permission of the publisher Lippincott Williams & Wilkins, 250 Waterloo Road, London, SE1 8RD, UK. Tel: +44 (0)20 7981 0700 Fax: +44 (0) 7981 0701

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