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Antimicrobial Agents and Chemotherapy, April 2002, p. 1086-1092, Vol. 46, No. 4
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.4.1086-1092.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Evolution of Primary Protease Inhibitor Resistance Mutations during Protease Inhibitor Salvage Therapy

Rami Kantor,1 W. Jeffrey Fessel,2 Andrew R. Zolopa,1 Dennis Israelski,1 Nancy Shulman,1 Jose G. Montoya,1 Michael Harbour,1 Jonathan M. Schapiro,3 and Robert W. Shafer1*

Division of Infectious Diseases and AIDS Research, Stanford University, Stanford,1 Kaiser Permanente, San Francisco, California,2 AIDS Service, National Hemophilia Center, Tel-Hashomer, Israel3

Received 31 August 2001/ Returned for modification 20 November 2001/ Accepted 15 January 2002

In order to track the evolution of primary protease inhibitor (PI) resistance mutations in human immunodeficiency virus type 1 (HIV-1) isolates, baseline and follow-up protease sequences were obtained from patients undergoing salvage PI therapy who presented initially with isolates containing a single primary PI resistance mutation. Among 78 patients meeting study selection criteria, baseline primary PI resistance mutations included L90M (42% of patients), V82A/F/T (27%), D30N (21%), G48V (6%), and I84V (4%). Despite the switching of treatment to a new PI, primary PI resistance mutations present at the baseline persisted in 66 of 78 (85%) patients. D30N persisted less frequently than L90M (50% versus 100%, respectively; P < 0.001) and V82A/F/T (50% versus 81%, respectively; P = 0.05). HIV-1 isolates from 38 (49%) patients failing PI salvage therapy developed new primary PI resistance mutations including L90M, I84V, V82A, and G48V. Common combinations of primary and secondary PI resistance mutations after salvage therapy included mutations at amino acid positions 10, 82, and 46 and/or 54 in 16 patients; 10, 90, and 71 and/or 73 in 14 patients; 10, 73, 84, 90, and 46 and/or 54 in 5 patients; 10, 48, and 82 in 5 patients; and 30, 88 and 90 in 5 patients. In summary, during salvage PI therapy, most HIV-1 isolates with a single primary PI resistance mutation maintained their original mutations, and 49% developed additional primary PI resistance mutations. The persistence of L90M, V82A/F/T, G48V, and I84V during salvage therapy suggests that these mutations play a role in clinical resistance to multiple PIs.

* Corresponding author. Mailing address: Division of Infectious Diseases, Room S-156, Stanford University Medical Center, Stanford, CA 94301. Phone: (650) 725-2946. Fax: (650) 723-8596. E-mail: rshafer{at}cmgm.stanford.edu.

Antimicrobial Agents and Chemotherapy, April 2002, p. 1086-1092, Vol. 46, No. 4
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.4.1086-1092.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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