title: Evolution of primary protease inhibitor resistance mutations during protease inhibitor salvage therapy.
abstract: 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.
authors.affiliation: Division of Infectious Diseases and AIDS Research, Stanford University, Stanford, California 94301, USA.
authors.forename: Rami
authors.initials: R
authors.lastname: Kantor
authors.forename: W Jeffrey
authors.initials: WJ
authors.lastname: Fessel
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Zolopa
authors.forename: Dennis
authors.initials: D
authors.lastname: Israelski
authors.forename: Nancy
authors.initials: N
authors.lastname: Shulman
authors.forename: Jose G
authors.initials: JG
authors.lastname: Montoya
authors.forename: Michael
authors.initials: M
authors.lastname: Harbour
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schapiro
authors.forename: Robert W
authors.initials: RW
authors.lastname: Shafer
mesh_terms: D004352:Drug Resistance, Microbial; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D012367:RNA, Viral / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D016879:Salvage Therapy
chemical_list: D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D016333:HIV Protease