title: Development of elvitegravir resistance and linkage of integrase inhibitor mutations with protease and reverse transcriptase resistance mutations.
abstract: Failure of antiretroviral regimens containing elvitegravir (EVG) and raltegravir (RAL) can result in the appearance of integrase inhibitor (INI) drug-resistance mutations (DRMs). While several INI DRMs have been identified, the evolution of EVG DRMs and the linkage of these DRMs with protease inhibitor (PI) and reverse transcriptase inhibitor (RTI) DRMs have not been studied at the clonal level. We examined the development of INI DRMs in 10 patients failing EVG-containing regimens over time, and the linkage of INI DRMs with PI and RTI DRMs in these patients plus 6 RAL-treated patients. A one-step RT-nested PCR protocol was used to generate a 2.7 kB amplicon that included the PR, RT, and IN coding region, and standard cloning and sequencing techniques were used to determine DRMs in 1,277 clones (mean 21 clones per time point). Results showed all patients had multiple PI, NRTI, and/or NNRTI DRMs at baseline, but no primary INI DRM. EVG-treated patients developed from 2 to 6 strains with different primary INI DRMs as early as 2 weeks after initiation of treatment, predominantly as single mutations. The prevalence of these strains fluctuated and new strains, and/or strains with new combinations of INI DRMs, developed over time. Final failure samples (weeks 14 to 48) typically showed a dominant strain with multiple mutations or N155H alone. Single N155H or multiple mutations were also observed in RAL-treated patients at virologic failure. All patient strains showed evidence of INI DRM co-located with single or multiple PI and/or RTI DRMs on the same viral strand. Our study shows that EVG treatment can select for a number of distinct INI-resistant strains whose prevalence fluctuates over time. Continued appearance of new INI DRMs after initial INI failure suggests a potent, highly dynamic selection of INI resistant strains that is unaffected by co-location with PI and RTI DRMs.
authors: AIDS Research Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America. Mark.winters@stanford.edu
authors: Mark A
authors: MA
authors: Winters
authors: Robert M
authors: RM
authors: Lloyd
authors: Robert W
authors: RW
authors: Shafer
authors: Michael J
authors: MJ
authors: Kozal
authors: Michael D
authors: MD
authors: Miller
authors: Mark
authors: M
authors: Holodniy
mesh_terms: D024882:Drug Resistance, Viral / Q000235:genetics*; D019427:HIV Integrase / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D016366:Open Reading Frames / Q000235:genetics; D010447:Peptide Hydrolases / Q000235:genetics*; D011480:Protease Inhibitors / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*
chemical_list: D019428:HIV Integrase Inhibitors; D011480:Protease Inhibitors; D015363:Quinolones; C509700:elvitegravir; D019427:HIV Integrase; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D010447:Peptide Hydrolases