Phenotypic testing predicts virological response in successive protease inhibitor-based regimens

Pérez-Elías, María-Jesús; Lanier, Randall; Muñoz, Vicente; García-Arata, Isabel; Casado, José L.; Martí-Belda, Paloma; Moreno, Ana; Dronda, Fernando; Antela, Antonio; Marco, Santiago F; Moreno, Santiago

doi:10.1097/00002030-200006160-00002

Cited by 21 publications

(8 citation statements)

References 16 publications

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“…These data suggest that this mutation may be sufficiently contributing to AZT resistance with D67N, K70R, and T215F without requiring the mutations generally required to generate high-level AZT resistance (i.e., M41L, L210W, and T215Y) (12). While the changes in drug susceptibility in this study were small, recent studies have shown that even relatively modest susceptibility changes can correlate with clinical outcome (6,16). Two other significant mutational associations were seen with codon 69 mutations.…”

Section: Vol 45 2001mentioning

confidence: 56%

Variants Other than Aspartic Acid at Codon 69 of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Gene Affect Susceptibility to Nucleoside Analogs

Winters

Merigan

2001

Antimicrob Agents Chemother

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The T69D mutation in the human immunodeficiency virus type 1 reverse transcriptase (RT) gene has been associated with reduced susceptibility to dideoxycytosine (ddC); however, several other mutations at codon 69 have been observed in antiretroviral drug-treated patients. The Stanford HIV RT and Protease Sequence Database was interrogated and showed that 23% of patients treated with nucleoside RT inhibitors (NRTI) had mutations at codon 69. These variants included T69N, -S, -A, -G, -E, -I, and -K mutations that were present in patients treated with NRTI but not in drug-naive patients. Treatment history information showed that a substantial percentage of these codon 69 changes occurred in patients administered non-ddC-containing regimens. Different and specific patterns of other RT gene mutations were associated with the various codon 69 mutations. Drug susceptibility assays showed that viral constructs containing codon 69 variants could have reduced susceptibility to ddC and other RT inhibitors. These results suggest that the T69D mutation is not the only codon 69 variant associated with drug resistance and that ddC is not the only drug affected.Nucleoside reverse transcriptase inhibitors (NRTI) are an important component of successful antiretroviral therapy. Combinations of two or more NRTI with protease inhibitors and/or nonnucleoside reverse transcriptase inhibitors (NNRTI) are currently the standard of care for the treatment of naive and antiretroviral drug-experienced individuals (5). Most patients, however, eventually show evidence of waning antiviral activity, as measured by increases in virus levels in plasma. Mutations in the protease and/or reverse transcriptase (RT) gene are typically evident at this time through genotyping assays (10). Many mutations in the RT gene have been associated with reduced susceptibility to NRTI (17). Several of these mutations arise in the ␤3-␤4 loop of the human immunodeficiency virus type 1 (HIV-1) RT enzyme (20). Specific amino acid changes at codons 65, 67, 69, 70, and 74 confer reduced susceptibility to one or more NRTI (17). These mutations directly cause or contribute to reduced susceptibility through mechanisms such as repositioning of the primer-template complex (4), increasing the enzyme's selectivity for deoxynucleoside triphosphates over dideoxynucleoside triphosphates (20), and enhancing pyrophosphorolytic activity (1).A mutation at codon 69 from threonine to aspartic acid has been shown to confer resistance to dideoxycytosine (ddC) (9). Recently, two amino acid insertions after codon 69 have been shown to confer resistance to nearly all NRTI alone or in combination with other RT gene mutations (7,14,21). Physician-requested genotyping has also revealed other mutations at codon 69 which have not yet been defined. In this report, the prevalence of codon 69 mutations was examined and the susceptibility of these variants to NRTI was studied. MATERIALS AND METHODS Database.The frequency of different mutations at codon 69 was examined through the Stanford HIV RT and ...

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Section: Vol 45 2001mentioning

confidence: 56%

Variants Other than Aspartic Acid at Codon 69 of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Gene Affect Susceptibility to Nucleoside Analogs

Winters

Merigan

2001

Antimicrob Agents Chemother

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“…This recombinant virus can be tested in vitro against a variety of RT and PR inhibitors. Susceptibilities are reported as fold-changes in drug inhibiting concentrations (IC 50 ) as measured by comparing the mean inhibiting concentrations at which 50% replication is suppressed (IC 50 ) of the patients' HIV RT and PR genes to that of a reference HXB2 HIV strain Hanna and D'Aquila, 2001;Hirsch et al, 2003;Larder et al, 2001;Perez-Elias et al, 2000). One of the problems with phenotyping assays is that susceptibility can only be defined for one drug at a time, leaving important questions about drug interaction effects unanswered (Volberding and Lange, 2001).…”

Section: Phenotypic/fitness Assaysmentioning

confidence: 99%

Transmission of HIV-1 drug resistance

Tang

Pillay

2004

Journal of Clinical Virology

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“…The extent of antiretroviral resistance, measured prior to initiating new antiretroviral therapy, has been found to correlate with the likelihood of achieving viral suppression [8][9][10][11]. As the duration of follow-up in clinical trials has generally been 6 months or less [3][4][5][6], there are few or no data on the implications of antiretroviral resistance for clinical outcomes in HIV-1-infected individuals.…”

Section: Introductionmentioning

confidence: 99%

Relationship between drug resistance and HIV-1 disease progression or death in patients undergoing resistance testing

Lucas

Gallant

Moore

2004

AIDS

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Phenotypic testing predicts virological response in successive protease inhibitor-based regimens

Cited by 21 publications

References 16 publications

Variants Other than Aspartic Acid at Codon 69 of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Gene Affect Susceptibility to Nucleoside Analogs

Variants Other than Aspartic Acid at Codon 69 of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Gene Affect Susceptibility to Nucleoside Analogs

Transmission of HIV-1 drug resistance

Relationship between drug resistance and HIV-1 disease progression or death in patients undergoing resistance testing

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