Phenotypic and Genotypic HIV-1 Drug Resistance Assays Provide Complementary Information

Parkin, Neil; Chappey, Colombe; Maroldo, Laura; Bates, Michael; Hellmann, Nicholas S.; Petropoulos, Christos J.

doi:10.1097/00126334-200210010-00002

Cited by 48 publications

(29 citation statements)

References 47 publications

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“…Multiple studies have compared different genotypic assays (8,20,25,64,85), genotype versus phenotype (8,16,49,72), and different phenotypic (52,64,76,86) drug resistance assays. In the case of phenotypic assays, agreement among the tests varies with drug classes, usually showing better a correlation for PIs and lower correlation for NRTIs (64,86).…”

Section: Discussionmentioning

confidence: 99%

Novel Method for Simultaneous Quantification of Phenotypic Resistance to Maturation, Protease, Reverse Transcriptase, and Integrase HIV Inhibitors Based on 3′Gag(p2/p7/p1/p6)/PR/RT/INT-Recombinant Viruses: a Useful Tool in the Multitarget Era of Antiretroviral Therapy

Weber¹,

Vázquez²,

Winner³

et al. 2011

Antimicrob Agents Chemother

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Section: Discussionmentioning

confidence: 99%

Novel Method for Simultaneous Quantification of Phenotypic Resistance to Maturation, Protease, Reverse Transcriptase, and Integrase HIV Inhibitors Based on 3′Gag(p2/p7/p1/p6)/PR/RT/INT-Recombinant Viruses: a Useful Tool in the Multitarget Era of Antiretroviral Therapy

Weber¹,

Vázquez²,

Winner³

et al. 2011

Antimicrob Agents Chemother

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“…Viral genotyping, in which virus is analyzed for specific mutations known to impart resistance to RT and protease inhibitors, is becoming increasingly common (53,54). We anticipate that the use of entry inhibitors will have implications for clinical monitoring.…”

Section: Implications For Clinical Monitoring and Treatmentmentioning

confidence: 99%

The entry of entry inhibitors: A fusion of science and medicine

Moore

Doms

2003

Proc. Natl. Acad. Sci. U.S.A.

254

192

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For HIV-1 to enter a cell, its envelope protein (Env) must sequentially engage CD4 and a chemokine coreceptor, triggering conformational changes in Env that ultimately lead to fusion between the viral and host cell membranes. Each step of the virus entry pathway is a potential target for novel antiviral agents termed entry inhibitors. A growing number of entry inhibitors are under clinical development, with one having already been licensed by the Food and Drug Administration. With the emergence of virus strains that are largely resistant to existing reverse transcriptase and protease inhibitors, the development of entry inhibitors comes at an opportune time. Nonetheless, because all entry inhibitors target in some manner the highly variable Env protein of HIV-1, there are likely to be challenges in their efficient application that are unique to this class of drugs. Env density, receptor expression levels, and differences in affinity and receptor presentation are all factors that could influence the clinical response to this promising class of new antiviral agents.

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“…The availability of large databases of matched protease-RT genotype and drug susceptibility data, as well as the increasing clinical use of combined phenotype-genotype resistance assays, enables more thorough and comprehensive analyses of concordance between the interpretation of both types of assays (6,8,12). While concordance rates are high for NNRTIs, infrequent cases of reduction in phenotypic susceptibility not explained by known mutations can be dramatic (10-fold to more than 100-fold change in 50% inhibitory concentration [IC 50 ]), in a range that is clinically significant.…”

mentioning

confidence: 99%

The K101P and K103R/V179D Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confer Resistance to Nonnucleoside Reverse Transcriptase Inhibitors

Parkin¹,

Gupta²,

Chappey³

et al. 2006

Antimicrob Agents Chemother

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Genotypic patterns associated with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance in the absence of well-characterized resistance mutations were identified using a database (n > 47,000) of phenotypegenotype data. Among samples with no known NNRTI mutations, the most resistant samples contained K101P (n ‫؍‬ 35) or a combination of K103R and V179D (n ‫؍‬ 41). Site-directed mutagenesis confirmed the importance of these mutations.Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) of human immunodeficiency virus type 1 (HIV-1) are an important component of highly active antiretroviral therapy regimens (14). Resistance to NNRTIs is common in virus from treated patients and is typically accompanied by the development of one or more recognized mutations in the target enzyme. These mutations, derived from a combination of in vitro and in vivo data, form the basis for predicting NNRTI resistance in genotype-based resistance assays (13).The availability of large databases of matched protease-RT genotype and drug susceptibility data, as well as the increasing clinical use of combined phenotype-genotype resistance assays, enables more thorough and comprehensive analyses of concordance between the interpretation of both types of assays (6,8,12). While concordance rates are high for NNRTIs, infrequent cases of reduction in phenotypic susceptibility not explained by known mutations can be dramatic (10-fold to more than 100-fold change in 50% inhibitory concentration [IC 50 ]), in a range that is clinically significant. We investigated the underlying causes for such discordance in a large database of genotype and phenotype resistance assay results from clinical samples submitted to the Monogram Biosciences (formerly ViroLogic) Clinical Reference Laboratory for routine testing.As of April 2005, the Monogram Biosciences phenotypegenotype database contained data for more than 47,000 individual clinical samples, 24,151 of which lacked any commonly recognized NNRTI resistance mutations (A98G, K101E, K103N/S, V106A/M, P225H, M230L, P236L, or any substitution at position L100, Y181, Y188, G190, or F227). There were 577 samples that displayed a fold change in IC 50 (FC) for at least one NNRTI of fivefold or greater, and 196 had an FC of 10-fold or greater. Several samples had IC 50 s above the highest concentration tested in the assay: 28 samples for nevirapine (NVP), 10 samples for delavirdine (DLV), and 1 sample for efavirenz (EFV). For statistical purposes, these samples were assigned FC values of 400-, 250-, and 700-fold for NVP, DLV, and EFV, respectively. These maximum FC values are derived from the ratio of the highest drug concentration tested to the distribution of IC 50 s for the drug-sensitive reference virus over a 1-year time period.To explore the genotypic correlates of this unexplained NNRTI resistance, we performed univariate analysis, testing for the association of all mutations in RT which occur in more than 1% of the samples with an elevated NNRTI FC. We used an arbitrary threshold of five...

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Phenotypic and Genotypic HIV-1 Drug Resistance Assays Provide Complementary Information

Cited by 48 publications

References 47 publications

Novel Method for Simultaneous Quantification of Phenotypic Resistance to Maturation, Protease, Reverse Transcriptase, and Integrase HIV Inhibitors Based on 3′Gag(p2/p7/p1/p6)/PR/RT/INT-Recombinant Viruses: a Useful Tool in the Multitarget Era of Antiretroviral Therapy

Novel Method for Simultaneous Quantification of Phenotypic Resistance to Maturation, Protease, Reverse Transcriptase, and Integrase HIV Inhibitors Based on 3′Gag(p2/p7/p1/p6)/PR/RT/INT-Recombinant Viruses: a Useful Tool in the Multitarget Era of Antiretroviral Therapy

The entry of entry inhibitors: A fusion of science and medicine

The K101P and K103R/V179D Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confer Resistance to Nonnucleoside Reverse Transcriptase Inhibitors

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