The clinical relevance of non-nucleoside reverse transcriptase inhibitor hypersusceptibility

Haubrich, Richard; Kemper, Carol A.; Hellmann, Nicholas S.; Keiser, Philip; Witt, Mallory D.; Forthal, Donald N.; Leedom, John M.; Leibowitz, Matthew; Whitcomb, Jeannette M.; Richman, Douglas D.; McCutchan, J. Allen

doi:10.1097/00002030-200210180-00001

Cited by 60 publications

(48 citation statements)

References 2 publications

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“…The routine use of highly reproducible phenotypic assays (24) revealed that many clinical HIV-1 isolates exhibited significant hypersusceptibility (defined as a change in the 50% inhibitory concentration versus the reference of Յ0.4-fold) to the non-nucleoside reverse transcriptase inhibitor class (12,31,34). This phenomenon is associated with previous nucleoside analogue treatment and with an increase in the efficacy of salvage antiretroviral regimens including non-nucleoside reverse transcriptase inhibitors (12,31,32,34).…”

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confidence: 99%

“…This phenomenon is associated with previous nucleoside analogue treatment and with an increase in the efficacy of salvage antiretroviral regimens including non-nucleoside reverse transcriptase inhibitors (12,31,32,34). In chronically infected antiretroviral-experienced patients, amprenavir hypersusceptibility is associated with the N88S mutation in protease, which is not seen in drug-naïve patients (26,35).…”

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confidence: 99%

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Phenotypic Hypersusceptibility to Multiple Protease Inhibitors and Low Replicative Capacity in Patients Who Are Chronically Infected with Human Immunodeficiency Virus Type 1

Martínez-Picado

Wrin

Frost

et al. 2005

J Virol

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Increased susceptibility to the protease inhibitors saquinavir and amprenavir has been observed in human immunodeficiency virus type 1 (HIV-1) with specific mutations in protease (V82T and N88S). Increased susceptibility to ritonavir has also been described in some viruses from antiretroviral agent-naïve patients with primary HIV-1 infection in association with combinations of amino acid changes at polymorphic sites in the protease. Many of the viruses displaying increased susceptibility to protease inhibitors also had low replication capacity. In this retrospective study, we analyze the drug susceptibility phenotype and the replication capacity of virus isolates obtained at the peaks of viremia during five consecutive structured treatment interruptions in 12 chronically HIV-1-infected patients. Ten out of 12 patients had at least one sample with protease inhibitor hypersusceptibility (change <0.4-fold) to one or more protease inhibitor. Hypersusceptibility to different protease inhibitors was observed at variable frequency, ranging from 38% to amprenavir to 11% to nelfinavir. Pairwise comparisons between susceptibilities for the protease inhibitors showed a consistent correlation among all pairs. There was also a significant relationship between susceptibility to protease inhibitors and replication capacity in all patients. Replication capacity remained stable over the course of repetitive cycles of structured treatment interruptions. We could find no association between in vitro replication capacity and in vivo plasma viral load doubling time and CD4؉ and CD8 ؉ T-cell counts at each treatment interruption. Several mutations were associated with hypersusceptibility to each protease inhibitor in a univariate analysis. This study extends the association between hypersusceptibility to protease inhibitors and low replication capacity to virus isolated from chronically infected patients and highlights the complexity of determining the genetic basis of this phenomenon. The potential clinical relevance of protease inhibitor hypersusceptibility and low replication capacity to virologic response to protease inhibitor-based therapies deserves to be investigated further.

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confidence: 99%

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confidence: 99%

Phenotypic Hypersusceptibility to Multiple Protease Inhibitors and Low Replicative Capacity in Patients Who Are Chronically Infected with Human Immunodeficiency Virus Type 1

Martínez-Picado

Wrin

Frost

et al. 2005

J Virol

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“…Hypersusceptibility (HS) to ARV drugs, defined here as susceptibility Յ0.4-fold that of HIV-1 NL4-3 , is another phenotype that was first described in the context of patients who had been treated with a failing ARV regimen; HS to nonnucleoside reverse transcriptase inhibitors has recently been shown to be clinically significant (4). In one study, among those who had acquired a virus strain resistant to nelfinavir, Ͼ6% were found to be HS to amprenavir (18).…”

Section: The Initial Virus Strains From As Many As 12% Of Individualsmentioning

confidence: 99%

Genetic Basis of Hypersusceptibility to Protease Inhibitors and Low Replicative Capacity of Human Immunodeficiency Virus Type 1 Strains in Primary Infection

Brown

Frost

Good

et al. 2004

J Virol

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The initial virus strains from as many as 12% of individuals with primary human immunodeficiency virus (HIV) infection have a 50% inhibitory concentration <0.4-fold that of HIV type 1 NL4-3 (HIV-1 NL4-3 ) to ritonavir (hypersusceptibility [HS]). There is also substantial variation in replicative capacity (RC) or an in vitro assay of the contributions of protease (PR) and reverse transcriptase to viral fitness. In chronically infected antiretrovirally treated patients, amprenavir HS has been associated with the mutation N88S in PR, but this mutation is not seen in untreated patients. In this study, virus strains from 182 cases of primary HIV infection were analyzed, and a highly significant association between HS and low RC (<10% that of HIV-1 NL4-3 ) was observed (P < 10 ؊6 ). Multivariate analysis was used to determine the genotypic basis of ritonavir HS, analyzing all polymorphic amino acid sites and insertions from p7gag through PR. Decision tree models developed on the entire Gag-plus-PR data set and on PR alone gave overall correct classifications of 73 and 72%, respectively, on cross-validation. They were also able to predict low RC, with sensitivities of 69 and 62% and specificities of 84 and 70%, respectively. The analysis shows that ritonavir HS in untreated primary HIV infection is not associated with single mutations but with combinations of amino acids at polymorphic sites and that the same genotypes which confer HS to PR inhibitors confer low RC. This supports the view that variation in PR function is directly responsible for variation in fitness among strains in primary infection.

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“…Phenotypic hypersusceptibility of HIV-1, defined as having a greater than 2.5 fold increase in susceptibility to a drug compared with a wild-type reference strain using the phenotypic resistance assay by Monogram Biosciences (formerly ViroLogic), occurs with protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) [17][18][19][20] . HIV-1 variants with phenotypic NNRTI hypersusceptibility are more likely to be resistant to nucleoside analogs 17,[20][21][22] . In patients, the presence of HIV-1 with NNRTIhypersusceptibility is associated with improved responses to an NNRTI-containing regimen compared to patients with variants that are not hypersusceptible 8,20,21,23 .…”

Section: Introductionmentioning

confidence: 99%

“…HIV-1 variants with phenotypic NNRTI hypersusceptibility are more likely to be resistant to nucleoside analogs 17,[20][21][22] . In patients, the presence of HIV-1 with NNRTIhypersusceptibility is associated with improved responses to an NNRTI-containing regimen compared to patients with variants that are not hypersusceptible 8,20,21,23 .…”

Section: Introductionmentioning

confidence: 99%

Association of Efavirenz Hypersusceptibility with Virologic Response in ACTG 368, a Randomized Trial of Abacavir (ABC) in Combination with Efavirenz (EFV) and Indinavir (IDV) in HIV-Infected Subjects with Prior Nucleoside Analog Experience

Demeter

DeGruttola

Lustgarten

et al. 2008

HIV Clinical Trials

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Purpose-To evaluate the association of efavirenz hypersusceptibility (EFV-HS) with clinical outcome in a double-blind, placebo-controlled, randomized trial of EFV plus indinavir (EFV+IDV) vs. EFV+IDV plus abacavir (ABC) in 283 nucleoside-experienced HIV-infected patients.Methods and Results-Rates of virologic failure were similar in the 2 arms at week 16 (p=0.509). Treatment discontinuations were more common in the ABC arm (p=0.001). Using logistic regression, there was no association between virologic failure and either baseline ABC resistance or regimen sensitivity score. Using 3 different genotypic scoring systems, EFV-HS was significantly associated with reduced virologic failure at week 16, independent of treatment assignment. In some patients on the nucleoside-sparing arm, the nucleoside-resistant mutant L74V was selected for in combination with the uncommonly occurring EFV-resistant mutant K103N+L100I; L74V was not detected as a minority variant, using clonal sequence analysis, when the nucleoside-sparing regimen was initiated.Conclusions-Premature treatment discontinuations in the ABC arm and the presence of EFVhypersusceptible HIV variants in this patient population likely made it difficult to detect a benefit of

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The clinical relevance of non-nucleoside reverse transcriptase inhibitor hypersusceptibility

Abstract: NNRTI hypersusceptibility occurred in more than 20% of nucleoside-experienced patients and was associated with greater reduction of HIV RNA and increase in CD4 cells.

Cited by 60 publications

References 2 publications

Phenotypic Hypersusceptibility to Multiple Protease Inhibitors and Low Replicative Capacity in Patients Who Are Chronically Infected with Human Immunodeficiency Virus Type 1

Phenotypic Hypersusceptibility to Multiple Protease Inhibitors and Low Replicative Capacity in Patients Who Are Chronically Infected with Human Immunodeficiency Virus Type 1

Genetic Basis of Hypersusceptibility to Protease Inhibitors and Low Replicative Capacity of Human Immunodeficiency Virus Type 1 Strains in Primary Infection

Association of Efavirenz Hypersusceptibility with Virologic Response in ACTG 368, a Randomized Trial of Abacavir (ABC) in Combination with Efavirenz (EFV) and Indinavir (IDV) in HIV-Infected Subjects with Prior Nucleoside Analog Experience

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