Hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1

Whitcomb, Jeannette M.; Huang, Wei; Limoli, Kay; Paxinos, Ellen E.; Wrin, Terri; Skowron, Gail; Deeks, Steven G.; Bates, Michael; Hellmann, Nicholas S.; Petropoulos, Christos J.

doi:10.1097/00002030-200210180-00002

Cited by 84 publications

(50 citation statements)

References 8 publications

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“…The same model could also be used to explain the hypersusceptibility to two of the protease inhibitors where the selected mutations did not provide cross-resistance. However, we cannot exclude the possibility that some RTV resistance-associated mutations simply enhance binding of some inhibitors, as has been suggested for some reverse transcriptase inhibitors (69).…”

Section: Discussionmentioning

confidence: 89%

Evolution of Human Immunodeficiency Virus Type 1 Protease Genotypes and Phenotypes In Vivo under Selective Pressure of the Protease Inhibitor Ritonavir

Resch¹,

Parkin

Watkins

et al. 2005

J Virol

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We examined the population dynamics of human immunodeficiency virus type 1 pro variants during the evolution of resistance to the protease inhibitor ritonavir (RTV) in vivo. pro variants were followed in subjects who had added RTV to their previously failed reverse transcriptase inhibitor therapy using a heteroduplex tracking assay designed to detect common resistance-associated mutations. In most cases the initial variant appeared rapidly within 2 to 3 months followed by one or more subsequent population turnovers. Some of the subsequent transitions between variants were rapid, and some were prolonged with the coexistence of multiple variants. In several cases variants without resistance mutations persisted despite the emergence of new variants with an increasing number of resistance-associated mutations. Based on the rate of turnover of pro variants in the RTV-treated subjects we estimated that the mean fitness of newly emerging variants was increased 1.2-fold (range, 1.02 to 1.8) relative to their predecessors. A subset of pro genes was introduced into infectious molecular clones. The corresponding viruses displayed impaired replication capacity and reduced susceptibility to RTV. A subset of these clones also showed increased susceptibility to two nonnucleoside reverse transcriptase inhibitors and the protease inhibitor saquinavir. Finally, a significant correlation between the reduced replication capacity and reduced processing at the gag NC-p1 processing site was noted. Our results reveal a complexity of patterns in the evolution of resistance to a protease inhibitor. In addition, these results suggest that selection for resistance to one protease inhibitor can have pleiotropic effects that can affect fitness and susceptibility to other drugs.Protease inhibitors (PIs) potently inhibit human immunodeficiency virus type 1 (HIV-1) replication, and their initial introduction into combination antiretroviral therapy was associated with a significant decrease of HIV-1-associated mortality and morbidity (41, 45). However, in clinical practice, virologic failure of protease inhibitor-containing therapy occurs in a significant fraction of the treated population (19,22,42,46,52,70). Virologic failure of protease inhibitor treatment is often due to the selection of HIV-1 strains with mutations in the pro gene, which encodes the viral protease (PR), and in specific protease cleavage sites encoded in the gag gene that collectively confer reduced drug susceptibility to the harboring strain (11,12,28,36,43,47,72).The resistance mutations are hypothesized to be largely preexisting, generated by the highly error-prone and rapid replication of HIV-1 in large virus populations (5, 10, 57). However, in PI-naïve subjects, some critical resistance mutations cannot be detected or can only be detected at very low levels, suggesting that these mutations may confer a selective disadvantage relative to wild-type HIV-1 strains (3,18,25,32,34,63). Indeed, it has been shown that the catalytic efficiency of protease is reduced by PI resis...

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Section: Discussionmentioning

confidence: 89%

Evolution of Human Immunodeficiency Virus Type 1 Protease Genotypes and Phenotypes In Vivo under Selective Pressure of the Protease Inhibitor Ritonavir

Resch¹,

Parkin

Watkins

et al. 2005

J Virol

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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).…”

mentioning

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).…”

mentioning

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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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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“…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%

“…Early reports identified an association between phenotypic NNRTI-hypersusceptibility and thymidine analog mutations (i.e., those at codons 41, 67, 70, 210, 215 and 219 of reverse transcriptase) 17,22 . One study reported a correlation between phenotypic efavirenz hypersusceptibility and a number of different reverse transcriptase mutations in univariate analyses, including T215Y/F, D67N, H208Y, K103R, and V179D 24 .…”

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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Hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1

Cited by 84 publications

References 8 publications

Evolution of Human Immunodeficiency Virus Type 1 Protease Genotypes and Phenotypes In Vivo under Selective Pressure of the Protease Inhibitor Ritonavir

Evolution of Human Immunodeficiency Virus Type 1 Protease Genotypes and Phenotypes In Vivo under Selective Pressure of the Protease Inhibitor Ritonavir

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

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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