Sensitive Assessment of the Virologic Outcomes of Stopping and Restarting Non-Nucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy

Anna Maria Geretti, Zoe Fox, Jeffrey A. Johnson, Clare Booth, Jonathan Lipscomb, Lieven J. Stuyver, Gilda Tachedjian, John Baxter, Giota Touloumi, Clara Lehmann, Andrew R Owen, Andrew Phillips

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Abstract

Background:Non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants have been shown to emerge after interruption of suppressive NNRTI-based antiretroviral therapy (ART) using routine testing. The aim of this study was to quantify the risk of resistance by sensitive testing and correlate the detection of resistance with NNRTI concentrations after treatment interruption and virologic responses after treatment resumption.Methods:Resistance-associated mutations (RAMs) and NNRTI concentrations were studied in plasma from 132 patients who interrupted suppressive ART within SMART. RAMs were detected by Sanger sequencing, allele-specific PCR, and ultra-deep sequencing. NNRTI concentrations were measured by sensitive high-performance liquid chromatography.Results:Four weeks after NNRTI interruption, 19/31 (61.3%) and 34/39 (87.2%) patients showed measurable nevirapine (>0.25 ng/ml) or efavirenz (>5 ng/ml) concentrations, respectively. Median eight weeks after interruption, 22/131 (16.8%) patients showed ≥1 NNRTI-RAM, including eight patients with NNRTI-RAMs detected only by sensitive testing. The adjusted odds ratio (OR) of NNRTI-RAM detection was 7.62 (95% confidence interval [CI] 1.52, 38.30; p = 0.01) with nevirapine or efavirenz concentrations above vs. below the median measured in the study population. Staggered interruption, whereby nucleos(t)ide reverse transcriptase inhibitors (NRTIs) were continued for median nine days after NNRTI interruption, did not prevent NNRTI-RAMs, but increased detection of NRTI-RAMs (OR 4.25; 95% CI 1.02, 17.77; p = 0.03). After restarting NNRTI-based ART (n = 90), virologic suppression rates <400 copies/ml were 8/13 (61.5%) with NNRTI-RAMs, 7/11 (63.6%) with NRTI-RAMs only, and 51/59 (86.4%) without RAMs. The ORs of re-suppression were 0.18 (95% CI 0.03, 0.89) and 0.17 (95% CI 0.03, 1.15) for patients with NNRTI-RAMs or NRTI-RAMs only respectively vs. those without RAMs (p = 0.04).Conclusions:Detection of resistant mutants in the rebound viremia after interruption of efavirenz- or nevirapine-based ART affects outcomes once these drugs are restarted. Further studies are needed to determine RAM persistence in untreated patients and impact on newer NNRTIs.

Original languageEnglish
Article numbere69266
JournalPLoS ONE
Volume8
Issue number7
DOIs
Publication statusPublished - 18 Jul 2013
Externally publishedYes

Cite this

Geretti, Anna Maria ; Fox, Zoe ; Johnson, Jeffrey A. ; Booth, Clare ; Lipscomb, Jonathan ; Stuyver, Lieven J. ; Tachedjian, Gilda ; Baxter, John ; Touloumi, Giota ; Lehmann, Clara ; Owen, Andrew R ; Phillips, Andrew. / Sensitive Assessment of the Virologic Outcomes of Stopping and Restarting Non-Nucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy. In: PLoS ONE. 2013 ; Vol. 8, No. 7.
@article{af95731c8a114cdfa7c6381a8748d435,
title = "Sensitive Assessment of the Virologic Outcomes of Stopping and Restarting Non-Nucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy",
abstract = "Background:Non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants have been shown to emerge after interruption of suppressive NNRTI-based antiretroviral therapy (ART) using routine testing. The aim of this study was to quantify the risk of resistance by sensitive testing and correlate the detection of resistance with NNRTI concentrations after treatment interruption and virologic responses after treatment resumption.Methods:Resistance-associated mutations (RAMs) and NNRTI concentrations were studied in plasma from 132 patients who interrupted suppressive ART within SMART. RAMs were detected by Sanger sequencing, allele-specific PCR, and ultra-deep sequencing. NNRTI concentrations were measured by sensitive high-performance liquid chromatography.Results:Four weeks after NNRTI interruption, 19/31 (61.3{\%}) and 34/39 (87.2{\%}) patients showed measurable nevirapine (>0.25 ng/ml) or efavirenz (>5 ng/ml) concentrations, respectively. Median eight weeks after interruption, 22/131 (16.8{\%}) patients showed ≥1 NNRTI-RAM, including eight patients with NNRTI-RAMs detected only by sensitive testing. The adjusted odds ratio (OR) of NNRTI-RAM detection was 7.62 (95{\%} confidence interval [CI] 1.52, 38.30; p = 0.01) with nevirapine or efavirenz concentrations above vs. below the median measured in the study population. Staggered interruption, whereby nucleos(t)ide reverse transcriptase inhibitors (NRTIs) were continued for median nine days after NNRTI interruption, did not prevent NNRTI-RAMs, but increased detection of NRTI-RAMs (OR 4.25; 95{\%} CI 1.02, 17.77; p = 0.03). After restarting NNRTI-based ART (n = 90), virologic suppression rates <400 copies/ml were 8/13 (61.5{\%}) with NNRTI-RAMs, 7/11 (63.6{\%}) with NRTI-RAMs only, and 51/59 (86.4{\%}) without RAMs. The ORs of re-suppression were 0.18 (95{\%} CI 0.03, 0.89) and 0.17 (95{\%} CI 0.03, 1.15) for patients with NNRTI-RAMs or NRTI-RAMs only respectively vs. those without RAMs (p = 0.04).Conclusions:Detection of resistant mutants in the rebound viremia after interruption of efavirenz- or nevirapine-based ART affects outcomes once these drugs are restarted. Further studies are needed to determine RAM persistence in untreated patients and impact on newer NNRTIs.",
author = "Geretti, {Anna Maria} and Zoe Fox and Johnson, {Jeffrey A.} and Clare Booth and Jonathan Lipscomb and Stuyver, {Lieven J.} and Gilda Tachedjian and John Baxter and Giota Touloumi and Clara Lehmann and Owen, {Andrew R} and Andrew Phillips",
year = "2013",
month = "7",
day = "18",
doi = "10.1371/journal.pone.0069266",
language = "English",
volume = "8",
journal = "PLoS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "7",

}

Geretti, AM, Fox, Z, Johnson, JA, Booth, C, Lipscomb, J, Stuyver, LJ, Tachedjian, G, Baxter, J, Touloumi, G, Lehmann, C, Owen, AR & Phillips, A 2013, 'Sensitive Assessment of the Virologic Outcomes of Stopping and Restarting Non-Nucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy', PLoS ONE, vol. 8, no. 7, e69266. https://doi.org/10.1371/journal.pone.0069266

Sensitive Assessment of the Virologic Outcomes of Stopping and Restarting Non-Nucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy. / Geretti, Anna Maria; Fox, Zoe; Johnson, Jeffrey A.; Booth, Clare; Lipscomb, Jonathan; Stuyver, Lieven J.; Tachedjian, Gilda; Baxter, John; Touloumi, Giota; Lehmann, Clara; Owen, Andrew R; Phillips, Andrew.

In: PLoS ONE, Vol. 8, No. 7, e69266, 18.07.2013.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Sensitive Assessment of the Virologic Outcomes of Stopping and Restarting Non-Nucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy

AU - Geretti, Anna Maria

AU - Fox, Zoe

AU - Johnson, Jeffrey A.

AU - Booth, Clare

AU - Lipscomb, Jonathan

AU - Stuyver, Lieven J.

AU - Tachedjian, Gilda

AU - Baxter, John

AU - Touloumi, Giota

AU - Lehmann, Clara

AU - Owen, Andrew R

AU - Phillips, Andrew

PY - 2013/7/18

Y1 - 2013/7/18

N2 - Background:Non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants have been shown to emerge after interruption of suppressive NNRTI-based antiretroviral therapy (ART) using routine testing. The aim of this study was to quantify the risk of resistance by sensitive testing and correlate the detection of resistance with NNRTI concentrations after treatment interruption and virologic responses after treatment resumption.Methods:Resistance-associated mutations (RAMs) and NNRTI concentrations were studied in plasma from 132 patients who interrupted suppressive ART within SMART. RAMs were detected by Sanger sequencing, allele-specific PCR, and ultra-deep sequencing. NNRTI concentrations were measured by sensitive high-performance liquid chromatography.Results:Four weeks after NNRTI interruption, 19/31 (61.3%) and 34/39 (87.2%) patients showed measurable nevirapine (>0.25 ng/ml) or efavirenz (>5 ng/ml) concentrations, respectively. Median eight weeks after interruption, 22/131 (16.8%) patients showed ≥1 NNRTI-RAM, including eight patients with NNRTI-RAMs detected only by sensitive testing. The adjusted odds ratio (OR) of NNRTI-RAM detection was 7.62 (95% confidence interval [CI] 1.52, 38.30; p = 0.01) with nevirapine or efavirenz concentrations above vs. below the median measured in the study population. Staggered interruption, whereby nucleos(t)ide reverse transcriptase inhibitors (NRTIs) were continued for median nine days after NNRTI interruption, did not prevent NNRTI-RAMs, but increased detection of NRTI-RAMs (OR 4.25; 95% CI 1.02, 17.77; p = 0.03). After restarting NNRTI-based ART (n = 90), virologic suppression rates <400 copies/ml were 8/13 (61.5%) with NNRTI-RAMs, 7/11 (63.6%) with NRTI-RAMs only, and 51/59 (86.4%) without RAMs. The ORs of re-suppression were 0.18 (95% CI 0.03, 0.89) and 0.17 (95% CI 0.03, 1.15) for patients with NNRTI-RAMs or NRTI-RAMs only respectively vs. those without RAMs (p = 0.04).Conclusions:Detection of resistant mutants in the rebound viremia after interruption of efavirenz- or nevirapine-based ART affects outcomes once these drugs are restarted. Further studies are needed to determine RAM persistence in untreated patients and impact on newer NNRTIs.

AB - Background:Non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants have been shown to emerge after interruption of suppressive NNRTI-based antiretroviral therapy (ART) using routine testing. The aim of this study was to quantify the risk of resistance by sensitive testing and correlate the detection of resistance with NNRTI concentrations after treatment interruption and virologic responses after treatment resumption.Methods:Resistance-associated mutations (RAMs) and NNRTI concentrations were studied in plasma from 132 patients who interrupted suppressive ART within SMART. RAMs were detected by Sanger sequencing, allele-specific PCR, and ultra-deep sequencing. NNRTI concentrations were measured by sensitive high-performance liquid chromatography.Results:Four weeks after NNRTI interruption, 19/31 (61.3%) and 34/39 (87.2%) patients showed measurable nevirapine (>0.25 ng/ml) or efavirenz (>5 ng/ml) concentrations, respectively. Median eight weeks after interruption, 22/131 (16.8%) patients showed ≥1 NNRTI-RAM, including eight patients with NNRTI-RAMs detected only by sensitive testing. The adjusted odds ratio (OR) of NNRTI-RAM detection was 7.62 (95% confidence interval [CI] 1.52, 38.30; p = 0.01) with nevirapine or efavirenz concentrations above vs. below the median measured in the study population. Staggered interruption, whereby nucleos(t)ide reverse transcriptase inhibitors (NRTIs) were continued for median nine days after NNRTI interruption, did not prevent NNRTI-RAMs, but increased detection of NRTI-RAMs (OR 4.25; 95% CI 1.02, 17.77; p = 0.03). After restarting NNRTI-based ART (n = 90), virologic suppression rates <400 copies/ml were 8/13 (61.5%) with NNRTI-RAMs, 7/11 (63.6%) with NRTI-RAMs only, and 51/59 (86.4%) without RAMs. The ORs of re-suppression were 0.18 (95% CI 0.03, 0.89) and 0.17 (95% CI 0.03, 1.15) for patients with NNRTI-RAMs or NRTI-RAMs only respectively vs. those without RAMs (p = 0.04).Conclusions:Detection of resistant mutants in the rebound viremia after interruption of efavirenz- or nevirapine-based ART affects outcomes once these drugs are restarted. Further studies are needed to determine RAM persistence in untreated patients and impact on newer NNRTIs.

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