Sensitive assessment of the virologic outcomes of stopping and restarting non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy.
<h4>Background</h4>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 sensitiv...
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Public Library of Science (PLoS)
2013-01-01
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| author | Anna Maria Geretti Zoe Fox Jeffrey A Johnson Clare Booth Jonathan Lipscomb Lieven J Stuyver Gilda Tachedjian John Baxter Giota Touloumi Clara Lehmann Andrew Owen Andrew Phillips INSIGHT Strategies for Management of Antiretroviral Therapy (SMART) Study Group |
| author_facet | Anna Maria Geretti Zoe Fox Jeffrey A Johnson Clare Booth Jonathan Lipscomb Lieven J Stuyver Gilda Tachedjian John Baxter Giota Touloumi Clara Lehmann Andrew Owen Andrew Phillips INSIGHT Strategies for Management of Antiretroviral Therapy (SMART) Study Group |
| author_sort | Anna Maria Geretti |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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).<h4>Conclusions</h4>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. |
| format | Article |
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| institution | OA Journals |
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| language | English |
| publishDate | 2013-01-01 |
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| spelling | doaj-art-e99c580f9fbc475fa9fb7646e0ee7b362025-08-20T02:30:38ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0187e6926610.1371/journal.pone.0069266Sensitive assessment of the virologic outcomes of stopping and restarting non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy.Anna Maria GerettiZoe FoxJeffrey A JohnsonClare BoothJonathan LipscombLieven J StuyverGilda TachedjianJohn BaxterGiota TouloumiClara LehmannAndrew OwenAndrew PhillipsINSIGHT Strategies for Management of Antiretroviral Therapy (SMART) Study Group<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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).<h4>Conclusions</h4>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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0069266&type=printable |
| spellingShingle | Anna Maria Geretti Zoe Fox Jeffrey A Johnson Clare Booth Jonathan Lipscomb Lieven J Stuyver Gilda Tachedjian John Baxter Giota Touloumi Clara Lehmann Andrew Owen Andrew Phillips INSIGHT Strategies for Management of Antiretroviral Therapy (SMART) Study Group Sensitive assessment of the virologic outcomes of stopping and restarting non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy. PLoS ONE |
| title | Sensitive assessment of the virologic outcomes of stopping and restarting non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy. |
| title_full | Sensitive assessment of the virologic outcomes of stopping and restarting non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy. |
| title_fullStr | Sensitive assessment of the virologic outcomes of stopping and restarting non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy. |
| title_full_unstemmed | Sensitive assessment of the virologic outcomes of stopping and restarting non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy. |
| title_short | Sensitive assessment of the virologic outcomes of stopping and restarting non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy. |
| title_sort | sensitive assessment of the virologic outcomes of stopping and restarting non nucleoside reverse transcriptase inhibitor based antiretroviral therapy |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0069266&type=printable |
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