Sensitive assessment of the virologic outcomes of stopping and restarting non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy
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 det...
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| Veröffentlicht in: | PloS one 2013-07, Vol.8 (7), p.e69266-e69266 |
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| creator | 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 Phillips, Andrew |
| description | 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.
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.
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 |
| doi_str_mv | 10.1371/journal.pone.0069266 |
| format | Article |
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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.
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).
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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0069266</identifier><identifier>PMID: 23874928</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acquired immune deficiency syndrome ; Adult ; AIDS ; Alkynes ; Analysis ; Anti-Retroviral Agents - therapeutic use ; Antiretroviral agents ; Antiretroviral drugs ; Antiretroviral therapy ; Benzoxazines - blood ; Biological products industry ; Biology ; Chromatography ; Chromatography, High Pressure Liquid ; Confidence intervals ; Cyclopropanes ; DNA Mutational Analysis ; DNA polymerases ; DNA sequencing ; Drug resistance ; Drug Resistance, Viral - genetics ; Drugs ; Efavirenz ; Female ; High performance liquid chromatography ; High-Throughput Nucleotide Sequencing ; Highly active antiretroviral therapy ; HIV ; HIV Infections - drug therapy ; HIV-1 - genetics ; Human immunodeficiency virus ; Humans ; Inhibitors ; Interruption ; Liquid chromatography ; Logistic Models ; Male ; Medical research ; Medicine ; Middle Aged ; Mutants ; Mutation ; Nevirapine ; Nevirapine - blood ; Nucleosides ; Odds Ratio ; Patients ; Population studies ; Protease inhibitors ; Rams ; Resistant mutant ; Restarting ; Reverse Transcriptase Inhibitors - blood ; Reverse Transcriptase Inhibitors - therapeutic use ; RNA-directed DNA polymerase ; Therapy ; Viremia</subject><ispartof>PloS one, 2013-07, Vol.8 (7), p.e69266-e69266</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Geretti et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Geretti et al 2013 Geretti et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-b8f967498e47a4f579300b2ea7edd22cb13c1c9d923eb1de2f8f4866d8b2fdfe3</citedby><cites>FETCH-LOGICAL-c692t-b8f967498e47a4f579300b2ea7edd22cb13c1c9d923eb1de2f8f4866d8b2fdfe3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715458/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715458/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23874928$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ambrose, Zandrea</contributor><creatorcontrib>Geretti, Anna Maria</creatorcontrib><creatorcontrib>Fox, Zoe</creatorcontrib><creatorcontrib>Johnson, Jeffrey A</creatorcontrib><creatorcontrib>Booth, Clare</creatorcontrib><creatorcontrib>Lipscomb, Jonathan</creatorcontrib><creatorcontrib>Stuyver, Lieven J</creatorcontrib><creatorcontrib>Tachedjian, Gilda</creatorcontrib><creatorcontrib>Baxter, John</creatorcontrib><creatorcontrib>Touloumi, Giota</creatorcontrib><creatorcontrib>Lehmann, Clara</creatorcontrib><creatorcontrib>Owen, Andrew</creatorcontrib><creatorcontrib>Phillips, Andrew</creatorcontrib><creatorcontrib>INSIGHT Strategies for Management of Antiretroviral Therapy (SMART) Study Group</creatorcontrib><creatorcontrib>for the INSIGHT Strategies for Management of Antiretroviral Therapy (SMART) Study Group</creatorcontrib><title>Sensitive assessment of the virologic outcomes of stopping and restarting non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.
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.
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).
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.</description><subject>Acquired immune deficiency syndrome</subject><subject>Adult</subject><subject>AIDS</subject><subject>Alkynes</subject><subject>Analysis</subject><subject>Anti-Retroviral Agents - therapeutic use</subject><subject>Antiretroviral agents</subject><subject>Antiretroviral drugs</subject><subject>Antiretroviral therapy</subject><subject>Benzoxazines - blood</subject><subject>Biological products industry</subject><subject>Biology</subject><subject>Chromatography</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Confidence intervals</subject><subject>Cyclopropanes</subject><subject>DNA Mutational Analysis</subject><subject>DNA polymerases</subject><subject>DNA sequencing</subject><subject>Drug resistance</subject><subject>Drug Resistance, Viral - genetics</subject><subject>Drugs</subject><subject>Efavirenz</subject><subject>Female</subject><subject>High performance liquid chromatography</subject><subject>High-Throughput Nucleotide Sequencing</subject><subject>Highly active antiretroviral therapy</subject><subject>HIV</subject><subject>HIV Infections - drug therapy</subject><subject>HIV-1 - genetics</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Interruption</subject><subject>Liquid chromatography</subject><subject>Logistic Models</subject><subject>Male</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Middle Aged</subject><subject>Mutants</subject><subject>Mutation</subject><subject>Nevirapine</subject><subject>Nevirapine - blood</subject><subject>Nucleosides</subject><subject>Odds Ratio</subject><subject>Patients</subject><subject>Population studies</subject><subject>Protease inhibitors</subject><subject>Rams</subject><subject>Resistant mutant</subject><subject>Restarting</subject><subject>Reverse Transcriptase Inhibitors - blood</subject><subject>Reverse Transcriptase Inhibitors - therapeutic use</subject><subject>RNA-directed DNA polymerase</subject><subject>Therapy</subject><subject>Viremia</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk89u1DAQxiMEoqXwBggiISE4ZEnsxEkuSFXFn5UqVaLA1XKccdarrJ3azoo-CO_LhE2rDeoB5RCP_Ztv8o0zUfQyS1cZLbMPWzs6I_rVYA2s0pTVhLFH0WlWU5IwktLHR-uT6Jn32zQtaMXY0-iE0KrMa1KdRr-vwXgd9B5i4T14vwMTYqvisIF4r53tbadlbMcg7Q78dOKDHQZtuliYNnbgg3BhCo01iRllD9brFvBkD85DHJwwXjo9BIGRNhvd6GBd0mDYokbQDoKzWEv0U1Unhtvn0RMleg8v5vdZ9OPzp-8XX5PLqy_ri_PLRKLdkDSVqhkaqSAvRa6KsqZp2hAQJbQtIbLJqMxk3daEQpO1QFSlcuxAWzVEtQroWfT6oDv01vO5o55nOSlpSbK8RmJ9IFortnxweifcLbdC878b1nV8so-uOdS1LKpU1aqReVkogYuS5QxSgLKhDLU-ztXGZgetxE6j54Xo8sToDe_snuN1F3lRocC7WcDZmxE7z3faS-h7YcCO03dnGaOEFSWib_5BH3Y3U51AA9ooi3XlJMrP87IipMjJVHb1AIVPCzst8fdTGvcXCe8XCcgE-BU6MXrP19ff_p-9-rlk3x6xGxB92Hjbj0Fb45dgfgCls947UPdNzlI-Tc9dN_g0PXyeHkx7dXxB90l340L_AHCIGro</recordid><startdate>20130718</startdate><enddate>20130718</enddate><creator>Geretti, 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Geretti, Anna Maria</au><au>Fox, Zoe</au><au>Johnson, Jeffrey A</au><au>Booth, Clare</au><au>Lipscomb, Jonathan</au><au>Stuyver, Lieven J</au><au>Tachedjian, Gilda</au><au>Baxter, John</au><au>Touloumi, Giota</au><au>Lehmann, Clara</au><au>Owen, Andrew</au><au>Phillips, Andrew</au><au>Ambrose, Zandrea</au><aucorp>INSIGHT Strategies for Management of Antiretroviral Therapy (SMART) Study Group</aucorp><aucorp>for the INSIGHT Strategies for Management of Antiretroviral Therapy (SMART) Study Group</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sensitive assessment of the virologic outcomes of stopping and restarting non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-07-18</date><risdate>2013</risdate><volume>8</volume><issue>7</issue><spage>e69266</spage><epage>e69266</epage><pages>e69266-e69266</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.
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.
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).
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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23874928</pmid><doi>10.1371/journal.pone.0069266</doi><tpages>e69266</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-07, Vol.8 (7), p.e69266-e69266 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1427372149 |
| source | PubMed (Medline); MEDLINE; Public Library of Science; Directory of Open Access Journals; Free Full-Text Journals in Chemistry; EZB Electronic Journals Library |
| subjects | Acquired immune deficiency syndrome Adult AIDS Alkynes Analysis Anti-Retroviral Agents - therapeutic use Antiretroviral agents Antiretroviral drugs Antiretroviral therapy Benzoxazines - blood Biological products industry Biology Chromatography Chromatography, High Pressure Liquid Confidence intervals Cyclopropanes DNA Mutational Analysis DNA polymerases DNA sequencing Drug resistance Drug Resistance, Viral - genetics Drugs Efavirenz Female High performance liquid chromatography High-Throughput Nucleotide Sequencing Highly active antiretroviral therapy HIV HIV Infections - drug therapy HIV-1 - genetics Human immunodeficiency virus Humans Inhibitors Interruption Liquid chromatography Logistic Models Male Medical research Medicine Middle Aged Mutants Mutation Nevirapine Nevirapine - blood Nucleosides Odds Ratio Patients Population studies Protease inhibitors Rams Resistant mutant Restarting Reverse Transcriptase Inhibitors - blood Reverse Transcriptase Inhibitors - therapeutic use RNA-directed DNA polymerase Therapy Viremia |
| title | Sensitive assessment of the virologic outcomes of stopping and restarting non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy |
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