Evolution of Protease Inhibitor Resistance in Human Immunodeficiency Virus Type 1 Infected Patients Failing Protease Inhibitor Monotherapy as Second-line Therapy in Low-income Countries : An Observational Analysis Within the EARNEST Randomized Trial
© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissionsoup.com..
BACKGROUND: Limited viral load (VL) testing in human immunodeficiency virus (HIV) treatment programs in low-income countries often delays detection of treatment failure. The impact of remaining on failing protease inhibitor (PI)-containing regimens is unclear.
METHODS: We retrospectively tested VL in 2164 stored plasma samples from 386 patients randomized to receive lopinavir monotherapy (after initial raltegravir induction) in the Europe-Africa Research Network for Evaluation of Second-line Therapy (EARNEST) trial. Protease genotypic resistance testing was performed when VL >1000 copies/mL. We assessed evolution of PI resistance mutations from virological failure (confirmed VL >1000 copies/mL) until PI monotherapy discontinuation and examined associations using mixed-effects models.
RESULTS: Median post-failure follow-up (in 118 patients) was 68 (interquartile range, 48-88) weeks. At failure, 20% had intermediate/high-level resistance to lopinavir. At 40-48 weeks post-failure, 68% and 51% had intermediate/high-level resistance to lopinavir and atazanavir; 17% had intermediate-level resistance (none high) to darunavir. Common PI mutations were M46I, I54V, and V82A. On average, 1.7 (95% confidence interval 1.5-2.0) PI mutations developed per year; increasing after the first mutation; decreasing with subsequent mutations (P < .0001). VL changes were modest, mainly driven by nonadherence (P = .006) and PI mutation development (P = .0002); I47A was associated with a larger increase in VL than other mutations (P = .05).
CONCLUSIONS: Most patients develop intermediate/high-level lopinavir resistance within 1 year of ongoing viral replication on monotherapy but retain susceptibility to darunavir. Viral load increased slowly after failure, driven by non-adherence and PI mutation development.
CLINICAL TRIALS REGISTRATION: NCT00988039.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:68 |
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| Enthalten in: |
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America - 68(2019), 7 vom: 19. März, Seite 1184-1192 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Thompson, Jennifer A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 06.05.2020 Date Revised 09.01.2021 published: Print ClinicalTrials.gov: NCT00988039 Citation Status MEDLINE |
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| doi: |
10.1093/cid/ciy589 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM28699917X |
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| 100 | 1 | |a Thompson, Jennifer A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Evolution of Protease Inhibitor Resistance in Human Immunodeficiency Virus Type 1 Infected Patients Failing Protease Inhibitor Monotherapy as Second-line Therapy in Low-income Countries |b An Observational Analysis Within the EARNEST Randomized Trial |
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| 500 | |a Date Completed 06.05.2020 | ||
| 500 | |a Date Revised 09.01.2021 | ||
| 500 | |a published: Print | ||
| 500 | |a ClinicalTrials.gov: NCT00988039 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissionsoup.com. | ||
| 520 | |a BACKGROUND: Limited viral load (VL) testing in human immunodeficiency virus (HIV) treatment programs in low-income countries often delays detection of treatment failure. The impact of remaining on failing protease inhibitor (PI)-containing regimens is unclear | ||
| 520 | |a METHODS: We retrospectively tested VL in 2164 stored plasma samples from 386 patients randomized to receive lopinavir monotherapy (after initial raltegravir induction) in the Europe-Africa Research Network for Evaluation of Second-line Therapy (EARNEST) trial. Protease genotypic resistance testing was performed when VL >1000 copies/mL. We assessed evolution of PI resistance mutations from virological failure (confirmed VL >1000 copies/mL) until PI monotherapy discontinuation and examined associations using mixed-effects models | ||
| 520 | |a RESULTS: Median post-failure follow-up (in 118 patients) was 68 (interquartile range, 48-88) weeks. At failure, 20% had intermediate/high-level resistance to lopinavir. At 40-48 weeks post-failure, 68% and 51% had intermediate/high-level resistance to lopinavir and atazanavir; 17% had intermediate-level resistance (none high) to darunavir. Common PI mutations were M46I, I54V, and V82A. On average, 1.7 (95% confidence interval 1.5-2.0) PI mutations developed per year; increasing after the first mutation; decreasing with subsequent mutations (P < .0001). VL changes were modest, mainly driven by nonadherence (P = .006) and PI mutation development (P = .0002); I47A was associated with a larger increase in VL than other mutations (P = .05) | ||
| 520 | |a CONCLUSIONS: Most patients develop intermediate/high-level lopinavir resistance within 1 year of ongoing viral replication on monotherapy but retain susceptibility to darunavir. Viral load increased slowly after failure, driven by non-adherence and PI mutation development | ||
| 520 | |a CLINICAL TRIALS REGISTRATION: NCT00988039 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Observational Study | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a HIV-1 | |
| 650 | 4 | |a drug resistance | |
| 650 | 4 | |a protease inhibitor | |
| 650 | 4 | |a second-line antiretroviral therapy | |
| 650 | 4 | |a sub-Saharan Africa | |
| 650 | 7 | |a HIV Protease Inhibitors |2 NLM | |
| 650 | 7 | |a Lopinavir |2 NLM | |
| 650 | 7 | |a 2494G1JF75 |2 NLM | |
| 700 | 1 | |a Kityo, Cissy |e verfasserin |4 aut | |
| 700 | 1 | |a Dunn, David |e verfasserin |4 aut | |
| 700 | 1 | |a Hoppe, Anne |e verfasserin |4 aut | |
| 700 | 1 | |a Ndashimye, Emmanuel |e verfasserin |4 aut | |
| 700 | 1 | |a Hakim, James |e verfasserin |4 aut | |
| 700 | 1 | |a Kambugu, Andrew |e verfasserin |4 aut | |
| 700 | 1 | |a van Oosterhout, Joep J |e verfasserin |4 aut | |
| 700 | 1 | |a Arribas, Jose |e verfasserin |4 aut | |
| 700 | 1 | |a Mugyenyi, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Walker, A Sarah |e verfasserin |4 aut | |
| 700 | 1 | |a Paton, Nicholas I |e verfasserin |4 aut | |
| 700 | 0 | |a Europe–Africa Research Network for Evaluation of Second-line Therapy (EARNEST) Trial Team |e verfasserin |4 aut | |
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