The rate of accumulation of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance in patients kept on a virologically failing regimen containing an NNRTI

A. Cozzi-Lepri, R. Paredes, A. N. Phillips, B. Clotet, J. Kjær, V. von Wyl, G. Kronborg, A. Castagna, J. R. Bogner, J. D. Lundgren

Research output: Contribution to journalArticle

Abstract

Background: Virological failure of first-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs) can compromise the efficacy of etravirine as a result of the accumulation of NNRTI resistance mutations. How quickly NNRTI resistance accumulates in patients with a delayed switch from nevirapine or efavirenz despite virological failure, when these drugs are used as a component of combination antiretroviral therapy (cART), remains unclear. Methods: The rate of NNRTI resistance accumulation was estimated in patients in EuroSIDA with at least two available genotypic resistance tests (GRTs), provided that (1) the date of the first GRT (t0) was after the date of the first virological failure (VF) of an NNRTI, and (2) patients were receiving an NNRTI and HIV RNA was >500HIV-1 RNA copies/mL in all measurements between GRTs. Results: A total of 227 patients were included in the study, contributing 467 GRT pairs. At baseline-t0, a median of 3 months after VF, 66% of patients had at least one NNRTI mutation: 103N (34%), 181C (22%) and 190A (20%) were the most common mutations. Overall, 180 additional NNRTI mutations were found to have accumulated over 295 years [1 new/1.6 years; 95% confidence interval (CI) 1.5-1.8]. The rate of accumulation was faster in the first 6 months from VF (1 new/1.1 years), and slower in patients exposed to nevirapine vs. those receiving efavirenz [relative risk (RR) 0.66; 95% CI 0.46-0.95; P=0.03]. Conclusions: There is an initial phase of rapid accumulation of NNRTI mutations close to the time of VF followed by a phase of slower accumulation. We predict that it should take approximately one year of exposure to a virologically failing first-generation NNRTI-based cART regimen to reduce etravirine activity from fully susceptible to intermediate resistant, and possibly longer in patients kept on a failing nevirapine-containing regimen.

Original languageEnglish
Pages (from-to)62-72
Number of pages11
JournalHIV Medicine
Volume13
Issue number1
DOIs
Publication statusPublished - Jan 2012

Fingerprint

Reverse Transcriptase Inhibitors
efavirenz
etravirine
Nevirapine
Mutation
RNA
Confidence Intervals
HIV

Keywords

  • Nonnucleoside reverse transcriptase inhibitor mutations
  • Ongoing viraemia
  • Poisson regression
  • Rate of accumulation

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)
  • Health Policy

Cite this

The rate of accumulation of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance in patients kept on a virologically failing regimen containing an NNRTI. / Cozzi-Lepri, A.; Paredes, R.; Phillips, A. N.; Clotet, B.; Kjær, J.; von Wyl, V.; Kronborg, G.; Castagna, A.; Bogner, J. R.; Lundgren, J. D.

In: HIV Medicine, Vol. 13, No. 1, 01.2012, p. 62-72.

Research output: Contribution to journalArticle

Cozzi-Lepri, A. ; Paredes, R. ; Phillips, A. N. ; Clotet, B. ; Kjær, J. ; von Wyl, V. ; Kronborg, G. ; Castagna, A. ; Bogner, J. R. ; Lundgren, J. D. / The rate of accumulation of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance in patients kept on a virologically failing regimen containing an NNRTI. In: HIV Medicine. 2012 ; Vol. 13, No. 1. pp. 62-72.
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abstract = "Background: Virological failure of first-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs) can compromise the efficacy of etravirine as a result of the accumulation of NNRTI resistance mutations. How quickly NNRTI resistance accumulates in patients with a delayed switch from nevirapine or efavirenz despite virological failure, when these drugs are used as a component of combination antiretroviral therapy (cART), remains unclear. Methods: The rate of NNRTI resistance accumulation was estimated in patients in EuroSIDA with at least two available genotypic resistance tests (GRTs), provided that (1) the date of the first GRT (t0) was after the date of the first virological failure (VF) of an NNRTI, and (2) patients were receiving an NNRTI and HIV RNA was >500HIV-1 RNA copies/mL in all measurements between GRTs. Results: A total of 227 patients were included in the study, contributing 467 GRT pairs. At baseline-t0, a median of 3 months after VF, 66{\%} of patients had at least one NNRTI mutation: 103N (34{\%}), 181C (22{\%}) and 190A (20{\%}) were the most common mutations. Overall, 180 additional NNRTI mutations were found to have accumulated over 295 years [1 new/1.6 years; 95{\%} confidence interval (CI) 1.5-1.8]. The rate of accumulation was faster in the first 6 months from VF (1 new/1.1 years), and slower in patients exposed to nevirapine vs. those receiving efavirenz [relative risk (RR) 0.66; 95{\%} CI 0.46-0.95; P=0.03]. Conclusions: There is an initial phase of rapid accumulation of NNRTI mutations close to the time of VF followed by a phase of slower accumulation. We predict that it should take approximately one year of exposure to a virologically failing first-generation NNRTI-based cART regimen to reduce etravirine activity from fully susceptible to intermediate resistant, and possibly longer in patients kept on a failing nevirapine-containing regimen.",
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AU - Cozzi-Lepri, A.

AU - Paredes, R.

AU - Phillips, A. N.

AU - Clotet, B.

AU - Kjær, J.

AU - von Wyl, V.

AU - Kronborg, G.

AU - Castagna, A.

AU - Bogner, J. R.

AU - Lundgren, J. D.

PY - 2012/1

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N2 - Background: Virological failure of first-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs) can compromise the efficacy of etravirine as a result of the accumulation of NNRTI resistance mutations. How quickly NNRTI resistance accumulates in patients with a delayed switch from nevirapine or efavirenz despite virological failure, when these drugs are used as a component of combination antiretroviral therapy (cART), remains unclear. Methods: The rate of NNRTI resistance accumulation was estimated in patients in EuroSIDA with at least two available genotypic resistance tests (GRTs), provided that (1) the date of the first GRT (t0) was after the date of the first virological failure (VF) of an NNRTI, and (2) patients were receiving an NNRTI and HIV RNA was >500HIV-1 RNA copies/mL in all measurements between GRTs. Results: A total of 227 patients were included in the study, contributing 467 GRT pairs. At baseline-t0, a median of 3 months after VF, 66% of patients had at least one NNRTI mutation: 103N (34%), 181C (22%) and 190A (20%) were the most common mutations. Overall, 180 additional NNRTI mutations were found to have accumulated over 295 years [1 new/1.6 years; 95% confidence interval (CI) 1.5-1.8]. The rate of accumulation was faster in the first 6 months from VF (1 new/1.1 years), and slower in patients exposed to nevirapine vs. those receiving efavirenz [relative risk (RR) 0.66; 95% CI 0.46-0.95; P=0.03]. Conclusions: There is an initial phase of rapid accumulation of NNRTI mutations close to the time of VF followed by a phase of slower accumulation. We predict that it should take approximately one year of exposure to a virologically failing first-generation NNRTI-based cART regimen to reduce etravirine activity from fully susceptible to intermediate resistant, and possibly longer in patients kept on a failing nevirapine-containing regimen.

AB - Background: Virological failure of first-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs) can compromise the efficacy of etravirine as a result of the accumulation of NNRTI resistance mutations. How quickly NNRTI resistance accumulates in patients with a delayed switch from nevirapine or efavirenz despite virological failure, when these drugs are used as a component of combination antiretroviral therapy (cART), remains unclear. Methods: The rate of NNRTI resistance accumulation was estimated in patients in EuroSIDA with at least two available genotypic resistance tests (GRTs), provided that (1) the date of the first GRT (t0) was after the date of the first virological failure (VF) of an NNRTI, and (2) patients were receiving an NNRTI and HIV RNA was >500HIV-1 RNA copies/mL in all measurements between GRTs. Results: A total of 227 patients were included in the study, contributing 467 GRT pairs. At baseline-t0, a median of 3 months after VF, 66% of patients had at least one NNRTI mutation: 103N (34%), 181C (22%) and 190A (20%) were the most common mutations. Overall, 180 additional NNRTI mutations were found to have accumulated over 295 years [1 new/1.6 years; 95% confidence interval (CI) 1.5-1.8]. The rate of accumulation was faster in the first 6 months from VF (1 new/1.1 years), and slower in patients exposed to nevirapine vs. those receiving efavirenz [relative risk (RR) 0.66; 95% CI 0.46-0.95; P=0.03]. Conclusions: There is an initial phase of rapid accumulation of NNRTI mutations close to the time of VF followed by a phase of slower accumulation. We predict that it should take approximately one year of exposure to a virologically failing first-generation NNRTI-based cART regimen to reduce etravirine activity from fully susceptible to intermediate resistant, and possibly longer in patients kept on a failing nevirapine-containing regimen.

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KW - Ongoing viraemia

KW - Poisson regression

KW - Rate of accumulation

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