The association between detected drug resistance mutations and CD4+ T-cell decline in HIV-positive individuals maintained on a failing treatment regimen

Anna Schultze; Roger Paredes; Caroline Sabin; Andrew N Phillips; Deenan Pillay; Nicola Mackie; Antonella Castagna; David Chadwick; Karolin Falconer; Anna Maria Geretti; Frank A Post; Teresa Hill; Ole Kirk; Anton Pozniak; Mark Nelson; Anna Tostevin; David Dunn; Jens Lundgren; Alessandro Cozzi-Lepri

doi:10.3851/IMP3178

The association between detected drug resistance mutations and CD4⁺ T-cell decline in HIV-positive individuals maintained on a failing treatment regimen

Anna Schultze, Roger Paredes, Caroline Sabin, Andrew N Phillips, Deenan Pillay, Nicola Mackie, Antonella Castagna, David Chadwick, Karolin Falconer, Anna Maria Geretti, Frank A Post, Teresa Hill, Ole Kirk, Anton Pozniak, Mark Nelson, Anna Tostevin, David Dunn, Jens Lundgren, Alessandro Cozzi-Lepri

Department of Clinical Medicine

1 Citation (Scopus)

Abstract

Background: To analyse the effect of drug resistance mutations (DRM) on CD4+ T-cell (CD4) trends in HIVpositive people maintained on virologically failing antiretroviral therapy (ART). Methods: Individuals from two large cohorts experiencing virological failure (VF) while maintained on ART with =1 CD4 count and =1 resistance test were included. CD4 slopes were estimated using linear mixed models. Principal component analysis (PCA) was used to assess the effect of clusters of mutations, defined using extracted component based scores from the PCA, on CD4 decline. Results: 5,357 individuals contributing 7,661 VF episodes were included: any DRM were detected in 88.8% of episodes. After adjustment, CD4 counts declined less steeply during episodes where DRM were detected compared to episodes with no DRM (difference =28 cells/mm3/year, 95% CI =18, 39; P<0.001). Among individuals with at least one DRM, we found evidence that any nucleoside/ nucleotide reverse transcriptase inhibitor (NRTI) resistance, the reverse transcriptase (RT) mutations M184V, D67N and T215Y as well as the protease mutations V82A and I54V were associated with reduced CD4 declines. The detection of any non-nucleoside reverse transcriptase inhibitor resistance, the RT mutations V179D and L74V were associated with steeper CD4 declines. The presence of some mutation patterns similar to the clusters identified by the PCA also affected the CD4 decline. Conclusions: Detection of resistance and of certain DRM during VF of ART has a small but significant favourable effect on CD4 decline.

Original language	English
Journal	Antiviral Therapy
Volume	23
Issue number	2
Pages (from-to)	105-116
Number of pages	12
ISSN	1359-6535
DOIs	https://doi.org/10.3851/IMP3178
Publication status	Published - 2018

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Schultze, A., Paredes, R., Sabin, C., Phillips, A. N., Pillay, D., Mackie, N., Castagna, A., Chadwick, D., Falconer, K., Geretti, A. M., Post, F. A., Hill, T., Kirk, O., Pozniak, A., Nelson, M., Tostevin, A., Dunn, D., Lundgren, J., & Cozzi-Lepri, A. (2018). The association between detected drug resistance mutations and CD4⁺ T-cell decline in HIV-positive individuals maintained on a failing treatment regimen. Antiviral Therapy, 23(2), 105-116. https://doi.org/10.3851/IMP3178

Schultze, A, Paredes, R, Sabin, C, Phillips, AN, Pillay, D, Mackie, N, Castagna, A, Chadwick, D, Falconer, K, Geretti, AM, Post, FA, Hill, T, Kirk, O, Pozniak, A, Nelson, M, Tostevin, A, Dunn, D, Lundgren, J & Cozzi-Lepri, A 2018, 'The association between detected drug resistance mutations and CD4⁺ T-cell decline in HIV-positive individuals maintained on a failing treatment regimen', Antiviral Therapy, vol. 23, no. 2, pp. 105-116. https://doi.org/10.3851/IMP3178

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title = "The association between detected drug resistance mutations and CD4+ T-cell decline in HIV-positive individuals maintained on a failing treatment regimen",

abstract = "Background: To analyse the effect of drug resistance mutations (DRM) on CD4+ T-cell (CD4) trends in HIVpositive people maintained on virologically failing antiretroviral therapy (ART). Methods: Individuals from two large cohorts experiencing virological failure (VF) while maintained on ART with =1 CD4 count and =1 resistance test were included. CD4 slopes were estimated using linear mixed models. Principal component analysis (PCA) was used to assess the effect of clusters of mutations, defined using extracted component based scores from the PCA, on CD4 decline. Results: 5,357 individuals contributing 7,661 VF episodes were included: any DRM were detected in 88.8% of episodes. After adjustment, CD4 counts declined less steeply during episodes where DRM were detected compared to episodes with no DRM (difference =28 cells/mm3/year, 95% CI =18, 39; P<0.001). Among individuals with at least one DRM, we found evidence that any nucleoside/ nucleotide reverse transcriptase inhibitor (NRTI) resistance, the reverse transcriptase (RT) mutations M184V, D67N and T215Y as well as the protease mutations V82A and I54V were associated with reduced CD4 declines. The detection of any non-nucleoside reverse transcriptase inhibitor resistance, the RT mutations V179D and L74V were associated with steeper CD4 declines. The presence of some mutation patterns similar to the clusters identified by the PCA also affected the CD4 decline. Conclusions: Detection of resistance and of certain DRM during VF of ART has a small but significant favourable effect on CD4 decline.",

author = "Anna Schultze and Roger Paredes and Caroline Sabin and Phillips, {Andrew N} and Deenan Pillay and Nicola Mackie and Antonella Castagna and David Chadwick and Karolin Falconer and Geretti, {Anna Maria} and Post, {Frank A} and Teresa Hill and Ole Kirk and Anton Pozniak and Mark Nelson and Anna Tostevin and David Dunn and Jens Lundgren and Alessandro Cozzi-Lepri",

year = "2018",

doi = "10.3851/IMP3178",

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T1 - The association between detected drug resistance mutations and CD4+ T-cell decline in HIV-positive individuals maintained on a failing treatment regimen

AU - Schultze, Anna

AU - Paredes, Roger

AU - Sabin, Caroline

AU - Phillips, Andrew N

AU - Pillay, Deenan

AU - Mackie, Nicola

AU - Castagna, Antonella

AU - Chadwick, David

AU - Falconer, Karolin

AU - Geretti, Anna Maria

AU - Post, Frank A

AU - Hill, Teresa

AU - Kirk, Ole

AU - Pozniak, Anton

AU - Nelson, Mark

AU - Tostevin, Anna

AU - Dunn, David

AU - Lundgren, Jens

AU - Cozzi-Lepri, Alessandro

PY - 2018

Y1 - 2018

N2 - Background: To analyse the effect of drug resistance mutations (DRM) on CD4+ T-cell (CD4) trends in HIVpositive people maintained on virologically failing antiretroviral therapy (ART). Methods: Individuals from two large cohorts experiencing virological failure (VF) while maintained on ART with =1 CD4 count and =1 resistance test were included. CD4 slopes were estimated using linear mixed models. Principal component analysis (PCA) was used to assess the effect of clusters of mutations, defined using extracted component based scores from the PCA, on CD4 decline. Results: 5,357 individuals contributing 7,661 VF episodes were included: any DRM were detected in 88.8% of episodes. After adjustment, CD4 counts declined less steeply during episodes where DRM were detected compared to episodes with no DRM (difference =28 cells/mm3/year, 95% CI =18, 39; P<0.001). Among individuals with at least one DRM, we found evidence that any nucleoside/ nucleotide reverse transcriptase inhibitor (NRTI) resistance, the reverse transcriptase (RT) mutations M184V, D67N and T215Y as well as the protease mutations V82A and I54V were associated with reduced CD4 declines. The detection of any non-nucleoside reverse transcriptase inhibitor resistance, the RT mutations V179D and L74V were associated with steeper CD4 declines. The presence of some mutation patterns similar to the clusters identified by the PCA also affected the CD4 decline. Conclusions: Detection of resistance and of certain DRM during VF of ART has a small but significant favourable effect on CD4 decline.

AB - Background: To analyse the effect of drug resistance mutations (DRM) on CD4+ T-cell (CD4) trends in HIVpositive people maintained on virologically failing antiretroviral therapy (ART). Methods: Individuals from two large cohorts experiencing virological failure (VF) while maintained on ART with =1 CD4 count and =1 resistance test were included. CD4 slopes were estimated using linear mixed models. Principal component analysis (PCA) was used to assess the effect of clusters of mutations, defined using extracted component based scores from the PCA, on CD4 decline. Results: 5,357 individuals contributing 7,661 VF episodes were included: any DRM were detected in 88.8% of episodes. After adjustment, CD4 counts declined less steeply during episodes where DRM were detected compared to episodes with no DRM (difference =28 cells/mm3/year, 95% CI =18, 39; P<0.001). Among individuals with at least one DRM, we found evidence that any nucleoside/ nucleotide reverse transcriptase inhibitor (NRTI) resistance, the reverse transcriptase (RT) mutations M184V, D67N and T215Y as well as the protease mutations V82A and I54V were associated with reduced CD4 declines. The detection of any non-nucleoside reverse transcriptase inhibitor resistance, the RT mutations V179D and L74V were associated with steeper CD4 declines. The presence of some mutation patterns similar to the clusters identified by the PCA also affected the CD4 decline. Conclusions: Detection of resistance and of certain DRM during VF of ART has a small but significant favourable effect on CD4 decline.

U2 - 10.3851/IMP3178

DO - 10.3851/IMP3178

M3 - Journal article

C2 - 28627486

SN - 1359-6535

VL - 23

SP - 105

EP - 116

JO - Antiviral Therapy

JF - Antiviral Therapy

IS - 2

ER -