Frequency and patterns of protease gene resistance mutations in HIV-infected patients treated with lopinavir/ritonavir as their first protease inhibitor

Tristan J. Barber; Linda Harrison; David Asboe; Ian Williams; Stuart Kirk; Richard Gilson; Loveleen Bansi; Deenan Pillay; David Dunn; Jane Anderson; Anton Pozniak; Sheila Cameron; Patricia Cane; David Chadwick; Duncan Churchill; Duncan Clark; Simon Collins; Valerie Delpech; Linda Lazarus; Jonathan Crofts; David Dolling; Esther Fearnhill; Hannah Castro; Kholoud Porter; Mark Zuckerman; Maria Geretti Anna Maria Geretti; David Goldberg; Mark Gompels; Antony Hale; Steve Kaye; Paul Kellam; Andrew Leigh-Brown; Nicola Mackie; Chloe Orkin; Andrew Phillips; Caroline Sabin; Erasmus Smit; Kate Templeton; Peter Tilston; William Tong; Hongyi Zhang; Ines Ushiro-Lumb; Tony Oliver; David Bibby; Suzanne Mitchell; Tamyo Mbisa; Adrian Wildfire; Jill Shepherd; Alasdair MacLean; Rory Gunson; Celia Aitken; Diane Bennett; Mark Hopkins; Brendan Payne; Clare Booth; Ana Garcia-Diaz; Jonathan Ainsworth; Abdel Babiker; Martin Fisher; Brian Gazzard; Teresa Hill; Margaret Johnson; Clifford Leen; Mark Nelson; Adrian Palfreeman; Frank Post; Memory Sachikonye; Achim Schwenk; John Walsh; Susie Huntington; Adam Glabay; N. Garrett; J. Lynch; J. Hand; C. de Souza; N. Perry; S. Tilbury; M. Waxman; S. Mandalia; S. Munshi; H. Korat; C. Taylor; Z. Gleisner; F. Ibrahim; L. Campbell; N. Brima; C. Wood; S. Miller; M. Youle; F. Lampe; C. Smith; H. Grabowska; C. Chaloner; D. Puradiredja; J. Weber; F. Ramzan; A. Winston; Mark Carder; A. Wilson; S. Allan; A. Moore; K. Wakeman

doi:10.1093/jac/dkr569

Frequency and patterns of protease gene resistance mutations in HIV-infected patients treated with lopinavir/ritonavir as their first protease inhibitor

Tristan J. Barber^*, Linda Harrison, David Asboe, Ian Williams, Stuart Kirk, Richard Gilson, Loveleen Bansi, Deenan Pillay, David Dunn, Jane Anderson, Anton Pozniak, Sheila Cameron, Patricia Cane, David Chadwick, Duncan Churchill, Duncan Clark, Simon Collins, Valerie Delpech, Linda Lazarus, Jonathan CroftsDavid Dolling, Esther Fearnhill, Hannah Castro, Kholoud Porter, Mark Zuckerman, Maria Geretti Anna Maria Geretti, David Goldberg, Mark Gompels, Antony Hale, Steve Kaye, Paul Kellam, Andrew Leigh-Brown, Nicola Mackie, Chloe Orkin, Andrew Phillips, Caroline Sabin, Erasmus Smit, Kate Templeton, Peter Tilston, William Tong, Hongyi Zhang, Ines Ushiro-Lumb, Tony Oliver, David Bibby, Suzanne Mitchell, Tamyo Mbisa, Adrian Wildfire, Jill Shepherd, Alasdair MacLean, Rory Gunson, Celia Aitken, Diane Bennett, Mark Hopkins, Brendan Payne, Clare Booth, Ana Garcia-Diaz, Jonathan Ainsworth, Abdel Babiker, Martin Fisher, Brian Gazzard, Teresa Hill, Margaret Johnson, Clifford Leen, Mark Nelson, Adrian Palfreeman, Frank Post, Memory Sachikonye, Achim Schwenk, John Walsh, Susie Huntington, Adam Glabay, N. Garrett, J. Lynch, J. Hand, C. de Souza, N. Perry, S. Tilbury, M. Waxman, S. Mandalia, S. Munshi, H. Korat, C. Taylor, Z. Gleisner, F. Ibrahim, L. Campbell, N. Brima, C. Wood, S. Miller, M. Youle, F. Lampe, C. Smith, H. Grabowska, C. Chaloner, D. Puradiredja, J. Weber, F. Ramzan, A. Winston, Mark Carder, A. Wilson, S. Allan, A. Moore, K. Wakeman

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

23 Citations (Scopus)

Abstract

Background: Selection of protease mutations on antiretroviral therapy (ART) including a ritonavir-boosted protease inhibitor (PI) has been reported infrequently. Scarce data exist from long-term cohorts on resistance incidence or mutational patterns emerging to different PIs. Methods: We studied UK patients receiving lopinavir/ritonavir as their first PI, either while naive to ART or having previously received non-PI-based ART. Virological failure was defined as viral load ≥400 copies/mL after previous suppression <400 copies/mL, or failure to achieve <400 copies/mL during the first 6 months. pol sequences whilst failing lopinavir or within 30 days after stopping were analysed. Major and minor mutations (IAS-USA 2008-after exclusion of polymorphisms) were considered. Predicted susceptibility was determined using the Stanford HIVdb algorithm. Results: Three thousand and fifty-six patients were followed for a median (IQR) of 14 (6-30) months, of whom 811 (27%) experienced virological failure. Of these, resistance test results were available on 291 (36%). One or more protease mutations were detected in 32 (11%) patients; the most frequent were I54V (n = 12), M46I (n = 11), V82A (n = 7) and L76V (n = 3). No association with viral subtype was evident. Many patients retained virus predicted to be susceptible to lopinavir (14, 44%), tipranavir (26, 81%) and darunavir (27, 84%). Conclusions: This study reflects the experience of patients in routine care. Selection of protease gene mutations by lopinavir/ritonavir occurred at a much higher rate than in clinical trials. The mutations observed showed only partial overlap with those previously identified by structural chemistry models, serial cell culture passage and genotype-phenotype analyses. There remained a low degree of predicted cross-resistance to other widely used PIs.

Original language	English
Article number	dkr569
Pages (from-to)	995-1000
Number of pages	6
Journal	Journal of Antimicrobial Chemotherapy
Volume	67
Issue number	4
DOIs	https://doi.org/10.1093/jac/dkr569
Publication status	Published - Apr 2012

Bibliographical note

Funding Information:
This work was supported by the UK Medical Research Council (MRC). The UK HIV Drug Resistance Database and UK CHIC are funded by the UK Medical Research Council (grant G0900274). Additional support was provided by the European Community’s 7th Framework (FP7/2007–2013) under the project Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN; 223131). The UK HIV Drug Resistance Database was originally established through funding from the Department of Health. Additional support has been provided by Janssen-Cilag Ltd, Bristol-Myers Squibb, Gilead, Pfizer and Roche. UK CHIC is funded by the Medical Research Council (MRC), UK (grants G00001999 and G0600337).

Keywords

Antiretroviral
Genotype
Genotypic

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/jac/dkr569

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Barber, T. J., Harrison, L., Asboe, D., Williams, I., Kirk, S., Gilson, R., Bansi, L., Pillay, D., Dunn, D., Anderson, J., Pozniak, A., Cameron, S., Cane, P., Chadwick, D., Churchill, D., Clark, D., Collins, S., Delpech, V., Lazarus, L., ... Wakeman, K. (2012). Frequency and patterns of protease gene resistance mutations in HIV-infected patients treated with lopinavir/ritonavir as their first protease inhibitor. Journal of Antimicrobial Chemotherapy, 67(4), 995-1000. [dkr569]. https://doi.org/10.1093/jac/dkr569

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title = "Frequency and patterns of protease gene resistance mutations in HIV-infected patients treated with lopinavir/ritonavir as their first protease inhibitor",

abstract = "Background: Selection of protease mutations on antiretroviral therapy (ART) including a ritonavir-boosted protease inhibitor (PI) has been reported infrequently. Scarce data exist from long-term cohorts on resistance incidence or mutational patterns emerging to different PIs. Methods: We studied UK patients receiving lopinavir/ritonavir as their first PI, either while naive to ART or having previously received non-PI-based ART. Virological failure was defined as viral load ≥400 copies/mL after previous suppression <400 copies/mL, or failure to achieve <400 copies/mL during the first 6 months. pol sequences whilst failing lopinavir or within 30 days after stopping were analysed. Major and minor mutations (IAS-USA 2008-after exclusion of polymorphisms) were considered. Predicted susceptibility was determined using the Stanford HIVdb algorithm. Results: Three thousand and fifty-six patients were followed for a median (IQR) of 14 (6-30) months, of whom 811 (27%) experienced virological failure. Of these, resistance test results were available on 291 (36%). One or more protease mutations were detected in 32 (11%) patients; the most frequent were I54V (n = 12), M46I (n = 11), V82A (n = 7) and L76V (n = 3). No association with viral subtype was evident. Many patients retained virus predicted to be susceptible to lopinavir (14, 44%), tipranavir (26, 81%) and darunavir (27, 84%). Conclusions: This study reflects the experience of patients in routine care. Selection of protease gene mutations by lopinavir/ritonavir occurred at a much higher rate than in clinical trials. The mutations observed showed only partial overlap with those previously identified by structural chemistry models, serial cell culture passage and genotype-phenotype analyses. There remained a low degree of predicted cross-resistance to other widely used PIs.",

keywords = "Antiretroviral, Genotype, Genotypic",

author = "Barber, {Tristan J.} and Linda Harrison and David Asboe and Ian Williams and Stuart Kirk and Richard Gilson and Loveleen Bansi and Deenan Pillay and David Dunn and Jane Anderson and Anton Pozniak and Sheila Cameron and Patricia Cane and David Chadwick and Duncan Churchill and Duncan Clark and Simon Collins and Valerie Delpech and Linda Lazarus and Jonathan Crofts and David Dolling and Esther Fearnhill and Hannah Castro and Kholoud Porter and Mark Zuckerman and {Anna Maria Geretti}, {Maria Geretti} and David Goldberg and Mark Gompels and Antony Hale and Steve Kaye and Paul Kellam and Andrew Leigh-Brown and Nicola Mackie and Chloe Orkin and Andrew Phillips and Caroline Sabin and Erasmus Smit and Kate Templeton and Peter Tilston and William Tong and Hongyi Zhang and Ines Ushiro-Lumb and Tony Oliver and David Bibby and Suzanne Mitchell and Tamyo Mbisa and Adrian Wildfire and Jill Shepherd and Alasdair MacLean and Rory Gunson and Celia Aitken and Diane Bennett and Mark Hopkins and Brendan Payne and Clare Booth and Ana Garcia-Diaz and Jonathan Ainsworth and Abdel Babiker and Martin Fisher and Brian Gazzard and Teresa Hill and Margaret Johnson and Clifford Leen and Mark Nelson and Adrian Palfreeman and Frank Post and Memory Sachikonye and Achim Schwenk and John Walsh and Susie Huntington and Adam Glabay and N. Garrett and J. Lynch and J. Hand and {de Souza}, C. and N. Perry and S. Tilbury and M. Waxman and S. Mandalia and S. Munshi and H. Korat and C. Taylor and Z. Gleisner and F. Ibrahim and L. Campbell and N. Brima and C. Wood and S. Miller and M. Youle and F. Lampe and C. Smith and H. Grabowska and C. Chaloner and D. Puradiredja and J. Weber and F. Ramzan and A. Winston and Mark Carder and A. Wilson and S. Allan and A. Moore and K. Wakeman",

note = "Funding Information: This work was supported by the UK Medical Research Council (MRC). The UK HIV Drug Resistance Database and UK CHIC are funded by the UK Medical Research Council (grant G0900274). Additional support was provided by the European Community{\textquoteright}s 7th Framework (FP7/2007–2013) under the project Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN; 223131). The UK HIV Drug Resistance Database was originally established through funding from the Department of Health. Additional support has been provided by Janssen-Cilag Ltd, Bristol-Myers Squibb, Gilead, Pfizer and Roche. UK CHIC is funded by the Medical Research Council (MRC), UK (grants G00001999 and G0600337).",

year = "2012",

month = apr,

doi = "10.1093/jac/dkr569",

language = "English",

volume = "67",

pages = "995--1000",

journal = "Journal of Antimicrobial Chemotherapy",

issn = "0305-7453",

publisher = "Oxford University Press",

number = "4",

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Barber, TJ, Harrison, L, Asboe, D, Williams, I, Kirk, S, Gilson, R, Bansi, L, Pillay, D, Dunn, D, Anderson, J, Pozniak, A, Cameron, S, Cane, P, Chadwick, D, Churchill, D, Clark, D, Collins, S, Delpech, V, Lazarus, L, Crofts, J, Dolling, D, Fearnhill, E, Castro, H, Porter, K, Zuckerman, M, Anna Maria Geretti, MG, Goldberg, D, Gompels, M, Hale, A, Kaye, S, Kellam, P, Leigh-Brown, A, Mackie, N, Orkin, C, Phillips, A, Sabin, C, Smit, E, Templeton, K, Tilston, P, Tong, W, Zhang, H, Ushiro-Lumb, I, Oliver, T, Bibby, D, Mitchell, S, Mbisa, T, Wildfire, A, Shepherd, J, MacLean, A, Gunson, R, Aitken, C, Bennett, D, Hopkins, M, Payne, B, Booth, C, Garcia-Diaz, A, Ainsworth, J, Babiker, A, Fisher, M, Gazzard, B, Hill, T, Johnson, M, Leen, C, Nelson, M, Palfreeman, A, Post, F, Sachikonye, M, Schwenk, A, Walsh, J, Huntington, S, Glabay, A, Garrett, N, Lynch, J, Hand, J, de Souza, C, Perry, N, Tilbury, S, Waxman, M, Mandalia, S, Munshi, S, Korat, H, Taylor, C, Gleisner, Z, Ibrahim, F, Campbell, L, Brima, N, Wood, C, Miller, S, Youle, M, Lampe, F, Smith, C, Grabowska, H, Chaloner, C, Puradiredja, D, Weber, J, Ramzan, F, Winston, A, Carder, M, Wilson, A, Allan, S, Moore, A & Wakeman, K 2012, 'Frequency and patterns of protease gene resistance mutations in HIV-infected patients treated with lopinavir/ritonavir as their first protease inhibitor', Journal of Antimicrobial Chemotherapy, vol. 67, no. 4, dkr569, pp. 995-1000. https://doi.org/10.1093/jac/dkr569

TY - JOUR

T1 - Frequency and patterns of protease gene resistance mutations in HIV-infected patients treated with lopinavir/ritonavir as their first protease inhibitor

AU - Barber, Tristan J.

AU - Harrison, Linda

AU - Asboe, David

AU - Williams, Ian

AU - Kirk, Stuart

AU - Gilson, Richard

AU - Bansi, Loveleen

AU - Pillay, Deenan

AU - Dunn, David

AU - Anderson, Jane

AU - Pozniak, Anton

AU - Cameron, Sheila

AU - Cane, Patricia

AU - Chadwick, David

AU - Churchill, Duncan

AU - Clark, Duncan

AU - Collins, Simon

AU - Delpech, Valerie

AU - Lazarus, Linda

AU - Crofts, Jonathan

AU - Dolling, David

AU - Fearnhill, Esther

AU - Castro, Hannah

AU - Porter, Kholoud

AU - Zuckerman, Mark

AU - Anna Maria Geretti, Maria Geretti

AU - Goldberg, David

AU - Gompels, Mark

AU - Hale, Antony

AU - Kaye, Steve

AU - Kellam, Paul

AU - Leigh-Brown, Andrew

AU - Mackie, Nicola

AU - Orkin, Chloe

AU - Phillips, Andrew

AU - Sabin, Caroline

AU - Smit, Erasmus

AU - Templeton, Kate

AU - Tilston, Peter

AU - Tong, William

AU - Zhang, Hongyi

AU - Ushiro-Lumb, Ines

AU - Oliver, Tony

AU - Bibby, David

AU - Mitchell, Suzanne

AU - Mbisa, Tamyo

AU - Wildfire, Adrian

AU - Shepherd, Jill

AU - MacLean, Alasdair

AU - Gunson, Rory

AU - Aitken, Celia

AU - Bennett, Diane

AU - Hopkins, Mark

AU - Payne, Brendan

AU - Booth, Clare

AU - Garcia-Diaz, Ana

AU - Ainsworth, Jonathan

AU - Babiker, Abdel

AU - Fisher, Martin

AU - Gazzard, Brian

AU - Hill, Teresa

AU - Johnson, Margaret

AU - Leen, Clifford

AU - Nelson, Mark

AU - Palfreeman, Adrian

AU - Post, Frank

AU - Sachikonye, Memory

AU - Schwenk, Achim

AU - Walsh, John

AU - Huntington, Susie

AU - Glabay, Adam

AU - Garrett, N.

AU - Lynch, J.

AU - Hand, J.

AU - de Souza, C.

AU - Perry, N.

AU - Tilbury, S.

AU - Waxman, M.

AU - Mandalia, S.

AU - Munshi, S.

AU - Korat, H.

AU - Taylor, C.

AU - Gleisner, Z.

AU - Ibrahim, F.

AU - Campbell, L.

AU - Brima, N.

AU - Wood, C.

AU - Miller, S.

AU - Youle, M.

AU - Lampe, F.

AU - Smith, C.

AU - Grabowska, H.

AU - Chaloner, C.

AU - Puradiredja, D.

AU - Weber, J.

AU - Ramzan, F.

AU - Winston, A.

AU - Carder, Mark

AU - Wilson, A.

AU - Allan, S.

AU - Moore, A.

AU - Wakeman, K.

N1 - Funding Information: This work was supported by the UK Medical Research Council (MRC). The UK HIV Drug Resistance Database and UK CHIC are funded by the UK Medical Research Council (grant G0900274). Additional support was provided by the European Community’s 7th Framework (FP7/2007–2013) under the project Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN; 223131). The UK HIV Drug Resistance Database was originally established through funding from the Department of Health. Additional support has been provided by Janssen-Cilag Ltd, Bristol-Myers Squibb, Gilead, Pfizer and Roche. UK CHIC is funded by the Medical Research Council (MRC), UK (grants G00001999 and G0600337).

PY - 2012/4

Y1 - 2012/4

N2 - Background: Selection of protease mutations on antiretroviral therapy (ART) including a ritonavir-boosted protease inhibitor (PI) has been reported infrequently. Scarce data exist from long-term cohorts on resistance incidence or mutational patterns emerging to different PIs. Methods: We studied UK patients receiving lopinavir/ritonavir as their first PI, either while naive to ART or having previously received non-PI-based ART. Virological failure was defined as viral load ≥400 copies/mL after previous suppression <400 copies/mL, or failure to achieve <400 copies/mL during the first 6 months. pol sequences whilst failing lopinavir or within 30 days after stopping were analysed. Major and minor mutations (IAS-USA 2008-after exclusion of polymorphisms) were considered. Predicted susceptibility was determined using the Stanford HIVdb algorithm. Results: Three thousand and fifty-six patients were followed for a median (IQR) of 14 (6-30) months, of whom 811 (27%) experienced virological failure. Of these, resistance test results were available on 291 (36%). One or more protease mutations were detected in 32 (11%) patients; the most frequent were I54V (n = 12), M46I (n = 11), V82A (n = 7) and L76V (n = 3). No association with viral subtype was evident. Many patients retained virus predicted to be susceptible to lopinavir (14, 44%), tipranavir (26, 81%) and darunavir (27, 84%). Conclusions: This study reflects the experience of patients in routine care. Selection of protease gene mutations by lopinavir/ritonavir occurred at a much higher rate than in clinical trials. The mutations observed showed only partial overlap with those previously identified by structural chemistry models, serial cell culture passage and genotype-phenotype analyses. There remained a low degree of predicted cross-resistance to other widely used PIs.

AB - Background: Selection of protease mutations on antiretroviral therapy (ART) including a ritonavir-boosted protease inhibitor (PI) has been reported infrequently. Scarce data exist from long-term cohorts on resistance incidence or mutational patterns emerging to different PIs. Methods: We studied UK patients receiving lopinavir/ritonavir as their first PI, either while naive to ART or having previously received non-PI-based ART. Virological failure was defined as viral load ≥400 copies/mL after previous suppression <400 copies/mL, or failure to achieve <400 copies/mL during the first 6 months. pol sequences whilst failing lopinavir or within 30 days after stopping were analysed. Major and minor mutations (IAS-USA 2008-after exclusion of polymorphisms) were considered. Predicted susceptibility was determined using the Stanford HIVdb algorithm. Results: Three thousand and fifty-six patients were followed for a median (IQR) of 14 (6-30) months, of whom 811 (27%) experienced virological failure. Of these, resistance test results were available on 291 (36%). One or more protease mutations were detected in 32 (11%) patients; the most frequent were I54V (n = 12), M46I (n = 11), V82A (n = 7) and L76V (n = 3). No association with viral subtype was evident. Many patients retained virus predicted to be susceptible to lopinavir (14, 44%), tipranavir (26, 81%) and darunavir (27, 84%). Conclusions: This study reflects the experience of patients in routine care. Selection of protease gene mutations by lopinavir/ritonavir occurred at a much higher rate than in clinical trials. The mutations observed showed only partial overlap with those previously identified by structural chemistry models, serial cell culture passage and genotype-phenotype analyses. There remained a low degree of predicted cross-resistance to other widely used PIs.

KW - Antiretroviral

KW - Genotype

KW - Genotypic

UR - http://www.scopus.com/inward/record.url?scp=84863338393&partnerID=8YFLogxK

U2 - 10.1093/jac/dkr569

DO - 10.1093/jac/dkr569

M3 - Article

C2 - 22258921

AN - SCOPUS:84863338393

SN - 0305-7453

VL - 67

SP - 995

EP - 1000

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

IS - 4

M1 - dkr569

ER -

Frequency and patterns of protease gene resistance mutations in HIV-infected patients treated with lopinavir/ritonavir as their first protease inhibitor

Abstract

Bibliographical note

Keywords

UN SDGs

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