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 journalArticlepeer-review

23 Citations (Scopus)


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 languageEnglish
Article numberdkr569
Pages (from-to)995-1000
Number of pages6
JournalJournal of Antimicrobial Chemotherapy
Issue number4
Publication statusPublished - 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).


  • Antiretroviral
  • Genotype
  • Genotypic


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