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.
authors.affiliation: Medical Research Council Clinical Trials Unit, St Stephen's Centre, Chelsea and Westminster Hospital, 125 Kingsway, London, UK. t.barber@nhs.net
authors.forename: Tristan J
authors.initials: TJ
authors.lastname: Barber
authors.forename: Linda
authors.initials: L
authors.lastname: Harrison
authors.forename: David
authors.initials: D
authors.lastname: Asboe
authors.forename: Ian
authors.initials: I
authors.lastname: Williams
authors.forename: Stuart
authors.initials: S
authors.lastname: Kirk
authors.forename: Richard
authors.initials: R
authors.lastname: Gilson
authors.forename: Loveleen
authors.initials: L
authors.lastname: Bansi
authors.forename: Deenan
authors.initials: D
authors.lastname: Pillay
authors.forename: David
authors.initials: D
authors.lastname: Dunn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000494:pharmacology; D015331:Cohort Studies; D024882:Drug Resistance, Viral; D005260:Female; D006678:HIV / Q000187:drug effects* / Q000302:isolation & purification; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D061466:Lopinavir / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D012367:RNA, Viral / Q000235:genetics; D019438:Ritonavir / Q000008:administration & dosage* / Q000494:pharmacology; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D006113:United Kingdom; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D061466:Lopinavir; D019438:Ritonavir