title: Selection of resistance in protease inhibitor-experienced, human immunodeficiency virus type 1-infected subjects failing lopinavir- and ritonavir-based therapy: mutation patterns and baseline correlates.
abstract: The selection of in vivo resistance to lopinavir was characterized by analyzing the longitudinal isolates from 54 protease inhibitor-experienced subjects who either experienced incomplete virologic response or viral rebound subsequent to initial response while on treatment with lopinavir-ritonavir in Phase II and III studies. The evolution of incremental resistance to lopinavir (emergence of new mutation[s] and/or at least a twofold increase in phenotypic resistance compared to baseline isolates) was highly dependent on the baseline phenotype and genotype. Among the subjects demonstrating evolution of lopinavir resistance, mutations at positions 82, 54, and 46 in human immunodeficiency virus protease emerged frequently, suggesting that these mutations are important for conferring high-level resistance. Less common mutations, such as L33F, I50V, and V32I together with I47V/A, were also selected; however, new mutations at positions 84, 90, and 71 were not observed. The emergence of incremental resistance contrasts greatly with the low incidence of resistance observed after initiating lopinavir-ritonavir therapy in antiretroviral-naive patients, suggesting that partial resistance accumulated during prior protease inhibitor therapy can compromise the genetic barrier to resistance to lopinavir-ritonavir. The emergence of incremental resistance was uncommon in subjects whose baseline isolates contained eight or more mutations associated with lopinavir resistance and/or displayed >60-fold-reduced susceptibility to lopinavir, providing insight into suitable upper genotypic and phenotypic breakpoints for lopinavir-ritonavir.
authors.affiliation: Department R47D, Building AP52N, Abbott Laboratories, 200 Abbott Park Rd., Abbott Park, IL 60064-6217, USA. Hongmei.Mo@abbott.com
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
authors.forename: Martin S
authors.initials: MS
authors.lastname: King
authors.forename: Kathryn
authors.initials: K
authors.lastname: King
authors.forename: Akhteruzzaman
authors.initials: A
authors.lastname: Molla
authors.forename: Scott
authors.initials: S
authors.lastname: Brun
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Kempf
mesh_terms: D019943:Amino Acid Substitution; D024882:Drug Resistance, Viral / Q000235:genetics*; D004359:Drug Therapy, Combination; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D061466:Lopinavir; D008826:Microbial Sensitivity Tests; D009154:Mutation; D011744:Pyrimidinones / Q000494:pharmacology* / Q000627:therapeutic use; D012367:RNA, Viral / Q000235:genetics / Q000302:isolation & purification; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019438:Ritonavir / Q000494:pharmacology* / Q000627:therapeutic use; D017421:Sequence Analysis
chemical_list: D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D061466:Lopinavir; D016333:HIV Protease; D019438:Ritonavir
references.citation: Antimicrob Agents Chemother. 2000 Apr;44(4):920-8
references.pmid: 10722492
references.citation: AIDS. 1999 Oct 1;13(14):1863-71
references.pmid: 10513644
references.citation: AIDS. 2001 Jan 5;15(1):F1-9
references.pmid: 11192874
references.citation: J Virol. 2001 Aug;75(16):7462-9
references.pmid: 11462018
references.citation: Antimicrob Agents Chemother. 2002 Mar;46(3):731-8
references.pmid: 11850255
references.citation: J Infect Dis. 2002 Mar 1;185(5):599-607
references.pmid: 11865416
references.citation: AIDS. 2002 May 3;16(7):1009-17
references.pmid: 11953467
references.citation: Bioorg Med Chem. 2002 Aug;10(8):2803-6
references.pmid: 12057670
references.citation: N Engl J Med. 2002 Jun 27;346(26):2039-46
references.pmid: 12087139
references.citation: Antimicrob Agents Chemother. 2002 Sep;46(9):2926-32
references.pmid: 12183249
references.citation: Antivir Ther. 2002 Sep;7(3):165-74
references.pmid: 12487383
references.citation: Antimicrob Agents Chemother. 2003 Jan;47(1):350-9
references.pmid: 12499212
references.citation: Pediatr Infect Dis J. 2003 Mar;22(3):216-24
references.pmid: 12634581
references.citation: J Virol. 2003 Apr;77(8):4836-47
references.pmid: 12663790
references.citation: AIDS. 2003 May 2;17(7):955-61
references.pmid: 12700444
references.citation: Antivir Ther. 2003 Apr;8(2):111-20
references.pmid: 12741623
references.citation: Antiviral Res. 2003 Aug;59(3):173-80
references.pmid: 12927307
references.citation: J Infect Dis. 2003 Sep 1;188(5):653-60
references.pmid: 12934180
references.citation: J Infect Dis. 2004 Jan 1;189(1):51-60
references.pmid: 14702153
references.citation: AIDS. 2004 Mar 26;18(5):775-9
references.pmid: 15075512
references.citation: AIDS. 2004 Apr 30;18(7):1084-5
references.pmid: 15096819
references.citation: AIDS Res Hum Retroviruses. 2004 Mar;20(3):275-8
references.pmid: 15117450
references.citation: Antimicrob Agents Chemother. 2004 Aug;48(8):2911-7
references.pmid: 15273100
references.citation: AIDS. 2004 Sep 24;18(14):1965-6
references.pmid: 15353986
references.citation: Antivir Ther. 2004 Aug;9(4):465-78
references.pmid: 15456077
references.citation: Nature. 1995 Apr 6;374(6522):569-71
references.pmid: 7700387
references.citation: J Infect Dis. 1996 Jun;173(6):1379-87
references.pmid: 8648209
references.citation: Nat Med. 1996 Jul;2(7):760-6
references.pmid: 8673921
references.citation: J Antimicrob Chemother. 1997 Jun;39(6):771-9
references.pmid: 9222047
references.citation: Antimicrob Agents Chemother. 1998 Feb;42(2):269-76
references.pmid: 9527771
references.citation: J Virol. 1998 Apr;72(4):3459-63
references.pmid: 9525682
references.citation: J Virol. 1998 Sep;72(9):7532-41
references.pmid: 9696850
references.citation: Antiviral Res. 1998 Jul;39(1):1-23
references.pmid: 9754946
references.citation: Antimicrob Agents Chemother. 1998 Oct;42(10):2637-44
references.pmid: 9756769
references.citation: JAMA. 2000 May 10;283(18):2417-26
references.pmid: 10815085