Patterns of resistance development with integrase inhibitors in HIV

Infection and Drug Resistance

Volumn 4, Issue 1, 2011, Pages 65-76

  Mbisa, Jean L ^a   Martin, Supang A ^a   Cane, Patricia A ^a  

^a PUBLIC HEALTH ENGLAND   (United Kingdom)

Author keywords

Drug resistance; Elvitegravir; HIV; Integrase inhibitors; Raltegravir

Indexed keywords

ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; ANTIRETROVIRUS AGENT; ARGININE; ASPARAGINE; COBICISTAT; CYSTEINE; EFAVIRENZ PLUS EMTRICITABINE PLUS TENOFOVIR DISOPROXIL; ELVITEGRAVIR; EMTRICITABINE; GLUTAMINE; GLYCINE; GS 9350; HISTIDINE; INTEGRASE; INTEGRASE INHIBITOR; LYSINE; NUCLEOSIDE ANALOG; PLACEBO; PROTEINASE INHIBITOR; RALTEGRAVIR; S GSK 1265744; S GSK 1349572; SERINE; TENOFOVIR; TYROSINE; UNCLASSIFIED DRUG; ZIDOVUDINE;

AMINO ACID SUBSTITUTION; ANTIVIRAL ACTIVITY; ANTIVIRAL RESISTANCE; CLINICAL PRACTICE; DRUG EFFICACY; DRUG INHIBITION; DRUG METABOLISM; DRUG PROTEIN BINDING; DRUG STRUCTURE; DRUG SUBSTITUTION; DRUG TOLERABILITY; DRUG TREATMENT FAILURE; DRUG USE; DRUG WITHDRAWAL; ENZYME ACTIVITY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; MUTATIONAL ANALYSIS; NONHUMAN; REVIEW; UNSPECIFIED SIDE EFFECT; VIRUS DNA CELL DNA INTERACTION; VIRUS ENTRY; VIRUS LOAD; VIRUS REPLICATION;

EID: 79952669273     PISSN: 11786973     EISSN: None     Source Type: Journal    
DOI: 10.2147/IDR.S7775     Document Type: Review

References (81)

1. Broder S. The development of antiretroviral therapy and its impact onthe HIV-1/AIDS pandemic. Antiviral Res. 2010;85(1):1-18.
2. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidityand mortality among patients with advanced human immunodeficiencyvirus infection. HIV Outpatient Study Investigators. N Engl J Med.1998;338(13):853-860.
3. Walensky RP, Paltiel AD, Losina E, et al. The survival benefits of AIDStreatment in the United States. J Infect Dis. 2006;194(1):11-19.
4. Cihlar T, Ray AS. Nucleoside and nucleotide HIV reverse transcriptaseinhibitors: 25 years after zidovudine. Antiviral Res.2010;85(1):39-58.
5. De Bethune MP. Non-nucleoside reverse transcriptase inhibitors(NNRTIs), their discovery, development, and use in the treatment ofHIV-1 infection: a review of the last 20 years (1989-2009). AntiviralRes. 2010;85(1):75-90.
6. Wensing AM, van Maarseveen NM, Nijhuis M. Fifteen years of HIVprotease inhibitors: raising the barrier to resistance. Antiviral Res.2010;85(1):59-74.
7. Craigie R. HIV integrase, a brief overview from chemistry totherapeutics.J Biol Chem. 2001;276(26):23213-23216.
8. Engelman A. Reverse transcription and integration. In: Kurth A,BannertN, editors. Retroviruses: Molecular Biology, Genomics andPathogenesis.Norfolk (UK): Caister Academic Press; 2010:129-159.
9. Hazuda DJ, Felock P, Witmer M, et al. Inhibitors of strand transferthat prevent integration and inhibit HIV-1 replication in cells. Science.2000;287(5453):646-650.
10. Pommier Y, Johnson AA, Marchand C. Integrase inhibitors to treatHIV/AIDS. Nat Rev Drug Discov. 2005;4(3):236-248.
11. Markowitz M, Nguyen BY, Gotuzzo E, et al; Protocol 004 Part II StudyTeam. Rapid and durable antiretroviral effect of the HIV-1 integraseinhibitor raltegravir as part of combination therapy in treatment-naïvepatients with HIV-1 infection: results of a 48-week controlled study.J Acquir Immune Defic Syndr. 2007;46(2):125-133.
12. Cooper DA, Steigbigel RT, Gatell JM, et al; BENCHMRK StudyTeams. Subgroup and resistance analyses of raltegravir for resistantHIV-1 infection. N Engl J Med. 2008;359(4):355-365.
13. Steigbigel RT, Cooper DA, Kumar PN, et al; BENCHMRK StudyTeams. Raltegravir with optimized background therapy for resistantHIV-1 infection. N Engl J Med. 2008;359(4):339-354.
14. Bukrinsky MI, Sharova N, McDonald TL, Pushkarskaya T, Tarpley WG, Stevenson M. Association of integrase, matrix, and reverse transcriptaseantigens of human immunodeficiency virus type 1 with viral nucleicacids following acute infection. Proc Natl Acad Sci U S A. 1993;90(13):6125-6129.
15. Miller MD, Farnet CM, Bushman FD. Human immunodeficiency virustype 1 preintegration complexes: studies of organization and composition.J Virol. 1997;71(7):5382-5390.
16. Bushman FD. Host proteins in retroviral cDNA integration. Adv VirusRes. 1999;52:301-317.
17. Lin CW, Engelman A. The barrier-to-autointegration factor is a componentof functional human immunodeficiency virus type 1 preintegrationcomplexes. J Virol. 2003;77(8):5030-5036.
18. Raghavendra NK, Shkriabai N, Graham RLJ, Hess S, Kvaratskhelia M, Wu L. Identification of host proteins associated with HIV-1 preintegrationcomplexes isolated from infected CD4+ cells. Retrovirology.2010;7:66.
19. Woodward CL, Prakobwanakit S, Mosessian S, Chow SA. Integrase interactswith nucleoporin NUP153 to mediate the nuclear import of humanimmunodeficiency virus type 1. J Virol. 2009;83(13):6522-6533.
20. Yoder KE, Bushman FD. Repair of gaps in retroviral DNA integrationintermediates. J Virol. 2000;74(23):11191-11200.
21. Schroder AR, Shinn P, Chen H, Berry C, Ecker JR, Bushman F.HIV-1 integration in the human genome favors active genes and localhotspots. Cell. 2002;110(4):521-529.
22. Mitchell RS, Beitzel BF, Schroder AR, et al. Retroviral DNAintegration:ASLV, HIV, and MLV show distinct target site preferences.PLoS Biol. 2004;2(8):E234.
23. Wu X, Burgess SM. Integration target site selection for retrovirusesand transposable elements. Cell Mol Life Sci. 2004;61(19-20):2588-2596.
24. Maxfield LF, Fraize CD, Coffin JM. Relationship between retroviralDNA-integration-site selection and host cell transcription. Proc NatlAcad Sci U S A. 2005;102(5):1436-1441.
25. Dyda F, Hickman AB, Jenkins TM, Engelman A, Craigie R, Davies DR.Crystal structure of the catalytic domain of HIV-1 integrase: similarityto other polynucleotidyl transferases. Science. 1994;266(5193):1981-1986.
26. Chen JC, Krucinski J, Miercke LJ, et al. Crystal structure of theHIV-1 integrase catalytic core and C-terminal domains: a model for viralDNA binding. Proc Natl Acad Sci U S A. 2000;97(15):8233-8238.
27. Wang JY, Ling H, Yang W, Craigie R. Structure of a two-domain fragmentof HIV-1 integrase: implications for domain organization in theintact protein. EMBO J. 2001;20(24):7333-7343.
28. McColl DJ, Chen X. Strand transfer inhibitors of HIV-1 integrase: bringingIN a new era of antiretroviral therapy. Antiviral Res. 2010;85(1):101-118.
29. Engelman A, Hickman AB, Craigie R. The core and carboxyl-terminaldomains of the integrase protein of human immunodeficiency virustype 1 each contribute to nonspecific DNA binding. J Virol. 1994;68(9):5911-5917.
30. Krishnan L, Li X, Naraharisetty HL, Hare S, Cherepanov P, Engelman A. Structure-based modeling of the functional HIV-1intasomeand its inhibition. Proc Natl Acad Sci U S A. 2010;107(36):15910-15915.
31. Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P. Retroviralintasome assembly and inhibition of DNA strand transfer. Nature.2010;464(7286):232-236.
32. Marchand C, Maddali K, Metifiot M, Pommier Y. HIV-1 IN inhibitors:2010 update and perspectives. Curr Top Med Chem. 2009;9(11):1016-1037.
33. Kobayashi M, Nakahara K, Seki T, et al. Selection of diverse andclinicallyrelevant integrase inhibitor-resistant human immunodeficiencyvirus type 1 mutants. Antiviral Res. 2008;80(2):213-222.
34. Pace P, Rowley M. Integrase inhibitors for the treatment of HIV infection.Curr Opin Drug Discov Devel. 2008;11(4):471-479.
35. Shimura K, Kodama E, Sakagami Y, et al. Broad antiretroviral activityand resistance profile of the novel human immunodeficiency virusintegrase inhibitor elvitegravir (JTK-303/GS-9137). J Virol. 2008;82(2):764-774.
36. Goodman D, Hluhanich R, Waters J, et al. Integrase inhibitor resistanceinvolves complex interactions among primary and secondary resistancemutations: a novel mutation L68V/I associates with E92Q and increasesresistance [abstract]. Antivir Ther. 2008;13 Suppl 3:A15.
37. Fun A, van Baelen K, van Lelyveld SF, et al. Mutation Q95Kenhances N155H-mediated integrase inhibitor resistance and improvesviral replication capacity. J Antimicrob Chemother. 2010;65(11):2300-2304.
38. Ferns RB, Kirk S, Bennett J, Williams I, Edwards S, Pillay D. Thedynamics of appearance and disappearance of HIV-1 integrase mutationsduring and after withdrawal of raltegravir therapy. AIDS. 2009;23(16):2159-2164.
39. Ceccherini-Silberstein F, Armenia D, D'Arrigo R, et al. Virologicalresponse and resistance in multi-experienced patients treated withraltegravir [abstract]. Antivir Ther. 2008;13 Suppl 3:A20.
40. Canducci F, Marinozzi MC, Sampaolo M, et al. Genotypic/phenotypicpatterns of HIV-1 integrase resistance to raltegravir. J AntimicrobChemother. 2010;65(3):425-433.
41. Myers RE, Pillay D. Analysis of natural sequence variation and covariationin human immunodeficiency virus type 1 integrase. J Virol. 2008;82(18):9228-9235.
42. Fransen S, Gupta S, Danovich R, et al. Loss of raltegravir susceptibilityby human immunodeficiency virus type 1 is conferred via multiple nonoverlappinggenetic pathways. J Virol. 2009;83(22):11440-11446.
43. Rhee SY, Liu TF, Kiuchi M, et al. Natural variation of HIV-1 group Mintegrase: implications for a new class of antiretroviral inhibitors.Retrovirology. 2008;5:74.
44. Delelis O, Malet I, Na L, et al. The G140S mutation in HIV integrasesfrom raltegravir-resistant patients rescues catalytic defect dueto the resistance Q148H mutation. Nucleic Acids Res. 2009;37(4):1193-1201.
45. Malet I, Delelis O, Soulie C, et al. Quasispecies variant dynamics duringemergence of resistance to raltegravir in HIV-1-infected patients.J Antimicrob Chemother. 2009;63(4):795-804.
46. Nakahara K, Wakasa-Morimoto C, Kobayashi M, et al. Secondarymutations in viruses resistant to HIV-1 integrase inhibitors thatrestore viral infectivity and replication kinetics. Antiviral Res. 2009;81(2):141-146.
47. Metifiot M, Maddali K, Naumova A, Zhang X, Marchand C, Pommier Y. Biochemical and pharmacological analyses of HIV-1integrase flexible loop mutants resistant to raltegravir. Biochemistry.2010;49(17):3715-3722.
48. Reigadas S, Anies G, Masquelier B, et al. The HIV-1 integrase mutationsY143C/R are an alternative pathway for resistance to raltegravirand impact the enzyme functions. PLoS One. 2010;5(4):e10311.
49. Malet I, Delelis O, Valantin MA, et al. Mutations associated with failureof raltegravir treatment affect integrase sensitivity to the inhibitorin vitro. Antimicrob Agents Chemother. 2008;52(4):1351-1358.
50. Grobler JA, Stillmock KA, Miller MD, Hazuda DJ. Mechanism bywhich the HIV integrase active-site mutation N155H confers resistanceto raltegravir [abstract]. Antivir Ther. 2008;13 Suppl 3:A41.
51. Delelis O, Thierry S, Subra F, et al. Impact of Y143 HIV-1 integrasemutations on resistance to raltegravir in vitro and in vivo. AntimicrobAgents Chemother. 2010;54(1):491-501.
52. Charpentier C, Karmochkine M, Laureillard D, et al. Drug resistanceprofiles for the HIV integrase gene in patients failing raltegravir salvagetherapy. HIV Med. 2008;9(9):765-770.
53. Sichtig N, Sierra S, Kaiser R, et al. Evolution of raltegravir resistanceduring therapy. J Antimicrob Chemother. 2009;64(1):25-32.
54. Prada N, Markowitz M. Novel integrase inhibitors for HIV. ExpertOpin Investig Drugs. 2010;19(9):1087-1098.
55. Underwood M, Johns B, Sato A, Fujiwara T, Spreen W. S/GSK1349572:a next generation integrase inhibitor with activity against integraseinhibitor-resistant clinical isolates from patients experiencing virologicfailure while on raltegravir therapy [abstract]. 5th IAS Conference onHIV Pathogenesis, Treatment and Prevention; 2009 Jul 19-22; CapeTown, South Africa.
56. Sato A, Kobayashi M, Yoshinaga T, et al. S/GSK1349572 is a potentnext generation HIV integrase inhibitor [abstract]. 5th IAS Conferenceon HIV Pathogenesis, Treatment and Prevention; 2009 Jul 19-22; CapeTown, South Africa.
57. Seki T, Kobayashi M, Wakasa-Morimoto C, et al. S/GSK1349572 is apotent next generation HIV integrase inhibitor and demonstrates a superiorresistance profile substantiated with 60 integrase mutant molecularclones [abstract]. 17th Conference on Retroviruses and OpportunisticInfections; 2010 Feb 16-19; San Francisco, CA.
58. World Health Organization (WHO). Antiretroviral therapy for HIVinfection in adults and adolescents: recommendations for a publichealth approach. 2010. Available from: http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf. Accessed January 13, 2011.
59. Steigbigel RT, Cooper DA, Teppler H, et al; BENCHMRK StudyTeams. Long-term efficacy and safety of raltegravir combined withoptimized background therapy in treatment-experienced patients withdrug-resistant HIV infection: week 96 results of the BENCHMRK 1and 2 Phase III trials. Clin Infect Dis. 2010;50(4):605-612.
60. Lennox JL, DeJesus E, Lazzarin A, et al; STARTMRK Investigators.Safety and efficacy of raltegravir-based versus efavirenz-based combinationtherapy in treatment-naïve patients with HIV-1 infection:a multicentre, double-blind randomised controlled trial. Lancet. 2009;374(9692):796-806.
61. Reynes J, Lawal A, Pulido F, et al. Lopinavir/ritonavir combined withraltegravir demonstrated similar antiviral efficacy and safety as lopinavir/ritonavir combined with tenofovir disoproxil fumarate/emtricitabineintreatment-naïve HIV-1 infected subjects [abstract]. XVIII InternationalAIDS Conference; 2010 Jul 18-23; Vienna, Austria.
62. Kozal M, Lupo S, DeJesus E, et al.; SPARTAN Study Team. TheSPARTAN study: a pilot study to assess the safety and efficacy of aninvestigational NRTI- and RTV-sparing regimen of atazanavir (ATV)experimental dose of 300 mg BID plus raltegravir (RAL) 400 mg BID(ATV+RAL) in treatment-naïve HIV-infected subjects [abstract]. XVIIIInternational AIDS Conference; 2010 Jul 18-23; Vienna, Austria.
63. Powderly WG. Integrase inhibitors in the treatment of HIV-1 infection.J Antimicrob Chemother. 2010;65(12):2485-2488.
64. Cohen C, Shamblaw D, Ruane P, et al. Singlet-tablet, fixed-doseregimen of elvitegravir/emtricitabine/tenofovir disoproxil fumarate/GS-9350 achieves a high rate of virologic suppression and GS-9350 isan effective booster [abstract]. 17th Conference on Retroviruses andOpportunistic Infections; 2010 Feb 16-19; San Francisco, CA.
65. Eron JJ, Young B, Cooper DA, et al; SWITCHMRK 1 and 2 Investigators.Switch to a raltegravir-based regimen versus continuation ofa lopinavir-ritonavir-based regimen in stable HIV-infected patientswith suppressed viraemia (SWITCHMRK 1 and 2): two multicentre,double-blind, randomised controlled trials. Lancet. 2010;375(9712):396-407.
66. Martinez E, Larrousse M, Llibre JM, et al; SPIRAL Study Group.Substitutionof raltegravir for ritonavir-boosted protease inhibitorsin HIV-infected patients: the SPIRAL study. AIDS. 2010;24(11):1697-1707.
67. Finzi D, Blankson J, Siliciano JD, et al. Latent infection of CD4+ T cellsprovides a mechanism for lifelong persistence of HIV-1, even in patientson effective combination therapy. Nat Med. 1999;5(5):512-517.
68. Palmer S, Maldarelli F, Wiegand A, et al. Low-level viremia persistsfor at least 7 years in patients on suppressive antiretroviral therapy.Proc Natl Acad Sci U S A. 2008;105(10):3879-3884.
69. Croteau D, Letendre S, Best BM, et al; CHARTER Group. Totalraltegravir concentrations in cerebrospinal fluid exceed the 50-percentinhibitory concentration for wild-type HIV-1. Antimicrob AgentsChemother. 2010;54(12):5156-5160.
70. Archin NM, Cheema M, Parker D, et al. Antiretroviral intensificationand valproic acid lack sustained effect on residual HIV-1 viremia orresting CD4+ cell infection. PLoS One. 2010;5(2):e9390.
71. Gandhi R, Zheng S, Bosch R, et al. Raltegravir (RAL) intensificationdoes not reduce low-level residual viremia in HIV-1-infected patientson antiretroviral therapy (ART): results from ACTG A5244 [abstract].5th IAS Conference on HIV Pathogenesis, Treatment and Prevention;2009 Jul 19-22; Cape Town, South Africa.
72. Goethals O, Vos A, van Ginderen M, et al. Primary mutations selectedin vitro with raltegravir confer large fold changes in susceptibilitytofirst-generation integrase inhibitors, but minor fold changes to inhibitorswith second-generation resistance profiles. Virology. 2010;402(2):338-346.
73. Anies G, Da Silva D, Recordon-Pinson P, et al. Clonal analysis ofraltegravir-resistant patterns including mutations at positions 143 and155 [abstract]. 16th Conference on Retroviruses and OpportunisticInfections; 2009 Feb 8-11; Montreal, Canada.
74. Goethals O, Clayton R, van Ginderen M, et al. Resistance mutationsin human immunodeficiency virus type 1 integrase selected withelvitegravir confer reduced susceptibility to a wide range of integraseinhibitors. J Virol. 2008;82(21):10366-10374.
75. Miller MD, Danovich RM, Ke Y, et al. on behalf of the P005 StudyTeam. Longitudinal analysis of resistance to the HIV-1 integraseinhibitor raltegravir: results from P005, a phase II study in treatmentexperiencedpatients [abstract]. Antivir Ther. 2008;13 Suppl 3:A8.
76. Hu Z, Kuritzkes DR. Effect of raltegravir resistance mutations inHIV-1 integrase on viral fitness. J Acquir Immune Defic Syndr. 2010;55(2):148-155.
77. Geretti AM, Fearnhill E, Ceccherini-Silberstein F, et al. Prevalence andpatterns of raltegravir resistance in treated patients in Europe [abstract].Antivir Ther. 2010;15 Suppl 2:A62.
78. Blanco JL, Buzon MJ, Calvo M, et al. Evolution of viral load andintegraseresistance mutations after interrupting raltegravir (RAL) inHIV-infected subjects with virological failure on a RAL-containingregimen: the Raldyn study [abstract]. Antivir Ther. 2010;15 Suppl 2:A133.
79. Baldanti F, Paolucci S, Gulminetti R, Brandolini M, Barbarini G, Maserati R. Early emergence of raltegravir resistance mutations inpatients receiving HAART salvage regimens. J Med Virol. 2010;82(1):116-122.
80. McColl DJ, Fransen S, Gupta S, et al. Resistance and cross-resistanceto first generation integrase inihibitors: insights from a Phase II study ofelvitegravir (GS-9137) [abstract]. Antivir Ther. 2007;12 Suppl 1:S11.
81. Gallien S, Delaugerre C, Hu Z, et al. Integrase inhibitor resistancemutations in treatment-experienced HIV-1-infected patients with lowlevelviraemia receiving raltegravir-containing antiretroviral therapy:an ANRS 138-EASIER Trial substudy [abstract]. Antivir Ther. 2010;15Suppl 2:A60.