Investigational agents for salvage

Current Opinion in HIV and AIDS

Volumn 4, Issue 6, 2009, Pages 524-530

  Pozniak, Anton L ^a  

^a CHELSEA AND WESTMINSTER HOSPITAL NHS FOUNDATION TRUST   (United Kingdom)

Author keywords

Drugs; Efficacy; Investigational; Resistance; Safety; Salvage

Indexed keywords

AMDOXOVIR; AMPRENAVIR; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; APRICITABINE; BCH 10618; BEVIRAMAT; DARUNAVIR; EFAVIRENZ; ELVUCITABINE; EMTRICITABINE; ETRAVIRINE; GSK 1349572; IDX 899; LAMIVUDINE; LERSIVIRINE; LOPINAVIR; MPC 4326; MYCOPHENOLIC ACID; NEVIRAPINE; NUCLEOTIDE DERIVATIVE; PLACEBO; PPL 100; PRO 140; RDEA 806 427; RITONAVIR; RNA DIRECTED DNA POLYMERASE INHIBITOR; SPI 256; STAVUDINE; TENOFOVIR; THYMIDINE DERIVATIVE; UK 453 061; UNCLASSIFIED DRUG; UNINDEXED DRUG; ZIDOVUDINE;

CLINICAL TRIAL; DIARRHEA; DRUG CLASSIFICATION; DRUG HALF LIFE; DRUG MECHANISM; DRUG RESEARCH; DRUG TARGETING; DRUG TREATMENT FAILURE; DYSPEPSIA; GASTROINTESTINAL SYMPTOM; GENE THERAPY; HEADACHE; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; NAUSEA; NONHUMAN; PRIORITY JOURNAL; REVIEW; SALVAGE THERAPY; UNSPECIFIED SIDE EFFECT; VIRUS LOAD;

ANTI-RETROVIRAL AGENTS; DRUG RESISTANCE, VIRAL; HIV INFECTIONS; HIV-1; HUMANS; SALVAGE THERAPY;

EID: 70350173935     PISSN: 1746630X     EISSN: 17466318     Source Type: Journal    
DOI: 10.1097/COH.0b013e328331d56f     Document Type: Review

References (98)

1. Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008; 372:293-299.
2. Ceccherini-Silberstein F, Svicher V, Sing T, et al. Characterization and structural analysis of novel mutations in human immunodeficiency virus type 1 reverse transcriptase involved in the regulation of resistance to nonnucleoside inhibitors. J Virol 2007; 81:11507-11519.
3. Clavel F, Hance AJ. HIV drug resistance. N Engl J Med 2004; 350:1023-1035.
4. Cozzi-Lepri A, Ruiz L, Loveday L, et al. Thymidine analogue mutation profiles: factors associated with acquiring specific profiles and their impact on the virological response to therapy. Antivir Ther 2005; 10:791-802.
5. Hanna G, Johnson V, Kuritzkes D, et al. Patterns of resistance mutations selected by treatment of human immunodeficiency virus type 1 infection with zidovudine, didanosine, and nevirapine. J Infect Dis 2000; 181:904-911.
6. Johnson VA, Brun-Vézinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: spring 2008. Top HIV Med 2008; 16:62-68.
7. Larder B, Kemp S. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science 1989; 246:1155-1158.
8. Perno CF, Cozzi-Lepri A, Balotta C, et al. Secondary mutations in the protease region of human immunodeficiency virus and virologic failure in drug-naý v̈e patients treated with protease inhibitor-based therapy. J Infect Dis 2001; 184:983-991.
9. Rhee SY, Taylor J, Wadhera G, et al. Genotypic predictors of human immunodeficiency virus type 1 drug resistance. Proc Natl Acad Sci U S A 2006; 103:17355-17360.
10. Svicher V, Ceccherini-Silberstein F, Erba F, et al. Novel human immunode- ficiency virus type 1 protease mutations potentially involved in resistance to protease inhibitors. Antimicrob Agents Chemother 2005; 49:2015-2025.
11. Svicher V, Sing T, Santoro MM, et al. Involvement of novel human immunodeficiency virus type 1 reverse transcriptase mutations in the regulation of resistance to nucleoside inhibitors. J Virol 2006; 80:7186-7198.
12. Shafer RW, Schapiro JM. HIV-1 drug resistance mutations: an updated framework for the second decade of HAART. AIDS Rev 2008; 10:67-84.
13. Lataillade M, Kozal MJ. The hunt for HIV-1 integrase inhibitors. AIDS Patient Care STDS 2006; 20:489-501.
14. Pommier Y, Johnson AA, Marchand C. Integrase inhibitors to treat HIV/AIDS. Nat Rev Drug Discov 2005; 4:236-248.
15. Semenova EA, Marchand C, Pommier Y. HIV-1 integrase inhibitors: update and perspectives. Adv Pharmacol 2008; 56:199-228.
16. Grinsztejn B, Nguyen BY, Katlama C, et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment experienced patients with multidrug resistant virus: a phase II randomised controlled trial. Lancet 2007; 369:1261-1269.
17. Cooper DA, Steigbigel RT, Gatell JM, et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 2008; 359:355-365.
18. McColl DJ, Fransen S, Gupta S, et al. Resistance and cross-resistance to first generation integrase inhibitors: insights from a phase 2 study of elvitegravir (GS-9137). Antivir Ther 2007; 12:S11.
19. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008; 359:339-354.
20. Zolopa AR, Mullen M, Berger D, Ruane P, et al. The HIV integrase inhibitor GS-9137 demonstrates potent antiretroviral activity in treatment-experienced patients. 14th Conference on Retrovirus and Opportunistic Infection; 25-28 February 2007; Los Angeles, CA, USA; abstract 143LB.
21. Coffin JM, Hughes SH, Varmus HE. Retroviruses. New York: Cold Spring Harbor Laboratory Press; 1997.
22. Rice P, Craigie R, Davies DR. Retroviral integrases and their cousins. Curr Opin Struct Biol 1996; 6:76-83.
23. Engelman A, Craigie R. Identification of conserved amino acid residues critical for human immunodeficiency virus type 1 integrase function in vitro. J Virol 1992; 66:6361-6369.
24. Polard P, Chandler M. Bacterial transposases and retroviral integrases. Mol Microbiol 1995; 15:13-23.
25. Burke CJ, Sanyal G, Bruner MW, et al. Structural implications of spectroscopic characterization of a putative zinc finger peptide from HIV-1 integrase. J Biol Chem 1992; 267:9639-9644.
26. Lee SP, Xiao J, Knutson JR, et al. Zn2p promotes the self-association of human immunodeficiency virus type-1 integrase in vitro. Biochemistry 1997; 36:173-180.
27. Zheng R, Jenkins TM, Craigie R. Zinc folds the N-terminal domain of HIV-1 integrase, promotes multimerization, and enhances catalytic activity. Proc Natl Acad Sci U S A 1996; 93:13659-13664.
28. Avidan O, Hizi A. Expression and characterization of the integrase of bovine immunodeficiency virus. Virology 2008; 371:309-321.
29. Kulkosky J, Katz RA, Merkel G, Skalka AM. Activities and substrate specificity of the evolutionarily conserved central domain of retroviral integrase. Virology 1995; 206:448-456.
30. Bouyac-Bertoia M, Dvorin JD, Fouchier RA, et al. HIV-1 infection requires a functional integrase NLS. Mol Cell 2001; 7:1025-1035.
31. Berthoux L, Sebastian S, Muesing MA, Luban J. The role of lysine 186 in HIV-1 integrase multimerization. Virology 2007; 364:227-236.
32. Wang JY, Ling H, Yang W, Craigie R. Structure of a two-domain fragment of HIV-1 integrase: implications for domain organization in the intact protein. EMBO J 2001; 20:7333-7343.
33. Busschots K, Voet A, De Maeyer M, et al. Identification of the LEDGF/p75 binding site in HIV-1 integrase. J Mol Biol 2007; 365:1480-1492.
34. Cherepanov P, Sun ZY, Rahman S, et al. Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75. Nat Struct Mol Biol 2005; 12:526-532.
35. Hombrouck A, De Rijck J, Hendrix J, et al. Virus evolution reveals an exclusive role for LEDGF/p75 in chromosomal tethering of HIV. PLoS Pathog 2007; 3:e47.
36. Maertens G, Cherepanov P, Pluymers W, et al. LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells. J Biol Chem 2003; 278:33528-33539. (Pubitemid 37055807)
37. Rahman S, Lu R, Vandegraaff N, et al. Structure-based mutagenesis of the integrase-LEDGF/p75 interface uncouples a strict correlation between in vitro protein binding and HIV-1 fitness. Virology 2007; 357:79-90.
38. Engelman A, Hickman AB, Craigie R. The core and carboxyl-terminal domains of the integrase protein of human immunodeficiency virus type 1 each contribute to nonspecific DNA binding. J Virol 1994; 68:5911-5917.
39. Lutzke RA, Plasterk RH. Structure-based mutational analysis of the C-terminal DNA-binding domain of human immunodeficiency virus type 1 integrase: critical residues for protein oligomerization and DNA binding. J Virol 1998; 72:4841-4848.
40. Lutzke RA, Vink C, Plasterk RH. Characterization of the minimal DNA-binding domain of the HIV integrase protein. Nucleic Acids Res 1994; 22:4125-4131.
41. Vink C, Oude Groeneger AM, Plasterk RH. Identification of the catalytic and DNA-binding region of the human immunodeficiency virus type I integrase protein. Nucleic Acids Res 1993; 21:1419-1425.
42. Engelman A, Mizuuchi K, Craigie R. HIV-1 DNA integration: mechanism of viral DNA cleavage and DNA strand transfer. Cell 1991; 67:1211-1221.
43. Miller MD, Farnet CM, Bushman FD. Human immunodeficiency virus type 1 preintegration complexes: studies of organization and composition. J Virol 1997; 71:5382-5390.
44. Mulder LC, Chakrabarti LA, Muesing MA. Interaction of HIV-1 integrase with DNA repair protein hRad18. J Biol Chem 2002; 277:27489-27493.
45. Yoder K, Bushman FD. Repair of gaps in retroviral DNA integration intermediates. J Virol 2000; 74:11191-11200.
46. Fikkert V, Hombrouck A, Van Remoortel B, et al. Multiple mutations in HIV-1 integrase confer resistance to the clinical trial drug S-1360. AIDS 2004; 18:2019-2028.
47. Hazuda D, Anthony N, Gomez R, et al. A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase. Proc Natl Acad Sci U S A 2004; 101:11233-11238.
48. Ceccherini-Silberstein F, Van Baelen K, Armenia D, et al. Novel HIV-1 integrase mutations, found as minority quasispecies in patients naý v̈e to integrase inhibitors, are associated with decreased susceptibility to integrase inhibitors in vitro. 15th Conference on Retrovirus and Opportunistic Infection; 3-6 February 2008; Boston, MA, USA; abstract 876.
49. integrase-naive HIV-1 subtype B-infected patients.
50. Hazuda DJ, Miller MD, Nguyen BY, Zhao J, for the P005 Study Team. Resistance to the HIV-integrase inhibitor raltegravir: analysis of protocol 005, a Phase II study in patients with triple-class resistant HIV-1 infection. Antivir Ther 2007; 12:S10.
51. Lataillade M, Chiarella J, Kozal MJ. Natural polymorphism of the HIV-1 integrase gene and mutations associated with integrase inhibitor resistance. Antivir Ther 2007; 12:563-570.
52. Shimura K, Kodama E, Sakagami Y, et al. Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137). J Virol 2008; 82:764-774.
53. Steigbigel R, Kumar P, Eron J, et al. Results of BENCHMRK-2, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 14th Conference on Retrovirus and Opportunistic Infection; 25-28 February 2007; Los Angeles, CA, USA; abstract 105bLB.
54. Wai J, Fisher T, Embrey M, et al. Next generation of inhibitors of HIV-1 integrase strand transfer inhibitor: structural diversity and resistance profiles. 14th Conference on Retrovirus and Opportunistic Infection; 25-28 February 2007; Los Angeles, CA, USA; abstract 87.
55. Goethals O, Clayton R, Van Ginderen M, et al. Resistance mutations in HIV-1 integrase selected with Elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors. J Virol 2008; 82:10366-10374.
56. Fransen S, Gupta S, Danovich R, et al. Loss of raltegravir susceptibility in treated patients is conferred by multiple nonoverlapping genetic pathways [abstract 7]. Antivir Ther 2008; 13 (Suppl 3):A9.
57. Malet I, Delelis O, Valantin MA, et al. Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob Agents Chemother 2008; 52:1351-1358.
58. Goodman D, Hluhanich R, Waters J, et al. Integrase inhibitor resistance involves complex interactions among primary and secondary resistance mutations: a novel mutation L68V/I associates with E92Q and increases resistance [abstract 13]. Antviral Ther 2008; 13 (Suppl 3):A15.
59. Hatano H, Lampiris H, Huang W, et al. Virological and immunological outcomes in a cohort of patients failing integrase inhibitors [abstract 10]. Antivir Ther 2008; 13 (Suppl 3):A12.
60. Katlama C, Caby F, Andrade R, et al. Virological evolution in HIV treatmentexperienced patients with raltegravir-based salvage regimens [abstract 11]. Antivir Ther 2008; 13 (Suppl 3):A13.
61. Da Silva D, Pellgrin I, Anies G, et al. Mutational patterns in the HIV-1 integrase related to virological failures on raltegravir-containing regimens [abstract 12]. Antivir Ther 2008; 13 (Suppl 3):A14.
62. Ceccherini-Silberstein F, Armenia D, D'Arrigo R, et al. Virological response and resistance in multiexperienced patients treated with raltegravir [abstract 18]. Antivir Ther 2008; 13 (Suppl 3):A20.
63. DeJesus E, Cohen C, Elion R, et al. First report of raltegravir (RAL, MK-0518) use after virologic rebound on elvitegravir (EVT, GS 9137). 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention; 22-25 July 2007; Sydney, Australia; abstract TUPEB032.
64. Hackett J Jr, Harris B, Holzmayer V, et al. Naturally occurring polymorphisms in HIV-1 group M, N, and O integrase: implications for integrase inhibitors. 15th Conference on Retrovirus and Opportunistic Infection; 3-6 February 2008; Boston, MA, USA; abstract 872.
65. Myers RE, Pillay D. HIV Analysis of natural sequence variation and covariation in human immunodeficiency virus type 1 integrase. J Virol 2008; 82:9228-9235.
66. Rhee SY, Liu TF, Kiuchi M, et al. Natural variation of HIV-1 group M integrase: implications for a new class of antiretroviral inhibitors. Retrovirology 2008; 5:74.
67. Ceccherini-Silberstein F, Malet I, Fabeni L, et al. Specific mutations related to resistance to HIV-1 integrase inhibitors are associated with reverse transcriptase mutations in HAART-treated patients. Antivir Ther 2007; 12:S6.
68. Sander O, Altmann A, Lenguauer T. Computational analysis of covariation and interactions between HIV-1 reverse transcriptase and integrase. 6th European HIV Drug Resistance Workshop; 2008; 10-14 June 2008; Sitges, Spain; abstract 108.
69. Van Eygen V, Van Marck H, Smits V, et al. Identification of residues in HIV-1 integrase, RNaseH and the RT connection domain associated with the presence of thymidine analogue-associated resistance. 6th European HIV Drug Resistance Workshop; 10-14 June 2008, Sitges, Spain; abstract 53.
70. Brenner BG, Oliveira M, Doualla-Bell F, et al. HIV-1 subtype C viruses rapidly develop K65R resistance to tenofovir in cell culture. AIDS 2006; 20:F9-F13.
71. Brenner B, Turner D, Oliveira M, et al. A V106M mutation in HIV-1 clade C viruses exposed to efavirenz confers cross-resistance to nonnucleoside reverse transcriptase inhibitors. AIDS 2003; 17:F1-F5.
72. Calazans A, Brindeiro R, Brindeiro P, et al. Low accumulation of L90M in protease from subtype F HIV-1 with resistance to protease inhibitors is caused by the L89M polymorphism. J Infect Dis 2005; 191:1961-1970.
73. Doualla-Bell F, Avalos A, Brenner B, et al. High prevalence of the K65R mutation in human immunodeficiency virus type 1 subtype C isolates from infected patients in Botswana treated with didanosine-based regimens. Antimicrob Agents Chemother 2005; 50:4182-4185.
74. Grossman Z, Istomin V, Averbuch D, et al. Genetic variation at NNRTI resistance-associated positions in patients infected with HIV-1 subtype C. AIDS 2004; 18:909-915.
75. Grossman Z, Paxinos EE, Averbuch D, et al. Mutation D30N is not preferentially selected by human immunodeficiency virus type 1 subtype C in the development of resistance to nelfinavir. Antimicrob Agents Chemother 2004; 48:2159-2165.
76. Gupta RK, Chrystie IL, O'Shea S, et al. K65R and Y181C are less prevalent in HAART-experienced HIV-1 subtype A patients. AIDS 2005; 19:1916-1919.
77. Kantor R, Katzenstein DA, Efron B, et al. Impact of HIV-1 subtype and antiretroviral therapy on protease and reverse transcriptase genotype: results of a global collaboration. PLoS Med 2005; 2:e112.
78. Loemba H, Brenner B, Parniak MA, et al. Genetic divergence of human immunodeficiency virus type 1 Ethiopian clade C reverse transcriptase (RT) and rapid development of resistance against nonnucleoside inhibitors of RT. Antimicrob Agents Chemother 2002; 46:2087-2094.
79. Miller MD, Margot N, McColl D, Cheng AK. K65R development among subtype C HIV-1-infected patients in tenofovir DF clinical trials. AIDS 2007; 21:265-266.
80. Soares EA, Santos RP, Pellegrini JA, et al. Epidemiologic and molecular characterization of human immunodeficiency virus type 1 in southern Brazil. J Acquir Immune Defic Syndr 2003; 34:520-526.
81. Taylor BS, Sobieszczyk ME, McCutchan FE, Hammer SM. The challenge of HIV-1 subtype diversity. N Engl J Med 2008; 358:1590-1602.
82. Roquebert B, Damond F, Collin G, et al. HIV-2 integrase gene polymorphism and phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitors raltegravir and elvitegravir in vitro. J Antimicrob Chemother 2008; 62:914-920.
83. Van Baelen K, Van Eygen V, Rondelez E, Stuyver LJ. Clade-specific HIV-1 integrase polymorphisms do not reduce raltegravir and elvitegravir phenotypic susceptibility. AIDS 2008; 22:1877-1880.
84. Damond F, Lariven S, Roquebert B, et al. Virological and immunological response to HAART regimen containing integrase inhibitors in HIV-2-infected patients. AIDS 2008; 22:665-666.
85. Garrett N, Xu L, Smit E, et al. Raltegravir treatment response in an HIV-2 infected patient: a case report. AIDS 2008; 22:1091-1092.
86. Roquebert B, Blum L, Collin G, et al. Selection of the Q148R integrase inhibitor resistance mutation in a failing raltegravir containing regimen. AIDS 2008; 22:2045-2046.
87. Withrouw M, Pannecouque C, Switzer WM, et al. Susceptibility of HIV-2, SIV and SHIV to various anti-HIV-1 compounds: implications for treatment and postexposure prophylaxis. Antivir Ther 2004; 9:57-65.
88. Underwood M, Johns B, Sato A, et al. S/GSK1349572: a next generation integrase inhibitor with activity against integrase inhibitor-resistant clinical isolates from patients experiencing virologic failure while on raltegravir therapy. IAS 2009; 19-22 July 2009; Cape Town, South Africa; #WEPEA098.
89. Berger EA, Murphy PM, Farber JM. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 1999; 17:657-700.
90. Poveda E, Briz V, Quinones-MateuM, Soriano V. HIV tropism: diagnostic tools and implications for disease progression and treatment with entry inhibitors. AIDS 2006; 20:1359-1367.
91. Briggs DR, Tuttle DL, Sleasman JW, Goodenow MM. Envelope V3 amino acid sequence predicts HIV-1 phenotype (co-receptor usage and tropism for macrophages). AIDS 2000; 14:2937-2939.
92. Jensen MA, Li FS, van 't Wout AB, et al. Improved coreceptor usage prediction and genotypic monitoring of R5-to-X4 transition by motif analysis of human immunodeficiency virus type 1 env V3 loop sequences. J Virol 2003; 77:13376-13388.
93. Fouchier RA, Groenink M, Kootstra NA, et al. Phenotype-associated sequence variation in the third variable domain of the human immunodefi- ciency virus type 1 gp120 molecule. J Virol 1992; 66:3183-3187.
94. Lewis M, Simpson P, Whitcomb J, et al. Changes in V3 loop sequence associated with failure of maraviroc treatment in patients enrolled in the MOTIVATE 1 and 2 Trials. 15th Conference on Retroviruses and Opportunistic Infections; 3-6 February 2008; Boston, MA, USA.
95. Westby M, Smith-Burchnell C, Mori J, et al. Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry. J Virol 2007; 81:2359-2371.
96. Tsibris AM, Sagar M, Gulick RM, et al. In vivo emergence of vicriviroc resistance in an HIV-1 subtype C-infected subject. J Virol 2008; 82:8210-8214.
97. Soulié C, Malet I, Lambert-Niclot S, et al. Primary genotypic resistance of HIV- 1 to CCR5 antagonists in CCR5 antagonist treatment-naive patients. AIDS 2008; 22:2212-2214.
98. Mori J, Lewis M, Simpson P, et al. Characterization of maraviroc resistance in patients failing treatment with CCR5-tropic HIV-1 in MOTIVATE 1 and MOTIVATE 2. XVI International HIV Drug Resistance Workshop; 12-16 June 2007; Barbados, West Indies.