The influence of protease inhibitor resistance profiles on selection of HIV therapy in treatment-naive patients

Antiviral Therapy

Volumn 9, Issue 3, 2004, Pages 301-314

  Turner, Dan ^a   Schapiro, Jonathan M ^b,c   Brenner, Bluma G ^a   Wainberg, Mark A ^a  

^a MCGILL UNIVERSITY   (Canada)

^b STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c Tel Hashomer Hospital   (Israel)

Author keywords

[No Author keywords available]

Indexed keywords

ABACAVIR; AMPRENAVIR; AMPRENAVIR PHOSPHATE; ANTIRETROVIRUS AGENT; ATAZANAVIR; DARUNAVIR; EFAVIRENZ; INDINAVIR; LAMIVUDINE; LOPINAVIR; NELFINAVIR; PROTEINASE INHIBITOR; RITONAVIR; RNA DIRECTED DNA POLYMERASE INHIBITOR; SAQUINAVIR; STAVUDINE; TENOFOVIR; TIPRANAVIR; UNCLASSIFIED DRUG; ZIDOVUDINE;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; AMINO ACID SUBSTITUTION; ANTIVIRAL ACTIVITY; CARDIOTOXICITY; CLINICAL TRIAL; CROSS RESISTANCE; DRUG EFFICACY; DRUG HYPERSENSITIVITY; DRUG POTENCY; EXPERIENCE; GENETIC SUSCEPTIBILITY; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; LIPODYSTROPHY; MULTIDRUG RESISTANCE; NEPHROTOXICITY; OUTCOMES RESEARCH; PATIENT SELECTION; PRIORITY JOURNAL; REVIEW; RISK BENEFIT ANALYSIS; SIDE EFFECT; VIRUS REPLICATION;

AMINO ACID SUBSTITUTION; ANTIRETROVIRAL THERAPY, HIGHLY ACTIVE; CLINICAL TRIALS, PHASE III; DRUG RESISTANCE, VIRAL; HIV; HIV INFECTIONS; HIV PROTEASE; HIV PROTEASE INHIBITORS; HUMANS; INDINAVIR; MUTATION; PYRIDINES; PYRONES; RITONAVIR; SAQUINAVIR; VARIATION (GENETICS);

EID: 3042855671     PISSN: 13596535     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (119)

1. Kakuda TN, Struble KA & Piscitelli SC. Protease inhibitors for the treatment of human immunodeficiency virus infection. American Journal of Health-System Pharmacy 1998; 55:233-254.
2. Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA_071403.pdf. Accessed September 5, 2003.
3. Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, Eron JJ Jr, Feinberg JE, Balfour HH Jr, Deyton LR, Chodakewitz JA, Fischl MA, Phair JP, Spreen W, Pedneault L, Nguygen BY & Cook JC for the AIDS Clinical Trials Group 320 Study Team. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. New England Journal of Medicine 1997; 337:725-733.
4. Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, Richman DD, Valentine FT, Jonas L, Meibohm A, Emini EA, Chodakewitz JA, Deutsch P, Holder D, Schleif WA & Condra JH. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. New England Journal of Medicine 1997; 337:734-739.
5. Deeks SG, Hecht FM, Swanson M, Elbeik T, Loftus R, Cohen PT & Grant RM. HIV RNA and CD4 cell count response to protease inhibitor therapy in an urban AIDS clinic: response to both initial and salvage therapy. AIDS 1999; 13:F35-F43.
6. Lucas GM, Chaisson RE & Moore RD. Highly active antiretroviral therapy in a large urban clinic: risk factors for virologic failure and adverse drug reactions. Annals of Internal Medicine 1999; 131:81-87.
7. Ledergerber B, Egger M, Opravil M, Telenti A, Hirschel B, Battegay M, Vernazza P, Sudre P, Flepp M, Furrer H, Francioli P & Weber R for the Swiss HIV Cohort Study. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Lancet 1999; 353:863-868.
8. Mocroft A, Ruiz L, Reiss P, Ledergerber B, Katlama C, Lazzarin A, Goebel FD, Phillips AN, Clotet B & Lundgren JD; EuroSIDA study group. Virological rebound after suppression on highly active antiretroviral therapy. AIDS 2003; 17:1741-1751.
9. Fätkenheuer G, Theisen A, Rockstroh J, Grabow T, Wicke C, Becker K, Wieland U, Pfister H, Reiser M, Hegener P, Franzen C, Schwenk A & Salzberger B. Virological treatment failure of protease inhibitor therapy in an unselected cohort of HIV-infected patients. AIDS 1997; 11:F113-F116.
10. Salomon H, Wainberg MA, Brenner B, Quan Y, Rouleau D, Coté P, LeBlanc R, Lefebvre E, Spira B, Tsoukas C, Sekaly R-P, Conway B, Mayers D & Routy JP for the Investigators of the Quebec Primary Infection Study. Prevalence of HIV-1 resistant to antiretroviral drugs in 81 individuals newly infected by sexual contact or injecting drug use. AIDS 2000; 14:F17-F23.
11. Brenner B, Wainberg MA, Salomon H, Rouleau D, Dascal A, Spira B, Sekaly R-P, Conway B & Routy J-P, Investigators of the Quebec Primary Infection Study. Resistance to antiretroviral drugs in patients with primary HIV-1 infection. International Journal of Antimicrobial Agents 2000; 16:429-434.
12. Walmsley S, Bernstein B, King M, Arribas J, Beall G, Ruane P, Johnson M, Johnson D, Lalonde R, Japour A, Brun S & Sun E; M98-863 Study Team. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. New England Journal of Medicine 2002; 346:2039-2046.
13. Gulick RM, Ribaudo HJ, Shikuma CM, Lusgarten S, Meyer WA, Kligman K, Squires KE, Snyder S & Kuritzkes DR. ACTG 5095: a comparative study of 3 protease inhibitor-sparing antiretroviral regimens for the initial treatment of HIV infection. 2nd IAS Conference on HIV Pathogenesis & Treatment. Paris, France, July 2003. Antiviral Therapy 2003; 8:S194. Abstract 41.
14. Gallant JE, Rodriguez AE, Weinberg W, Young B, Berger D, Lim ML, Liao Q, Ross L, Johnson J & Shaefer MS. Early non-response to tenofovir (TDF)+abacavir (ABC) and lamivudine (3TC) in a randomised trial compared to efavirenz (EFV)+ABC and 3TC: ESS30009 unplanned interim analysis. 43rd Annual ICAAC. Chicago, Ill., USA, September 2003. Abstract H-1722a.
15. Peng C, Ho BK, Chang TW & Chang NT. Role of human immunodeficiency virus type 1-specific protease in core protein maturation and viral infectivity. Journal of Virology 1989; 63:2550-2556.
16. Kohl NE, Emini EA, Schleif WA, Davis LJ, Heimbach JC, Dixon RA, Scolnick EM & Sigal IS. Active human immunodeficiency virus protease is required for viral infectivity. Proceedings of the National Academy of Sciences, USA 1988; 85:4686-4690.
17. Lin Y, Lin X, Hong L, Foundling S, Heinrikson RL, Thaisrivongs S, Leelamanit W, Raterman D, Shah M, Dunn BM & Tang J. Effect of point mutations on the kinetics and the inhibition of human immunodeficiency virus type 1 protease: relationship to drug resistance. Biochemistry 1995; 34:1143-1152.
18. Eberle J, Bechowsky B, Rose D, Hauser U, von der HK, Gürtler L & Nitschko H. Resistance of HIV type 1 to proteinase inhibitor Ro 31-8959. AIDS Research & Human Retroviruses 1995; 11:671-676.
19. Todd MJ, Luque I, Velázquez-Campoy A & Freire E. Thermodynamic basis of resistance to HIV-1 protease inhibition: calorimetric analysis of the V82F/I84V active site resistant mutant. Biochemistry 2000; 39:11876-11883.
20. Roberts NA, Martin JA, Kinchington D, Broadhurst AV, Craig JC, Duncan IB, Galpin SA, Handa BK, Kay J, Krohn A, Kröhn A, Lambert RW, Merrett JH, Mills JS, Parkes KEB, Redshaw S, Ritchie AJ, Taylor DL, Thomas GJ & Machin PJ. Rational design of peptide-based HIV proteinase inhibitors. Science 1990; 248:358-361.
21. Hirsch MS, Brun-Vezinet F, Clotet B, Conway B, Kuritzkes DR, D'Aquila RT, Demeter LM, Hammer SM, Johnson VA, Loveday C, Mellors JW, Jacobsen DM & Richman DD. Antiretroviral drug resistance testing in adults infected with human immunodeficiency virus type 1: 2003 recommendations of an International AIDS Society-USA Panel. Clinical Infectious Diseases 2003; 37:113-128.
22. Chen Z, Li Y, Schock HB, Hall D, Chen E & Kuo LC. Three-dimensional structure of a mutant HIV-1 protease displaying cross-resistance to all protease inhibitors in clinical trials. Journal of Biological Chemistry 1995; 270:21433-21436.
23. Chen Z, Li Y, Chen E, Hall DL, Darke PL, Culberson C, Shafer JA & Kuo LC. Crystal structure at 1.9-A resolution of human immunodeficiency virus (HIV) II protease complexed with L-735,524, an orally bioavailable inhibitor of the HIV proteases. Journal of Biological Chemistry 1994; 269:26344-26348.
24. Prabu-Jeyabalan M, Nalivaika EA, King NM & Schiffer CA. Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy. Journal of Virology 2003; 77:1306-1315.
25. Markowitz M, Mo H, Kempf DJ, Norbeck DW, Bhat TN, Erickson JW & Ho DD. Selection and analysis of human immunodeficiency virus type 1 variants with increased resistance to ABT-538, a novel protease inhibitor. Journal of Virology 1995; 69:701-706.
26. Miller V. International perspectives on antiretroviral resistance. Resistance to protease inhibitors. Journal of Acquired Immune Deficiency Syndromes 2001; 26(Suppl. 1):S34-S50.
27. D'Aquila RT, Schapiro JM, Brun-Vézinet F, Clotet B, Conway B, Demeter LM, Grant RM, Johnson VA, Kuritzkes DR, Loveday C, Shafer RW & Richman DD. Drug resistance mutations in HIV-1. Topics in HIV Medicine 2003; 11:92-96.
28. Colonno RJ, Friborg J, Rose RE, Lam E & Parkin N. Identification of amino acid substitutions correlated with reduced atazanavir susceptibility in patients treated with atazanavir containing regimens. Antiviral Therapy 2002; 7(Suppl. 1):S6. Abstract 4.
29. Colonno RJ, Thiry A & Parkin NT. Amino acid substitutions that correlate with decreased susceptibility to atazanavir and other HIV-1 protease inhibitors. 42nd Interscience Conference on Antimicrobial Agents & Chemotherapy. San Diego, Calif., USA, September 2002. Abstract Book. Herndon, VA: ASM Press; 291. Abstract H-2049.
30. Frost SD, Nijhuis M, Schuurman R, Boucher CA & Brown AJ. Evolution of lamivudine resistance in human immunodeficiency virus type 1-infected individuals: the relative roles of drift and selection. Journal of Virology 2000; 74:6262-6268.
31. Gotte M & Wainberg MA. Biochemical mechanisms involved in overcoming HIV resistance to nucleoside inhibitors of reverse transcriptase. Drug Resistance Update 2000; 3:30-38.
32. Loveday C. International perspectives on antiretroviral resistance. Nucleoside reverse transcriptase inhibitor resistance. Journal of Acquired Immune Deficiency Syndrome 2001; 26:S10-S24.
33. Quan Y, Gu Z, Li X, Li Z, Morrow CD & Wainberg MA. Endogenous reverse transcription assays reveal high-level resistance to the triphosphate of 2′-dideoxy-3′-thiacytidine by mutated M184V human immunodeficiency virus type 1. Journal of Virology 1996; 70:5642-5645.
34. Deeks SG. International perspectives on antiretroviral resistance. Nonnucleoside reverse transcriptase inhibitor resistance. Journal of Acquired Immune Deficiency Syndrome 2001; 26:S25-S33.
35. Jacobsen H, Hänggi M, Ott M, Duncan IB, Owen S, Andreoni M, Vella S & Mous J. In vivo resistance to a human immunodeficiency virus type 1 proteinase inhibitor: mutations, kinetics, and frequencies. Journal of Infectious Diseases 1996; 173:1379-1387.
36. Erickson JW, Gulnik SV & Markowitz M. Protease inhibitors: resistance, cross-resistance, fitness and the choice of initial and salvage therapies. AIDS 1999; 13(Suppl. A):S189-S204.
37. Eastman PS, Mittler J, Kelso R, Gee C, Boyer E, Kolberg J, Urdea M, Leonard JM, Norbeck DW, Mo H & Markowitz M. Genotypic changes in human immunodeficiency virus type 1 associated with loss of suppression of plasma viral RNA levels in subjects treated with ritonavir (Norvir) monotherapy. Journal of Virology 1998; 72:5154-5164.
38. Colonno RJ, Thiry A, Limoli K & Parkin N. Activities of atazanavir (BMS-232632) against a large panel of human immunodeficiency virus type 1 clinical isolates resistant to one or more approved protease inhibitors. Antimicrobial Agents & Chemotherapy 2003; 47:1324-1333.
39. Wu TD, Schiffer CA, Gonzales MJ, Taylor J, Kantor R, Chou S, Israelski D, Zolopa AR, Fessel WJ & Shafer RW. Mutation patterns and structural correlates in human immunodeficiency virus type 1 protease following different protease inhibitor treatments. Journal of Virology 2003; 77:4836-4847.
40. Aleman S, Söderbarg K, Visco-Comandini U, Sitbon G & Sönnerborg A. Drug resistance at low viraemia in HIV-1-infected patients with antiretroviral combination therapy. AIDS 2002; 16:1039-1044.
41. van Heeswijk RPG, Veldkamp A, Mulder JW, Meenhorst PL, Lange JMA, Beijnen JH & Hoetelmans RM. Combination of protease inhibitors for the treatment of HIV-1-infected patients: a review of pharmacokinetics and clinical experience. Antiviral Therapy 2001; 6:201-229.
42. Holland J, Spindler K, Horodyski F, Grabau E, Nichol S & VandePol S. Rapid evolution of RNA genomes. Science 1982; 215:1577-1585.
43. Coffin JM. HIV population dynamics in vivo: implications for genetic variation, pathogenesis and therapy. Science 1995; 267:483-489.
44. Gatanaga H, Suzuki Y, Tsang H, Yoshimura K, Kavlick MF, Nagashima K, Gorlick RJ, Mardy S, Tang C, Summers MF & Mitsuya H. Amino acid substitutions in Gag protein at non-cleavage sites are indispensable for the development of a high multitude of HIV-1 resistance against protease inhibitors. Journal of Biological Chemistry 2002; 277:5952-5961.
45. Charpentier C, Lecossier D, Clavel F & Hance AJ. Role of resistance and fitness in driving the evolution of the protease in patients failing treatment with protease inhibitors. 10th Conference on Retroviruses & Opportunistic Infections. Boston, Mass., USA, February 2003. Abstract 601.
46. Condra JH. Resistance to HIV protease inhibitors. Haemophilia 1998; 4:610-615.
47. Nijhuis M, Schuurman R, de Jong D, Erickson J, Gustchina E, Albert J, Schipper P, Gulnik S & Boucher CA. Increased fitness of drug resistant HIV-1 protease as a result of acquisition of compensatory mutations during suboptimal therapy. AIDS 1999; 13:2349-2359.
48. Resch W, Ziermann R, Parkin N, Gamarnik A & Swanstrom R. Nelfinavir-resistant, amprenavir-hypersusceptible strains of human immunodeficiency virus type 1 carrying an N88S mutation in protease have reduce infectivity, reduced replication capacity, and reduced fitness and process the gag polyprotein precursor aberrantly. Journal of Virology 2002; 76:8659-8666.
49. Prado JG, Wrin T, Beauchaine J, Ruiz L, Petropoulos CJ, Frost SDW, Clotet B, D'Aquila RT & Martinez-Picado J. Amprenavir-resistant HIV-1 exhibits lopinavir cross-resistance and reduced replication capacity. AIDS 2002; 16:1009-1017.
50. Molla A, Korneyeva M, Gao Q, Vasavanonda S, Schipper PJ, Mo HM, Markowitz M, Chernyavskiy T, Niu P, Lyons N, Hsu A, Granneman GR, Ho DD, Boucher CA, Leonard JM, Norbeck DW & Kempf DJ. Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nature Medicine 1996; 2:760-766.
51. Gong Y-F, Robinson BS, Rose RE, Deminie C, Spicer TP, Stock D, Colonno RJ & Lin P-F. In vitro resistance profile of the human immunodeficiency virus type 1 protease inhibitor BMS-232632. Antimicrobial Agents & Chemotherapy 2000; 44:2319-2326.
52. Condra JH, Schleif WA, Blahy OM, Gabryelski LJ, Graham DJ, Quintero JC, Rhodes A, Robbins HL, Roth E, Shivaprakash M, Titus D, Yang T, Teppler H, Squires KE, Deutsch PJ & Emini EA. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature 1995; 374:569-571.
53. Hertogs K, Bloor S, Kemp SD, van den Eynde C, Alcorn TM, Pauwels R, Van Houtte M, Staszewski S, Miller V & Larder BA. Phenotypic and genotypic analysis of clinical HIV-1 isolates reveals extensive protease inhibitor cross-resistance: a survey of over 6000 samples. AIDS 2000; 14:1203-1210.
54. Larder BA, Hertogs K, Bloor S, van den Eynde C, DeCian W, Wang Y, Freimuth WW & Tarpley G. Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples. AIDS 2000; 14:1943-1948.
55. Jacobsen H, Yasargil K, Winslow DL, Craig JC, Kröhn A, Duncan IB & Mous J. Characterization of human immunodeficiency virus type 1 mutants with decreased sensitivity to proteinase inhibitor Ro 31-8959. Virology 1995; 206:527-534.
56. Winters MA, Schapiro JM, Lawrence J & Merigan TC. Human immunodeficiency virus type 1 protease genotypes and in vitro protease inhibitor susceptibilities of isolates from individuals who were switched to other protease inhibitors after long-term saquinavir treatment. Journal of Virology 1998; 72:5303-5306.
57. Velazquez-Campoy A, Vega S & Freire E. Amplification of the effects of drug resistance mutations by background polymorphisms in HIV-1 protease from African subtypes. Biochemistry 2002; 41:8613-8619.
58. Boden D & Markowitz M. Resistance to human immunodeficiency virus type 1 protease inhibitors. Antimicrobial Agents & Chemotherapy 1998; 42:2775-2783.
59. Schmidt B, Walter H, Moschik B, Paatz C, van Vaerenbergh K, Vandamme A-M, Schmitt M, Harrer T, Überla K & Korn K. Simple algorithm derived from a geno-/phenotypic database to predict HIV-1 protease inhibitor resistance. AIDS 2000; 14:1731-1738.
60. Schmit JC, Ruiz L, Clotet B, Raventos A, Tor J, Leonard J, Desmyter J, De Clercq E & Vandamme AM. Resistance-related mutations in the HIV-1 protease gene of patients treated for 1 year with the protease inhibitor ritonavir (ABT-538). AIDS 1996; 10:995-999.
61. Tisdale M, Myers RE, Maschera B, Parry NR, Oliver NM & Blair ED. Cross-resistance analysis of human immunodeficiency virus type 1 variants individually selected for resistance to five different protease inhibitors. Antimicrobial Agents & Chemotherapy 1995; 39:1704-1710.
62. Condra JH, Holder DJ, Schleif WA, Blahy OM, Danovich RM, Gabryelski LJ, Graham DJ, Laird D, Quintero JC, Rhodes A, Robbins HL, Roth E, Shivaprakash M, Yang T, Chodakewitz JA, Deutsch PJ, Leavitt RY, Massari FE, Mellors JW, Squires KE, Steigbigel RT, Teppler H & Emini EA. Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor. Journal of Virology 1996; 70:8270-8276.
63. Zhang YM, Imamichi H, Imamichi T, Lane HC, Falloon J, Vasudevachari MB & Salzman NP. Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its gag substrate cleavage sites. Journal of Virology 1997; 71:6662-6670.
64. Patick AK, Duran M, Cao Y, Shugarts D, Keller MR, Mazabel E, Knowles M, Chapman S, Kuritzkes DR & Markowitz M. Genotypic and phenotypic characterization of human immunodeficiency virus type 1 variants isolated from patients treated with the protease inhibitor nelfinavir. Antimicrobial Agents & Chemotherapy 1998; 42:2637-2644.
65. Condra JH, Holder DJ & Schleif WA. Genetic correlates of virological response to an indinavir-containing salvage regimen in patients with nelfinavir failure. Antiviral Therapy 1999; 4(Suppl. 1):44.
66. Nunez M, De Mendoza C, Valer L, Casas E, López-Calvo S, Castro Á, Rosón B, Podzamczer D, Rubio A, Berenguer J & Soriano V. Resistance mutations in HIV-infected patients experiencing early failure with nelfinavir-containing triple combinations. Medical Science Monitor 2002; 8:CR620-CR623.
67. Clotet B, Ruiz L, Martinez-Picado J, Negredo E, Hill A & Popescu M. Prevalence of HIV protease mutations on failure of nelfinavir-containing HAART: a retrospective analysis of four clinical studies and two observational cohorts. HIV Clinical Trials 2002; 3:316-323.
68. Sugiura W, Matsuda Z, Yokomaku Y, Hertogs K, Larder B, Oishi T, Okano A, Shiino T, Tatsumi M, Matsuda M, Abumi H, Takata N, Shirahata S, Yamada K, Yoshikura H & Nagai Y. Interference between D30N and L90M in selection and development of protease inhibitor-resistant human immunodeficiency virus type 1. Antimicrobial Agents & Chemotherapy 2002; 46:708-715.
69. Markowitz M, Conant M, Hurley A, Schluger R, Duran M, Peterkin J, Chapman S, Patick A, Hendricks A, Yuen GJ, Hoskins W, Clendeninn N & Ho DD. A preliminary evaluation of nelfinavir mesylate, an inhibitor of human immunodeficiency virus (HIV)-1 protease, to treat HIV infection. Journal of Infectious Diseases 1998; 177:1533-1540.
70. Grossman Z, Paxinos E, Auerbuch D, Maayan S, Parkin N, Engelhard D, Lorber M, Kedem E, Mileguir F, Vardinon N, Bentwich Z, Petropoulos C & Schapiro JM. XI International HIV Drug Resistance Workshop. Seville, Spain, 2002. Abstract 34.
71. Ariyoshi K, Matsuda M, Miura H, Tateishi S, Yamada K & Sugiura W. Patterns of point mutations associated with antiretroviral drug treatment failure in CRF01_AE (subtype E) infection differ from subtype B infection. Journal of Acquired Immune Deficiency Syndrome 2003; 33:3336-3342.
72. Maguire M, Shortino D, Klein A, Harris W, Manohitharajah V, Tisdale M, Elston R, Yeo J, Randall S, Xu F, Parker H, May J & Snowden W. Emergence of resistance to protease inhibitor amprenavir in human immunodeficiency virus type 1-infected patients: selection of four alternative viral protease genotypes and influence of viral susceptibility to coadministered reverse transcriptase nucleoside inhibitors. Antimicrobial Agents & Chemotherapy 2002; 46:731-738.
73. Paulsen D, Liao Q, Fusco G, St Clair M, Shaefer M & Ross L. Genotypic and phenotypic cross-resistance patterns to lopinavir and amprenavir in protease inhibitor-experienced patients with HIV viremia. AIDS Research & Human Retroviruses 2002; 18:1011-1019.
74. Ait-Khaled M, Rakik A, Griffin P, Stone C, Richards N, Thomas D, Falloon J & Tisdale M for the CNA2007 International Study Team. HIV-1 reverse transcriptase and protease resistance mutations selected during 16-72 weeks of therapy in isolates from antiretroviral therapy-experienced patients receiving abacavir/efavirenz/amprenavir in the CNA2007 study. Antiviral Therapy 2003; 8:111-120.
75. Eron JJ, Haubrich R, Lang W, Pagano G, Millard J, Wolfram J, Snowden W, Pedneault L & Tisdale M. A phase II trial of dual protease inhibitor therapy: amprenavir in combination with indinavir, nelfinavir or saquinavir. Journal of Acquired Immune Deficiency Syndromes 2001; 26:458-461.
76. Macmanus S, Yates P, White S, Richards N & Snowden W. GW433908 in ART-naive subjects: absence of resistance at 48 weeks with boosted regimen and APV-like resistance profile with unboosted regimen. 10th Conference on Retroviruses & Opportunistic Infections. Boston, Mass., USA, February 2003. Abstract 598.
77. Carrillo A, Stewart KD, Sham HL, Norbeck DW, Kohlbrenner WE, Leonard JM, Kempf DJ & Molla A. In vitro selection and characterization of human immunodeficiency virus type 1 variants with increased resistance to ABT-378, a novel protease inhibitor. Journal of Virology 1998; 72:7532-7541.
78. Kempf DJ, Isaacson JD, King MS, Brun SC, Sylte J, Richards B, Bernstein B, Rode R & Sun E. Analysis of the virological response with respect to baseline viral phenotype and genotype in protease inhibitor-experienced HIV-1-infected patients receiving lopinavir/ritonavir therapy. Antiviral Therapy 2002; 7:165-174.
79. Kempf DJ, Isaacson JD, King MS, Brun SC, Xu Y, Real K, Bernstein BM, Japour AJ, Sun E & Rode RA. Identification of genotypic changes in human immunodeficiency virus protease that correlate with reduced susceptibility to the protease inhibitor lopinavir among viral isolates from protease inhibitor-experienced patients. Journal of Virology 2001; 75:7462-7469.
80. Parkin NT, Chappey C & Petropoulos CJ. Improving lopinavir genotype algorithm through phenotype correlations: novel mutation patterns and amprenavir cross-resistance. AIDS 2003; 17:955-961.
81. Brun S, Kempf DJ, Bernstein B, Hsu A, Molla A, Mo H, Deetz C, Real K, Renz C, Xu Y, Marsh T, Freimuth W, Granneman GR & Sun E. Examination of the genetic barrier to in vivo resistance to ABT-378/ritonavir (ABT-378/r) in protease inhibitor experienced patients using the ABT-378 mutation score. 5th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland, October 2000. Abstract P333.
82. Masquelier B, Breilh D, Neau D, Lawson-Ayayi S, Lavignolle V, Ragnaud J-M, Dupon M, Morlat P, Dabis F, Fleury H & the Groupe d- Epidémiologie Clinique du SIDA en Aquitaine. Human immunodeficiency virus type 1 genotypic and pharmacokinetic determinants of the virological response to lopinavir-ritonavir-containing therapy in protease inhibitor-experienced patients. Antimicrobial Agents & Chemotherapy 2002; 46:2926-2932.
83. Colonno R, Rose R, Cianci C, Aldrovandi G, Parkin N & Friborg J. Emergence of atazanavir resistance and maintenance of susceptibility to other PIs is associated with an I50L substitution in HIV protease. 10th Conference on Retroviruses & Opportunistic Infections. Boston, Mass., USA, February 2003. Abstract 597.
84. Back NKT, van Wijk A, Remmerswaal D, van Monfort M, Nijhuis M, Schuurman R & Boucher CAB. In-vitro tipranavir susceptibility of HIV-1 isolates with reduced susceptibility to other protease inhibitors. AIDS 2000; 14:101-102.
85. Rusconi S, La Seta CS, Citterio P, Kurtagic S, Violin M, Balotta C, Moroni M, Galli M & d'Arminio-Monforte A. Susceptibility to PNU-140690 (tipranavir) of human immunodeficiency virus type 1 isolates derived from patients with multidrug resistance to other protease inhibitors. Antimicrobial Agents & Chemotherapy 2000; 44:1328-1332.
86. Cooper D, Hall D, Jayaweera D, Moreno S, Katlama C, Schneider S, Minoli L, Yeni P, Steigbigel R, McCallister S, Kohlbrenner V, Cauresma E, Sabo J & Mayers D. Baseline phenotypic susceptibility to tipranavir/ritonavir is retained in isolates from patients with multiple protease inhibitor experience (BI 1182.52). 10th Conference on Retroviruses & Opportunistic Infections. Boston, Mass., USA, February 2003. Abstract 596.
87. Larder B, Bloor S, Hertogs K, van den Eynde C, DeCian W, Wang Y & Freimuth W. Tipranavir is active against a large selection of highly protease inhibitor-resistant HIV-1 clinical samples. Antiviral Therapy 1999; 4(Suppl. 1):5. Abstract 5.
88. McCallister S, Kohlbrenner V, Squires K, Lazzarin A, Kumar P, Dejesus E, Nadler J, Gallant J, Wealmsley S, Yeni P, Leith J, Dohnanyi C, Hall D, Sabo JP, MacGregor TR, Verbiest W, McKenna P & Mayers D. Characterization of the impact of genotype, phenotype and inhibitory quotient on antiviral activity of tipranavir in highly treatment-experienced patients. Antiviral Therapy 2003; 8:S15. Abstract 12.
89. Condra JH, Petropoulos CJ, Ziermann R, Schleif WA, Shivaprakash M & Emini EA. Drug resistance and predicted virologic responses to human immunodeficiency virus type 1 protease inhibitor therapy. Journal of Infectious Diseases 2000; 182:758-765.
90. Katner HP, Paar DP, Nadler JP, Jensen EH, Wilson HM, Finn TS, Petruschke RA & Zeldin RK J. Open-label study of a twice-daily indinavir 800-mg/ritonavir 200-mg regimen in HIV-infected adults failing a protease inhibitor regimen. Journal of Acquired Immune Deficiency Syndromes 2002; 31:483-487.
91. Campo RE, Moreno JN, Suarez G, Miller N, Kolber MA, Holder DJ, Shivaprakash M, DeAngelis DM, Wright JL, Schleif WA, Emini EA & Condra JH. Efficacy of indinavir-ritonavir-based regimens in HIV-1-infected patients with prior protease inhibitor failures. AIDS 2003; 17:1933-1939.
92. Johnson VA, Brun-Vézinet F, Clotet B, Conway B, D'Aquila RT, Demeter LM, Kuritzkes D, Pillay D, Schapiro JM, Telenti A & Richman DD. Drug resistance mutations in HIV-1. International AIDS Society - USA. Topics in HIV Medicine 2003; 11:215-221.
93. Shafer RW, Winters MA, Palmer S & Merigan TC. Multiple concurrent reverse transcriptase and protease mutations and multidrug resistance of HIV-1 isolates from heavily treated patients. Annals of Internal Medicine 1998; 128:906-911.
94. Palmer S, Shafer RW & Merigan TC. Highly drug-resistant HIV-1 clinical isolates are cross-resistant to many antiretroviral compounds in current clinical development. AIDS 1999; 13:661-667.
95. Meyer DS, Peeters M, Jordens C, McKennna P, Van Der Geest R, Pauwels R & de Bethune M-P. A potent next-generation protease inhibitor: characterization of antiviral activity in multiple protease inhibitor- experienced patients participating in a phase IIa study. Antiviral Therapy 2003; 8:S18. Abstract 15.
96. King N, Prabu-Jeyabalan M, Wigerinck P, Bethune M-P & Schiffer CA. TMC-114 binds within the substrate envelope of HIV-1 protease, which could account for its efficacy against multi-protease inhibitor-resistant virus. Antiviral Therapy 2003; 8:S19. Abstract 16.
97. Johnson E, Winters MA, Vyas K, Merigan TC & Shafer RW. Preliminary characterization of a newly described protease substrate cleft mutation at position 23. Antiviral Therapy 2003; 8:S53. Abstract 48.
98. Ziermann R, Limoli K, Das K, Arnold E, Petropoulos CJ & Parkin NT. A mutation in human immunodeficiency virus type 1 protease, N88S, that causes in vitro hypersensitivity to amprenavir. Journal of Virology 2000; 74:4414-4419.
99. Schooley R, Haubrich R, Thompson M, Margolis D, Schneider S, Richman D, Kappa K, Yau L, Hassenthaler S & Hernandez J. Effect of amprenavir hype-susceptibility on the response to APV/ritonavir-based therapy in ART-experienced adults selected by baseline susceptibility (ESS40006): 24 weeks data. 10th Conference on Retroviruses & Opportunistic Infections. Boston, Mass., USA, February 2003. Abstract 143.
100. Romano L, Venturi G, Giomi S, Pippi L, Valensin PE & Zazzi M. Development and significance of resistance to protease inhibitors in HIV-1-infected adults under triple-drug therapy in clinical practice. Journal of Medical Virology 2002; 66:143-150.
101. Smeaton LM, DeGruttola V, Robbins GK & Shafer RW. ACTG (AIDS Clinical Trials Group) 384: a strategy trial comparing consecutive treatments for HIV-1. Controlled Clinical Trials 2001; 22:142-159.
102. Robbins G, Shafer R, Smeaton L, DeGruttola V, Pettinelli C, Snyder S, D'Aquila R & Vella S. Antiretroviral strategies in naive HIV+ subjects: comparison of sequential 3-drug regimens (ACTG 384). 14th International AIDS Conference. Barcelona, Spain, July 2002. Abstract LbOr20A.
103. Shafer R, Robbins G, Smeaton L, DeGruttola V, Pettinelli C, Snyder S, D'Aquila R & Vella S. Antiretroviral strategies in naive HIV+ subjects: comparison of 4-drug versus sequential 3-drug regimens (ACTG 384). XIV International AIDS Conference. Barcelona, Spain, July 2002. Abstract LbOr20B.
104. Kempf DJ, King MS, Bernstein B, Cernohous P, Bauer E, Moseley J, Gu K, Hsu A, Brun S & Sun E. Incidence of resistance in a double-blind study comparing lopinavir/ritonavir plus stavudine and lamivudine to nelfinavir plus stavudine and lamivudine. Journal of Infectious Diseases 2004; 189:51-60.
105. Staszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, Skiest D, Stanford J, Stryker R, Johnson P, Labriola DF, Farina D, Manion DJ & Ruiz NM, for the Study 006 Team. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivuine in the treatment of HIV-1 infection in adults. New England Journal of Medicine 1999; 341:1865-1873.
106. Khanna N, Kaufmann G, Weber R, Telenti A, Vernazza P, Bernasconi E, Hirschel B & Battegay M. Possible beneficial effect of sequential use of HAART regimens in individuals with undetectable viral load changing therapy due to drug intolerance. 10th Conference on Retroviruses & Opportunistic Infections. Boston, Mass., USA, February 2003. Abstract 571.
107. Iloeje U, Yuan Y, Tuomari A, L'Italien G, Mauskopf J & Moore R. Protease inhibitors may increase risk of cardiovascular disease in HIV-infected patients. 10th Conference on Retroviruses & Opportunistic Infections, Boston, Mass., USA, February 2003. Poster 746.
108. Murphy R, Pokrovsky V, Rozenbaum W, Wood R, Percival L, Odeshoo L & Giordano M. Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or ATV: 108-week results of BMS Study 008/044. 10th Conference on Retroviruses & Opportunistic Infections, Boston, Mass., USA, February 2003. Abstract 555.
109. Falloon J, Piscitelli S, Vogel S, Sadler B, Mitsuya H, Kavlick MF, Yoshimura K, Rogers M, LaFon S, Manion DJ, Lane HC & Masur H. Combination therapy with amprenavir, abacavir, and efavirenz in human immunodeficiency virus (HIV)-infected patients failing a protease-inhibitor regimen: pharmacokinetic drug interactions and antiviral activity. Clinical Infectious Diseases 2000; 30:313-318.
110. Race E, Dam E, Obry V, Paulous S & Clavel F. Analysis of HIV cross-resistance to protease inhibitors using a rapid single-cycle recombinant virus assay for patients failing on combination therapies. AIDS 1999; 13:2061-2068.
111. Schmidt B, Korn K, Moschik B, Paatz C & Uberla K & Walter H. Low level of cross-resistance to amprenavir (141W94) in samples from patients pretreated with other protease inhibitors. Antimicrobial Agents & Chemotherapy 2000; 44:3213-3216.
112. Duval X, Lamotte C, Race E, Descamps D, Damond F, Clavel F, Leport C, Peytavin G & Vilde JL. Amprenavir inhibitory quotient and virological response in human immunodeficiency virus-infected patients on an amprenavir-containing salvage regimen without or with ritonavir. Antimicrobial Agents & Chemotherapy 2002; 46:570-574.
113. Little SJ, Holte S, Routy J-P, Daar ES, Markowitz M, Collier AC, Koup RA, Mellors JW, Connick E, Conway B, Kilby M, Wang L, Whitcomb JM, Hellmann NS & Richman DD. Antiretroviral-drug resistance among patients recently infected with HIV. New England Journal of Medicine 2002; 347:385-394.
114. Ammaranond P, Cunningham P, Oelrichs R, Suzuki K, Harris C, Leas L, Grulich A, Cooper DA & Kelleher AD. Rates of transmission of antiretroviral drug resistant strains of HIV-1. Journal of Clinical Virology 2003; 26:153-161.
115. Wegner SA, Brodine SK, Mascola JR, Tasker SA, Shaffer RA, Starkey MJ, Barile A, Martin GJ, Aronson N, Emmons WW, Stephan K, Bloor S, Vingerhoets J, Hertogs K & Larder B. Prevalence of genotypic and phenotypic resistance to anti-retroviral drugs in a cohort of therapy-naive HIV-1 infected US military personnel. AIDS 2000; 14:1009-1015.
116. Ammaranond P, Cunningham P, Oelrichs R, Suzuki K, Harris C, Leas L, Grulich A, Cooper DA & Kelleher AD. No increase in protease resistance and a decrease in reverse transcriptase resistance mutations in primary HIV-1 infection: 1992-2001. AIDS 2003; 17:264-267.
117. Bennett DE, Zaidi IF, Heneine W, Woods T, Garcia-Lerma JG, Smith AJ, McCormick L & Weinstock HS. Prevalence of mutations associated with antiretroviral drug resistance among men and women newly diagnosed with HIV in 10 US cities, 1997-2001. Antiviral Therapy 2003; 8:S133. Abstract 119.
118. Grant RM, Hecht FM, Warmerdam M, Liu L, Liegler T, Petropoulos CJ, Hellmann NS, Chesney M, Busch MP & Kahn JO. Time trends in primary HIV-1 drug resistance among recently infected persons. Journal of the American Medical Association 2002; 288:181-188.
119. Hirsch MS. When and what antiretroviral therapy to start. 10th Conference on Retroviruses & Opportunistic Infections. Boston, Mass., USA, February 2003. Abstract 187.