Protease inhibitor resistance in HIV-infected patients: molecular and clinical perspectives.

The problem of HIV-1 drug resistance has established a need for new compounds that retain activity against mutated resistant viral isolates. Fortunately, a number of new compounds have recently been developed that possess excellent activity against HIV-1 strains that contain as many as eight relevant drug-resistance mutations in the viral protease (PR) gene. These newer protease inhibitors (PI) are characterized by higher genetic barrier for drug resistance, meaning that higher numbers of mutations are required for resistance to develop in comparison with older members of the PI family of drugs. Thus, different PIs can be used sequentially in HIV therapy in a manner that can overcome previous drug resistance and potentially forestall the development of additional resistance mutations in the viral PR. All currently used PIs, in general, require ritonavir to be used as a pharmacological boosting agent. There is a need to develop novel PIs, that will not require such boosting, and that are also characterized by potent antiviral activity and a high genetic barrier for resistance.

[1]  E A Emini,et al.  Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. , 1997, The New England journal of medicine.

[2]  R. Weber,et al.  Cardiovascular disease in HIV infection. , 2006, American heart journal.

[3]  R. Rathbun,et al.  Low-Dose Ritonavir for Protease Inhibitor Pharmacokinetic Enhancement , 2002, The Annals of pharmacotherapy.

[4]  Hsinyi Tsang,et al.  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* , 2002, The Journal of Biological Chemistry.

[5]  A. Molla,et al.  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 , 2005, Journal of Virology.

[6]  W. Prince,et al.  Pharmacokinetics of GW433908, a Prodrug of Amprenavir, in Healthy Male Volunteers , 2002, Journal of clinical pharmacology.

[7]  Anne-Mieke Vandamme,et al.  Investigation of Baseline Susceptibility to Protease Inhibitors in HIV-1 Subtypes C, F, G and Crf02_Ag , 2005, Antiviral therapy.

[8]  A. Winston,et al.  The normalized inhibitory quotient of boosted protease inhibitors is predictive of viral load response in treatment-experienced HIV-1-infected individuals , 2005, AIDS.

[9]  Arun K. Ghosh,et al.  A Potent Human Immunodeficiency Virus Type 1 Protease Inhibitor, UIC-94003 (TMC-126), and Selection of a Novel (A28S) Mutation in the Protease Active Site , 2002, Journal of Virology.

[10]  A. Mocroft,et al.  Virological rebound after suppression on highly active antiretroviral therapy , 2003, AIDS.

[11]  A. Lazzarin,et al.  Comparison of a rule-based algorithm with a phenotype-based algorithm for the interpretation of HIV genotypes in guiding salvage regimens in HIV-infected patients by a randomized clinical trial: the mutations and salvage study. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[12]  J. Martinez-Picado,et al.  Replicative Fitness of Protease Inhibitor-Resistant Mutants of Human Immunodeficiency Virus Type 1 , 1999, Journal of Virology.

[13]  C. Flexner.  Dual protease inhibitor therapy in HIV-infected patients: pharmacologic rationale and clinical benefits. , 2000, Annual review of pharmacology and toxicology.

[14]  L. Naeger,et al.  Food and Drug Administration analysis of tipranavir clinical resistance in HIV-1-infected treatment-experienced patients , 2007, AIDS.

[15]  Darren K Mcguire,et al.  Impaired glucose tolerance and impaired fasting glucose — a review of diagnosis, clinical implications and management , 2005, Diabetes & vascular disease research.

[16]  A. Telenti,et al.  Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study , 1999, The Lancet.

[17]  R. Swanstrom,et al.  Nelfinavir-Resistant, Amprenavir-Hypersusceptible Strains of Human Immunodeficiency Virus Type 1 Carrying an N88S Mutation in Protease Have Reduced Infectivity, Reduced Replication Capacity, and Reduced Fitness and Process the Gag Polyprotein Precursor Aberrantly , 2002, Journal of Virology.

[18]  P. Das.  XVI International AIDS Conference. , 2006, The Lancet. Infectious diseases.

[19]  B. Hirschel,et al.  Absence of Resistance Mutations in Antiretroviral-Naive Patients Treated with Ritonavir-Boosted Saquinavir , 2005, Antiviral therapy.

[20]  I. Luque,et al.  Structure-based prediction of binding affinities and molecular design of peptide ligands. , 1998, Methods in enzymology.

[21]  V. Soriano,et al.  Plasma levels of atazanavir and the risk of hyperbilirubinemia are predicted by the 3435C-->T polymorphism at the multidrug resistance gene 1. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[22]  Elizabeth Connick,et al.  Antiretroviral-drug resistance among patients recently infected with HIV. , 2002, The New England journal of medicine.

[23]  R. Elston,et al.  Long-term (120-Week) antiviral efficacy and tolerability of fosamprenavir/ritonavir once daily in therapy-naive patients with HIV-1 infection: an uncontrolled, open-label, single-arm follow-on study. , 2006, Clinical therapeutics.

[24]  W. Heneine,et al.  Susceptibility of HIV-2, Siv and Shiv to Various Anti-HIV-1 Compounds: Implications for Treatment and Postexposure Prophylaxis , 2004, Antiviral therapy.

[25]  P. Narciso,et al.  Variable prediction of antiretroviral treatment outcome by different systems for interpreting genotypic human immunodeficiency virus type 1 drug resistance. , 2003, Journal of Infectious Diseases.

[26]  R. Chaisson,et al.  Highly Active Antiretroviral Therapy in a Large Urban Clinic: Risk Factors for Virologic Failure and Adverse Drug Reactions , 1999, Annals of Internal Medicine.

[27]  A. Velázquez‐Campoy,et al.  Amplification of the effects of drug resistance mutations by background polymorphisms in HIV-1 protease from African subtypes. , 2002, Biochemistry.

[28]  J. Weber,et al.  Emergence of resistant variants of HIV in vivo during monotherapy with the proteinase inhibitor saquinavir. , 1997, The Journal of antimicrobial chemotherapy.

[29]  Bradley Efron,et al.  The Effect of High-Dose Saquinavir on Viral Load and CD4+ T-Cell Counts in HIV-Infected Patients , 1996, Annals of Internal Medicine.

[30]  C. Tinelli,et al.  Real versus virtual phenotype to guide treatment in heavily pretreated patients: 48-week follow-up of the Genotipo-Fenotipo di Resistenza (GenPheRex) trial. , 2003, Journal of acquired immune deficiency syndromes.

[31]  P. Harrigan,et al.  Influence of polymorphisms within the CX3CR1 and MDR-1 genes on initial antiretroviral therapy response , 2003, AIDS.

[32]  C. Petropoulos,et al.  Drug resistance and predicted virologic responses to human immunodeficiency virus type 1 protease inhibitor therapy. , 2000, The Journal of infectious diseases.

[33]  V. Calvez,et al.  Virological and Pharmacological Parameters Predicting the Response to Lopinavir-Ritonavir in Heavily Protease Inhibitor-Experienced Patients , 2005, Antimicrobial Agents and Chemotherapy.

[34]  C. Flexner,et al.  Protease Inhibitors in AIDS Therapy , 2001 .

[35]  J S Mills,et al.  Antiviral properties of Ro 31-8959, an inhibitor of human immunodeficiency virus (HIV) proteinase. , 1991, Antiviral research.

[36]  A. D. Rodrigues,et al.  Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir , 1997, Antimicrobial agents and chemotherapy.

[37]  E. Arts,et al.  Fitness of drug resistant HIV-1: methodology and clinical implications. , 2002, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[38]  B. Masquelier,et al.  Human Immunodeficiency Virus Type 1 Genotypic and Pharmacokinetic Determinants of the Virological Response to Lopinavir-Ritonavir-Containing Therapy in Protease Inhibitor-Experienced Patients , 2002, Antimicrobial Agents and Chemotherapy.

[39]  D. Lamarre,et al.  Second locus involved in human immunodeficiency virus type 1 resistance to protease inhibitors , 1996, Journal of virology.

[40]  Jonathan M. Schapiro,et al.  Genotypic Changes in Human Immunodeficiency Virus Type 1 Protease Associated with Reduced Susceptibility and Virologic Response to the Protease Inhibitor Tipranavir , 2006, Journal of Virology.

[41]  D. Greenblatt,et al.  Inhibition of desipramine hydroxylation (Cytochrome P450-2D6) in vitro by quinidine and by viral protease inhibitors: relation to drug interactions in vivo. , 1998, Journal of pharmaceutical sciences.

[42]  Lines drawn in epitope wars , 1995, Nature.

[43]  C. Cohen.  Ritonavir-boosted protease inhibitors, Part 1: strategies for balancing efficacy with effects on lipids. , 2005, The AIDS reader.

[44]  D. Torre,et al.  Antiretroviral drug resistance testing in patients with HIV-1 infection: A meta-analysis study , 2002, HIV clinical trials.

[45]  A. Velázquez‐Campoy,et al.  Structural and thermodynamic basis of resistance to HIV-1 protease inhibition: implications for inhibitor design. , 2003, Current drug targets. Infectious disorders.

[46]  M A Fischl,et al.  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. AIDS Clinical Trials Group 320 Study Team. , 1997, The New England journal of medicine.

[47]  A. Wu,et al.  Self‐Reported Symptoms and Medication Side Effects Influence Adherence to Highly Active Antiretroviral Therapy in Persons With HIV Infection , 2001, Journal of acquired immune deficiency syndromes.

[48]  Maureen M Goodenow,et al.  Secondary mutations M36I and A71V in the human immunodeficiency virus type 1 protease can provide an advantage for the emergence of the primary mutation D30N. , 2003, Biochemistry.

[49]  S. Hammer,et al.  Detection of drug-resistant minority variants of HIV-1 during virologic failure of indinavir, lamivudine, and zidovudine. , 2004, The Journal of infectious diseases.

[50]  Dan Engelhard,et al.  Mutation D30N Is Not Preferentially Selected by Human Immunodeficiency Virus Type 1 Subtype C in the Development of Resistance to Nelfinavir , 2004, Antimicrobial Agents and Chemotherapy.

[51]  Lidia Ruiz,et al.  Prevalence of HIV Protease Mutations on Failure of Nelfinavir-Containing HAART: A Retrospective Analysis of Four Clinical Studies and Two Observational Cohorts , 2002, HIV clinical trials.

[52]  M. Wainberg,et al.  Natural Polymorphisms in the Human Immunodeficiency Virus Type 2 Protease Can Accelerate Time to Development of Resistance to Protease Inhibitors , 2006, Antimicrobial Agents and Chemotherapy.

[53]  R. Elston,et al.  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 , 2002, Antimicrobial Agents and Chemotherapy.

[54]  M. Galindo,et al.  Recomendaciones GESIDA/SEFH/PNS para mejorar la adherencia al tratamiento antirretroviral en el año 2004 , 1999 .

[55]  V. Soriano,et al.  Prediction of virological response to lopinavir/ritonavir using the genotypic inhibitory quotient. , 2004, AIDS research and human retroviruses.

[56]  Guy Burtonboy,et al.  Variant Human Immunodeficiency Virus Type 1 Proteases and Response to Combination Therapy Including a Protease Inhibitor , 2001, Antimicrobial Agents and Chemotherapy.

[57]  B. Schmidt,et al.  Distinct cross-resistance profiles of the new protease inhibitors amprenavir, lopinavir, and atazanavir in a panel of clinical samples , 2003, AIDS.

[58]  J. Mellors,et al.  Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor , 1996, Journal of virology.

[59]  Ladislau C. Kovari,et al.  Crystal Structures of a Multidrug-Resistant Human Immunodeficiency Virus Type 1 Protease Reveal an Expanded Active-Site Cavity , 2004, Journal of Virology.

[60]  D. Podzamczer,et al.  Genotype and phenotype at baseline and at failure in human immunodeficiency virus-infected antiretroviral-naive patients in a randomized trial comparing zidovudine and lamivudine plus nelfinavir or nevirapine. , 2003, The Journal of infectious diseases.

[61]  Jacques Fellay,et al.  Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study , 2002, The Lancet.

[62]  J. Falloon,et al.  Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its Gag substrate cleavage sites , 1997, Journal of virology.

[63]  E. Acosta,et al.  Pharmacokinetic Enhancement of Protease Inhibitor Therapy , 2004, Clinical pharmacokinetics.

[64]  L. Bacheler,et al.  Prevalence of the HIV-1 protease mutation I47A in clinical practice and association with lopinavir resistance , 2006, AIDS.

[65]  B. Efron,et al.  Resistance mutations to zidovudine and saquinavir in patients receiving zidovudine plus saquinavir or zidovudine and zalcitabine plus saquinavir in AIDS clinical trials group 229. , 1999, The Journal of infectious diseases.

[66]  P. Clevenbergh,et al.  Variable Virological Outcomes According to the Center Providing Antiretroviral Therapy Within the PharmAdapt Clinical Trial , 2003, HIV clinical trials.

[67]  R L Juliano,et al.  A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. , 1976, Biochimica et biophysica acta.

[68]  M. Moroni,et al.  Susceptibility to PNU-140690 (Tipranavir) of Human Immunodeficiency Virus Type 1 Isolates Derived from Patients with Multidrug Resistance to Other Protease Inhibitors , 2000, Antimicrobial Agents and Chemotherapy.

[69]  D. Bangsberg,et al.  Modeling the HIV protease inhibitor adherence-resistance curve by use of empirically derived estimates. , 2004, The Journal of infectious diseases.

[70]  Wei-Shau Hu,et al.  Retroviral recombination and reverse transcription. , 1990, Science.

[71]  Peter J Piliero,et al.  Atazanavir: a novel HIV-1 protease inhibitor , 2002, Expert opinion on investigational drugs.

[72]  R. Haubrich,et al.  The Correlation between Plasma Concentrations of Protease Inhibitors, Medication Adherence and Virological Outcome in HIV-Infected Patients , 2004, Antiviral therapy.

[73]  W. Venter,et al.  Failure of lopinavir-ritonavir (Kaletra)-containing regimen in an antiretroviral-naive patient. , 2004, AIDS.

[74]  Evolution of resistance during first-line treatment with boosted fosamprenavir is associated with baseline mutations. , 2006, AIDS.

[75]  S. Khoo,et al.  Modulation of the intracellular accumulation of saquinavir in peripheral blood mononuclear cells by inhibitors of MRP1, MRP2, P-gp and BCRP , 2005, AIDS.

[76]  D. Bangsberg,et al.  Paradoxes of adherence and drug resistance to HIV antiretroviral therapy. , 2004, The Journal of antimicrobial chemotherapy.

[77]  S. Gulnik,et al.  Protease inhibitors: resistance, cross-resistance, fitness and the choice of initial and salvage therapies. , 1999, AIDS.

[78]  K. Hertogs,et al.  Impact of frequent natural polymorphisms at the protease gene on the in vitro susceptibility to protease inhibitors in HIV-1 non-B subtypes. , 2004, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[79]  B Clotet,et al.  Antiretroviral drug resistance testing in adults with HIV infection: implications for clinical management. International AIDS Society--USA Panel. , 1998, JAMA.

[80]  V. Calvez,et al.  Clinical validation of atazanavir/ritonavir genotypic resistance score in protease inhibitor-experienced patients , 2006, AIDS.

[81]  I. Pastan,et al.  Biochemistry of multidrug resistance mediated by the multidrug transporter. , 1993, Annual review of biochemistry.

[82]  G R Wilkinson,et al.  Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[83]  P. Harrigan,et al.  Adherence–resistance relationships for protease and non-nucleoside reverse transcriptase inhibitors explained by virological fitness , 2006, AIDS.

[84]  Donald W. Miller,et al.  Quantitative Assessment of HIV-1 Protease Inhibitor Interactions with Drug Efflux Transporters in the Blood–Brain Barrier , 2005, Pharmaceutical Research.

[85]  D. Nauwelaers,et al.  The NIQ of Lopinavir is Predictive of a 48-Week Virological Response in Highly Treatment-Experienced HIV-1-Infected Subjects Treated with a Lopinavir/Ritonavir-Containing Regimen , 2003, Antiviral Therapy.

[86]  S. A. Thomas,et al.  Anti-HIV drug distribution to the central nervous system. , 2004, Current pharmaceutical design.

[87]  J. Schapiro,et al.  Drug-resistance genotyping in HIV-1 therapy: the VIRAD APT randomi sed controlled trial , 1999, The Lancet.

[88]  E. Martinez,et al.  Metabolic abnormalities and body fat redistribution in HIV-1 infected patients: the lipodystrophy syndrome. , 1999, Current opinion in infectious diseases.

[89]  Dale J. Kempf,et al.  Virtual Inhibitory Quotient Predicts Response to Ritonavir Boosting of Indinavir-Based Therapy in Human Immunodeficiency Virus-Infected Patients with Ongoing Viremia , 2002, Antimicrobial Agents and Chemotherapy.

[90]  G. Friedland,et al.  Attaining higher goals in HIV treatment: the central importance of adherence. , 1999, AIDS.

[91]  S. Thaisrivongs,et al.  Structure-based discovery of Tipranavir disodium (PNU-140690E): a potent, orally bioavailable, nonpeptidic HIV protease inhibitor. , 1999, Biopolymers.

[92]  M. Drachler,et al.  Characteristics of HIV antiretroviral regimen and treatment adherence. , 2003, The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases.

[93]  P. Sinko,et al.  P-Glycoprotein and Mutlidrug Resistance-Associated Proteins Limit the Brain Uptake of Saquinavir in Mice , 2005, Journal of Pharmacology and Experimental Therapeutics.

[94]  B. Rodés,et al.  High rate of proV47A selection in HIV-2 patients failing lopinavir-based HAART , 2006, AIDS.

[95]  A. Zolopa,et al.  High levels of adherence do not prevent accumulation of HIV drug resistance mutations , 2003, AIDS.

[96]  T. Elbeik,et al.  In vivo emergence of drug-resistant mutations at less than 50 HIV-1 RNA copies/mL that are maintained at viral rebound in longitudinal plasma samples from human immunodeficiency virus type-1-infected patients on highly active antiretroviral therapy. , 2001, Journal of human virology.

[97]  V. Calvez,et al.  Mechanisms of virologic failure in previously untreated HIV-infected patients from a trial of induction-maintenance therapy. Trilège (Agence Nationale de Recherches sur le SIDA 072) Study Team). , 2000, JAMA.

[98]  A. Velázquez‐Campoy,et al.  Overcoming drug resistance in HIV‐1 chemotherapy: The binding thermodynamics of Amprenavir and TMC‐126 to wild‐type and drug‐resistant mutants of the HIV‐1 protease , 2002, Protein science : a publication of the Protein Society.

[99]  David J. Livingston,et al.  Kinetic Characterization of Human Immunodeficiency Virus Type-1 Protease-resistant Variants* , 1996, The Journal of Biological Chemistry.

[100]  E. Daar,et al.  Dual protease inhibitor therapy in the management of the HIV-1 , 2000, Expert opinion on pharmacotherapy.

[101]  A. Antinori,et al.  Selection of Antiretroviral Therapy Guided by Genotypic or Phenotypic Resistance Testing: An Open-Label, Randomized, Multicenter Study (PhenGen) , 2004, Journal of acquired immune deficiency syndromes.

[102]  J. Condra,et al.  In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors , 1995, Nature.

[103]  F. Maggiolo,et al.  Similar adherence rates favor different virologic outcomes for patients treated with nonnucleoside analogues or protease inhibitors. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[104]  A. Velázquez‐Campoy,et al.  Thermodynamic rules for the design of high affinity HIV-1 protease inhibitors with adaptability to mutations and high selectivity towards unwanted targets. , 2004, The international journal of biochemistry & cell biology.

[105]  Irene Luque,et al.  Structural parameterization of the binding enthalpy of small ligands , 2002, Proteins.

[106]  S. Hammer,et al.  The Relation between Baseline HIV Drug Resistance and Response to Antiretroviral Therapy: Re-Analysis of Retrospective and Prospective Studies Using a Standardized Data Analysis Plan , 2000, Antiviral therapy.

[107]  I B Duncan,et al.  Characterization of human immunodeficiency virus type 1 mutants with decreased sensitivity to proteinase inhibitor Ro 31-8959. , 1995, Virology.

[108]  Richard A. Rode,et al.  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 , 2001, Journal of Virology.

[109]  Dale J. Kempf,et al.  In Vitro Selection and Characterization of Human Immunodeficiency Virus Type 1 Variants with Increased Resistance to ABT-378, a Novel Protease Inhibitor , 1998, Journal of Virology.

[110]  T. Macgregor,et al.  A 14-Day Dose-Response Study of the Efficacy, Safety, and Pharmacokinetics of the Nonpeptidic Protease Inhibitor Tipranavir in Treatment-Naive HIV-1–Infected Patients , 2004, Journal of acquired immune deficiency syndromes.

[111]  Susan Swindells,et al.  Adherence to Protease Inhibitor Therapy and Outcomes in Patients with HIV Infection , 2000, Annals of Internal Medicine.

[112]  A. Aleixo,et al.  HIV-1 genotypes related to failure of nelfinavir as the first protease inhibitor treatment. , 2005, The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases.

[113]  J. Schubert,et al.  No influence of the P-glycoprotein genotype (MDR1 C3435T) on plasma levels of lopinavir and efavirenz during antiretroviral treatment. , 2003, European journal of medical research.

[114]  V. Calvez,et al.  GENOPHAR: a randomized study of plasma drug measurements in association with genotypic resistance testing and expert advice to optimize therapy in patients failing antiretroviral therapy * , 2004, HIV medicine.

[115]  Celia A Schiffer,et al.  Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor. , 2005, Journal of medicinal chemistry.

[116]  C. Petropoulos,et al.  Improving lopinavir genotype algorithm through phenotype correlations: novel mutation patterns and amprenavir cross-resistance , 2003, AIDS.

[117]  Neil Parkin,et al.  Identification of I50L as the signature atazanavir (ATV)-resistance mutation in treatment-naive HIV-1-infected patients receiving ATV-containing regimens. , 2004, The Journal of infectious diseases.

[118]  Jeffrey N. Martin,et al.  Isolated lopinavir resistance after virological rebound of a ritonavir/lopinavir-based regimen. , 2004, AIDS.

[119]  I. Duncan,et al.  Correlation of response to treatment and HIV genotypic changes during Phase III trials with saquinavir and reverse transcriptase inhibitor combination therapy , 1998, AIDS.

[120]  T. Merigan,et al.  "Wide-open" 1.3 A structure of a multidrug-resistant HIV-1 protease as a drug target. , 2005, Structure.

[121]  M. Lederman,et al.  Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy , 2003, AIDS.

[122]  Joel E Gallant,et al.  Association between adherence to antiretroviral therapy and human immunodeficiency virus drug resistance. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[123]  L. Mayer,et al.  Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. , 2000, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[124]  J. Ioannidis,et al.  Limited benefit of antiretroviral resistance testing in treatment-experienced patients: a meta-analysis , 2004, AIDS.

[125]  D. R. Kuritzkes,et al.  Genotypic and Phenotypic Characterization of Human Immunodeficiency Virus Type 1 Variants Isolated from Patients Treated with the Protease Inhibitor Nelfinavir , 1998, Antimicrobial Agents and Chemotherapy.

[126]  L. Loeb,et al.  Fidelity of HIV-1 reverse transcriptase. , 1988, Science.

[127]  D. Richman,et al.  2022 update of the drug resistance mutations in HIV-1. , 2022, Topics in antiviral medicine.

[128]  D. Back,et al.  Principles and practice of HIV‐protease inhibitor pharmacoenhancement , 2001, HIV medicine.

[129]  Amalio Telenti,et al.  CD4-cell count in HIV-1-infected individuals remaining viraemic with highly active antiretroviral therapy (HAART) , 1998, The Lancet.

[130]  J. Arribas,et al.  Lipid disorders in antiretroviral-naive patients treated with lopinavir/ritonavir-based HAART: frequency, characterization and risk factors. , 2005, The Journal of antimicrobial chemotherapy.

[131]  S. Moreno,et al.  Individualizing salvage regimens: the inhibitory quotient (Ctrough/IC50) as predictor of virological response. , 2003, AIDS.

[132]  Richard A. Loftus,et al.  HIV RNA and CD4 cell count response to protease inhibitor therapy in an urban AIDS clinic: response to both initial and salvage therapy. , 1999, AIDS.

[133]  B. Hirschel,et al.  A Prospective Study of Efficacy and Safety of Once-Daily Saquinavir/Ritonavir plus Two Nucleoside Reverse Transcriptase Inhibitors in Treatment-Naive Thai Patients , 2005, Antiviral therapy.

[134]  Kaneo Yamada,et al.  Gag Non-Cleavage Site Mutations Contribute to Full Recovery of Viral Fitness in Protease Inhibitor-Resistant Human Immunodeficiency Virus Type 1 , 2004, Antimicrobial Agents and Chemotherapy.

[135]  David A. Stock,et al.  BMS-232632, a Highly Potent Human Immunodeficiency Virus Protease Inhibitor That Can Be Used in Combination with Other Available Antiretroviral Agents , 2000, Antimicrobial Agents and Chemotherapy.

[136]  M. Segal,et al.  Persistence of primary drug resistance among recently HIV-1 infected adults , 2004, AIDS.

[137]  L. Calza,et al.  Dyslipidaemia associated with antiretroviral therapy in HIV-infected patients. , 2003, The Journal of antimicrobial chemotherapy.

[138]  Masayuki Hata,et al.  Resistant mechanism against nelfinavir of human immunodeficiency virus type 1 proteases. , 2005 .

[139]  C. Rouzioux,et al.  HIV-1 resistant strains acquired at the time of primary infection massively fuel the cellular reservoir and persist for lengthy periods of time , 2006, AIDS.

[140]  Lidia Ruiz,et al.  Clinical utility of HIV-1 genotyping and expert advice: the Havana trial , 2002, AIDS.

[141]  JD Lundgren,et al.  Updated European Recommendations for the Clinical Use of HIV Drug Resistance Testing , 2004, Antiviral therapy.

[142]  Laura Monno,et al.  Drug resistance mutations and newly recognized treatment‐related substitutions in the HIV‐1 protease gene: Prevalence and associations with drug exposure and real or virtual phenotypic resistance to protease inhibitors in two clinical cohorts of antiretroviral experienced patients , 2004, Journal of medical virology.

[143]  V. Calvez,et al.  Genotypic Inhibitory Quotient as Predictor of Virological Response to Ritonavir-Amprenavir in Human Immunodeficiency Virus Type 1 Protease Inhibitor-Experienced Patients , 2003, Antimicrobial Agents and Chemotherapy.

[144]  M. Wainberg,et al.  Persistence of multidrug-resistant HIV-1 in primary infection leading to superinfection , 2004, AIDS.

[145]  O. Adeyemi,et al.  How does expert advice impact genotypic resistance testing in clinical practice? , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[146]  D. McIntire,et al.  Effect of Protease Inhibitor Therapy on Glucose Intolerance in Pregnancy , 2006, Obstetrics and gynecology.

[147]  D. Ho,et al.  Ordered accumulation of mutations in HIV protease confers resistance to ritonavir , 1996, Nature Medicine.

[148]  E. Acosta.  Pharmacokinetic Enhancement of Protease Inhibitors , 2002, Journal of acquired immune deficiency syndromes.

[149]  L. Sandvik,et al.  An algorithm‐based genotypic resistance score is associated with clinical outcome in HIV‐1‐infected adults on antiretroviral therapy , 2004, HIV medicine.

[150]  D. Bangsberg,et al.  Higher Rates of Viral Suppression with Nonnucleoside Reverse Transcriptase Inhibitors Compared to Single Protease Inhibitors Are Not Explained by Better Adherence , 2004, HIV clinical trials.

[151]  D. Kempf,et al.  Relationship between adherence and the development of resistance in antiretroviral-naive, HIV-1-infected patients receiving lopinavir/ritonavir or nelfinavir. , 2005, The Journal of infectious diseases.

[152]  O. Kirk,et al.  Resistance profiles and adherence at primary virological failure in three different highly active antiretroviral therapy regimens: analysis of failure rates in a randomized study , 2004, HIV medicine.

[153]  M. Hirsch,et al.  Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens. , 2000, JAMA.

[154]  D. Ho,et al.  Infection with multidrug resistant, dual-tropic HIV-1 and rapid progression to AIDS: a case report , 2005, The Lancet.

[155]  N. Parkin,et al.  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 , 2003, Antimicrobial Agents and Chemotherapy.

[156]  S. Khoo,et al.  The intracellular pharmacology of antiretroviral protease inhibitors. , 2004, The Journal of antimicrobial chemotherapy.

[157]  C. Rouzioux,et al.  Genotypic drug resistance during HIV-1 primary infection in France (1996-1999): frequency and response to treatment. , 2002, AIDS.

[158]  D. Faulds,et al.  Saquinavir. A review of its pharmacology and clinical potential in the management of HIV infection. , 1996, Drugs.

[159]  R. Myers,et al.  In vitro selection and characterization of human immunodeficiency virus type 1 (HIV-1) isolates with reduced sensitivity to hydroxyethylamino sulfonamide inhibitors of HIV-1 aspartyl protease , 1995, Journal of virology.

[160]  Brendan A. Larder,et al.  Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples , 2000, AIDS.

[161]  B. Brew,et al.  Independent Evolution of Human Immunodeficiency Virus (HIV) Drug Resistance Mutations in Diverse Areas of the Brain in HIV-Infected Patients, with and without Dementia, on Antiretroviral Treatment , 2004, Journal of Virology.

[162]  Amalio Telenti,et al.  Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia. , 2005, The Journal of infectious diseases.

[163]  P. Harrigan,et al.  Predictors of HIV drug-resistance mutations in a large antiretroviral-naive cohort initiating triple antiretroviral therapy. , 2005, The Journal of infectious diseases.

[164]  R. Elston,et al.  Changes in Human Immunodeficiency Virus Type 1 Gag at Positions L449 and P453 Are Linked to I50V Protease Mutants In Vivo and Cause Reduction of Sensitivity to Amprenavir and Improved Viral Fitness In Vitro , 2002, Journal of Virology.

[165]  F. Sharom,et al.  Functional reconstitution of drug transport and ATPase activity in proteoliposomes containing partially purified P-glycoprotein. , 1993, The Journal of biological chemistry.

[166]  M. Hughes,et al.  Pharmacokinetics of Saquinavir plus Low-Dose Ritonavir in Human Immunodeficiency Virus-Infected Pregnant Women , 2004, Antimicrobial Agents and Chemotherapy.

[167]  D. Ho,et al.  Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic human immunodeficiency virus protease inhibitor , 1997, Antimicrobial agents and chemotherapy.