This Article  • Full text  • PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (425)  • Contact me when this article is cited  Related Content  • Related articles  • Similar articles in JAMA  Topic Collections  • HIV/AIDS  • Alert me on articles by topic

Implications for Clinical Management

Martin S. Hirsch, MD; Brian Conway, MD; Richard T. D'Aquila, MD; Victoria A. Johnson, MD; Françoise Brun-Vézinet, MD; Bonaventura Clotet, MD, PhD; Lisa M. Demeter, MD; Scott M. Hammer, MD; Donna M. Jacobsen; Daniel R. Kuritzkes, MD; Clive Loveday, MD, PhD; John W. Mellors, MD; Stefano Vella, MD; Douglas D. Richman, MD; for the International AIDS Society–USA Panel

JAMA. 1998;279:1984-1991.

Objectives.— To review current knowledge of the biology and clinical implications of human immunodeficiency virus (HIV) resistance to antiretroviral drugs, describe assays for measuring resistance, and assess their use in clinical practice.

Participants.— The International AIDS Society-USA assembled a panel of 13 physicians with expertise in basic science, clinical research, and patient care relevant to HIV resistance to antiretroviral drugs.

Evidence.— We reviewed available data from published reports and presented at national and international research conferences. Basic science research, clinical trial results, and expert opinions were used to form the basis of this report. Data on methods for and characteristics of specific genotypic and phenotypic assays were obtained from manufacturers and service providers.

Consensus Process.— The panel met regularly between October 1997 and April 1998. Panel subgroups developed and discussed different sections of the report before discussing them with the entire panel. Conclusions and suggested approaches to the use of resistance testing were determined by group consensus.

Conclusions.— Plasma HIV RNA level and CD4⁺ cell count are the primary values that should be used to guide the initiation of antiretroviral therapy and subsequent changes in therapy. Possible causes of treatment failure other than development of drug resistance that should be considered are adherence, drug potency, and pharmacokinetic issues. Genotypic and phenotypic testing for HIV resistance to antiretroviral drugs may prove useful for individual patient management. Assays under development need validation, standardization, and a clearer definition of their clinical roles. Possible current roles of resistance testing for choosing an initial regimen or changing antiretroviral therapy, as well as possible implications of the presence or absence of phenotypic resistance and genotypic changes, are discussed.

From Harvard Medical School, Boston, Mass (Drs Hirsch, Hammer, and D'Aquila); St. Paul's Hospital, Vancouver, British Columbia (Dr Conway); University of Alabama at Birmingham School of Medicine and Birmingham Veterans Affairs Medical Center, Birmingham (Dr Johnson); Hôpital Bichat-Claude Bernard, Paris, France (Dr Brun-Vézinet); Fundacio irsaCaixa and HIV Unit, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain (Dr Clotet); University of Rochester, Rochester, NY (Dr Demeter); The International AIDS Society–USA, San Francisco, Calif (Ms Jacobsen); University of Colorado Health Sciences Center, Denver (Dr Kuritzkes); The Royal Free Hospital Medical School, London, England (Dr Loveday); University of Pittsburgh Medical Center, Pittsburgh, Pa (Dr Mellors); Istituto Superiore di Sanità, Rome, Italy (Dr Vella); and University of California San Diego and San Diego Veterans Affairs Medical Center, San Diego (Dr Richman).

RELATED ARTICLES

Public Health Implications of Antiretroviral Therapy and HIV Drug Resistance
Mark A. Wainberg and Gerald Friedland
JAMA. 1998;279(24):1977-1983.
ABSTRACT | FULL TEXT  

Drug-Resistant HIV-1: The Virus Strikes Back
Douglas L. Mayers
JAMA. 1998;279(24):2000-2002.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Pharmacoepidemiological approach to the predisposing factors for highly active antiretroviral therapy failure in an HIV-positive cohort from Cordoba City (Argentina) 1995-2005
Soria et al.
Int J STD AIDS 2008;19:335-338.
ABSTRACT | FULL TEXT  

Treatment for Adult HIV Infection: 2006 Recommendations of the International AIDS Society-USA Panel
Hammer et al.
JAMA 2006;296:827-843.
ABSTRACT | FULL TEXT  

DEPENDENCE OF NELFINAVIR BRAIN UPTAKE ON DOSE AND TISSUE CONCENTRATIONS OF THE SELECTIVE P-GLYCOPROTEIN INHIBITOR ZOSUQUIDAR IN RATS
Anderson et al.
Drug Metab. Dispos. 2006;34:653-659.
ABSTRACT | FULL TEXT  

Antiretroviral activity and safety of lopinavir/ritonavir in protease inhibitor-experienced HIV-infected children with severe-moderate immunodeficiency
Resino et al.
J Antimicrob Chemother 2006;57:579-582.
FULL TEXT  

GH treatment reduces trunkal adiposity in HIV-infected patients with lipodystrophy: a randomized placebo-controlled study
Luzi et al.
Eur J Endocrinol 2005;153:781-789.
ABSTRACT | FULL TEXT  

Outcome of Critically Ill Human Immunodeficiency Virus-Infected Patients in the Era of Highly Active Antiretroviral Therapy
Khouli et al.
J Intensive Care Med 2005;20:279-285.
ABSTRACT  

Gln145Met/Leu Changes in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confer Resistance to Nucleoside and Nonnucleoside Analogs and Impair Virus Replication
Paolucci et al.
Antimicrob. Agents Chemother. 2004;48:4611-4617.
ABSTRACT | FULL TEXT  

Positive virological outcome after lopinavir/ritonavir salvage therapy in protease inhibitor-experienced HIV-1-infected children: a prospective cohort study
Resino et al.
J Antimicrob Chemother 2004;54:921-931.
ABSTRACT | FULL TEXT  

Technology And The Boundaries Of The Hospital: Three Emerging Technologies
Goldsmith
Health Aff (Millwood) 2004;23:149-156.
ABSTRACT | FULL TEXT  

Rapid Human Immunodeficiency Virus Decay in Highly Active Antiretroviral Therapy (HAART)-Experienced Children after Starting Mega-HAART
Plipat et al.
J. Virol. 2004;78:11272-11275.
ABSTRACT | FULL TEXT  

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
Smit et al.
J. Virol. 2004;78:10133-10148.
ABSTRACT | FULL TEXT  

Inhibition of Human Immunodeficiency Virus Type 1 Tat-trans-Activation-Responsive Region Interaction by an Antiviral Quinolone Derivative
Richter et al.
Antimicrob. Agents Chemother. 2004;48:1895-1899.
ABSTRACT | FULL TEXT  

Benefits and limitations of testing for resistance to HIV drugs
Richman
J Antimicrob Chemother 2004;53:555-557.
ABSTRACT | FULL TEXT  

Crystal Structures of a Multidrug-Resistant Human Immunodeficiency Virus Type 1 Protease Reveal an Expanded Active-Site Cavity
Logsdon et al.
J. Virol. 2004;78:3123-3132.
ABSTRACT | FULL TEXT  

Discordant Outcomes following Failure of Antiretroviral Therapy Are Associated with Substantial Differences in Human Immunodeficiency Virus-Specific Cellular Immunity
Price et al.
J. Virol. 2003;77:6041-6049.
ABSTRACT | FULL TEXT  

New Anti-Human Immunodeficiency Virus Type 1 6-Aminoquinolones: Mechanism of Action
Parolin et al.
Antimicrob. Agents Chemother. 2003;47:889-896.
ABSTRACT | FULL TEXT  

Impact of clade diversity on HIV-1 virulence, antiretroviral drug sensitivity and drug resistance
Spira et al.
J Antimicrob Chemother 2003;51:229-240.
ABSTRACT | FULL TEXT  

Quality Assessment Program for Genotypic Antiretroviral Testing Improves Detection of Drug Resistance Mutations
Sayer et al.
J. Clin. Microbiol. 2003;41:227-236.
ABSTRACT | FULL TEXT  

Inhibition of Human Immunodeficiency Virus Type 1 (HIV-1) Replication by a Two-Amino-Acid Insertion in HIV-1 Vif from a Nonprogressing Mother and Child
Alexander et al.
J. Virol. 2002;76:10533-10539.
ABSTRACT | FULL TEXT  

Insertions in the Reverse Transcriptase Increase both Drug Resistance and Viral Fitness in a Human Immunodeficiency Virus Type 1 Isolate Harboring the Multi-Nucleoside Reverse Transcriptase Inhibitor Resistance 69 Insertion Complex Mutation
Quinones-Mateu et al.
J. Virol. 2002;76:10546-10552.
ABSTRACT | FULL TEXT  

Antiretroviral Treatment for Adult HIV Infection in 2002: Updated Recommendations of the International AIDS Society-USA Panel
Yeni et al.
JAMA 2002;288:222-235.
ABSTRACT | FULL TEXT  

Interference between D30N and L90M in Selection and Development of Protease Inhibitor-Resistant Human Immunodeficiency Virus Type 1
Sugiura et al.
Antimicrob. Agents Chemother. 2002;46:708-715.
ABSTRACT | FULL TEXT  

Human Immunodeficiency Virus Type 1 Group M Protease in Cameroon: Genetic Diversity and Protease Inhibitor Mutational Features
Fonjungo et al.
J. Clin. Microbiol. 2002;40:837-845.
ABSTRACT | FULL TEXT  

Persistence and Fitness of Multidrug-Resistant Human Immunodeficiency Virus Type 1 Acquired in Primary Infection
Brenner et al.
J. Virol. 2002;76:1753-1761.
ABSTRACT | FULL TEXT  

Comparative Analysis of Two Commercial Phenotypic Assays for Drug Susceptibility Testing of Human Immunodeficiency Virus Type 1
Qari et al.
J. Clin. Microbiol. 2002;40:31-35.
ABSTRACT | FULL TEXT  

Profiling of Cancer Cells Using Protein Microarrays: Discovery of Novel Radiation-regulated Proteins
Sreekumar et al.
Cancer Res. 2001;61:7585-7593.
ABSTRACT | FULL TEXT  

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
Kempf et al.
J. Virol. 2001;75:7462-7469.
ABSTRACT | FULL TEXT  

Nelfinavir, Efavirenz, or Both after the Failure of Nucleoside Treatment of HIV Infection
Albrecht et al.
NEJM 2001;345:398-407.
ABSTRACT | FULL TEXT  

Successful Testing Protocols in Virology
Kelley and Caliendo
Clin. Chem. 2001;47:1559-1562.
ABSTRACT | FULL TEXT  

Human Immunodeficiency Virus Type 1 Drug Resistance Testing: a Comparison of Three Sequence-Based Methods
Erali et al.
J. Clin. Microbiol. 2001;39:2157-2165.
ABSTRACT | FULL TEXT  

Circulating Metabolites of the Human Immunodeficiency Virus Protease Inhibitor Nelfinavir in Humans: Structural Identification, Levels in Plasma, and Antiviral Activities
Zhang et al.
Antimicrob. Agents Chemother. 2001;45:1086-1093.
ABSTRACT | FULL TEXT  

Performance of the Applied Biosystems ViroSeq Human Immunodeficiency Virus Type 1 (HIV-1) Genotyping System for Sequence-Based Analysis of HIV-1 in Pediatric Plasma Samples
Cunningham et al.
J. Clin. Microbiol. 2001;39:1254-1257.
ABSTRACT | FULL TEXT  

Rapid and Simple Phenotypic Assay for Drug Susceptibility of Human Immunodeficiency Virus Type 1 Using CCR5-Expressing HeLa/CD4+ Cell Clone 1-10 (MAGIC-5)
Hachiya et al.
Antimicrob. Agents Chemother. 2001;45:495-501.
ABSTRACT | FULL TEXT  

Monitoring Resistance to Human Immunodeficiency Virus Type 1 Protease Inhibitors by Pyrosequencing
O'Meara et al.
J. Clin. Microbiol. 2001;39:464-473.
ABSTRACT | FULL TEXT  

Human Immunodeficiency Virus Type 1 Protease Cleavage Site Mutations Associated with Protease Inhibitor Cross-Resistance Selected by Indinavir, Ritonavir, and/or Saquinavir
Côté et al.
J. Virol. 2001;75:589-594.
ABSTRACT | FULL TEXT  

Establishment of New Transmissible and Drug-Sensitive Human Immunodeficiency Virus Type 1 Wild Types due to Transmission of Nucleoside Analogue-Resistant Virus
de Ronde et al.
J. Virol. 2001;75:595-602.
ABSTRACT | FULL TEXT  

Gay Men and HIV/AIDS Risk Management
Flowers
Health (London) 2001;5:50-75.
ABSTRACT  

Sensitive Genetic Screen for Protease Activity Based on a Cyclic AMP Signaling Cascade in Escherichia coli
Dautin et al.
J. Bacteriol. 2000;182:7060-7066.
ABSTRACT | FULL TEXT  

Comparison of Human Immunodeficiency Virus Type 1 RNA Sequence Heterogeneity in Cerebrospinal Fluid and Plasma
Tang et al.
J. Clin. Microbiol. 2000;38:4637-4639.
ABSTRACT | FULL TEXT  

Antiretroviral Resistance: Mechanisms, Detection and Clinical Implications
Sharma
Journal of Pharmacy Practice 2000;13:442-456.
ABSTRACT  

Genotypic, Phenotypic, and Modeling Studies of a Deletion in the beta 3-beta 4 Region of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Gene That Is Associated with Resistance to Nucleoside Reverse Transcriptase Inhibitors
Winters et al.
J. Virol. 2000;74:10707-10713.
ABSTRACT | FULL TEXT  

Genetic Diversity of Protease and Reverse Transcriptase Sequences in Non-Subtype-B Human Immunodeficiency Virus Type 1 Strains: Evidence of Many Minor Drug Resistance Mutations in Treatment-Naive Patients
Vergne et al.
J. Clin. Microbiol. 2000;38:3919-3925.
ABSTRACT | FULL TEXT  

Infections in AIDS: Proceedings of the Sixth Liverpool Tropical School Bayer Symposium on Microbial Diseases held on 6 February 1999
HART et al.
J Med Microbiol 2000;49:947-967.
FULL TEXT  

The Role of Genotypic Resistance Testing in Selecting Therapy for HIV
Perez-Molina et al.
JAMA 2000;284:1649-1650.
FULL TEXT  

Antiretroviral resistance during successful therapy of HIV type 1 infection
Martinez-Picado et al.
Proc. Natl. Acad. Sci. USA 2000;97:10948-10953.
ABSTRACT | FULL TEXT  

Mutants of Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcriptase Resistant to Nonnucleoside Reverse Transcriptase Inhibitors Demonstrate Altered Rates of RNase H Cleavage That Correlate with HIV-1 Replication Fitness in Cell Culture
Archer et al.
J. Virol. 2000;74:8390-8401.
ABSTRACT | FULL TEXT  

Human Immunodeficiency Virus Type 1 Mutations Selected in Patients Failing Efavirenz Combination Therapy
Bacheler et al.
Antimicrob. Agents Chemother. 2000;44:2475-2484.
ABSTRACT | FULL TEXT  

Comparative Evaluation of Three Human Immunodeficiency Virus Genotyping Systems: the HIV-GenotypR Method, the HIV PRT GeneChip Assay, and the HIV-1 RT Line Probe Assay
Wilson et al.
J. Clin. Microbiol. 2000;38:3022-3028.
ABSTRACT | FULL TEXT  

Production of resistant HIV mutants during antiretroviral therapy
Ribeiro and Bonhoeffer
Proc. Natl. Acad. Sci. USA 2000;97:7681-7686.
ABSTRACT | FULL TEXT  

Comparison of Sequencing by Hybridization and Cycle Sequencing for Genotyping of Human Immunodeficiency Virus Type 1 Reverse Transcriptase
Hanna et al.
J. Clin. Microbiol. 2000;38:2715-2721.
ABSTRACT | FULL TEXT  

Response to Antiretroviral Therapy in a Patient with an Uncommon Codon 69 Insertion in the Human Immunodeficiency Virus Type 1 Reverse Transcriptase
Bonfanti et al.
Antimicrob. Agents Chemother. 2000;44:1767-1768.
FULL TEXT  

Antiretroviral Drug Resistance Testing in Adult HIV-1 Infection: Recommendations of an International AIDS Society-USA Panel
Hirsch et al.
JAMA 2000;283:2417-2426.
ABSTRACT | FULL TEXT  

Selection and Characterization of Human Immunodeficiency Virus Type 1 Variants Resistant to the (+) and (-) Enantiomers of 2'-Deoxy-3'-Oxa-4'-Thio-5-Fluorocytidine
Richard et al.
Antimicrob. Agents Chemother. 2000;44:1127-1131.
ABSTRACT | FULL TEXT  

A Bacteriophage Lambda-Based Genetic Screen for Characterization of the Activity and Phenotype of the Human Immunodeficiency Virus Type 1 Protease
Martínez et al.
Antimicrob. Agents Chemother. 2000;44:1132-1139.
ABSTRACT | FULL TEXT  

A Mutation in Human Immunodeficiency Virus Type 1 Protease, N88S, That Causes In Vitro Hypersensitivity to Amprenavir
Ziermann et al.
J. Virol. 2000;74:4414-4419.
ABSTRACT | FULL TEXT  

Predictors of Virological Success and Ensuing Failure in HIV-Positive Patients Starting Highly Active Antiretroviral Therapy in Europe: Results From the EuroSIDA Study
Paredes et al.
Arch Intern Med 2000;160:1123-1132.
ABSTRACT | FULL TEXT  

A Novel Phenotypic Drug Susceptibility Assay for Human Immunodeficiency Virus Type 1
Petropoulos et al.
Antimicrob. Agents Chemother. 2000;44:920-928.
ABSTRACT | FULL TEXT  

Strategies for Long-term Success in the Treatment of HIV Infection
Gallant
JAMA 2000;283:1329-1334.
ABSTRACT | FULL TEXT  

Prophylactic and Therapeutic Benefits of Short-Term 9-[2-(R)-(Phosphonomethoxy)Propyl]Adenine (PMPA) Administration to Newborn Macaques following Oral Inoculation with Simian Immunodeficiency Virus with Reduced Susceptibility to PMPA
Van Rompay et al.
J. Virol. 2000;74:1767-1774.
ABSTRACT | FULL TEXT  

The Case for More Cautious, Patient-Focused Antiretroviral Therapy
Henry
ANN INTERN MED 2000;132:306-311.
ABSTRACT | FULL TEXT  

Antiretroviral Therapy in Adults: Updated Recommendations of the International AIDS Society-USA Panel
Carpenter et al.
JAMA 2000;283:381-390.
ABSTRACT | FULL TEXT  

Mechanisms of Virologic Failure in Previously Untreated HIV-Infected Patients From a Trial of Induction-Maintenance Therapy
Descamps et al.
JAMA 2000;283:205-211.
ABSTRACT | FULL TEXT  

Drug Susceptibility in HIV Infection After Viral Rebound in Patients Receiving Indinavir-Containing Regimens
Havlir et al.
JAMA 2000;283:229-234.
ABSTRACT | FULL TEXT  

Human immunodeficiency virus type 1 population bottleneck during indinavir therapy causes a genetic drift in the env quasispecies
Ibáñez et al.
J. Gen. Virol. 2000;81:85-95.
ABSTRACT | FULL TEXT  

Recovery and Analysis of Human Immunodeficiency Virus Type 1 (HIV) RNA Sequences from Plasma Samples with Low HIV RNA Levels
Niubò et al.
J. Clin. Microbiol. 2000;38:309-312.
ABSTRACT | FULL TEXT  

Human Immunodeficiency Virus Reverse Transcriptase and Protease Sequence Database
Shafer et al.
Nucleic Acids Res 2000;28:346-348.
ABSTRACT | FULL TEXT  

HIV-1 Genotypic Resistance Patterns Predict Response to saquinavir-ritonavir Therapy in Patients in Whom Previous Protease Inhibitor Therapy Had Failed
Zolopa et al.
ANN INTERN MED 1999;131:813-821.
ABSTRACT | FULL TEXT  

Mutation Patterns of the Reverse Transcriptase and Protease Genes in Human Immunodeficiency Virus Type 1-Infected Patients Undergoing Combination Therapy: Survey of 787 Sequences
Yahi et al.
J. Clin. Microbiol. 1999;37:4099-4106.
ABSTRACT | FULL TEXT  

Drug Resistance Patterns, Genetic Subtypes, Clinical Features, and Risk Factors in Military Personnel with HIV-1 Seroconversion
Brodine et al.
ANN INTERN MED 1999;131:502-506.
ABSTRACT | FULL TEXT  

Reduced Antiretroviral Drug Susceptibility Among Patients With Primary HIV Infection
Little et al.
JAMA 1999;282:1142-1149.
ABSTRACT | FULL TEXT  

Primary HIV-1 Resistance: A New Phase in the Epidemic?
Pomerantz
JAMA 1999;282:1177-1179.
FULL TEXT  

Human Immunodeficiency Virus Type 1 Cloning Vectors for Antiretroviral Resistance Testing
Martinez-Picado et al.
J. Clin. Microbiol. 1999;37:2943-2951.
ABSTRACT | FULL TEXT  

A Family of Insertion Mutations between Codons 67 and 70 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confer Multinucleoside Analog Resistance
Larder et al.
Antimicrob. Agents Chemother. 1999;43:1961-1967.
ABSTRACT | FULL TEXT  

Reconstitution of Human Thymic Implants Is Limited by Human Immunodeficiency Virus Breakthrough during Antiretroviral Therapy
Amado et al.
J. Virol. 1999;73:6361-6369.
ABSTRACT | FULL TEXT  

Optimizing Care for Persons with HIV Infection
Hecht et al.
ANN INTERN MED 1999;131:136-143.
ABSTRACT | FULL TEXT  

Sequence Diversity of the Reverse Transcriptase of Human Immunodeficiency Virus Type 1 from Untreated Brazilian Individuals
Brindeiro et al.
Antimicrob. Agents Chemother. 1999;43:1674-1680.
ABSTRACT | FULL TEXT  

The P236L Delavirdine-Resistant Human Immunodeficiency Virus Type 1 Mutant Is Replication Defective and Demonstrates Alterations in both RNA 5'-End- and DNA 3'-End-Directed RNase H Activities
Gerondelis et al.
J. Virol. 1999;73:5803-5813.
ABSTRACT | FULL TEXT  

Monitoring Adherence to HIV Therapy
Tuldra et al.
Arch Intern Med 1999;159:1376-1377.
FULL TEXT  

Comparison of Human Immunodeficiency Virus Type 1 (HIV-1) Protease Mutations in HIV-1 Genomes Detected in Plasma and in Peripheral Blood Mononuclear Cells from Patients Receiving Combination Drug Therapy
Koch et al.
J. Clin. Microbiol. 1999;37:1595-1597.
ABSTRACT | FULL TEXT  

The Costs, Clinical Benefits, and Cost-Effectiveness of Screening for Cervical Cancer in HIV-Infected Women
Goldie et al.
ANN INTERN MED 1999;130:97-107.
ABSTRACT | FULL TEXT  

HIV-1 Drug Resistance Assays in Clinical Management
AIDS Clin Care 1998;1998:1-1.
FULL TEXT  

Antiviral drug resistance
Pillay and Zambon
BMJ 1998;317:660-662.
FULL TEXT  

Transmission of Multidrug-Resistant Human Immunodeficiency Virus -- The Wake-Up Call
Cohen and Fauci
NEJM 1998;339:341-343.
FULL TEXT  

Antiretroviral Therapy for HIV Infection in 1998: Updated Recommendations of the International AIDS Society-USA Panel
Carpenter et al.
JAMA 1998;280:78-86.
ABSTRACT | FULL TEXT  

Drug-Resistant HIV-1: The Virus Strikes Back
Mayers
JAMA 1998;279:2000-2002.
FULL TEXT  

A multiple-site-specific heteroduplex tracking assay as a tool for the study of viral population dynamics
Resch et al.
Proc. Natl. Acad. Sci. USA 2001;98:176-181.
ABSTRACT | FULL TEXT