Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-669899f699-b58lm Total loading time: 0 Render date: 2025-05-02T11:11:02.641Z Has data issue: false hasContentIssue false

14 - HIV drug resistance

Published online by Cambridge University Press:  23 December 2009

By
Frank Maldarelli
Edited by
Steven L. Zeichner  and
Jennifer S. Read
Frank Maldarelli
Affiliation:
HIV-1 Drug Resistance Program, National Cancer Institute, National Institutes of Health, Bethesda, MD
Steven L. Zeichner
Affiliation:
National Cancer Institute, Bethesda, Maryland
Jennifer S. Read
Affiliation:
National Institutes of Health, Bethesda, Maryland
Get access

Summary

Introduction

One of the most challenging limitations of antiretroviral therapy is the emergence of drug resistant mutants of HIV, which occurs in 30%–40% of treated patients. For the individual, drug resistance renders antiretroviral therapy much less effective, resulting in the return of HIV viremia and disease progression. Resistant variants are transmitted when new HIV infections occur, and the spread of resistant HIV to newly infected individuals is a growing public health concern. The benefits of HIV resistance testing have been reported in several clinical trials; resistance testing is recommended in certain clinical situations in adult populations. Many questions remain however, and methods to study and analyze HIV drug resistance continue to evolve. Several excellent reviews on HIV drug resistance testing have recently been published [1–8].

Collections of drug resistance mutations are often depicted in tables (see Tables 14.1 and 14.2); such tables, although useful, do not depict degrees of resistance or complexities of interactions among mutations. Online compendia of mutations, frequently updated (e.g., hivdb.stanford.edu, hiv-web.lanl.gov (a sequence compendium of utility for researchers), www.hivresistanceweb.com, www.iasusa.org/resistance_mutations/index.html) provide additional information concerning antiretroviral resistance mutations.

Mechanisms of drug resistance

Studies of HIV replication suggest that HIV populations in vivo are characterized by high genetic diversity; as a result it is likely that some HIV drug resistance mutations are present even prior to the initiation of antiviral therapy. Initiation of antiretrovirals serves to suppress sensitive HIV and permit growth of resistant virus.

Type
Chapter
Information
Handbook of Pediatric HIV Care , pp. 397 - 414
Publisher: Cambridge University Press
Print publication year: 2006

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Book purchase

Temporarily unavailable

References

Houtte, M., Update on resistance testing. J. human immunodeficiency virus Ther., 2001;6(3):61–64.Google ScholarPubMed
Geretti, A. M., Easterbrook, P.Antiretroviral resistance in clinical practice. Int. J. STD acquired immune deficiency syndrome, 2001;12(3):145–153.Google ScholarPubMed
Hanna, G.Aquila, R. T.Clinical use of genotypic and phenotypic drug resistance testing to monitor antiretroviral chemotherapy. Clin. Infect. Dis., 2001; 32(5): 774–782.Google ScholarPubMed
Rice, H. L., Zolopa, A. R.human immunodeficiency virus drug resistance testing: an update for the clinician. acquired immune deficiency syndrome Clin. Care, 2001;13(10): 89–91, 94–96, 100.Google ScholarPubMed
Schmidt, B., Walter, H., Zeitler, N., Karn, K.Genotypic drug resistance interpretation systems – the cutting edge of antiretroviral therapy. acquired immune deficiency syndrome Rev, 2002; 4(3): 148–156.Google ScholarPubMed
Shafer, R. W.Genotypic testing for human immunodeficiency virus type 1 drug resistance. Clin. Microbiol. Rev., 2002; 15(2):247–277.CrossRefGoogle ScholarPubMed
Haubrich, R., Demeter, L.International perspectives on antiretroviral resistance. Clinical utility of resistance testing: retrospective and prospective data supporting use and current recommendations. J. Acquir. Immune Defic. Syndr., 2001;26 Suppl 1: S51–S59.CrossRefGoogle ScholarPubMed
Lerma, J. G., Heneine, W.Resistance of human immunodeficiency virus type 1 to reverse transcriptase and protease inhibitors: genotypic and phenotypic testing. J. Clin. Virol., 2001;21(3):197–212.CrossRefGoogle Scholar
Larder, B. A., Bloor, S., Kemp, S. D.et al.A family of insertion mutations between codons 67 and 70 of human immunodeficiency virus type 1 reverse transcriptase confer multinucleoside analog resistance. Antimicrob. Agents Chemother., 1999;43(8):1961–1967.Google ScholarPubMed
Lobato, R. L., Kim, E. Y., Kagan, R. M., Merigan, T. C., Genotypic and phenotypic analysis of a novel 15-base insertion occurring between codons 69 and 70 of human immunodeficiency virus type 1 reverse transcriptase. acquired immune deficiency syndrome Res. Hum. Retroviruses, 2002; 18(10):733–736.Google Scholar
Lennerstrand, J., Stammers, D. K., Larder, B. A.Biochemical mechanism of human immunodeficiency virus type 1 reverse transcriptase resistance to stavudine. Antimicrob. Agents Chemother., 2001; 45(7):2144–2146.CrossRefGoogle ScholarPubMed
Mas, A., Parera, M., Briones, C.et al.Role of a dipeptide insertion between codons 69 and 70 of human immunodeficiency virus-1 reverse transcriptase in the mechanism of zidovudine (also known as zidovudine (also known as ZDV)) resistance. Embo. J, 2000; 19(21):5752–5761.CrossRefGoogle Scholar
Boyer, P. L., Sarafianos, S. G., Arnold, E., Hughes, S. H.Nucleoside analog resistance caused by insertions in the fingers of human immunodeficiency virus type 1 reverse transcriptase involves adenosine triphosphate-mediated excision. J. Virol., 2002; 76(18):9143–9151.CrossRefGoogle Scholar
Gao, H. Q., Boyer, P. L., Sarafianos, S. G., Arnold, E., Hughes, S. H.The role of steric hindrance in lamivudine resistance of human immunodeficiency virus type-1 reverse transcriptase. J. Mol. Biol., 2000; 300(2):403–418.CrossRefGoogle ScholarPubMed
Sarafianos, S. G., Das, K., Clark, A. D. Jr.et al.Lamivudine (lamivudine) resistance in human immunodeficiency virus-1 reverse transcriptase involves steric hindrance with beta-branched amino acids. Proc. Natl Acad. Sci. USA, 1999; 96(18):10027–10032.CrossRefGoogle ScholarPubMed
Frost, S. D., Nijhuis, M., Schuurman, R., Boucher, C. A., Brown, A. J.Evolution of lamivudine resistance in human immunodeficiency virus type 1-infected individuals: the relative roles of drift and selection. J. Virol., 2000; 74(14):6262–6268.CrossRefGoogle Scholar
Ray, A. S., Basavapathruni, A., Anderson, K. S.Mechanistic studies to understand the progressive development of resistance in human immunodeficiency virus type 1 reverse transcriptase to abacavir. J. Biol. Chem., 2002; 277(43):40479–40490.CrossRefGoogle ScholarPubMed
Huang, H., Chopra, R., Verdine, G. L., Harrison, S. C.Structure of a covalently trapped catalytic complex of human immunodeficiency virus-1 reverse transcriptase: implications for drug resistance. Science, 1998; 282(5394):1669–1675.CrossRefGoogle ScholarPubMed
Schmit, J. C., Ruiz, L., Stuyver, L.et al.Comparison of the LiPA human immunodeficiency virus-1 RT test, selective polymerase chain reaction and direct solid phase sequencing for the detection of human immunodeficiency virus-1 drug resistance mutations. J. Virol. Methods, 1998; 73(1):77–82.CrossRefGoogle ScholarPubMed
Hsiou, Y., Ding, J., Das, K.et al.The Lys103Asn mutation of human immunodeficiency virus-1 RT: a novel mechanism of drug resistance. J. Mol. Biol., 2001; 309(2):437–445.CrossRefGoogle ScholarPubMed
Swanstrom, R., Erona, J.Human immunodeficiency virus type-1 protease inhibitors: therapeutic successes and failures, suppression and resistance. Pharmacol Ther., 2000; 86(2):145–170.CrossRefGoogle ScholarPubMed
Kaplan, A. H., Zack, J. A., , Krigge M.et al.Partial inhibition of the human immunodeficiency virus type 1 protease results in aberrant virus assembly and the formation of noninfectious particles. J. Virol., 1993; 67(7):4050–4055.Google ScholarPubMed
Rose, R. E., Gong, Y. F., Greytok, J. A.et al.Human immunodeficiency virus type 1 viral background plays a major role in development of resistance to protease inhibitors. Proc. Natl Acad. Sci. USA, 1996; 93(4):1648–1653.CrossRefGoogle Scholar
Scott, W. R., Schiffer, C. A.Curling of flap tips in human immunodeficiency virus-1 protease as a mechanism for substrate entry and tolerance of drug resistance. Structure Fold Des. 2000; 8(12):1259–1265.CrossRefGoogle ScholarPubMed
Prabu-Jeyabalan, M., Nalivaika, E., Schiffer, C. A.Substrate shape determines specificity of recognition for human immunodeficiency virus-1 protease: analysis of crystal structures of six substrate complexes. Structure (Camb), 2002; 10(3):369–381.CrossRefGoogle ScholarPubMed
Pettit, S. C., Gulnik, S., Everitt, L., Kaplan, A. H.The dimer interfaces of protease and extra-protease domains influence the activation of protease and the specificity of GagPol cleavage. J. Virol. 2003; 77(1):366–374.CrossRefGoogle ScholarPubMed
Hertogs, K., Bloor, S., Kemp, S. D.et al.Phenotypic and genotypic analysis of clinical human immunodeficiency virus-1 isolates reveals extensive protease inhibitor cross-resistance: a survey of over 6000 samples. acquired immune deficiency syndrome, 2000; 14(9):1203–1210.Google ScholarPubMed
Shafer, R. W., Winters, M. A., Palmer, S., Merigan, T. C.Multiple concurrent reverse transcriptase and protease mutations and multidrug resistance of human immunodeficiency virus-1 isolates from heavily treated patients. Ann. Intern. Med., 1998; 128(11):906–911.CrossRefGoogle ScholarPubMed
Harrigan, P. R., Larder, B. A.Extent of cross-resistance between agents used to treat human immunodeficiency virus type 1 infection in clinically derived isolates. Antimicrob. Agents Chemother., 2002; 46(3):909–912.CrossRefGoogle ScholarPubMed
Robinson, L. H., Myers, R. E., Snowden, B. W., Tisdale, M., Blair, E. D.human immunodeficiency virus type 1 protease cleavage site mutations and viral fitness: implications for drug susceptibility phenotyping assays. acquired immune deficiency syndrome Res. Hum. Retroviruses, 2000; 16(12):1149–1156.Google ScholarPubMed
Doyon, L., Croteau, G., Thibeault, D., Poulin, E., Pilote, L., Lamarre, D.Second locus involved in human immunodeficiency virus type 1 resistance to protease inhibitors. J. Virol., 1996; 70(6):3763–3769.Google ScholarPubMed
Croteau, G., Doyon, L., Thibeault, D., McKercher, G., Pilote, L., Lamarre, D.Impaired fitness of human immunodeficiency virus type 1 variants with high-level resistance to protease inhibitors. J. Virol., 1997; 71(2):1089–1096.Google ScholarPubMed
Zhang, Y. M., Imamichi, H., Imamichi, T.et al.Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its Gag substrate cleavage sites. J. Virol., 1997; 71(9):6662–6670.Google ScholarPubMed
Kilby, J. M., Hopkins, S., Venetta, T. M.et al.Potent suppression of human immunodeficiency virus-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat. Med. 1998; 4(11):1302–1307.CrossRefGoogle ScholarPubMed
Wei, X., Decker, J. M., Liu, H.et al.Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob. Agents Chemother., 2002; 46(6):1896–1905.CrossRefGoogle ScholarPubMed
Cunningham, S., Ank, B., Lewis, D.et al.Performance of the applied biosystems ViroSeq human immunodeficiency virus type 1 (human immunodeficiency virus-1) genotyping system for sequence-based analysis of human immunodeficiency virus-1 in pediatric plasma samples. J. Clin. Microbiol., 2001; 39(4):1254–1257.CrossRefGoogle ScholarPubMed
Hertogs, K., Bethune, M. P., Miller, V.et al.A rapid method for simultaneous detection of phenotypic resistance to inhibitors of protease and reverse transcriptase in recombinant human immunodeficiency virus type 1 isolates from patients treated with antiretroviral drugs. Antimicrob. Agents Chemother., 1998; 42(2):269–276.Google ScholarPubMed
Petropoulos, C. J., Parkin, N. T., Limoli, K. L.et al.A novel phenotypic drug susceptibility assay for human immunodeficiency virus type 1. Antimicrob. Agents Chemother., 2000; 44(4):920–928.CrossRefGoogle ScholarPubMed
Kellam, P., Larder, B. A.Recombinant virus assay: a rapid, phenotypic assay for assessment of drug susceptibility of human immunodeficiency virus type 1 isolates. Antimicrob. Agents Chemother., 1994; 38(1):23–30.CrossRefGoogle ScholarPubMed
Falloon, J., Ait-Khaled, M., Thomas, D. A.et al.human immunodeficiency virus-1 genotype and phenotype correlate with virological response to abacavir, amprenavir and efavirenz in treatment-experienced patients. acquired immune deficiency syndrome, 2002; 16(3):387–396.Google ScholarPubMed
Kempf, D. J., Isaacson, J. D., King, M. S.et al.Analysis of the virological response with respect to baseline viral phenotype and genotype in protease inhibitor-experienced human immunodeficiency virus-1-infected patients receiving lopinavir/ritonavir therapy. Antivirals. Ther., 2002; 7(3): 165–174.Google Scholar
Harrigan, P. R., Montaner, J. S., Wegner, S. A.et al.World-wide variation in human immunodeficiency virus-1 phenotypic susceptibility in untreated individuals: biologically relevant values for resistance testing. acquired immune deficiency syndrome, 2001; 15(13):1671–1677.Google ScholarPubMed
Qari, S. H., Respess, R., Weinstock, H.et al.Comparative analysis of two commercial phenotypic assays for drug susceptibility testing of human immunodeficiency virus type 1. J. Clin. Microbiol., 2002; 40(1):31–35.CrossRefGoogle ScholarPubMed
Tural, C., Ruiz, L., Holtzer, C.et al.Clinical utility of human immunodeficiency virus-1 genotyping and expert advice: the Havana trial. acquired immune deficiency syndrome, 2002; 16(2):209–218.Google ScholarPubMed
Meynard, J. L., Vray, M., Morand-Joubert, L.et al.Phenotypic or genotypic resistance testing for choosing antiretroviral therapy after treatment failure: a randomized trial. acquired immune deficiency syndrome, 2002; 16(5):727–736.Google ScholarPubMed
Melnick, J. R., Cameron, M. Snyder, M. et al. Impact of phenotypic antiretroviral drug resistance testing on the response to salvage antiretroviral therapy (antiretroviral therapy) in heavily experienced patients. 7th Conf. Retroviruses and Opportunistic Infect., 2000: Abstract 786.
Torre, D., Tambini, R.Antiretroviral drug resistance testing in patients with human immunodeficiency virus-1 infection: a meta-analysis study. human immunodeficiency virus Clin. Trials, 2002; 3(1):1–8.Google ScholarPubMed
Vandamme, A. M., Houyez, E., Banhegyi, D.et al.Laboratory guidelines for the practical use of human immunodeficiency virus drug resistance tests in patient follow-up. Antiviral Ther., 2001; 6(1):21–39.Google ScholarPubMed
Hirsch, M. S., Brun-Vezinet, E., D'Aquila, R. T.et al.Antiretroviral drug resistance testing in adult human immunodeficiency virus-1 infection: recommendations of an International acquired immune deficiency syndrome Society-USA Panel. J. Am. Med. Assoc., 2000; 283(18):2417–2426.CrossRefGoogle Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

  • HIV drug resistance
    • By Frank Maldarelli, HIV-1 Drug Resistance Program, National Cancer Institute, National Institutes of Health, Bethesda, MD
  • Edited by Steven L. Zeichner, National Cancer Institute, Bethesda, Maryland, Jennifer S. Read
  • Book: Handbook of Pediatric HIV Care
  • Online publication: 23 December 2009
  • Chapter DOI: https://doi.org/10.1017/CBO9780511544781.016
Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

  • HIV drug resistance
    • By Frank Maldarelli, HIV-1 Drug Resistance Program, National Cancer Institute, National Institutes of Health, Bethesda, MD
  • Edited by Steven L. Zeichner, National Cancer Institute, Bethesda, Maryland, Jennifer S. Read
  • Book: Handbook of Pediatric HIV Care
  • Online publication: 23 December 2009
  • Chapter DOI: https://doi.org/10.1017/CBO9780511544781.016
Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

  • HIV drug resistance
    • By Frank Maldarelli, HIV-1 Drug Resistance Program, National Cancer Institute, National Institutes of Health, Bethesda, MD
  • Edited by Steven L. Zeichner, National Cancer Institute, Bethesda, Maryland, Jennifer S. Read
  • Book: Handbook of Pediatric HIV Care
  • Online publication: 23 December 2009
  • Chapter DOI: https://doi.org/10.1017/CBO9780511544781.016
Available formats
×