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Science 4 August 1995:
Vol. 269. no. 5224, pp. 696 - 699
DOI: 10.1126/science.7542804
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Articles

Science, Vol 269, Issue 5224, 696-699
Copyright © 1995 by American Association for the Advancement of Science

articles

Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy

BA Larder, SD Kemp, and PR Harrigan

Antiviral Therapeutic Research Unit, Wellcome Research Laboratories, Beckenham, Kent, UK.

Combinations of antiretroviral drugs that prevent or delay the appearance of drug-resistant human immunodeficiency virus-type 1 (HIV-1) mutants are urgently required. Mutants resistant to 3'-azidothymidine (AZT, zidovudine) became phenotypically sensitive in vitro by mutation of residue 184 of viral reverse transcriptase to valine, which also induced resistance to (-)2'-deoxy-3'-thiacytidine (3TC). Furthermore, AZT-3TC coresistance was not observed during extensive in vitro selection with both drugs. In vivo AZT-3TC combination therapy resulted in a markedly greater decreased in serum HIV-1 RNA concentrations than treatment with AZT alone, even though valine-184 mutants rapidly emerged. Most samples assessed from the combination group remained AZT sensitive at 24 weeks of therapy, consistent with in vitro mutation studies.


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J. G. García Lerma, R. F. Schinazi, A. S. Juodawlkis, V. Soriano, Y. Lin, K. Tatti, D. Rimland, T. M. Folks, and W. Heneine (1999)
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Enhanced Binding of Azidothymidine-resistant Human Immunodeficiency Virus 1 Reverse Transcriptase to the 3'-Azido-3'-deoxythymidine 5'-Monophosphate-terminated Primer.
B. Canard, S. R. Sarfati, and C. C. Richardson (1998)
J. Biol. Chem. 273, 14596-14604
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3'-Azido-3'-Deoxythymidine (AZT) Mediates Cross-Resistance to Nucleoside Analogs in the Case of AZT-Resistant Human Immunodeficiency Virus Type 1 Variants.
E. J. Arts, M. E. Quinones-Mateu, J. L. Albright, J.-P. Marois, C. Hough, Z. Gu, and M. A. Wainberg (1998)
J. Virol. 72, 4858-4865
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A Novel Polymorphism at Codon 333 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Can Facilitate Dual Resistance to Zidovudine and L-2',3'-Dideoxy-3'-Thiacytidine.
S. D. Kemp, C. Shi, S. Bloor, P. R. Harrigan, J. W. Mellors, and B. A. Larder (1998)
J. Virol. 72, 5093-5098
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Relative Replicative Fitness of Zidovudine-Resistant Human Immunodeficiency Virus Type 1 Isolates In Vitro.
P. R. Harrigan, S. Bloor, and B. A. Larder (1998)
J. Virol. 72, 3773-3778
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A Novel Point Mutation at Position 156 of Reverse Transcriptase from Feline Immunodeficiency Virus Confers Resistance to the Combination of (-)-beta -2',3'-Dideoxy-3'-Thiacytidine and 3'-Azido-3'-Deoxythymidine.
R. A. Smith, K. M. Remington, B. D. Preston, R. F. Schinazi, and T. W. North (1998)
J. Virol. 72, 2335-2340
   Abstract »    Full Text »    PDF »
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.
S. M. Hammer, K. E. Squires, M. D. Hughes, J. M. Grimes, L. M. Demeter, J. S. Currier, J. J. Eron, J. E. Feinberg, H. H. Balfour, L. R. Deyton, et al. (1997)
N. Engl. J. Med. 337, 725-733
   Abstract »    Full Text »    PDF »
Virus dynamics and drug therapy.
S. Bonhoeffer, R. M. May, G. M. Shaw, and M. A. Nowak (1997)
PNAS 94, 6971-6976
   Abstract »    Full Text »    PDF »
A Trial Comparing Nucleoside Monotherapy with Combination Therapy in HIV-Infected Adults with CD4 Cell Counts from 200 to 500 per Cubic Millimeter.
S. M. Hammer, D. A. Katzenstein, M. D. Hughes, H. Gundacker, R. T. Schooley, R. H. Haubrich, W. K. Henry, M. M. Lederman, J. P. Phair, M. Niu, et al. (1996)
N. Engl. J. Med. 335, 1081-1090
   Abstract »    Full Text »    PDF »
Safety and Efficacy of Lamivudine-Zidovudine Combination Therapy in Zidovudine-Experienced Patients: A Randomized Controlled Comparison With Zidovudine Monotherapy.
S. Staszewski, C. Loveday, J. J. Picazo, P. Dellamonica, P. Skinhoj, M. A. Johnson, S. A. Danner, P. R. Harrigan, A. M. Hill, L. Verity, et al. (1996)
JAMA 276, 111-117
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Safety and Efficacy of Lamivudine-Zidovudine Combination Therapy in Antiretroviral-Naive Patients: A Randomized Controlled Comparison With Zidovudine Monotherapy.
C. Katlama, D. Ingrand, C. Loveday, N. Clumeck, J. Mallolas, S. Staszewski, M. Johnson, A. M. Hill, G. Pearce, and H. McDade (1996)
JAMA 276, 118-125
   Abstract »    PDF »
Roundtable: To Treat or Not to Treat -- Approaches to Antiretroviral Therapy.
(1996)
AIDS Clinical Care 1996, 1
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Treatment with Lamivudine, Zidovudine, or Both in HIV-Positive Patients with 200 to 500 CD4+ Cells per Cubic Millimeter.
J. J. Eron, S. L. Benoit, J. Jemsek, R. D. MacArthur, J. Santana, J. B. Quinn, D. R. Kuritzkes, M. A. Fallon, M. Rubin, and The North American HIV Working Party (1995)
N. Engl. J. Med. 333, 1662-1669
   Abstract »    Full Text »    PDF »
A Quarter-Century of Antiviral Therapy.
T. C. Merigan (1995)
N. Engl. J. Med. 333, 1704-1705
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Why AZT plus 3TC May Work.
(1995)
AIDS Clinical Care 1995, 8
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Toxicity of Antiviral Nucleoside Analogs and the Human Mitochondrial DNA Polymerase.
A. A. Johnson, A. S. Ray, J. Hanes, Z. Suo, J. M. Colacino, K. S. Anderson, and K. A. Johnson (2001)
J. Biol. Chem. 276, 40847-40857
   Abstract »    Full Text »    PDF »


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