Advertisement

Clinical Experience with Non-Nucleoside Reverse Transcriptase Inhibitors: L-697,661 and Nevirapine

  • J. Michael Kilby
  • Michael S. Saag
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 394)

Abstract

The four currently approved antiretrovirals all competitively inhibit the reverse transcriptase (RT) enzyme of HIV by acting as nucleoside analogs, causing chain termination when they are incorporated into viral CDNA during the process of reverse transcription.1 Zidovudine (AZT) delays the progression of HIV infection and improves mortality when given to symptomatic immunodeficient patients.2 Each of the other approved agents (didanosine, zalcitibine, and stavudine) has potent in vitro antiviral effects and provides a therapeutic alternative when patients are intolerant of zidovudine or have disease progression despite zidovudine.1 However, the benefit of prolonged monotherapy with currently available drugs is of limited durability,4 at least in part due to the selection of viral strains containing mutations in the RT gene that confer resistance to the therapies.3 There are also significant toxicities associated with these compounds, although the profile of adverse effects is different for each of the four drugs.1,5 Obviously, there is an urgent need to identify novel approaches to suppress HIV replication and prevent the manifestations of AIDS.

Keywords

34th Interscience Reverse Transcriptase Enzyme Reverse Transcriptase Gene High Therapeutic Index Nevirapine Therapy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Hirsch MS, D’Aquila RT. Therapy for HIV Infection. N Engl J Med 1993; 328: 1686–95.PubMedCrossRefGoogle Scholar
  2. 2.
    Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. a double-blind, placebo-controlled trial. N Engl J Med 1987; 317: 185–191.PubMedCrossRefGoogle Scholar
  3. 3.
    Richman DD. Viral resistance to antiretroviral therapy. In: Broder S, Merigan TC, Bolognesi D, eds. Textbook of AIDS medicine. Baltimore: Williams and Wilkins, 1994: 795–80.Google Scholar
  4. 4.
    Concorde Coordinating Committee. Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet 1994; 343: 871–81.CrossRefGoogle Scholar
  5. 5.
    Saag MS. Nucleoside analogues: adverse effects. Hosp Prac 1992; 27 (suppl 2): 26–36.Google Scholar
  6. 6.
    Miyasaka T, Tanaka H, Baba M, et al. A novel lead for specific anti-HIV-1 agents: 1-[2hydroxyethoxymethyl]-6-(phenylthio)thymine. J Med Chem 1989; 32: 2507.Google Scholar
  7. 7.
    Pauwels R, Andries K, Desmyter J, et al. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature 1990; 343: 4704.CrossRefGoogle Scholar
  8. 8.
    Pauwels R, Andries K, Debyser Z, et al. Potent and highly selective HIV-1 inhibition by a series of alphaanilinophenylacetamide derivatives targeted at HIV-1 RT. Proc Natl Acad Sci USA 1993; 90: 1711–15.PubMedCrossRefGoogle Scholar
  9. 9.
    Merluzzi VJ, Hargrave KD, Labadia M, et al. Inhibition of HIV-1 replication by a non-nucleoside RT inhibitor. Science 1990; 250: 1411–13.PubMedCrossRefGoogle Scholar
  10. 10.
    Goldman ME,Nunberg JH, O’Brien JA, et al. Pyridinone derivatives: specific HIV-1 RT inhibitors with antiviral activity. Proc Natl Acad Sci USA 1991; 88: 6863–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Romero DL, Busso M, Tan C-K, et al. Nonnucleoside RT inhibitors that potently and specifically block HIV-1 replication. Proc Natl Acad Sci USA 1991; 88: 8806–10.PubMedCrossRefGoogle Scholar
  12. 12.
    De Clercq E. HIV-1 specific inhibitors: highly selective inhibitors of HIV-1 that are specifically targeted at the reverse transcriptase. Med Res Rev 1993; 13: 229–58.PubMedCrossRefGoogle Scholar
  13. 13.
    Nunberg JH, Schleif WA, Boots EJ, et al. Viral resistance to HIV-1-specific pyridinone inhibitors. J Virol 1991; 65: 4887–92.PubMedGoogle Scholar
  14. 14.
    Saag MS, Emini EA, Laskin OL, et al. A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. N Engl J Med 1993; 329: 1065–72.PubMedCrossRefGoogle Scholar
  15. 15.
    Kohlstaedt LA, Wang J, Friedman JM, et al. Crystal structure at 3.5 angstrom resolution of HIV-1 RT complexed to an inhibitor. Science 1992; 256: 1783–90.PubMedCrossRefGoogle Scholar
  16. 16.
    Shih C-K, Rose JM, Hansen JL, et al. Chimeric HIV type 1/type 2 reverse transcriptases display reversed sensitivity to nonnucleoside analog inhibitors. Proc Natl Acad Sci USA 1991; 88: 9878–82.PubMedCrossRefGoogle Scholar
  17. 17.
    Richman DD, Shih C-K, Lowy,. HIV-1 mutants resistant to nonnucleoside inhibitors of RT arise in tissue culture. Proc Natl Acad Sci USA 1991; 88: 11241–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Cheeseman SH. Nevirapine alone and in combination with AZT: safety and activity[Abstract MoB0053]. Presented at the combined VIII International Conference on AIDS/HIV and the STD World Congress, Amsterdam, The Netherlands, 1992.Google Scholar
  19. 19.
    Saag M, Johnson V, Wei X, et al. Clinical, pharmacokinetic, and virologic results in adults treated with nevirapine in combination with AZT/ddC, AZT/ddl, or ddI alone: final report of the BI1009 study. [Abstract M16]. Presented at the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, FL, 1994.Google Scholar
  20. 20.
    Wei X, Ghosh SK, Taylor ME, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 1995; 373: 117–122.PubMedCrossRefGoogle Scholar
  21. 21.
    Ho DD, Neumann AU,Perelson AS. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995; 373: 123–126.PubMedCrossRefGoogle Scholar
  22. 22.
    Kilby JM, Taylor M, Wei X. In situ expression and functional analysis of HIV-1 reverse transcriptase (RT) in patients treated with nevirapine, AZT, and ddI. [Abstract I216]. Presented at the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, FL, 1994.Google Scholar
  23. 23.
    Kilby JM, Saag MS. Is there a role for non-nucleoside reverse transcriptase inhibitors in the treatment of HIV infection? Infectious Agents and Disease, 1994; 3: 313–323.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • J. Michael Kilby
  • Michael S. Saag

There are no affiliations available

Personalised recommendations