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.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Hirsch MS, D’Aquila RT. Therapy for HIV Infection. N Engl J Med 1993; 328: 1686–95.
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.
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.
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.
Saag MS. Nucleoside analogues: adverse effects. Hosp Prac 1992; 27 (suppl 2): 26–36.
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.
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.
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.
Merluzzi VJ, Hargrave KD, Labadia M, et al. Inhibition of HIV-1 replication by a non-nucleoside RT inhibitor. Science 1990; 250: 1411–13.
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.
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.
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.
Nunberg JH, Schleif WA, Boots EJ, et al. Viral resistance to HIV-1-specific pyridinone inhibitors. J Virol 1991; 65: 4887–92.
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.
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.
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.
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.
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.
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.
Wei X, Ghosh SK, Taylor ME, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 1995; 373: 117–122.
Ho DD, Neumann AU,Perelson AS. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995; 373: 123–126.
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.
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.
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1996 Springer Science+Business Media New York
About this chapter
Cite this chapter
Kilby, J.M., Saag, M.S. (1996). Clinical Experience with Non-Nucleoside Reverse Transcriptase Inhibitors: L-697,661 and Nevirapine. In: Mills, J., Volberding, P.A., Corey, L. (eds) Antiviral Chemotherapy 4. Advances in Experimental Medicine and Biology, vol 394. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-9209-6_26
Download citation
DOI: https://doi.org/10.1007/978-1-4757-9209-6_26
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4757-9211-9
Online ISBN: 978-1-4757-9209-6
eBook Packages: Springer Book Archive