Human immunodeficiency virus nonnucleoside reverse

Anderson MS, Kakuda TN, Hanley W, Miller J, Kost JT, Stoltz R, Wenning LA, Stone JA, Hoetehnans RM, Wagner JA, Iwamoto M. Minimal pharmacokinetic interaction between the human immunodeficiency virus nonnucleoside reverse transcriptase inhibitor etravirine and the integrase inhibitor raltegravir in healthy subjects. Antimicrob Agents Chemother 2008 52(12) 4228-32. 

Kleim JP, ROsner M, Winkler I, Paessens A, Kirsch R, Hsiou Y, Arnolds E, Riess G (1996) Selective pressure of a quinoxaline nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on HIV-1 replication results in the emergence of nucleoside RT-inhibitor-specific (RT Leu-74 -> Val or He and Val-75 - > Leu or He) HIV-1 mutants, Proc Natl Acad Sci USA 93 34-38... 

TC, lamivudine ABC, abacavir APV, amprenavir AST, aspartate aminotransferase ALT, alanine aminotransferase ATV, atazanavir CBC, complete blood cell count D/C, discontinue ddl, didano-sine d4T, stavudine EFV, efavirenz FTC, emtricitabine P1BV, hepatitis B virus F1CV, hepatitis C vims HIV, human immunodeficiency virus IDV, indinavir IV, intravenous LFT, liver function tests LPV/r, lopinavir + ritonavir NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor PT, prothrombin time T.bili, total bilirubin TDF, tenofovir disoproxiI fumarate TPV, tipranavir ULN, upper limit of normal ZDV, zidovudine. 

Nonnucleoside reverse transcriptase inhibitor (NNRTI) A noncompetitive inhibitor of the viral reverse transcriptase enzyme that binds to the active site of the enzyme itself, rather than by terminating the enzymatic product. NNRTIs are only active against human immunodeficiency virus-1. 

Richman D, Shih C-K, Lowy I, Rose J, Prodanovich P, Goff S, Griffin J. Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture. Proc Natl Acad Sci USA 1991 88 11241-11245. 

Byrnes VW, Sardana W, Schleif WA, Condra JH, Waterbury JA, Wolfgang JA, Long WJ, Schneider CL, Schlabach AJ, Wolanski BS, Graham DJ, Gotlib L, Rhodes A, Titus DL, Roth E, Blahy OM, Quintero JC, Staszewski S, Emini EA. Comprehensive mutant enzyme and viral variant assessment of human immunodeficiency virus type 1 reverse transcriptase resistance to nonnucleoside inhibitors. Antimicrob Agents Chemother 1993 37 1576-1579. 

Pyrrolopyridines substituted at the 2-position of dipyridodiazepinones have been prepared for study as nonnucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase <1997JME2430>. Compound 141, synthesized from pyrrolo[2,3-, ]pyridine as a starting material, has emerged as a novel inhibitor of HIV-1. Compound 141 acts by interfering with the initial viral entry process <2003JME4236>. 

Boyer PL, Ding J, Arnold E, Hughes SH. Drug resistance of human immunodeficiency virus type 1 reverse transcriptase subunit specificity of mutations that confer resistance to nonnucleoside inhibitors. Antimicrob Agents Chemother 1994 38 1909-1914. 

Rittinger K, Divita G, Goody R. Human immunodeficiency virus reverse transcriptase substrate-induced conformational changes and the mechanism of inhibition by nonnucleoside inhibitors. Proc Natl Acad Sci USA 1995 92 8046-8049. 

Boyer PL, Currens MJ, McMahon JB, Boyd MR, Hughes SH. Analysis of nonnucleoside drug-resistant variants of human immunodeficiency virus type 1 reverse transcriptase. J Virol 1993 67 2412-2420. 

Young SD, Britcher SF, Tran LO, Payne LS, et al. 1995. Erfavirenz A novel highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase. Antimi-crog Agents Chemother. 39 2602-2605. 

Fujihashi T, Hara H, Sakata T, Mori K, Higuchi H, Tanaka A, Kaji H, Kaji A (1995) Anti-Human Immunodeficiency Virus (HIV) Activities of Halogenated Gomisin J Derivatives, New Nonnucleoside Inhibitors of HIV Type 1 Reverse Transcriptase. Antimicrob Agents Chemother 39 2000... 

Smerdon, S. J., Jager, J., Wang, J., Kohlstaedt, L. A., Chirino, A.J., Friedman, J. M., Rice, P. A., and Steitz, T. A. (1994). Structure of the binding site for nonnucleoside inhibitors of the reverse transcriptase of human immunodeficiency virus type 1. Proc. Natl. Acad. Sd. USA91, 3911-3915. 

At the present time, there are at least 14 compounds that have been formally approved for the treatment of human immunodeficiency virus (HIV) infections. There are six nucleoside reverse transcriptase inhibitors (NRTIs) that, after their intracellular conversion to the 5 -triphosphate form, are able to interfere as competitive inhibitors of the normal substrates (dNTPs). These are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (ABC). There are three nonnucleoside reverse transcriptase inhibitors (NNRTIs) — nevirapine, delavirdine, and efavirenz — that, as such, directly interact with the reverse transcriptase at a nonsubstrate binding, allosteric site. There are five HIV protease inhibitors (Pis saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) that block the cleavage of precursor to mature HIV proteins, thus impairing the infectivity of the virus particles produced in the presence of these inhibitors. 

Schmit, J.-C., Cogniaux, J., Hermans, P Van Vaeck, C., Sprecher, S Van Remoortel, B., Witvrouw, M Balzarini, J., Desmyter, J., De Clercq, E., and Vandamme, A.-M. (1996) Multiple drug resistance to nucleoside analogues and nonnucleoside reverse transcriptase inhibitors in an efficiently replicating human immunodeficiency virus type 1 patient strain../. Infect. Dis. 174,962-968. 

Successful treatment of human immunodeficiency virus (HIV-1) infection has been achieved through successful implementation of highly active antiretroviral therapy, frequently referred to as HAART. This involves simultaneous administration of both nucleoside and nonnucleoside reverse transcriptase inhibitors and one or more protease inliibitors. The common nucleoside reverse transcriptase inhibitors are the thymidine analogs didanosine (ddl), lamivudine (3TC), and zalcitabine (ddC) and the non-thymidine analogs abacavir (Ziazen), stavudine (d4T), and zidovudine (AZT). The nonnucleoside reverse transcriptase inhibitors include delavirdine, efavirenz, and nevirapine. The protease inhibitors include indinavir, nelfinavir, ritonavir, and saquinavir. Response to therapy is monitored by quantification of HIV-RNA copies (viral load) and CD-4+ T-lymphocyte count. Successful therapy is indicated when viral load is reduced to <50 copies/mL and CD-4+ count >500 per mL. 

Mellors JW, Dutschman GE, Im GJ, et al. In vitro selection and molecular characterization of human immunodeficiency virus-1 resistant to nonnucleoside inhibitors of reverse transcriptase. Mol Pharmacol 1992 41 446-451. 

Nevirapine (NVP), a nonnucleoside reverse transcriptase inhibitor, is widely used for the treatment of human immunodeficiency virus (HIV) infections. It is the main option for the first-line treatment of HIV-1, together with two nucleoside reverse transcriptase inhibitors, in countries with limited resources. NVP is associated with two serious clinically restrictive side effects skin reactions and hepatotoxicity. Severe, life threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure, has been reported in HIV-infected patients taking NVP (DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents 2008). For this reason, NVP is given a black box warning for hepatotoxicity, and concern has been raised over NVP-based treatment. 

Corbett JW, Ko SS, Rodgers JD, Jeffrey S, Bacheler LT, Klabe RM, Diamond S, Lai CM, Rabel SR, Saye JA, Adams SP, Trainor GL, Anderson PS, Erickson-Wtanen SK (1999) Expanded-spectrum nonnucleoside reverse transcriptase inhibitors inhibit clinically relevant mutant variants of human immunodeficiency virus type 1. Antimicrob Agents Chemother 43 2893-2897... 

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