Nonnucleoside reverse transcriptase resistance

A general mechanism of resistance is reducing the affinity of the antiretroviral compound for its mutant target protein. Resistance mutations associated with reduced affinity are observed during treatment failure with a fusion inhibitor, nonnucleoside reverse transcriptase inhibitors (NNRTl), integrase inhibitor, and protease inhibitors as reviewed in Chaps. 3,4, 6, and 7 (Hazuda et al. 2007 Hsiou et al. 2001 King et al. 2002 Mink et al. 2005). 

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. 

The current standard of care recommends the use of potent three-drug combinations, which typically involves two nucleoside/nucleotide reverse transcriptase inhibitors with either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). By attacking HIV infection with three drugs at one time, practitioners seek to avoid the emergence of resistance strains within the patient. 

Rifabutin is derived from rifamycin and is related to rifampin. It has significant activity against M tuberculosis, M avium-intracellulare, and M fortuitum (see below). Its activity is similar to that of rifampin, and cross-resistance with rifampin is virtually complete. Some rifampin-resistant strains may appear susceptible to rifabutin in vitro, but a clinical response is unlikely because the molecular basis of resistance, rpoB mutation, is the same. Rifabutin is both substrate and inducer of cytochrome P450 enzymes. Because it is a less potent inducer, rifabutin is indicated in place of rifampin for treatment of tuberculosis in HIV-infected patients who are receiving concurrent antiretroviral therapy with a protease inhibitor or nonnucleoside reverse transcriptase inhibitor (eg, efavirenz)—drugs that also are cytochrome P450 substrates. 

Goldman ME, O Brien JA, Ruffing TL, Schleif WA, Sardana VV, Bynes VW, et al. A nonnucleoside reverse transcriptase inhibitor active on human immunodeficiency type 1 isolates resistant to related inhibitors. Antimicrob Agents Chemother 1993 37 947-949. 

Larder BA. AZT resistance suppressed by a mutation conferring HIV-1 resistance to nonnucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 1992 36 1171-1174. 

Efavirenz is a nonnucleoside reverse transcriptase inhibitor specific for HIV-1. After binding to a site distant from the active site on the HIV-1 reverse transcriptase, it disrupts catalytic activity of the enzyme by causing a conformational change and does not compete with deoxynucleoside triphosphates. Efavirenz does not inhibit HIV-2 reverse transcriptase and human DNA polymerases a, (3, 7 and 8. The resistance to the drug develops rapidly from site-directed mutagenesis specifically at codon 103, and also at codons 100, 106, 108, 181, 190 and 225 of viral reverse transcriptase. This resistance will be applicable for all nonnucleoside transcriptase inhibitors. 

Pata, J. D., Stirtan, W. G., Goldstein, S. W., and Steitz, T. A. (2004). Structure of HIV-1 reverse transcriptase bound to an inhibitor active against mutant reverse transcriptases resistant to other nonnucleoside inhibitors. Proc. Natl. Acad. Sri. USA 101, 10548-10553. 

The advent of highly active antiretroviral therapy (HAART) to minimize the rapid development of viral resistance in the treatment of HIV infection may result in multiple drug interactions (110-113). Both the nonnucleoside reverse transcriptase inhibitors and the protease inhibitors are substrates and inhibitors of some CYP enzymes, and some act as inducers as well (110,111). The major effects are on the CYP3A isoforms, and this has been used to advantage to increase concentrations of some HIV drugs. For example, delavirdine is a mechanism-based irreversible inhibitor of CYP3A4, and thereby is used to increase exposure to protease inhibitors (114). Ritonavir is a protease inhibitor, but it is used primarily for its ability as a potent inhibitor of CYP3A4 to increase concentrations of other protease inhibitors (115). 

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. 

Inhibition of human immunodeficiency vims type 1 reverse transcriptase by nucleosides such as AZT, DDC, DDI, D4T, and 3TC is a proven therapy for delaying the progression of AIDS. However, the rapid viral mutation to resistant strains requires the development of new therapeutic agents.The recent developments of both protease inhibitors and nonnucleoside reverse transcriptase inhibitors offer hope of effective treatment, especially when coadministered. " Efavirenz 290 is a nonnucleoside reverse transcriptase inhibitor that shows high potency against a variety of HIV-1 mutant strains. 

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. 

Schlabach AJ, Wolfgang JA, Condra JH. Functional analysis of HIV-1 reverse transcriptase amino acids involved in resistance to multiple nonnucleoside inhibitors. J Biol Chem 1992 267 17526-17530. 

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. 

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. 

Dueweke TJ, Pushkarskaya T, Poppe SM, Swaney SM, Zhao JQ, Chen ISY, et al. A mutation in reverse transcriptase of bis(heteroaryl) piperazine-resistant human immunodeficiency vims type 1 that confers increased sensitivity to other nonnucleoside inhibitors. Proc Natl Acad Sci USA 1993 90 4713 1717. 

Almerico, A.M., Lauria, A., Tutone, M., Diana, P., Barraja, P., Montalbano, A., Cirrincione, G. and Dattolo, G. (2003) A multivariate analysis on nonnucleoside HlV-1 reverse transcriptase inhibitors and resistance induced by mutation. QSAR Comb. Sci., 22, 984-996. 

Nonnucleoside RTIs that do not require metabolic activation (e.g., delavirdine and nevirapine, efavirenz, which are not myelosuppressants) and a nucleotide reverse-transcriptase inhibitor (adefovir) have been introduced. Resistance emerges rapidly if these drugs are used as individual agents for management of HIV infection. However, they may provide additive or synergistic activity against HIV if used in combination regimens with NRTIs and/or Pis. 

A. Mechanisms NNRTIs bind to a site on reverse transcriptase different from the binding site of NRTIs. Nonnucleoside drugs do not require phosphorylation to be active and do not compete with nucleoside triphosphates. There is no cross-resistance with NRTIs. Resistance due to mutations in the pol gene occur very rapidly if these agents are used as monotherapy. 

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. 

Tricyclic derivative 188 has been established to be active against multi-resistant gram-positive bacteria [90]. Also benzo annelated derivatives of fluorinated 3-hydroxyisoqumolindiones 189 exhibit antibacterial activity [115], It is worth noting, that derivatives of 6-flnoro-2(lH)quinolinone 190 are of interest as nonnucleoside inhibitors of reverse HIV transcriptase (Scheme 82) [116]. 

---