Nonnucleoside reverse transcriptase interactions

Rifabutin appears as effective as rifampin in the treatment of drug-susceptible tuberculosis and is used in the treatment of latent tuberculosis infection either alone or in combination with pyrazinamide. Clinical use of rifabutin has increased in recent years, especially in the treatment of HIV infection. It is a less potent inducer of cytochrome 450 enzymes pathways than rifampin and results in less drug interaction with the protease inhibitors and nonnucleoside reverse transcriptase inhibitors. Rifabutin is therefore commonly substituted for rifampin in the treatment of tuberculosis in HIV-infected patients. Another important use of rifabutin in the HIV-infected population is prevention and treatment of disseminated MAC. 

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. 

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). 

The cyclopropyl rest is less bulky than the isopropyl group for a maximal electron-donor effect. This electroiuc effect is involved when the cyclopropyl group of efavirenz, a nonnucleoside reverse transcriptase inhibitor, interacts with the aromatic ring of tyrlSl via a 7r-aryl interaction which is presumably favorable to binding. ... 

In HIV-infected patients, the substitution of rifabutin for rifampin minimizes drug interactions witii tiie HIV protease inhibitors and nonnucleoside reverse transcriptase inhibitors. 

Drug interactions are a special concern in patients receiving highly active antiretroviral therapy (H AART). The rifamycins accelerate the metabohsm of protease inhibitors and nonnucleoside reverse transcriptase inhibitors. Rifabutin has the least effect on serum levels and is indicated in this setting. 

Drug Interactions Between Nonnucleoside Reverse Transcriptase Inhibitors and HIV Protease Inhibitors ... 

Delavirdine, a nonnucleoside reverse transcriptase inhibitor, is used as part of antiretroviral therapy. Because of its moderate efficacy and inconvenient dosing (three times a day) as well as interaction with other protease inhibitors, delavirdine is currently rarely used (see footnote 1). 

Andrade RA, Evans RT, Hamill RJ, Zerai T, Giordano TP. Clinical evidence of interaction between itraconazole and nonnucleoside reverse transcriptase inhibitors in HIV-infected patients with... 

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. 

Nonnucleoside Inhibitors Nevirapine and efavirenz are active inhibitors of reverse transcriptase, that is, they do not require phosphorylation. Adverse reactions include rashes and interactions involving cytochrome P450 isozymes (CYP). 

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