Nonnucleoside reverse transcriptase with protease inhibitors

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). 

Treatment with two nucleoside reverse transcriptase inhibitors (NRTIs) and either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI) is the mainstay of treatment for HIV infection. 

Inhibiting viral replication with combination of potent antiretroviral therapy has been the most clinically successful strategy in the treatment of HIV infection. There have been three primary groups of drugs used nucleoside and nonnucleoside reverse transcriptase inhibitors and protease inhibitors (Pis) (Table 40-5). 

Isoniazid Daily for 9 months0 In HIV-infected patients, isoniazid may be administered concurrently with nucleoside reverse transcriptase inhibitors, protease inhibitors, or nonnucleoside reverse transcriptase inhibitors A (II) A (II)... 

HIV - The initial phase of a 6-month tuberculosis regimen consists of isoniazid, rifabutin, pyrazinamide, and ethambutol for patients receiving therapy with protease inhibitors or nonnucleoside reverse transcriptase inhibitors. These drugs are administered a) daily for at least the first 2 weeks, followed by twice weekly dosing for 6 weeks or b) daily for 8 weeks to complete the 2-month induction phase. The second phase of treatment consists of rifabutin and isoniazid administered twice weekly or daily for 4 months. 

HIV infection In combination with other antiretroviral agents (such as nonnucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection in adults. 

Delavirdine mesylate is a member of the /7w(heteroaryl)piperazine (BHAP) class of nonnucleoside HIV-1 reverse transcriptase inhibitors (Adams et al., 1998 Romero et al., 1993 Romero, 1994). This class of compounds was discovered by Upjohn scientists from a computer-directed dissimilarity analysis of the Pharmacia Upjohn chemical library to select compounds for screening against HIV-1 RT. The result of the in vitro assay (Deibel et al., 1990) is an IC50 of 0.260 p,M, which is comparable to AZT. In accordance with the previous NNRTIs, delavirdine is a noncompetitive inhibitor of reverse transcriptase, and has a synergistic effect with nucleoside transcriptase and protease inhibitors (Chong et al., 1994). 

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. 

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. 

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. 

Patients with AIDS who are taking protease inhibitors and nonnucleoside reverse transcriptase inhibitors are at risk of being subtherapeutically treated because these drugs are metabolized by CYP3A4. Studies have shown that combined use of St. John s wort and indinavir reduced the area under the... 

In addition to NRTIs, the two other important classes of antiretroviral drugs available are the protease inhibitors and the nonnucleoside reverse transcriptase inhibitors (NNRTIs). Most authorities recommend initiation of antiretroviral therapy in treatment-naive patients with viral RNA loads above 10,(XX) copies/mL even if the CD4 cell count is normal. Preferred highly active antiretroviral therapy (HAART) combines one drug from the class of protease inhibitors with two NRTIs. Alternatively, one NNRTI may be combined with two NRTIs. 

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). 

Duvivier, C., Kolta, S., Assoumou, L. et al. 2009. Greater decrease in bone mineral density with protease inhibitor regimens compared with nonnucleoside reverse transcriptase inhibitor regimens in HIV-1 infected naive patients. AIDS 27 817-824. 

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