NRTIs NNRTIs

NRTI NNRTI Fusion inhibitors Co-receptor antagonists ... 

The second class of agents comprises non-competitive inhibitors of reverse transcriptase. These agents are also referred to as non-nucleoside reverse transcriptase inhibitors (NNRTIs). Unlike NRTIs, NNRTIs do not require phosphorylation to be activated and do not compete with nucleoside triphosphates. The NNRTIs bind to a site on the viral reverse transcriptase that is close to but separate from the NRTI receptor site. This binding ultimately results in blockade of RNA- and DNA-dependent DNA... 

How do these NRRIs interact with their final target, the HCV RNA replicase They are phosphorylated to their 5 -triphosphate form, and then inhibit the HCV replicase. As they possess a 3 -hydroxyl function, they may not be considered as obligate chain terminators, but they may act as virtual chain terminators, viz. by steric hindrance exerted by the neighboring 2 -C-methyl and/or 4 -C-azido groups. Similar to their NRTI and NNRTI counterparts in the case of HIV reverse transcriptase, the NRRIs (2 -C-methylnucleosides) interact, upon their phosphorylation to the corresponding 5 -triphosphates, with a region of the HCV RNA replicase (or NS5B RNA-dependent RNA polymerase) that is clearly distinct from the site(s) of interaction of the NNRRIs (Tomei et al. 2005). 

Of the NNRTIs that were first approved, nevirapine and, even more so, efavirenz became cornerstones of HIV therapy because of their potential as a component of HAART (Staszewski et al. 1999). The most commonly used NNRTl drug is efavirenz. In addition, nevirapine was shown to effectively prevent HIV transmission from mother to baby. NNRTIs have proven beneficial when included in drug combination (triple or quadruple) therapy, preferably in the presence of protease inhibitors and NRTIs. 

Although the NNRTIs target HIV-1 RT, they are clearly different from the nucleoside RT inhibitors (NRTIs). They are highly selective for HlV-1 and do not inhibit HlV-2 or any other retrovirus. Moreover, the resistance spectrum of NNRTIs is different from that of NRTI, and, as a rule, NRTl-resistant mutant virus strains keep full sensitivity to the inhibitory effects of NNRTIs, and NNRTI-resistant mutant virus strains keep full sensitivity to the inhibitory effects of NRTIs. However, some influence of NRTI mutations on NNRTl susceptibility has been observed (Shuhnan etal. 2004). 

RT reverse transcriptase, NRTI nucleoside reverse transcriptase inhibitors, NNRTI Non-nucleoside reverse transcriptase inhibitors... 

Isoniazid Daily for 9 monthsc,d In human immunodeficiency virus (HlV)-infected patients, isoniazid may be administered concurrently with nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors, or non-nucleoside reverse transcriptase inhibitors (NNRTIs). A (II) A (II)... 

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. 

Triple NRTI therapy is recommended only when a first-line or alternative first-line therapy with either an NNRTI-based or Pi-based regimen cannot be used. Abacavir plus zidovudine plus lamivudine is the only regimen approved by the DHHS. The following triple nucleoside therapy combinations have shown poor or limited efficacy, and should be avoided abacavir plus tenofovir plus lamivudine (or emtricitabine), and didanosine plus tenofovir plus lamivudine (or emtricitabine). 

NRTIs (based on resistance testing) + NNRTI or PI (with or without low-dose ritonavir)... 

NRTI, nucleoside reverse transcriptase inhibitor NNRTI, nonnucleoside reverse transcriptase inhibitor PI, protease inhibitor. 

NNRTI—60% within first 12 weeks PI—weeks to months NRTI—months to years Symptoms... 

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) for combination with dual NRTIs (strength of recommendation in parentheses)... 

Nearly 40 million people are infected with the human immunodeficiency virus (HIV). Over half of those infected reside in sub-Saharan Africa. Worldwide during 2004, it is estimated that nearly 14,000 people a day were infected. Human immunodeficiency virus type 1 is the primary etiological source for the acquired immunodeficiency syndrome (AIDS). Fortunately, people infected with HIV are leading longer and more productive lives due to the availability of more effective therapies. Better medicines have evolved due to the efforts of scientists worldwide who find targets and compounds that inhibit the virus life-cycle. The current treatment for HIV infection is via a drug cocktail that usually includes a protease inhibitor (PI), a nucleoside reverse transcriptase inhibitor (NRTI), and a non-nucleoside reverse transcriptase inhibitor (NNRTI). 

Although the NNRTI are active at the same site as the NRTI inhibitors and also prevent the conversion of RNA to DNA, their mechanism of action is not... 

NRTI Nucleoside (or nucleotide) transcriptase inhibitor NNRTI Non-nucleoside reverse transcriptase inhibitor PI Protease inhibitor... 

In a patient whose antiretroviral regimen includes the NNRTI, efavirenz, and two NRTIs. 

The replicative cycle of HIV presents many opportunities for the targeting of antiviral agents. The drugs in clinical use are classified as nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NTRTIs), and protease inhibitors (PI). 

The NNRTIs inhibit viral reverse transcriptase by binding adjacent to its active site and inducing a conformational change that causes the enzyme s inactivation. When combined with NRTIs or protease inhibitors,... 

A. The NRTIs can produce a potentially fatal syndrome of lactic acidosis and severe hepatomegaly with hepatic steatosis. Risk factors associated with the development of this syndrome include female sex, obesity, alcoholism, and prolonged exposure to NRTIs. Peripheral neuropathy is a common side effect of some NRTIs (e.g., stavudine., didanosine, and zalcitabine) but not associated with these risk factors. Stevens-Johnson syndrome is rarely associated with NNRTIs, such as nevirapine, and not with these risk factors. Hyperuricemia is not associated with these risk factors. Hypersensitivity reaction may oc-... 

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