NRTIs Tenofovir

Tenofovir disoproxilfumarate is a prodrug that is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine. Like the NRTIs, tenofovir competitively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA. 

The 2, 3 -dideoxynucleoside (ddN) analogues (Fig. 3) encompass a vast group of compounds that have been found active against HIV and HBV, although they have been primarily pursued for the treatment of HIV infections (AIDS). They are targeted at the HIV-associated reverse transcriptase (RT) and therefore also referred to as nucleoside reverse transcriptase inhibitors (NRTIs). They have to be distinguished from the nucleotide reverse transcriptase inhibitors (NtRTIs) such as adefovir (PMEA) and tenofovir (PMPA) (see above) which, like the NRTIs, act as chain... 

In addition to the NRTI lamivudine (3TC) and the NtRTI adefovir dipivoxU and tenofovir disoproxil fumarate (which has been recently licensed for the treatment of chronic hepatitis B), two other nucleoside analogues, that is, entecavir and L-dT (tel-bivudine) (Fig.4aa), have been licensed for the treatment of HBV infections. Two other compounds 3 -Val-L-dC (valtorcitabine) and L-FMAU (clevudine) (Fig. 4aa) are in clinical development for the treatment of HBV infections, and yet two other compounds, that is, racivir and elvucitabine (Fig. 3), yield potential for the treatment of both HBV and HIV infections. 

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). 

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. 

Drugs that may affect tipranavir include aluminum- and magnesium-based antacids, azole antifungals, clarithromycin, efavirenz, loperamide, NRTIs (ie, didanosine, zidovudine), rifamycins (rifampin), St. John s wort, tenofovir. 

The present NRTIs available for the treatment of HIV are zidovudine (azidothymidine, AZT), stavu-dine (d4T), didanosine (ddl), lamivudine (3TC), dideoxycytidine (ddC, zalcitabine) and abacavir, emtricitabine and tenofovir disoproxil. Combination formulations are abcavir combined with zidovudine and lamivudine and the abacavir-lamivudine combination. 

Zidovudine (ZDV or AZT) is a nucleoside reverse transcriptase inhibitor (NRTI) and it was the first anti-HIV agent to be introduced. Other NRTIs include stavudine (d4T), lamivudine (3TC), didano-sine (ddl), abacavir (ABC) and zalcitabine (ddC). Recent additions to this class are emtricitabine (FTC) which has a molecular structure similar to 3TC and tenofovir (TDF) a nucleotide reverse transcriptase inhibitor. 

Tenofovir disoproxil fumarate (Viread) is a prodrug of tenofovir, a phosphorylated adenosine nucleoside analogue, and is the only available agent of its class. It is converted by cellular enzymes to tenofovir diphosphate, which competes with deoxyadenosine triphosphate (dATP) for access to reverse transcriptase and causes chain termination following its incorporation. Tenofovir was approved as part of a combination therapy for HIV in adults who failed treatment with other regimens it appears to be effective against HIV strains that are resistant to NRTIs. The pharmacokinetic properties of tenofovir are provided in Table 51.2. 

Tenofovir is taken once daily and is generally well tolerated, perhaps because it produces less mitochondrial toxicity than the NRTIs. Nausea, vomiting, flatulence, and diarrhea occur in 10% or fewer patients. Resistance to tenofovir has been documented, and cross-resistance to NRTIs may occur. 

Tenofovir should not be given to patients with renal insufficiency. Its coadministration with didanosine results in increased plasma levels of didanosine that can produce toxicity. Because lactic acidosis and severe hepatomegaly with steatosis have been reported with NRTIs, it is important to monitor patients with known risk factors during treatment with tenofovir. 

All NRTI agents, as well as tenofovir, carry the risk of lactic acidosis with hepatic steatosis as a potential adverse event. 

Several anti-HBV agents have anti-HIV activity as well, including lamivudine, adefovir dipivoxil, and tenofovir. Emtricitabine, an antiretroviral NRTI, is under clinical evaluation for HBV treatment. Because NRTI agents may be used in patients co-infected with HBV and HIV, it is important to note that acute exacerbation of hepatitis may occur upon discontinuation or interruption of these agents. 

Raltegravir, or Isentress (1), is the first FDA-approved inhibitor of HIV integrase. HIV/AIDS drugs are categorized according to their mode of action as nucleoside and nucleotide reverse transcriptase inhibitors [NRTIs, e.g., tenofovir (2)], nonnucleotide reverse transcriptase inhibitors [NNRTIs, e.g., efavirenz (3)] protease inhibitors [Pis, e.g., ritonavir (4)], fusion inhibitors [e.g., enfuvirtide (5)], entry inhibitors... 

NRTIs are phosphorylated and converted into diphosphate forms by nucleoside kinases. These acdvated forms have high levels of afdnity for HTV-1 reverse d anscriptase and compete with the natural deoxynucleoside diphosphates. Once incorporated into the growing chain of DNA, lack of a 3 -hydroxyl group that can form a phosphodiester bond with the incoming nucleoside causes chain terminadon. Tenofovir is an exception in this group as it is a nucleotide analogue rather than nucleoside and, as such, requires only tw o phosphorylation steps instead of three to become the active form. Pharmacological characteristics of FDA approved NRTIs are presented in Table 41.3. 

The nucleoside analogue reverse transcriptase inhibitors (NRTIs) include abacavir, didanosine, lamivudine, stavu-dine, tenofovir, zalcitabine, and zidovudine (all rINNs). The following abbreviations have been used and may still be encountered in published papers ... 

Nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of medications approved for the management of HIV infection. They are structural analogues of nucleic acids. They undergo intracellular phosphorylation to a triphosphate metabolite and it is this metabolite that is pharmacologically active against reverse transcriptase. Drugs in this class include abacavir, adefovir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine. 

NRTIs are faulty version reverse transcriptase. Reproduction of HIV is stalled when HIV uses NRTI instead of the normal reverse transcriptase. Dmgs within this category include Abacavir (Ziagen, ABC), Abacavir, Lamivudine (Epzicom), Abacavir, Lamivudine, Zidovudine (Trizivir), Didanosine (Videx, ddl, Videx EC), Emtricitabine (Emtriva, FTC, Coviracil), Emtricitabine, Tenofovir DF (Truvada), Lamivudine (Epivir, 3TC), Lamivudine, Zidovudine (Combivir), Stavudine (Zerit, d4T), Tenofovir DF (Viread, TDF), Zalcitabine (Hivid, ddC), and Zidovudine (Retrovir, AZT, AZV). 

In a placebo-controlled, crossover study in healthy subjects maraviroc 300 mg twice daily had no clinically relevant effect on the pharmacokinetics of zidovudine/lamivudine (Ctmbivir) 300/150 mg twice daily, when they were given together for one week. For the effect of other NRTIs in combination with protease inhibitors or NNRTIs on maraviroc, see CYP3A4 inhibitors , (p.780) and CYP3A4 inducers , (p.780), and for the effect of tenofovir, see Drugs that affect renal clearance , (above). 

Some combinations of NRTIs are potentially antagonistic (stavudine with zidovudine, lamivudine with zalcitabine) and some are expected to result in additive toxicity (didanosine with stavudine or zalcitabine, and possibly stavudine with zalcitabine). Some do not appear to result in additional benefits (emtricitabine with lamivudine), and some are considered inferior to other combinations (stavudine with lamivudine, zidovudine with zalcitabine or didanosine). None of these combinations are recommended. Combinations that are specifically recommended (with other antiretrovirals) include lamivudine with abacavir, didanosine or zidovudine, or didanosine with emtricitabine. Sole use of all triple NRTI regimens should generally be avoided, with the possible exception of abacavir or tenofovir , (p.806) with zidovudine and lamivudine. 

Tenofovir increases the levels of didanosine an increased risk of pancreatitis and peripheral neuropathy has been reported, and a high level of treatment failure. There is no pharmacokinetic interaction between tenofovir and abacavir, emtricitabine, lamivudine or stavudine. However, the combination of tenofovir, lamivudine and abacavir was unexpectedly associated with a high level of treatment failure. Triple-NRTI regimens invoiving tenofovir are not recommended, with the possibie exception of tenofovir, lamivudine and zidovudine. 

Note that tenofovir is a nucleotide (nucleoside monophosphate) analogue and is often classed as an NRTI. 

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