Tenofovir

However, acyclic nucleotide analogs (acyclic nucleoside phosphonates) have been developed, which carry one phosphonate moiety and require only the two subsequent phosphorylation steps (De Clercq et al. 1978). Independent of virus-encoded kinases, they display a broader spectrum of efficacy. This class comprises important drugs against HIV (tenofovir) and HBV (adefovir, tenofovir), as well as cidofovir, which is approved for use against CMV retinitis, but also displays an exceptionally broad efficacy profile against many herpesviruses, adenovirus, poxviruses, and papillomaviruses (De Clercq and Holy 2005). 

The prototype member of the ANPs is (5)-9-(3-hydroxy-2-phosphonyl-methoxypropyl)adenine (HPMPA) (Fig. 2), first described for its broad-spectrum anti-DNA virus activity in 1986 (De Clercq et al. 1986). Then followed by the description of various other acyclic nucleoside phosphonates in 1987 (De Clercq et al. 1987). At present three acyclic nucleoside phosphonates have been licensed for clinical use cidofovir, adefovir, and tenofovir (Fig. 2). 

Tenofovir in its prodrug form tenofovir, disoproxil fumarate (TDF), is indicated in the treatment of HIV infections (AIDS). It is administered as a single oral dose of 300 mg per day. When combined with emtricitabine and efavirenz, TDF has proven to be more efhcacious than the standard combination therapy of combivir (azidothymidine plus lamivudine) and efavirenz (Gallant et al. 2006) and less prone to cause adverse side effects (Pozniak et al. 2006 De Clercq 2007b). 

Appropriately designed prodrugs, for example, phosphonoamidates (Lee et al. 2005), may allow acyclic nucleoside phosphonates such as tenofovir to be specifically targeted at tissues, that is, lymphatic tissue, where the virus (i.e., HIV) replicates. This principle has been recently extended to another nucleotide analogue, GS-9148 (Cmiar et al. 2008) and its phosphonoamidate prodrug, GS-9131 (Ray et al. 2008). 

After me ANPs (i.e., cidofovir, adefovir, and tenofovir) have been released (intra-or extraceUularly) from their prodrugs through the mtervention of infra- or extracellular esterases, they need only two phosphorylation steps to be converted to their active metabolites (i.e., HPMPCpp, PMEApp, and PMPApp), which will then compete with the natural substrates (dCTP for HPMPCpp, and dATP for PMEApp and PMPApp) for incorporation into me viral DNA (Fig. 6a). 

As has been demonstrated for tenofovir, when incorporated at the 3 -end of reverse transcriptase (RT)-driven DNA chain allows the PMPA residue to adopt multiple conformations [in contrast with the more rigid conformation of the 2, 3 -dideoxynucleosides (see infra) (Tuske et al. 2004). This greater flexibility in conformation may impede development of resistance to tenofovir. 

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... 

All the nucleoside (and nucleotide) analogues that have entered the clinic for the treatment of HBV infections (i.e., nucleoside analogues lamivudine, entecavir, tel-bivudine nucleotide analogues adefovir and tenofovir) are fairly well tolerated without side effects that would preclude their long-term usage. The nucleoside analogues in (pre)clinical development for the treatment of HCV infections are not yet sufficiently advanced to assess their tolerability and/or safety. 

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. 

De Clercq E (2006) From adefovir to Atripla via tenofovir, Viread and Truvada. Future Virol 1 709-715... 

Landman R, Descamps D, Peytavin G, Trylesinski A, Katlama C, Girard PM, Bonnet B, Yeni P, Bentata M, Michelet C, Benalycherif A, Brun VF, Miller MD, Flandre P (2005) Early virologic failure and rescue therapy of tenofovir, abacavir, and lamivudine for initial treatment of HlV-1 infection TONUS study, HIV Clin Trials 6 291-301... 

Lanier ER, Hazen R, Ross L, Freeman A, Harvey R (2005) Lack of antagonism between abacavir, lamivudine, and tenofovir against wild-type and drug-resistant HlV-1, J Acquir Immune Defic Syndr 39 519-522... 

Podzamczer D, Ferrer E, GateU JM, Niubo J, Dalmau D, Leon A, Knobel H, Polo C, Iniguez D, Ruiz I (2005) Early virological failure with a combination of tenofovir, didanosine and efavirenz. Antivir Ther 10 171-177... 

Add adefovir or tenofovir Add lamivudine or telbivudine Switch to or add adefovir or tenofovir Add adefovir or tenofovir... 

Zidovudine Didanosine Stavudine Lamivudine Abacavir Tenofovir Emtricitabine Nevirapine Efavirenz TMC125 Saquinavir Indinavir Lopinavir Fosamprenavir Atazanavir Tipranavir Darunavir Raltegravir Elvitegravir Enluvirtide Maraviroc Vicriviroc Bevirimat... 

Tenofovir + Emtricitabine Zidovudine + Lamivudine Abacavir + Lamivudine Efavirenz or Nevirapine Lopinavir/r or Atazanavir/r or Eosamprenavir/r or Saquinavir/r... 

Other drugs that are commonly implicated in causing ARF include acyclovir, adefovir, carboplatin, cidofovir, cisplatin, foscarnet, ganciclovir, indinavir, methotrexate, pentamidine, ritonavir, sulfinpyrazone, and tenofovir.45... 

Atazanavir or fosamprenavir or nelfinavir or saquinavir/ ritonavir, and zidovudine or stavudine or tenofovir or abacavir or didanosine, and lamivudine or emtricitabine... 

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). 

Therapies not recommended for initial treatment due to poor potency or significant toxicity include delavirdine, nevirapine in patients with moderate to high CD4+ T-cell counts, indinavir or saquinavir used without ritonavir ( unboosted ), ritonavir used without another protease inhibitor, and tenofovir plus didanosine with an NNRTI. 

Tenofovir disoproxil 300 mg tab 300 mg qday CrCI None Asthenia, headache, Renal excretion... 

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