Nucleoside Reverse Transcriptase Inhibitors
Approved, nucleoside analogs:
Abacavir (ABC)
,
Didanosine (ddI) ,
Emtricitabine (FTC) ,
Lamivudine (3TC) ,
Stavudine (d4T) ,
Zidovudine/Azidothymidine (AZT) ,
Zalcitabine (ddC)
Approved, Cytosine analogues:
Tenofovir Disoproxil Fumarate (TDF) !(image)./resources/AIDSinfo.gif!,
Tenofovir alafenamide (TAF) !(image)./resources/AIDSinfo.gif!
Inhibition mechanism
Once HIV has entered the target host cell reverse transcription, initiated by the viral reverse transcriptase (RT) enzyme, occurs. During reverse transcription the HIV RNA genome is reverse transcribed to DNA which will be transported into the nucleus and integrated into the host genome for subsequent replication. Nucleoside reverse transcriptase inhibitors (NRTIs) are structural nucleoside analogues of DNA nucleotides which prevent reverse transcription of the HIV genome, thereby inhibiting the action of HIV-1 RT and viral replication 
. These nucleosides are defective in the sense that they prevent new 3' phosphodiesterase bonds with the next nucleotide in a growing DNA strand . These nucleoside analogues are phosphorylated by human cellular kinases to their triphosphate form where they are subsequently incorporated by RT into the growing DNA primer strand of HIV. This results in premature chain termination and the inhibition of successful HIV replication .
These drugs have been found highly effective for the treatment of HIV-1 and are generally regarded as safe to use but life-threatening adverse reactions, like mitochondrial toxicity, have been reported . Mitochondrial toxicity occurs due to the ability of NRTIs, except abacavir and lamivudine, to compete with human mitochondrial DNA polymerase gamma . This polymerase is responsible for excision repair of mitochondrial DNA that has been damaged by oxidation. Decrease in mitochondrial DNA excision repair results in a depletion of mitochondrial DNA and the subsequent disruption of oxidative phosphorylation leading to toxin accumulation and mitochondrial toxicity .
NRTIs have no CYP 450 interactions . They are subject to interactions of glucuronidation and absorption and metabolism differs with each drug.
Correlation between intracellular pharmacological activation of nucleoside analogues and HIV suppression in vitro
P. G. Hoggard, S. D. Sales, S. Kewn, D. Sunderland, S. H. Khoo, C. A. Hart, D. J. Back
Antivir. Chem. Chemother. November 2000; 11: 353?358
Antiretrovirals, Part II: focus on non-protease inhibitor antiretrovirals (NRTIs, NNRTIs, and fusion inhibitors)
Michael J. Zapor, Kelly L. Cozza, Gary H. Wynn, Glenn W. Wortmann, Scott C. Armstrong
Psychosomatics December 2004; 45: 524?535
Perspectives on the molecular mechanism of inhibition and toxicity of nucleoside analogs that target HIV-1 reverse transcriptase
Karen S. Anderson
Biochim. Biophys. Acta July 18, 2002; 1587: 296?299
Antiretrovirals, Part II: focus on non-protease inhibitor antiretrovirals (NRTIs, NNRTIs, and fusion inhibitors)
Michael J. Zapor, Kelly L. Cozza, Gary H. Wynn, Glenn W. Wortmann, Scott C. Armstrong
Psychosomatics December 2004; 45: 524?535
Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity
G. Moyle
Clin Ther August 2000; 22: 911?936; discussion 898
Dermatologic complications associated with administration of 2?,3?-dideoxycytidine in patients with human immunodeficiency virus infection
M. C. McNeely, R. Yarchoan, S. Broder, T. J. Lawley
J. Am. Acad. Dermatol. December 1989; 21: 1213?1217
Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. North American HIV Working Party
J. J. Eron, S. L. Benoit, J. Jemsek, R. D. MacArthur, J. Santana, J. B. Quinn, D. R. Kuritzkes, M. A. Fallon, M. Rubin
N. Engl. J. Med. December 21, 1995; 333: 1662?1669
Perspectives on the molecular mechanism of inhibition and toxicity of nucleoside analogs that target HIV-1 reverse transcriptase
Karen S. Anderson
Biochim. Biophys. Acta July 18, 2002; 1587: 296?299
Compact quadruple therapy with the lamivudine/zidovudine combination tablet plus abacavir and efavirenz, followed by the lamivudine/zidovudine/abacavir triple nucleoside tablet plus efavirenz in treatment-na?ve HIV-infected adults
Peter J. Ruane, David M. Parenti, David M. Margolis, David H. Shepp, Timothy J. Babinchak, Amy S. Van Kempen, Teresa L. Kauf, Susan A. Danehower, Linda Yau, Siegrid M. Hessenthaler, Diane Goodwin, Jaime E. Hernandez, COL30336 Study Team
HIV Clin Trials August 2003; 4: 231?243
Randomized, controlled, 48-week study of switching stavudine and/or protease inhibitors to combivir/abacavir to prevent or reverse lipoatrophy in HIV-infected patients
Mina John, Elizabeth J. McKinnon, Ian R. James, David A. Nolan, Susan E. Herrmann, Corey B. Moore, Alex J. White, Simon A. Mallal
J. Acquir. Immune Defic. Syndr. May 1, 2003; 33: 29?33
A 48-week, randomized, open-label comparison of three abacavir-based substitution approaches in the management of dyslipidemia and peripheral lipoatrophy
G. J. Moyle, C. Baldwin, B. Langroudi, S. Mandalia, B. G. Gazzard
J. Acquir. Immune Defic. Syndr. May 1, 2003; 33: 22?28
