Zidovudine

{{Short description|Antiretroviral medication}} {{Redirect|AZT}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Use mdy dates|date=July 2023}} {{infobox drug | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 441946513 | drug_name = | image = Zidovudine.svg | image_class = skin-invert-image | alt = | width = 155 | image2 = Zidovudine-from-xtal-3D-bs-17.png | image_class2 = bg-transparent | alt2 =

| pronounce = {{IPAc-en|z|aɪ|ˈ|d|oʊ|v|j|uː|ˌ|d|iː|n}} {{respell|zy|DOH|vyoo|deen}} | tradename = Retrovir, others | Drugs.com = {{drugs.com|monograph|zidovudine}} | MedlinePlus = a687007 | DailyMedID = Zidovudine | pregnancy_AU = B3 | licence_EU = yes | routes_of_administration = By mouth, intravenous, rectal suppository | ATC_prefix = J05 | ATC_suffix = AF01

| legal_AU =  | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA =  | legal_CA_comment = | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK = POM | legal_UK_comment =<ref>{{cite web | title=Retrovir 100mg Capsules – Summary of Product Characteristics (SmPC) | website=(emc) | date=December 14, 2018 | url=https://www.medicines.org.uk/emc/product/6811/smpc | access-date=January 23, 2021}}</ref> | legal_US = Rx-only | legal_US_comment =<ref>{{cite web | title=Retrovir – zidovudine capsule Retrovir – zidovudine solution Retrovir – zidovudine injection, solution | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6df09f15-b102-431c-adde-d7aeef6f5d84 | access-date=January 23, 2021}}</ref> | legal_EU = Rx-only | legal_EU_comment =<ref>{{cite web | title = Active substance: Zidovudine | url = https://www.ema.europa.eu/en/documents/psusa/zidovudine-list-nationally-authorised-medicinal-products-psusa/00003143/201703_en.pdf | work = European Medicines Agency | date = November 30, 2017 }}</ref> | legal_UN =  | legal_UN_comment = | legal_status = Rx-only

| bioavailability = Complete absorption, following first-pass metabolism systemic availability 75% (range 52 to 75%) | protein_bound = 30 to 38% | metabolism = Liver | elimination_half-life = 0.5 to 3 hours | excretion = Kidney and Bile duct

| IUPHAR_ligand = 4825 | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 30516-87-1 | PubChem = 35370 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00495 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 32555 | NIAID_ChemDB = 000001 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 4B9XT59T7S | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D00413 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 10110 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 129 | PDB_ligand = AZZ

| IUPAC_name = 3'-deoxy-3'-azido-thymidine 1-[(2''R'',4''S'',5''S'')-4-Azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione<ref>{{PubChem|35370|Zidovudine}}</ref> | C=10 | H=13 | N=5 | O=4 | SMILES = O=C1NC(C(C)=CN1[C@@H]2O[C@H](CO)[C@@H](N=[N+]=[N-])C2)=O | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C10H13N5O4/c1-5-3-15(10(18)12-9(5)17)8-2-6(13-14-11)7(4-16)19-8/h3,6-8,16H,2,4H2,1H3,(H,12,17,18)/t6-,7+,8+/m0/s1 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = HBOMLICNUCNMMY-XLPZGREQSA-N }}

'''Zidovudine''' ('''ZDV'''), also known as '''azidothymidine''' ('''AZT'''), was the first antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals.<ref name=AHFS2016/> It may be used to prevent mother-to-child spread during birth or after a needlestick injury or other potential exposure.<ref name=AHFS2016/> It is sold both by itself and together as lamivudine/zidovudine and abacavir/lamivudine/zidovudine.<ref name=AHFS2016/> It can be used by mouth or by slow injection into a vein.<ref name=AHFS2016>{{cite web|title=Zidovudine|url=https://www.drugs.com/monograph/zidovudine.html|publisher=The American Society of Health-System Pharmacists|access-date=November 28, 2016|url-status=live|archive-url=https://web.archive.org/web/20161221005642/https://www.drugs.com/monograph/zidovudine.html|archive-date=December 21, 2016}}</ref>

Common side effects include headaches, fever, and nausea.<ref name=AHFS2016/> Serious side effects include liver problems, muscle damage, and high blood lactate levels.<ref name=AHFS2016/> It is commonly used in pregnancy and appears to be safe for the fetus.<ref name=AHFS2016/> ZDV is of the nucleoside analog reverse-transcriptase inhibitor (NRTI) class.<ref name=AHFS2016/> It works by inhibiting the enzyme reverse transcriptase that HIV uses to make DNA and therefore decreases replication of the virus.<ref name=AHFS2016/>

Zidovudine was first described in 1964.<ref>{{cite book| vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons|isbn=978-3-527-60749-5|page=505|url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA505|url-status=live|archive-url=https://web.archive.org/web/20170908213935/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA505|archive-date=September 8, 2017}}</ref> It was resynthesized from a public-domain formula by Burroughs Wellcome.<ref name="latimes.com">{{Cite web | vauthors = Marsa L |date=1993-06-20 |title=TOXIC HOPE : WIDELY EMBRACED, THE AIDS DRUG IS NOW UNDER HEAVY FIRE.: THE AZT STORY |url=https://www.latimes.com/archives/la-xpm-1993-06-20-tm-10183-story.html |website=Los Angeles Times |language=en-US}}</ref> It was approved in the United States in 1987 and was the first treatment for HIV.<ref name=AHFS2016/><ref>{{cite book | vauthors = Reeves JD, Derdeyn CA |title=Entry Inhibitors in HIV Therapy |date=2007 |publisher=Springer Science & Business Media |isbn=978-3-7643-7783-0 |page=179 |url=https://books.google.com/books?id=zNCJmuWgHAoC&pg=PA179 }}</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">{{cite book | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> It is available as a generic medication.<ref name=AHFS2016/>

==Medical uses==

===HIV treatment=== AZT was usually dosed twice a day in combination with other antiretroviral therapies. This approach is referred to as Highly Active Antiretroviral Therapy (HAART) and is used to prevent the likelihood of HIV resistance.<ref>{{cite journal | vauthors = De Clercq E | title = HIV resistance to reverse transcriptase inhibitors | journal = Biochemical Pharmacology | volume = 47 | issue = 2 | pages = 155–169 | date = January 1994 | pmid = 7508227 | doi = 10.1016/0006-2952(94)90001-9 }}</ref><ref>{{cite journal | vauthors = Yarchoan R, Mitsuya H, Broder S | title = AIDS therapies | journal = Scientific American | volume = 259 | issue = 4 | pages = 110–119 | date = October 1988 | pmid = 3072667 | doi = 10.1038/scientificamerican1088-110 | bibcode = 1988SciAm.259d.110Y }}</ref> As of 2019, the standard is a three-drug once-daily oral treatment that can include AZT.<ref>{{cite journal | vauthors = Phanuphak N, Gulick RM | title = HIV treatment and prevention 2019: current standards of care | journal = Current Opinion in HIV and AIDS | volume = 15 | issue = 1 | pages = 4–12 | date = January 2020 | pmid = 31658110 | doi = 10.1097/COH.0000000000000588 | s2cid = 204952772}}</ref>

===HIV prevention=== AZT has been used for post-exposure prophylaxis (PEP) in combination with another antiretroviral drug called lamivudine. Together they work to substantially reduce the risk of HIV infection following the first single exposure to the virus.<ref>{{cite journal |vauthors=Panlilio AL, Cardo DM, Grohskopf LA, Heneine W, Ross CS |title=Updated U.S. Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis |journal=MMWR Recomm Rep |volume=54 |issue=RR-9 |pages=1–17 |date=September 2005 |pmid=16195697 |url=https://www.cdc.gov/mmwr/PDF/rr/rr5409.pdf}}</ref> More recently, AZT has been replaced by other antiretrovirals such as tenofovir to provide PEP.<ref>{{cite web | url = http://www.bhiva.org/PEPSE.aspx | title = UK guideline for the use of post-exposure prophylaxis for HIV following sexual exposure (2011) | access-date = April 7, 2014 | url-status = live | archive-url = https://web.archive.org/web/20140408214056/http://www.bhiva.org/PEPSE.aspx | archive-date = April 8, 2014}}</ref> Before tenofovir, a principal part of the clinical pathway for both pre-exposure prophylaxis and post-exposure treatment of mother-to-child transmission of HIV during pregnancy, labor, and delivery and has been proven to be integral to uninfected siblings' perinatal and neonatal development.<ref>{{cite web | url = http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf | title = Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health | date = November 17, 2005 | access-date = March 29, 2006 | archive-url = https://web.archive.org/web/20060422113223/http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf | archive-date = April 22, 2006 | work = AIDSinfo | publisher = U.S. Department of Health and Human Services }}</ref><ref name="pmid17476315">{{cite journal | vauthors = Briand N, Lallemant M, Jourdain G, Techapalokul S, Tunthanathip P, Suphanich S, Chanpoo T, Traisathit P, McIntosh K, Le Coeur S | title = Haematological safety of perinatal zidovudine in pregnant HIV-1-infected women in Thailand: secondary analysis of a randomized trial | journal = PLOS Clinical Trials | volume = 2 | issue = 4 | pages = e11 | date = April 2007 | pmid = 17476315 | pmc = 1863515 | doi = 10.1371/journal.pctr.0020011 | doi-access = free }}</ref> AZT has been shown to reduce this risk to 8% when given in a three-part regimen post-conception, delivery, and six weeks post-delivery. Consistent and proactive precautionary measures, such as the rigorous use of antiretroviral medications, cesarean section, face masks, heavy-duty rubber gloves, clinically segregated disposable diapers, and avoidance of mouth contact will further reduce child-attendant transmission of HIV to as little as 1–2%.<ref>CIDRZ. Prevention of AIDS Transmission (PMTCT). {{cite web |url=http://www.cidrz.org/pmtct |title=Prevention of mother-to-child HIV transmission (PMTCT) | CIDRZ |access-date=March 31, 2012 |archive-url=https://web.archive.org/web/20120214203337/http://www.cidrz.org/pmtct |archive-date=February 14, 2012 }}</ref><ref>Transmission of HIV from infants {{cite web |url=http://aidsperspective.net/blog/?p=868 |title=Transmission of HIV from infants to women who breastfeed them. | work = Aids Perspective | date = July 1, 2012 |access-date=August 3, 2012 |archive-url=https://web.archive.org/web/20131203030636/http://aidsperspective.net/blog/?p=868 |archive-date=December 3, 2013 }}</ref><ref>{{cite journal |vauthors=Connor E, Sperling R, Gelber R, Kiselev P, Scott G, O'Sullivan M, VanDyke R, Bey M, Shearer W, Jacobson R | title=Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group | journal=N Engl J Med | volume=331 | issue=18 | pages=1173–80 | year=1994 | pmid=7935654 | doi=10.1056/NEJM199411033311801| s2cid=13457499 | doi-access=free }}</ref>

During 1994 to 1999, AZT was the primary form of prevention of mother-to-child HIV transmission. AZT prophylaxis prevented more than 1000 parental and infant deaths from AIDS in the United States.<ref name="pmid16741877">{{cite journal | vauthors = Walensky RP, Paltiel AD, Losina E, Mercincavage LM, Schackman BR, Sax PE, Weinstein MC, Freedberg KA | title = The survival benefits of AIDS treatment in the United States | journal = The Journal of Infectious Diseases | volume = 194 | issue = 1 | pages = 11–19 | date = July 2006 | pmid = 16741877 | doi = 10.1086/505147 | doi-access = free }}</ref> In the U.S. at that time, the accepted standard of care for HIV-positive mothers was known as the 076 regimen and involved five daily doses of AZT from the second trimester onwards, as well as AZT intravenously administered during labour.<ref>{{cite journal | vauthors = Morris K | title = Short course of AZT halves HIV-1 perinatal transmission | journal = Lancet | volume = 351 | issue = 9103 | page = 651 | date = February 1998 | pmid = 9500334 | doi = 10.1016/S0140-6736(05)78436-1 | s2cid = 8293828 }}</ref> As this treatment was lengthy and expensive, it was deemed unfeasible in the Global South, where mother-to-child transmission was a significant problem. A number of studies were initiated in the late 1990s that sought to test the efficacy of a shorter, simpler regimen for use in 'resource-poor' countries.<ref name="Crane, Johanna 2010">{{cite journal | vauthors = Crane J | title = Adverse events and placebo effects: African scientists, HIV, and ethics in the 'global health sciences' | journal = Social Studies of Science | volume = 40 | issue = 6 | pages = 843–870 | date = December 2010 | pmid = 21553555 | doi = 10.1177/0306312710371145 | s2cid = 26027925 }}</ref> This AZT short course was an inferior standard of care and would have been considered malpractice if trialed in the US; however, it was nonetheless a treatment that would improve the care and survival of impoverished subjects.<ref name="Crane, Johanna 2010"/>

=== Antibacterial properties === Zidovudine also has antibacterial properties,<ref>{{cite journal | vauthors = DeSarno AE, Parcell BJ, Coote PJ | title = Repurposing the anti-viral drug zidovudine (AZT) in combination with meropenem as an effective treatment for infections with multi-drug resistant, carbapenemase-producing strains of Klebsiella pneumoniae | journal = Pathogens and Disease | volume = 78 | issue = 9 | article-number = ftaa063 | date = December 2020 | pmid = 33053176 | doi = 10.1093/femspd/ftaa063 | doi-access = free | hdl = 10023/24137 | hdl-access = free }}</ref> though not routinely used in clinical settings. It acts on bacteria with a mechanism of action still not fully explained. Promising results from ''in vitro'' and ''in vivo'' studies showed the efficacy of AZT also against multidrug-resistant gram-negative bacteria (including mcr-1 carrying and metallo-β-lactamase producing isolates), especially in combination with other active agents (e.g., fosfomycin, colistin, tigecycline).<ref>{{cite journal | vauthors = Zhou YF, Liu P, Dai SH, Sun J, Liu YH, Liao XP | title = Activity of Tigecycline or Colistin in Combination with Zidovudine against Escherichia coli Harboring ''tet''(X) and ''mcr-1'' | journal = Antimicrobial Agents and Chemotherapy | volume = 65 | issue = 1 | date = December 2020 | article-number = e01172-20 | pmid = 33020156 | pmc = 7927862 | doi = 10.1128/AAC.01172-20 }}</ref><ref>{{cite journal | vauthors = Antonello RM, Di Bella S, Betts J, La Ragione R, Bressan R, Principe L, Morabito S, Gigliucci F, Tozzoli R, Busetti M, Knezevich A, Furlanis L, Fontana F, Luzzaro F, Luzzati R, Lagatolla C | title = Zidovudine in synergistic combination with fosfomycin: an in vitro and in vivo evaluation against multidrug-resistant Enterobacterales | journal = International Journal of Antimicrobial Agents | volume = 58 | issue = 1 | article-number = 106362 | date = July 2021 | pmid = 34010710 | doi = 10.1016/j.ijantimicag.2021.106362 | s2cid = 234791392 | hdl = 11368/2991331 | hdl-access = free }}</ref>

==Side effects== Most common side effects include nausea, vomiting, acid reflux (heartburn), headache, cosmetic reduction in abdominal body fat, trouble sleeping, and loss of appetite. Less common side effects include faint discoloration of fingernails and toenails, mood elevation, occasional tingling or transient numbness of the hands or feet, and minor skin discoloration. Allergic reactions are rare.<ref>{{cite web|url=http://www.medicinenet.com/zidovudine_azt-oral/page2.htm|title=zidovudine, Retrovir|date=August 12, 2010|publisher=Medicinenet.com|access-date=December 14, 2010|url-status=live|archive-url=https://web.archive.org/web/20101220035237/http://www.medicinenet.com/zidovudine_azt-oral/page2.htm|archive-date=December 20, 2010}}</ref>

Early long-term higher-dose therapy with AZT was initially associated with side effects that sometimes limited therapy, including anemia, neutropenia, hepatotoxicity, cardiomyopathy, and myopathy. All of these conditions were generally found to be reversible upon reduction of AZT dosages. They have been attributed to several possible causes, including transient depletion of mitochondrial DNA, sensitivity of the γ-DNA polymerase in some cell mitochondria,<ref>{{cite journal | vauthors = Sun R, Eriksson S, Wang L | title = Identification and characterization of mitochondrial factors modulating thymidine kinase 2 activity | journal = Nucleosides, Nucleotides & Nucleic Acids | volume = 29 | issue = 4–6 | pages = 382–385 | date = June 2010 | pmid = 20544523 | doi = 10.1080/15257771003741018 | s2cid = 13539181 }}</ref> the depletion of thymidine triphosphate, oxidative stress, reduction of intracellular L-carnitine or apoptosis of the muscle cells.<ref name="Scruggs">{{cite journal | vauthors = Scruggs ER, Dirks Naylor AJ | title = Mechanisms of zidovudine-induced mitochondrial toxicity and myopathy | journal = Pharmacology | volume = 82 | issue = 2 | pages = 83–88 | year = 2008 | pmid = 18504416 | doi = 10.1159/000134943 | s2cid = 2044833 | doi-access = free }}</ref> Anemia due to AZT was successfully treated using erythropoetin to stimulate red blood cell production.<ref>{{cite journal | vauthors = Fisher JW | title = Erythropoietin: physiologic and pharmacologic aspects | journal = Proceedings of the Society for Experimental Biology and Medicine | volume = 216 | issue = 3 | pages = 358–369 | date = December 1997 | pmid = 9402140 | doi = 10.3181/00379727-216-44183 | s2cid = 26177904 }}</ref><ref>{{cite journal | vauthors = Fisher JW | title = Erythropoietin: physiology and pharmacology update | journal = Experimental Biology and Medicine | volume = 228 | issue = 1 | pages = 1–14 | date = January 2003 | pmid = 12524467 | doi = 10.1177/153537020322800101 | s2cid = 2829677 }}</ref> Drugs that inhibit hepatic glucuronidation, such as indomethacin, nordazepam, acetylsalicylic acid (aspirin) and trimethoprim decreased the elimination rate and increased the therapeutic strength of the medication.<ref>{{cite web | url=http://www.medicinenet.com/zidovudine_azt-oral/article.htm | title=ZIDOVUDINE (AZT) – ORAL (Retrovir) side effects, medical uses, and drug interactions | access-date=January 9, 2006 | publisher=MedicineNet | url-status=live | archive-url=https://web.archive.org/web/20050630080343/http://www.medicinenet.com/zidovudine_azt-oral/article.htm | archive-date=June 30, 2005 }}</ref> Today, side effects are much less common with the use of lower doses of AZT.<ref>Side Effects. NAM Aidsmap. {{cite web |url=http://www.aidsmap.com/Side-effects/page/1730907/ |title=Zidovudine (AZT, ''Retrovir'') |access-date=March 28, 2012 |url-status=live |archive-url=https://web.archive.org/web/20111226015716/http://www.aidsmap.com/Side-effects/page/1730907/ |archive-date=December 26, 2011 }}</ref> According to IARC, there is sufficient evidence in experimental animals for the carcinogenicity of zidovudine; it is possibly carcinogenic to humans (Group 2B).<ref>{{cite web|url=http://www.inchem.org/documents/iarc/vol76/zidovudine.html|title=Summary of Data Reported and Evaluation|year=2000|access-date=August 11, 2012|url-status=live|archive-url=https://web.archive.org/web/20120104162609/http://inchem.org/documents/iarc/vol76/zidovudine.html|archive-date=January 4, 2012}}</ref> In 2009, the State of California added zidovudine to its list of chemicals "known to the state of California to cause cancer and other reproductive harm."<ref>{{cite web |title=State of California Environmental Protection Agency Office of Environmental Hazard Assessment Safe Drinking Water and Toxic Enforcement Act of 1986 Chemicals Known to the State to Cause Cancer or Reproductive Toxicity July 29, 1011 |url=https://tig.org.za/AZT_OEHHA_listing/6.AZT_listed_as_a_chemical_known_to_the_state_of_California_to_cause_cancer_or_reproductive_toxicity_18_December_2009.pdf|access-date=November 14, 2022|date=July 29, 2011}}</ref>

===Viral resistance=== Even at the highest doses that can be tolerated in patients, AZT is not potent enough to prevent all HIV replication and may only slow the replication of the virus and progression of the disease. Prolonged AZT treatment can lead to HIV developing resistance to AZT by mutation of its reverse transcriptase.<ref>{{cite journal | vauthors = Richman DD | title = Susceptibility to nucleoside analogues of zidovudine-resistant isolates of human immunodeficiency virus | journal = The American Journal of Medicine | volume = 88 | issue = 5B | pages = 8S–10S | date = May 1990 | pmid = 2186629 | doi = 10.1016/0002-9343(90)90414-9 }}</ref><ref>{{cite journal | vauthors = Wainberg MA, Brenner BG, Turner D | title = Changing patterns in the selection of viral mutations among patients receiving nucleoside and nucleotide drug combinations directed against human immunodeficiency virus type 1 reverse transcriptase | journal = Antimicrobial Agents and Chemotherapy | volume = 49 | issue = 5 | pages = 1671–1678 | date = May 2005 | pmid = 15855480 | pmc = 1087622 | doi = 10.1128/AAC.49.5.1671-1678.2005 }}</ref> To slow the development of resistance, physicians generally recommend that AZT be given in combination with another reverse-transcriptase inhibitor and an antiretroviral from another group, such as a protease inhibitor, non-nucleoside reverse-transcriptase inhibitor, or integrase inhibitor; this type of therapy is known as HAART (Highly Active Anti Retroviral Therapy).

==Mechanism of action== thumb|right|250px|AZT in oral, injectable, and suppository form AZT is a thymidine analogue. AZT works by selectively inhibiting HIV's reverse transcriptase, the enzyme that the virus uses to make a DNA copy of its RNA. Reverse transcription is necessary for production of HIV's double-stranded DNA, which would be subsequently integrated into the genetic material of the infected cell (where it is called a provirus).<ref name=MitsuyaPNAS/><ref name="Yarchoan R, Klecker R, Weinhold K, Markham P, Lyerly H, Durack D, Gelmann E, Lehrman S, Blum R, Barry D 1986 575–80"/><ref>{{cite journal |vauthors=Mitsuya H, Yarchoan R, Broder S | title=Molecular targets for AIDS therapy | journal=Science | volume=249 | issue=4976 | pages=1533–44 | year=1990 | pmid=1699273 | doi=10.1126/science.1699273|bibcode = 1990Sci...249.1533M | url=https://zenodo.org/record/1230944 | type=Submitted manuscript }}</ref>

Cellular enzymes convert AZT into the effective 5'-triphosphate form. Some studies have shown that terminating synthesis of HIV's DNA chains is the specific inhibitory mechanism.<ref>{{cite journal | vauthors = Quan Y, Rong L, Liang C, Wainberg MA | title = Reverse transcriptase inhibitors can selectively block the synthesis of differently sized viral DNA transcripts in cells acutely infected with human immunodeficiency virus type 1 | journal = Journal of Virology | volume = 73 | issue = 8 | pages = 6700–6707 | date = August 1999 | pmid = 10400767 | pmc = 112754 | doi = 10.1128/JVI.73.8.6700-6707.1999 }}</ref>

At very high doses, AZT's triphosphate form may also inhibit DNA polymerase used by human cells to undergo cell division, but regardless of dosage AZT has an approximately 100-fold greater affinity for HIV's reverse transcriptase.<ref name=FurmanPNAS>{{cite journal | vauthors = Furman PA, Fyfe JA, St Clair MH, Weinhold K, Rideout JL, Freeman GA, Lehrman SN, Bolognesi DP, Broder S, Mitsuya H | title = Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 21 | pages = 8333–8337 | date = November 1986 | pmid = 2430286 | pmc = 386922 | doi = 10.1073/pnas.83.21.8333 | doi-access = free | bibcode = 1986PNAS...83.8333F }}</ref> The selectivity has been suggested to be due to the cell's ability to quickly repair its own DNA chain if it is disrupted by AZT during its formation, whereas the HIV virus lacks that ability.<ref name=":2">{{cite journal | vauthors = Ostertag W, Roesler G, Krieg CJ, Kind J, Cole T, Crozier T, Gaedicke G, Steinheider G, Kluge N, Dube S | title = Induction of endogenous virus and of thymidine kinase by bromodeoxyuridine in cell cultures transformed by Friend virus | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 71 | issue = 12 | pages = 4980–4985 | date = December 1974 | pmid = 4531031 | pmc = 434023 | doi = 10.1073/pnas.71.12.4980 | bibcode = 1974PNAS...71.4980O | doi-access = free }}</ref> Thus AZT inhibits HIV replication without affecting the function of uninfected cells.<ref name=MitsuyaPNAS/> At sufficiently high dosages, AZT begins to inhibit the cellular DNA polymerase used by mitochondria to replicate, accounting for its potentially toxic but reversible effects on cardiac and skeletal muscles, causing myositis.<ref name="Yarchoan R, Mitsuya H, Myers C, Broder S 1989 726–38"/><ref>{{cite journal | vauthors = Collins ML, Sondel N, Cesar D, Hellerstein MK | title = Effect of nucleoside reverse transcriptase inhibitors on mitochondrial DNA synthesis in rats and humans | journal = Journal of Acquired Immune Deficiency Syndromes | volume = 37 | issue = 1 | pages = 1132–1139 | date = September 2004 | pmid = 15319672 | doi = 10.1097/01.qai.0000131585.77530.64 | s2cid = 20020419 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Parker WB, White EL, Shaddix SC, Ross LJ, Buckheit RW, Germany JM, Secrist JA, Vince R, Shannon WM | title = Mechanism of inhibition of human immunodeficiency virus type 1 reverse transcriptase and human DNA polymerases alpha, beta, and gamma by the 5'-triphosphates of carbovir, 3'-azido-3'-deoxythymidine, 2',3'-dideoxyguanosine and 3'-deoxythymidine. A novel RNA template for the evaluation of antiretroviral drugs | journal = The Journal of Biological Chemistry | volume = 266 | issue = 3 | pages = 1754–1762 | date = January 1991 | pmid = 1703154 | doi = 10.1016/S0021-9258(18)52360-7 | doi-access = free }}</ref><ref>{{cite book | vauthors = Rang HP, Dale MM, Ritter JM | title=Pharmacology | edition=3rd | publisher=Pearson Professional Ltd | year=1995 | isbn=978-0-443-05974-2}}</ref><ref>{{cite journal | vauthors = Balzarini J, Naesens L, Aquaro S, Knispel T, Perno C, De Clercq E, Meier C | title = Intracellular metabolism of CycloSaligenyl 3'-azido-2', 3'-dideoxythymidine monophosphate, a prodrug of 3'-azido-2', 3'-dideoxythymidine (zidovudine) | journal = Molecular Pharmacology | volume = 56 | issue = 6 | pages = 1354–1361 | date = December 1999 | pmid = 10570065 | doi = 10.1124/mol.56.6.1354 | url = http://molpharm.aspetjournals.org/cgi/content/full/56/6/1354 | url-status = live | s2cid = 25678740 | archive-url = https://web.archive.org/web/20070921090344/http://molpharm.aspetjournals.org/cgi/content/full/56/6/1354 | archive-date = September 21, 2007 | url-access = subscription }}</ref>

==Chemistry== thumb|250px|A crystal of AZT, viewed under polarized light

Enantiopure AZT crystallizes in the monoclinic space group P21. The primary intermolecular bonding motif is a hydrogen bonded dimeric ring formed from two N-H...O interactions.<ref>{{cite journal |vauthors=Dyer I, Low JN, Tollin P, Wilson HR, Howie RA |title=Structure of 3'-azido-3'-deoxythymidine, AZT |journal=Acta Crystallogr C |volume=44 |issue= 4|pages=767–9 |date=April 1988 |pmid=3271074 |doi= 10.1107/S0108270188000368|bibcode=1988AcCrC..44..767D }}</ref><ref>{{cite journal |journal= Proc Natl Acad Sci USA |year= 1987 |volume= 84 |issue= 23 |pages= 8239–8242 |title= Azidothymidine: crystal structure and possible functional role of the azido group |vauthors= Camerman A, Mastropaolo D, Camerman N |pmid= 2446321 |doi=10.1073/pnas.84.23.8239 |pmc=299517|bibcode= 1987PNAS...84.8239C |doi-access= free }}</ref>

==History==

===Initial cancer research===

In the 1960s, the theory that most cancers were caused by environmental retroviruses gained clinical support and funding. It had recently become known, due to the work of Nobel laureates Howard Temin and David Baltimore,<ref name="test75">{{cite web|url=https://www.nobelprize.org/prizes/medicine/1975/temin/lecture/|archive-url=https://web.archive.org/web/20170103002308/http://www.nobelprize.org/nobel_prizes/medicine/laureates/1975/temin-lecture.html|title=The Nobel Prize in Physiology or Medicine 1975|archive-date=January 3, 2017|website=NobelPrize.org}}</ref> that nearly all avian cancers were caused by bird retroviruses, but corresponding human retroviruses had not yet been found.

In parallel work, other compounds that successfully blocked the synthesis of nucleic acids had been proven to be both antibacterial, antiviral, and anticancer agents, the leading work being done at the laboratory of Nobel laureates George H. Hitchings and Gertrude Elion, leading to the development of the antitumor agent 6-mercaptopurine.<ref name="test88">{{cite web|url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/1988/elion-lecture.pdf|archive-url=https://web.archive.org/web/20170808212611/http://www.nobelprize.org/nobel_prizes/medicine/laureates/1988/elion-lecture.pdf|title=The Purine Path To Chemotherapy|archive-date=August 8, 2017}}</ref>

Richard E. Beltz first synthesized AZT in 1961, but did not publish his research.<ref>{{cite news | vauthors = Marsa L |title=Toxic Hope: Widely Embraced, the AIDS Drug is now under Heavy Fire |url=https://www.latimes.com/archives/la-xpm-1993-06-20-tm-10183-story.html |work=Los Angeles Times |date=June 20, 1993}}</ref><ref>{{cite web | vauthors = Brinck A |title=Inventing AZT |url=http://www.tig.org.za/Inventing_AZT.pdf}}</ref>Jerome Horwitz of the Barbara Ann Karmanos Cancer Institute and Wayne State University School of Medicine synthesized AZT in 1964 under a US National Institutes of Health (NIH) grant.<ref name=pmid20018391>{{cite journal | vauthors = Broder S | title = The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic | journal = Antiviral Research | volume = 85 | issue = 1 | pages = 1–18 | date = January 2010 | pmid = 20018391 | pmc = 2815149 | doi = 10.1016/j.antiviral.2009.10.002 }}</ref><ref name=horwitz64>{{cite journal | title = The monomesylates of 1-(2-deoxy-bd-lyxofuranosyl) thymines| vauthors = Horwitz JP, Chua J, Noel MJ | journal = Org. Chem. Ser. Monogr | year = 1964 | volume = 29 | pages = 2076–9 |doi=10.1021/jo01030a546 | issue = 7}}</ref><ref name=filmazt2002>{{cite video | people = Detours V; Henry D (writers/directors) | title = I am alive today (history of an AIDS drug) | medium = Film | publisher = ADR Productions/Good & Bad News | date = 2002 }}</ref> Development was shelved after it proved biologically inert in mice.<ref name=pmid20018391/><ref name="nytimes">{{cite news | url = https://www.nytimes.com/1986/09/20/us/a-failure-led-to-drug-against-aids.html | title = A Failure Led to Drug Against AIDS | work = The New York Times | date = September 20, 1986 | access-date = June 30, 2010 | url-status = live | archive-url = https://web.archive.org/web/20090816081427/http://query.nytimes.com/gst/fullpage.html?sec=health | archive-date = August 16, 2009 }}</ref> In 1974, Wolfram Ostertag of the Max Planck Institute for Experimental Medicine in Göttingen, Germany, reported that AZT specifically targeted Friend virus (strain of murine leukemia virus).<ref name=":2" />

This report attracted little interest from other researchers as the Friend leukemia virus is a retrovirus, and at the time, there were no known human diseases caused by retroviruses.<ref name="Sneader 2006 260–261">{{cite book | vauthors = Sneader W |title=Drug Discovery – A History |url=https://archive.org/details/drugdiscoveryhis00snea |url-access=limited |publisher=Wiley |year=2006 |pages=[https://archive.org/details/drugdiscoveryhis00snea/page/n273 260]–261 |isbn=978-0-471-89980-8 }}</ref>

===HIV/AIDS research===

In 1983, researchers at the Institut Pasteur in Paris identified the retrovirus now known as the Human Immunodeficiency Virus (HIV) as the cause of acquired immunodeficiency syndrome (AIDS) in humans.<ref>{{cite journal | vauthors = Weiss RA | title = How does HIV cause AIDS? | journal = Science | volume = 260 | issue = 5112 | pages = 1273–1279 | date = May 1993 | pmid = 8493571 | doi = 10.1126/science.8493571 | bibcode = 1993Sci...260.1273W }}</ref><ref>{{cite journal | vauthors = Douek DC, Roederer M, Koup RA | title = Emerging concepts in the immunopathogenesis of AIDS | journal = Annual Review of Medicine | volume = 60 | pages = 471–484 | year = 2009 | pmid = 18947296 | pmc = 2716400 | doi = 10.1146/annurev.med.60.041807.123549 }}</ref> Shortly thereafter, Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan of the United States National Cancer Institute (NCI) initiated a program to develop therapies for HIV/AIDS.<ref>NIH Clinical Center's 50th Anniversary. {{cite web |url=http://www.cc.nih.gov/about/news/anniver50/_pdf/CC_50th_Anniversary_Celebration.pdf |title=Clinical Center 50th Anniversary Celebration |access-date=April 18, 2012 |archive-url=https://web.archive.org/web/20130619093432/http://www.cc.nih.gov/about/news/anniver50/_pdf/CC_50th_Anniversary_Celebration.pdf |archive-date=June 19, 2013 }}</ref> Using a line of CD4+ T cells that they had made, they developed an assay to screen drugs for their ability to protect CD4+ T cells from being killed by HIV. To expedite the process of discovering a drug, the NCI researchers actively sought collaborations with pharmaceutical companies having access to libraries of compounds with potential antiviral activity.<ref name=MitsuyaPNAS>{{cite journal | vauthors = Mitsuya H, Weinhold KJ, Furman PA, St Clair MH, Lehrman SN, Gallo RC, Bolognesi D, Barry DW, Broder S | title = 3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 20 | pages = 7096–7100 | date = October 1985 | pmid = 2413459 | pmc = 391317 | doi = 10.1073/pnas.82.20.7096 | doi-access = free | bibcode = 1985PNAS...82.7096M }}</ref> This assay could simultaneously test both the anti-HIV effect of the compounds and their toxicity against infected T cells.

In June 1984, Burroughs-Wellcome virologist Marty St. Clair set up a program to discover drugs with the potential to inhibit HIV replication. Burroughs-Wellcome had expertise in nucleoside analogs and viral diseases, led by researchers including George Hitchings, Gertrude Elion, David Barry, Paul (Chip) McGuirt Jr., Philip Furman, Martha St. Clair, Janet Rideout, Sandra Lehrman and others. Their research efforts were focused in part on the viral enzyme reverse transcriptase. Reverse transcriptase is an enzyme that retroviruses, including HIV, use to replicate themselves. Secondary testing was performed in mouse cells infected with the retroviruses Friend virus or Harvey sarcoma virus, as the Wellcome group did not have a viable in-house HIV antiviral assay in place at that time, and these other retroviruses were believed to represent reasonable surrogates. AZT proved to be a remarkably potent inhibitor of both Friend virus and Harvey sarcoma virus, and a search of the company's records showed that it had demonstrated low toxicity when tested for its antibacterial activity in rats many years earlier. Based in part on these results, AZT was selected by nucleoside chemist Janet Rideout as one of 11 compounds to send to the NCI for testing in that organization's HIV antiviral assay.<ref name="Sneader 2006 260–261"/>

In February 1985, NCI scientists found that AZT had potent efficacy in vitro.<ref name=MitsuyaPNAS/><ref name=pmid20018391/> Several months later, a Phase I clinical trial of AZT was initiated at the NCI and Duke University.<ref name="Yarchoan R, Klecker R, Weinhold K, Markham P, Lyerly H, Durack D, Gelmann E, Lehrman S, Blum R, Barry D 1986 575–80">{{cite journal |vauthors=Yarchoan R, Klecker R, Weinhold K, Markham P, Lyerly H, Durack D, Gelmann E, Lehrman S, Blum R, Barry D | title=Administration of 3'-azido-3'-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex | journal=Lancet | volume=1 | issue=8481 | pages=575–80 | year=1986 | pmid=2869302 | doi=10.1016/S0140-6736(86)92808-4| s2cid=37985276 }}</ref><ref name="Yarchoan R, Mitsuya H, Myers C, Broder S 1989 726–38">{{cite journal | doi=10.1056/NEJM198909143211106 |vauthors=Yarchoan R, Mitsuya H, Myers C, Broder S | title=Clinical pharmacology of 3'-azido-2',3'-dideoxythymidine (zidovudine) and related dideoxynucleosides | journal=N Engl J Med | volume=321 | issue=11 | pages=726–38 | year=1989 | pmid=2671731}}</ref><ref name=":0">{{cite journal |vauthors=Yarchoan R, Klecker RW, Weinhold KJ, Markham PD, Lyerly HK, Durack DT, Gelmann E, Lehrman SN, Blum RM, Barry DW |title=Administration of 3'-azido-3'-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex |journal=Lancet |volume=1 |issue=8481 |pages=575–80 |year=1986 |pmid=2869302 |doi= 10.1016/s0140-6736(86)92808-4|s2cid=37985276 }}</ref> The Phase I study was informed by prior clinical work involving suramin, another compound that had shown in vitro efficacy against HIV. The early clinical studies demonstrated that AZT was generally well tolerated in people with HIV infection and was associated with immunologic improvements, including increases in CD4+ lymphocyte counts and partial restoration of T cell function as assessed by delayed-type hypersensitivity skin testing. Participants also showed signs of clinical benefit such as weight gain in some advanced AIDS cases. In addition, these trials confirmed that anti-HIV concentrations demonstrated in vitro could be achieved in humans through systemic administration, and that AZT was capable of reaching the central nervous system.<ref name=":0" /><ref name=":1" />

===Patent filed and FDA approval===

A double-blind, placebo-controlled randomized trial of AZT was subsequently conducted by Burroughs-Wellcome and found that AZT prolonged the lives of people with HIV.<ref name=":1">{{cite journal | vauthors = Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Schooley RT | title = The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial | journal = The New England Journal of Medicine | volume = 317 | issue = 4 | pages = 185–191 | date = July 1987 | pmid = 3299089 | doi = 10.1056/NEJM198707233170401 }}</ref> This study was halted early due to ethical concerns of continuing to provide participants with a placebo in the face of such striking results.<ref name="Snopes AZT">{{cite web | url=https://www.snopes.com/news/2021/09/21/did-azt-kill-more-patients-than-aids/#A%20Fast-Track%20Approval%20Rife%20with%20Controversy | title=Did Controversial AZT Treatment Kill More Patients than AIDS in '80s, '90s? | date=September 21, 2021 }}</ref> Burroughs-Wellcome filed for a patent for AZT in 1985. The Anti-Infective Advisory Committee of the United States Food and Drug Administration (FDA) voted ten to one to recommend the approval of AZT.<ref>{{cite journal | vauthors = Brook I | title = Approval of zidovudine (AZT) for acquired immunodeficiency syndrome. A challenge to the medical and pharmaceutical communities | journal = JAMA | volume = 258 | issue = 11 | page = 1517 | date = September 1987 | pmid = 3306004 | doi = 10.1001/jama.1987.03400110099035 }}</ref> The FDA approved the drug for use against HIV, AIDS, and AIDS Related Complex (ARC, a now-obsolete medical term for pre-AIDS illness) on March 20, 1987.<ref name="Cimons">{{cite news | vauthors = Cimons M | title = U.S. Approves Sale of AZT to AIDS Patients | work = Los Angeles Times | page = 1 | date = March 21, 1987 }}</ref> The time between the first demonstration that AZT was active against HIV in the laboratory and its approval was 25 months. Criticism of the clinical trial and subsequent approval of AZT resurfaced in the early 2020s in a series of internet memes likely intended to discredit immunologist Dr. Anthony Fauci.<ref name="Snopes AZT"/>

AZT was subsequently approved unanimously for infants and children in 1990.<ref>AZT Approved for AIDS Children. {{cite news |url=https://www.latimes.com/archives/la-xpm-1990-05-03-mn-603-story.html |title= HEALTH: AZT Approved for AIDS Children |journal=Los Angeles Times |access-date=March 30, 2012 |url-status=live |archive-url=https://web.archive.org/web/20150504000547/http://articles.latimes.com/1990-05-03/news/mn-603_1_azt-approved-for-aids-children |archive-date=May 4, 2015 |date=May 3, 1990 | via = From Times Wire Services}}</ref> AZT was initially administered in significantly higher dosages than today, typically 400 mg every four hours, day and night, compared to modern dosage of 300 mg twice daily.<ref>{{cite web | url=https://www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540597/all/Zidovudine__AZT_ | title=Zidovudine (AZT) | Johns Hopkins ABX Guide }}</ref>

==Society and culture== {{See also|Cost of HIV treatment}}

Until 1991, 80% of the $420 million allocated to the National Institute of Health's AIDS Clinical Trials Group went toward studies of AZT. Aside from two similarly designed chemotherapies, ddI and ddC, from approval of AZT in 1987 until 1993, no other drugs against AIDS were approved, leading to criticism that research preoccupation with AZT and its close relatives, and the massive diverting of funds to such, had delayed the development of more efficacious drugs.<ref name="latimes.com" /> In 1991, the advocacy group Public Citizen filed a lawsuit claiming that the patents were invalid. Subsequently, Barr Laboratories and Novopharm Ltd. also challenged the patent, in part based on the assertion that NCI scientists Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan should have been named as inventors, and those two companies applied to the FDA to sell AZT as a generic drug. In response, Burroughs Wellcome Co. filed a lawsuit against the two companies. The United States Court of Appeals for the Federal Circuit ruled in 1992 in favor of Burroughs Wellcome, ruling that even though they had never tested it against HIV, they had conceived of it working before they sent it to the NCI scientists. This suit was appealed up to the Supreme Court of the US, but in 1996 the Court declined to formally review it.<ref>{{cite news| vauthors = Greenhouse L | title=Supreme Court Roundup;Justices Reject Challenge Of Patent for AIDS Drug|url=https://www.nytimes.com/1996/01/17/us/supreme-court-roundup-justices-reject-challenge-of-patent-for-aids-drug.html|work=The New York Times|date=January 17, 1996|url-status=live|archive-url=https://web.archive.org/web/20161117145258/http://www.nytimes.com/1996/01/17/us/supreme-court-roundup-justices-reject-challenge-of-patent-for-aids-drug.html|archive-date=November 17, 2016}}</ref> The case, ''Burroughs Wellcome Co. v. Barr Laboratories'', was a landmark in US law of inventorship.<ref>{{cite journal| vauthors = Armstrong M, Murphy Jr GM |title=Inventorship and ownership considerations and pitfalls with collaborative research: patent highlight.|journal=ACS Medicinal Chemistry Letters|date=April 26, 2012|volume=3|issue=5|pages=349–51|pmid=24900477|pmc=4025834|doi=10.1021/ml300084e}}</ref>

In 2002, another lawsuit was filed challenging the patent by the AIDS Healthcare Foundation, which also filed an antitrust case against GSK.<ref name=Law3602004>{{cite news| vauthors = Meland M |title=Judge Denies Request To Dismiss Patent Challenge Vs. Glaxo's AZT – Law360|url=http://www.law360.com/articles/1396/judge-denies-request-to-dismiss-patent-challenge-vs-glaxo-s-azt|work=Law360|date=May 3, 2004|url-status=live|archive-url=https://web.archive.org/web/20161117212239/http://www.law360.com/articles/1396/judge-denies-request-to-dismiss-patent-challenge-vs-glaxo-s-azt|archive-date=November 17, 2016}}</ref> The patent case was dismissed in 2003 and AHF filed a new case challenging the patent.<ref name=Law3602004/>

GSK's patents on AZT expired in 2005, and in September 2005, the FDA approved three generic versions.<ref>{{cite web|title=HIV/AIDS History of Approvals – HIV/AIDS Historical Time Line 2000 – 2010|url=https://www.fda.gov/ForPatients/Illness/HIVAIDS/History/ucm151081.htm|publisher=U.S. Food and Drug Administration (FDA)|date=August 8, 2014|archive-url=https://web.archive.org/web/20161023204558/https://www.fda.gov/ForPatients/Illness/HIVAIDS/History/ucm151081.htm|archive-date=October 23, 2016}}</ref>

==References== {{Reflist}}

==External links== * {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/zidovudine | archive-url = https://web.archive.org/web/20160818180842/https://druginfo.nlm.nih.gov/drugportal/name/Zidovudine | archive-date = August 18, 2016 | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Zidovudine }}

Category:Organoazides Category:Hepatotoxins Category:IARC Group 2B carcinogens Category:Nucleoside analog reverse transcriptase inhibitors Category:Thymine derivatives Category:Tetrahydrofurans Category:Drugs developed by GSK plc Category:World Health Organization essential medicines Category:Wikipedia medicine articles ready to translate Category:Hydroxymethyl compounds