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= Efavirenz =
{{Drugbox|Watchedfields=changed|verifiedrevid=458955867|IUPAC_name=(4''S'')-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1''H''-3,1-benzoxazin-2-one|image=Efavirenz.svg|width=125|image2=Efavirenz ball-and-stick model.png|width2=150  <!--Clinical data-->|tradename=Sustiva, Stocrin, others|Drugs.com={{drugs.com|monograph|efavirenz}}|MedlinePlus=a699004|pregnancy_US=D|legal_UK=POM|legal_US=Rx-only|legal_status=Rx-only|routes_of_administration=By mouth ([[Capsule (pharmacy)|capsules]], [[Tablet (pharmacy)|tablets]])  <!--Pharmacokinetic data-->|bioavailability=40–45% (under fasting conditions)|protein_bound=99.5–99.75%|metabolism=[[Liver|Hepatic]] ([[CYP2A6]] and [[CYP2B6]]-mediated)|onset=3–5 hours|elimination_half-life=40–55 hours|excretion=Urine (14–34%) and feces (16–61%)  <!--Identifiers-->|CAS_number_Ref={{cascite|correct|??}}|CAS_number=154598-52-4|ATC_prefix=J05|ATC_suffix=AG03|PubChem=64139|DrugBank_Ref={{drugbankcite|correct|drugbank}}|DrugBank=DB00625|ChemSpiderID_Ref={{chemspidercite|correct|chemspider}}|ChemSpiderID=57715|UNII_Ref={{fdacite|correct|FDA}}|UNII=JE6H2O27P8|KEGG_Ref={{keggcite|correct|kegg}}|KEGG=D00896|ChEBI_Ref={{ebicite|correct|EBI}}|ChEBI=119486|ChEMBL_Ref={{ebicite|correct|EBI}}|ChEMBL=223228|PDB_ligand=EFZ|NIAID_ChemDB=032934  <!--Chemical data-->|C=14|H=9|Cl=1|F=3|N=1|O=2|molecular_weight=315.675 g/mol|SMILES=FC(F)([C@]1(OC(NC2=CC=C(C=C21)Cl)=O)C#CC3CC3)F|StdInChI_Ref={{stdinchicite|correct|chemspider}}|StdInChI=1S/C14H9ClF3NO2/c15-9-3-4-11-10(7-9)13(14(16,17)18,21-12(20)19-11)6-5-8-1-2-8/h3-4,7-8H,1-2H2,(H,19,20)/t13-/m0/s1|StdInChIKey_Ref={{stdinchicite|correct|chemspider}}|StdInChIKey=XPOQHMRABVBWPR-ZDUSSCGKSA-N}}<!-- Definition and medical uses -->

'''Efavirenz''' ('''EFV'''), sold under the brand names '''Sustiva''' among others, is a [[non-nucleoside reverse transcriptase inhibitor]] (NNRTI). It is used as part of highly active [[Antiretroviral drug|antiretroviral therapy]] (HAART) for the treatment of a human immunodeficiency virus ([[HIV]]) type 1. Efavirenz is used in combination with [[tenofovir]]/[[emtricitabine]] (Truvada) as well as other [[antiretroviral]] medications.<!-- Side effects -->

It is usually taken on an empty stomach at bedtime to reduce [[neurological]] and [[psychiatric]] adverse effects.

Efavirenz was combined with the [[HIV]] medications [[tenofovir]] and [[emtricitabine]], both of which are [[Reverse transcriptase inhibitor|reverse transcriptase inhibitors]]. This combination of three medications under the brand name [[Atripla]], provides HAART in a single tablet taken once a day.<!-- Society and culture -->

Efavirenz was discovered at Merck Research Laboratories. It is on the [[WHO Model List of Essential Medicines]], the most important medication needed in a basic [[health system]].<ref>{{cite web|url=http://apps.who.int/iris/bitstream/10665/93142/1/EML_18_eng.pdf?ua=1|title=WHO Model List of EssentialMedicines|date=October 2013|work=World Health Organization|accessdate=22 April 2014}}</ref> As of 2015 the cost for a typical month of medication in the United States is more than 200 USD.<ref name="Ric2015">{{cite book|title=Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition|date=2015|publisher=Jones & Bartlett Learning|isbn=9781284057560|page=62|last1=Hamilton|first1=Richart}}</ref>

== Medical uses ==
For HIV infection that has not previously been treated, the [[United States Department of Health and Human Services]] Panel on Antiretroviral Guidelines currently recommends the use of efavirenz in combination with [[tenofovir]]/[[emtricitabine]] (Truvada) as one of the preferred NNRTI-based regimens in adults and adolescents.<ref>{{cite web|url=http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/0/|title=Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents|accessdate=10 May 2013}}</ref> Efavirenz is also used in combination with other [[antiretroviral]] agents as part of an expanded [[postexposure prophylaxis]] regimen to reduce the risk of HIV infection in people exposed to a significant risk (e.g. needlestick injuries, certain types of unprotected sex, etc.).<ref>{{Cite journal|last=Kuhar|first=David T.|last2=Henderson|first2=David K.|last3=Struble|first3=Kimberly A.|last4=Heneine|first4=Walid|last5=Thomas|first5=Vasavi|last6=Cheever|first6=Laura W.|last7=Gomaa|first7=Ahmed|last8=Panlilio|first8=Adelisa L.|date=2013-09-01|title=Updated US Public Health Service Guidelines for the Management of Occupational Exposures to Human Immunodeficiency Virus and Recommendations for Postexposure Prophylaxis|url=https://www.cambridge.org/core/journals/infection-control-and-hospital-epidemiology/article/updated-us-public-health-service-guidelines-for-the-management-of-occupational-exposures-to-human-immunodeficiency-virus-and-recommendations-for-postexposure-prophylaxis/FACD234C788E0D541E37BC3DEFB4C248|journal=Infection Control &amp; Hospital Epidemiology|volume=34|issue=9|pages=875–892|doi=10.1086/672271|issn=0899-823X}}</ref><ref>{{Cite web|url=http://www.cdc.gov/mmwr/PDF/rr/rr5402.pdf|title=Antiretroviral Postexposure Prophylaxis After Sexual, Injection-Drug Use, or Other Nonoccupational Exposure to HIV in the United States|last=|first=|date=|website=|publisher=Centers for Disease Control and Prevention|access-date=November 7, 2016}}</ref>

Since the preliminary publication of the results of the [[ACTG 5142]] trial in 2006 which compared efavirenz against [[lopinavir]], efavirenz has been used as first line treatment in preference to the [[Protease inhibitor (pharmacology)|protease inhibitors]].  The [[ACTG 5095]] trial showed that the potency of efavirenz is maintained at all CD4 counts and HIV viral loads.

== Adverse effects ==
* Psychiatric symptoms, including [[insomnia]], [[nightmares]], [[confusion]], [[memory loss]], [[Depression (mood)|depression]], and [[anxiety]], are common.<ref>{{cite journal|last2=Aberg|first2=JA|year=2006|title=Neuropsychiatric complications of antiretroviral therapy.|journal=Drug safety : an international journal of medical toxicology and drug experience|volume=29|issue=10|pages=865–74|doi=10.2165/00002018-200629100-00004|pmid=16970510|last1=Cespedes|first1=MS}}</ref> Post-marketing report suggest the potential for inducing more severe psychiatric events such as [[psychosis]] and [[aggression]].<ref>{{cite web|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020972s033,021360s021lbl.pdf|title=www.accessdata.fda.gov|format=|work=|accessdate=}}</ref>
* [[Rash]], [[nausea]], [[dizziness]] and [[headache]] may occur
* A general guideline about efavirenz and pregnancy states that efavirenz can cause [[birth defects]] and should not be used in women who might become pregnant.<ref name="dhhs">DHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (October 10, 2006). (Available for download from [http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1 AIDSInfo])</ref> A later study, however, found no increased risk of overall birth defects among women exposed to efavirenz during the first trimester of pregnancy compared with exposure to other antiretroviral drugs.<ref>{{Cite journal|last2=Mofenson|first2=L.|last3=Kranzer|first3=K.|last4=Medu|first4=L.|last5=Frigati|first5=L.|last6=Mills|first6=E. J.|last7=Calmy|first7=A.|year=2010|title=Safety of efavirenz in first-trimester of pregnancy: A systematic review and meta-analysis of outcomes from observational cohorts|journal=AIDS|volume=24|issue=10|pages=1461–1470|doi=10.1097/QAD.0b013e32833a2a14|pmid=20479637|last1=Ford|first1=N.}}</ref>
* Safety in children has not been established
* Use of efavirenz can produce a [[false positive]] result in some urine tests for [[Cannabis (drug)|marijuana]] <ref>{{cite journal|last2=Yaksh|first2=T|last3=Bentley|first3=H|last4=Van Den Brande|first4=G|last5=Grant|first5=I|last6=Ellis|first6=R|year=2006|title=Characterization of interference with 6 commercial delta9-tetrahydrocannabinol immunoassays by efavirenz (glucuronide) in urine|journal=Clinical Chemistry|volume=52|issue=5|pages=896–7|doi=10.1373/clinchem.2006.067058|pmid=16638958|last1=Rossi|first1=S}}</ref><ref>{{cite journal|last2=Heinrich|first2=T|last3=Gehrig|first3=AK|last4=Mikus|first4=G|year=2007|title=Misleading results of screening for illicit drugs during efavirenz treatment|journal=AIDS (London, England)|volume=21|issue=10|pages=1390–1|doi=10.1097/QAD.0b013e32814e6b3e|pmid=17545727|last1=Röder|first1=CS}}</ref>

== Drug interactions ==
* Efavirenz is metabolized in the liver, and is both a substrate and inducer of the [[CYP2B6|2B6]] and [[CYP3A4|3A4]] isoforms of the [[cytochrome P450]] system. This means efavirenz may interact with other drugs metabolized in the liver, requiring either increased or decreased dosages.
* Efavirenz lowers blood levels of most [[Protease inhibitor (pharmacology)|protease inhibitors]]. Dosages of [[amprenavir]], [[atazanavir]], or [[indinavir]] may need to be increased. The blood levels of [[saquinavir]] are dramatically lowered. This can result in incomplete inhibition of viral replication, which can allow multidrug-resistant viruses to evolve.  This condition can be potentially fatal.
* [[Hypericum perforatum|St John's wort]] and [[garlic]] supplements may decrease efavirenz blood levels.

== Mechanism of action ==

=== Anti-HIV effects ===
Efavirenz falls in the NNRTI class of antiretrovirals. Both nucleoside and non-nucleoside RTIs inhibit the same target, the [[reverse transcriptase]] enzyme, an essential viral enzyme which transcribes viral RNA into DNA. Unlike nucleoside RTIs, which bind at the enzyme's active site, NNRTIs act allosterically by binding to a distinct site away from the active site known as the NNRTI pocket.

Efavirenz is not effective against HIV-2, as the pocket of the HIV-2 reverse transcriptase has a different structure, which confers intrinsic resistance to the NNRTI class.<ref>{{cite journal|year=2002|title=Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors|journal=Proc Natl Acad Sci USA|volume=99|issue=22|pages=14410–15|doi=10.1073/pnas.222366699|pmc=137897|pmid=12386343|vauthors=Ren J, Bird LE, Chamberlain PP|display-authors=etal}}</ref>

As most NNRTIs bind within the same pocket, viral strains which are resistant to efavirenz are usually also resistant to the other NNRTIs, [[nevirapine]] and [[delavirdine]]. The most common mutation observed after efavirenz treatment is K103N, which is also observed with other NNRTIs.<ref>[http://www.bms.com/cgi-bin/anybin.pl?sql=select+PPI+from+TB_PRODUCT_PPI+where+PPI_SEQ=94&key=PPI Sustiva (efavirenz) capsules and tablets. Product information (April 2005)]</ref>

=== Neuropsychiatric effects ===
Recently, efavirenz has been found to act as a(n) [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]] [[partial agonist]] (K<sub>i</sub> = 2.2 μM),<ref name="pmid25113527">{{cite journal|year=2014|title=Efavirenz modulation of sleep spindles and sleep spectral profile|url=|journal=J Sleep Res|volume=24|issue=|pages=66–73|doi=10.1111/jsr.12196|pmid=25113527|vauthors=Simen AA, Ma J, Svetnik V, Mayleben D, Maynard J, Roth A, Mixson L, Mogg R, Shera D, George L, Mast TC, Beals C, Stoch A, Struyk A, Shire N, Fraser I}}</ref> [[5-HT2C receptor|5-HT<sub>2C</sub> receptor]] [[Ligand (biochemistry)|ligand]], [[serotonin]] and [[dopamine]] [[reuptake inhibitor]] (50% and 75% inhibition at 10 μM, respectively), [[vesicular monoamine transporter 2]] (VMAT2) inhibitor (60% inhibition at 10 μM), and [[positive allosteric modulator]] of the [[GABAA receptor|GABA<sub>A</sub> receptor]].<ref name="pmid23702798">{{cite journal|year=2013|title=The HIV antiretroviral drug efavirenz has LSD-like properties|url=http://dx.doi.org/10.1038/npp.2013.135|journal=Neuropsychopharmacology|volume=38|issue=12|pages=2373–84|doi=10.1038/npp.2013.135|pmc=3799056|pmid=23702798|vauthors=Gatch MB, Kozlenkov A, Huang RQ, Yang W, Nguyen JD, González-Maeso J, Rice KC, France CP, Dillon GH, Forster MJ, Schetz JA}}</ref> It is thought that these properties, especially its actions at the [[5-HT2 receptor|5-HT<sub>2</sub> receptors]], are involved in its [[neuropsychiatric]] [[Adverse effect|adverse effects]] (e.g., [[Depression (mood)|depression]], [[anxiety]], [[Hallucination|hallucinations]], [[aggression]], [[suicidal ideation]], and [[sleep disturbance]]),<ref name="pmid25113527" /><ref name="pmid23702798" /> as they are alleviated by [[cyproheptadine]], a drug with 5-HT<sub>2</sub> receptor antagonist actions.<ref name="pmid23442031">{{cite journal|year=2013|title=Cyproheptadine for prevention of neuropsychiatric adverse effects of efavirenz: a randomized clinical trial|url=http://dx.doi.org/10.1089/apc.2012.0410|journal=AIDS Patient Care STDS|volume=27|issue=3|pages=146–54|doi=10.1089/apc.2012.0410|pmid=23442031|vauthors=Dabaghzadeh F, Ghaeli P, Khalili H, Alimadadi A, Jafari S, Akhondzadeh S, Khazaeipour Z}}</ref><ref name="pmid23140169">{{cite journal|year=2012|title=Potential benefits of cyproheptadine in HIV-positive patients under treatment with antiretroviral drugs including efavirenz|url=http://informahealthcare.com/doi/abs/10.1517/14656566.2012.742887|journal=Expert Opin Pharmacother|volume=13|issue=18|pages=2613–24|doi=10.1517/14656566.2012.742887|pmid=23140169|vauthors=Dabaghzadeh F, Khalili H, Ghaeli P, Dashti-Khavidaki S}}</ref>

Despite its actions at the GABA<sub>A</sub> receptor and the [[Serotonin transporter|SERT]], [[Dopamine transporter|DAT]], and VMAT2, efavirenz fails to produce [[self-administration]] or [[conditioned place preference]] in animals, suggesting that it lacks positive reinforcing effects.<ref name="pmid23702798" /> However, efavirenz does show [[Lysergic acid diethylamide|LSD]]-like effects in animals, including producing the [[head-twitch response]] and positive drug discrimination responding for LSD in rodents, and there is evidence that efavirenz produces LSD-like [[hallucinogenic]] effects in humans at sufficiently high doses.<ref name="pmid23702798" />

== Chemical properties ==
Efavirenz is chemically described as (''S'')-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2''H''-3,1-benzoxazin-2-one. Its empirical formula is C<sub>14</sub>H<sub>9</sub>ClF<sub>3</sub>NO<sub>2</sub>. Efavirenz is a white to slightly pink crystalline powder with a molecular mass of 315.68 g/mol. It is practically [[insoluble]] in water (<10&nbsp;µg/mL).

== History ==
Efavirenz was approved by the FDA on September 21, 1998, making it the 14th approved antiretroviral drug.

== Society and culture ==

=== Pricing information ===
A one-month supply of 600&nbsp;mg tablets cost approximately $550 in April 2008.<ref>Price listed on http://drugstore.com website, 4/20/2008</ref> Merck provides efavirenz in certain developing countries at cost, currently about $0.65 per day.<ref>{{cite web|url=http://www.drugs.com/news/merck-amp-co-inc-again-reduces-price-stocrin-efavirenz-patients-least-developed-countries-countries-5302.html|title=Merck & Co., Inc., Again Reduces Price of Stocrin (efavirenz) for Patients in Least Developed Countries and Countries Hardest Hit by Epidemic - Drugs.com MedNews|work=|accessdate=}}</ref> Some emerging countries have opted to purchase Indian generics<ref>[http://www.indiadaily.com/editorial/16665.asp IndiaDaily - A new trend in emerging nations - Brazil opts for Indian generic drug ignoring US pharmaceutical giant Merck’s patent on AIDS drug Efavirenz<!-- Bot generated title -->]</ref> such as Efavir by Cipla Ltd.<ref>http://www.cipla.com</ref> In Thailand, one month supply of efavirenz + truvada, as of June 2012, costs THB 2900 ($90), there's also a social program for poorer patients who can't afford even this price. In South Africa, a license has been granted to generics giant [[Aspen Pharmacare]] to manufacture, and distribute to [[Sub-Saharan Africa]], a cost-effective [[antiretroviral]] drug.<ref name="OseweNkrumah2008">{{cite book|url=http://books.google.com/books?id=dPciaE2fP7gC&pg=PA35|title=Improving Access to HIV/AIDS Medicines in Africa: Trade-Related Aspects of Intellectual Property Rights (TRIPS) Flexibilities Utilization|date=15 June 2008|publisher=World Bank Publications|isbn=978-0-8213-7544-0|pages=35–39|author1=Patrick Lumumba Osewe|author2=Yvonne Korkoi Nkrumah|author3=Emmanuel K. Sackey|accessdate=30 June 2012}}</ref>

=== Brand names ===
* Sustiva<ref>http://www.sustiva.com/</ref> (USA, [[Bristol-Myers Squibb]])
* Stocrin<ref>http://www.medsafe.govt.nz/consumers/cmi/s/stocrin.pdf</ref> (EU, [[Merck & Co.|MSD]])
* Aspen Efavirenz (Sub-Saharan Africa, [[Aspen Pharmacare]])
Generic brands India:<ref>Drugsupdate.com generic brands list: http://www.drugsupdate.com/brand/generic/Efavirenz/87</ref>
* E.F (McNeil & Argus<ref>http://mcneilargusindia.com/</ref>)
* Efavir ([[Cipla]])
* Efcure ([[Emcure Pharmaceuticals]])
* Efferven ([[Ranbaxy Laboratories]])
* Estiva ([[Hetero Drugs|Hetero]])
* Evirenz (Alkem Laboratories<ref>http://www.alkemlabs.com/</ref>)
* Regast (Pharmasyntez)<ref>{{cite web|url=http://www.pharmasyntez.com/regast|title=Regast® (efavirenz) film-coated tablets.|website=http://www.pharmasyntez.com|publisher=Pharmasyntez, 2011|language=Russian|accessdate=28 June 2015}}</ref>
* Viranz ([[Aurobindo Pharma]])

=== Recreational use ===
Abuse of efavirenz by crushing and smoking the tablets for supposed [[hallucinogenic]] and [[dissociative]] effects has been reported in [[South Africa]], where it is used in a mixture known as [[whoonga]] and ''nyaope''.<ref>[http://www.iol.co.za/news/south-africa/thugs-get-high-on-stolen-aids-drugs-1.352686#.U0SpO_l_v_8 IOL: Thugs get high on stolen Aids drugs] IOL News May 12, 2007</ref><ref>[http://news.bbc.co.uk/2/hi/africa/7768059.stm Getting high on HIV drugs in S Africa. BBC News, 8 December 2008.]</ref><ref>[http://www.abcnews.go.com/Health/MindMoodNews/story?id=7227982&page=1 'No Turning Back': Teens Abuse HIV Drugs. ABC News, April 6, 2009.]</ref><ref>[https://www.youtube.com/watch?v=W7BCi5ax7jk Getting High On HIV Medication] Vice 7.04.2014.</ref> This is believed to be because of activity at a side target, the 5-HT<sub>2A</sub> receptor, which is better known as the target of drugs such as LSD.<ref>{{Cite journal|last2=Kozlenkov|first2=A.|last3=Huang|first3=R. Q.|last4=Yang|first4=W.|last5=Nguyen|first5=J. D.|last6=González-Maeso|first6=J.|last7=Rice|first7=K. C.|last8=France|first8=C. P.|last9=Dillon|first9=G. H.|year=2013|title=The HIV Antiretroviral Drug Efavirenz has LSD-Like Properties|journal=Neuropsychopharmacology|volume=38|issue=12|pages=2373–84|doi=10.1038/npp.2013.135|pmc=3799056|pmid=23702798|last1=Gatch|first1=M. B.|last10=Forster|first10=M. J.|last11=Schetz|first11=J. A.}}</ref>

== References ==
{{reflist|32em}}
* {{cite journal|last2=Vögele|first2=C.|last3=Gauggel|first3=S.|year=2010|title=Neuropsychiatric complications of Efavirenz therapy: suggestions for a new research paradigm|url=|journal=The Journal of Neuropsychiatry and Clinical Neurosciences|volume=22|issue=4|pages=361–369|doi=10.1176/jnp.2010.22.4.361|last1=Sütterlin|first1=S.}}

== External links ==
* [http://www.sustiva.com/ Manufacturer's site]
* [http://packageinserts.bms.com/pi/pi_sustiva.pdf Prescribing information]
{{HIVpharm}}
{{Hallucinogens}}
{{GABAA PAMs}}
{{Adrenergics}}
{{Estrogen receptor modulators}}
{{Nuclear receptor ligands}}