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Efavirenz

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Clinical data
Trade namesSustiva, Stocrin, others
AHFS/Drugs.comMonograph
MedlinePlusa699004
Routes of
administration		By mouth (capsules, tablets)
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability40–45% (under fasting conditions)
Protein binding99.5–99.75%
MetabolismHepatic (CYP2A6 and CYP2B6-mediated)
Onset of action3–5 hours
Elimination half-life40–55 hours
ExcretionUrine (14–34%) and feces (16–61%)
Identifiers
  • (4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
PDB ligand
Chemical and physical data
FormulaC14H9ClF3NO2
Molar mass315.675 g/mol g·mol−1
3D model (JSmol)
  • FC(F)([C@]1(OC(NC2=CC=C(C=C21)Cl)=O)C#CC3CC3)F
  • InChI=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  Y
  • Key:XPOQHMRABVBWPR-ZDUSSCGKSA-N  Y
  (verify)

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 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.

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 inhibitors. This combination of three medications under the brand name Atripla, provides HAART in a single tablet taken once a day.

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.[1] As of 2015 the cost for a typical month of medication in the United States is more than 200 USD.[2]

Medical uses

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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.[3] 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.).[4][5]

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 inhibitors. The ACTG 5095 trial showed that the potency of efavirenz is maintained at all CD4 counts and HIV viral loads.

Adverse effects

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  • Psychiatric symptoms, including insomnia, nightmares, confusion, memory loss, depression, and anxiety, are common.[6] Post-marketing report suggest the potential for inducing more severe psychiatric events such as psychosis and aggression.[7]
  • 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.[8] 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.[9]
  • Safety in children has not been established
  • Use of efavirenz can produce a false positive result in some urine tests for marijuana [10][11]

Drug interactions

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  • Efavirenz is metabolized in the liver, and is both a substrate and inducer of the 2B6 and 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 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.
  • St John's wort and garlic supplements may decrease efavirenz blood levels.

Mechanism of action

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Anti-HIV effects

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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.[12]

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.[13]

Neuropsychiatric effects

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Recently, efavirenz has been found to act as a(n) 5-HT2A receptor partial agonist (Ki = 2.2 μM),[14] 5-HT2C receptor 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.[15] It is thought that these properties, especially its actions at the 5-HT2 receptors, are involved in its neuropsychiatric adverse effects (e.g., depression, anxiety, hallucinations, aggression, suicidal ideation, and sleep disturbance),[14][15] as they are alleviated by cyproheptadine, a drug with 5-HT2 receptor antagonist actions.[16][17]

Despite its actions at the GABAA receptor and the SERT, DAT, and VMAT2, efavirenz fails to produce self-administration or conditioned place preference in animals, suggesting that it lacks positive reinforcing effects.[15] However, efavirenz does show 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.[15]

Chemical properties

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Efavirenz is chemically described as (S)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Its empirical formula is C14H9ClF3NO2. 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 µg/mL).

History

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

Society and culture

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Pricing information

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A one-month supply of 600 mg tablets cost approximately $550 in April 2008.[18] Merck provides efavirenz in certain developing countries at cost, currently about $0.65 per day.[19] Some emerging countries have opted to purchase Indian generics[20] such as Efavir by Cipla Ltd.[21] 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.[22]

Brand names

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Generic brands India:[25]

Recreational use

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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.[29][30][31][32] This is believed to be because of activity at a side target, the 5-HT2A receptor, which is better known as the target of drugs such as LSD.[33]

References

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  1. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  2. ^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 62. ISBN 9781284057560.
  3. ^ "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents". Retrieved 10 May 2013.
  4. ^ Kuhar, David T.; Henderson, David K.; Struble, Kimberly A.; Heneine, Walid; Thomas, Vasavi; Cheever, Laura W.; Gomaa, Ahmed; Panlilio, Adelisa L. (2013-09-01). "Updated US Public Health Service Guidelines for the Management of Occupational Exposures to Human Immunodeficiency Virus and Recommendations for Postexposure Prophylaxis". Infection Control & Hospital Epidemiology. 34 (9): 875–892. doi:10.1086/672271. ISSN 0899-823X.
  5. ^ "Antiretroviral Postexposure Prophylaxis After Sexual, Injection-Drug Use, or Other Nonoccupational Exposure to HIV in the United States" (PDF). Centers for Disease Control and Prevention. Retrieved November 7, 2016.
  6. ^ Cespedes, MS; Aberg, JA (2006). "Neuropsychiatric complications of antiretroviral therapy". Drug safety : an international journal of medical toxicology and drug experience. 29 (10): 865–74. doi:10.2165/00002018-200629100-00004. PMID 16970510.
  7. ^ "www.accessdata.fda.gov" (PDF).
  8. ^ DHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (October 10, 2006). (Available for download from AIDSInfo)
  9. ^ Ford, N.; Mofenson, L.; Kranzer, K.; Medu, L.; Frigati, L.; Mills, E. J.; Calmy, A. (2010). "Safety of efavirenz in first-trimester of pregnancy: A systematic review and meta-analysis of outcomes from observational cohorts". AIDS. 24 (10): 1461–1470. doi:10.1097/QAD.0b013e32833a2a14. PMID 20479637.
  10. ^ Rossi, S; Yaksh, T; Bentley, H; Van Den Brande, G; Grant, I; Ellis, R (2006). "Characterization of interference with 6 commercial delta9-tetrahydrocannabinol immunoassays by efavirenz (glucuronide) in urine". Clinical Chemistry. 52 (5): 896–7. doi:10.1373/clinchem.2006.067058. PMID 16638958.
  11. ^ Röder, CS; Heinrich, T; Gehrig, AK; Mikus, G (2007). "Misleading results of screening for illicit drugs during efavirenz treatment". AIDS (London, England). 21 (10): 1390–1. doi:10.1097/QAD.0b013e32814e6b3e. PMID 17545727.
  12. ^ Ren J, Bird LE, Chamberlain PP, et al. (2002). "Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors". Proc Natl Acad Sci USA. 99 (22): 14410–15. doi:10.1073/pnas.222366699. PMC 137897. PMID 12386343.
  13. ^ Sustiva (efavirenz) capsules and tablets. Product information (April 2005)
  14. ^ a b 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 (2014). "Efavirenz modulation of sleep spindles and sleep spectral profile". J Sleep Res. 24: 66–73. doi:10.1111/jsr.12196. PMID 25113527.
  15. ^ a b c d Gatch MB, Kozlenkov A, Huang RQ, Yang W, Nguyen JD, González-Maeso J, Rice KC, France CP, Dillon GH, Forster MJ, Schetz JA (2013). "The HIV antiretroviral drug efavirenz has LSD-like properties". Neuropsychopharmacology. 38 (12): 2373–84. doi:10.1038/npp.2013.135. PMC 3799056. PMID 23702798.
  16. ^ Dabaghzadeh F, Ghaeli P, Khalili H, Alimadadi A, Jafari S, Akhondzadeh S, Khazaeipour Z (2013). "Cyproheptadine for prevention of neuropsychiatric adverse effects of efavirenz: a randomized clinical trial". AIDS Patient Care STDS. 27 (3): 146–54. doi:10.1089/apc.2012.0410. PMID 23442031.
  17. ^ Dabaghzadeh F, Khalili H, Ghaeli P, Dashti-Khavidaki S (2012). "Potential benefits of cyproheptadine in HIV-positive patients under treatment with antiretroviral drugs including efavirenz". Expert Opin Pharmacother. 13 (18): 2613–24. doi:10.1517/14656566.2012.742887. PMID 23140169.
  18. ^ Price listed on http://drugstore.com website, 4/20/2008
  19. ^ "Merck & Co., Inc., Again Reduces Price of Stocrin (efavirenz) for Patients in Least Developed Countries and Countries Hardest Hit by Epidemic - Drugs.com MedNews".
  20. ^ IndiaDaily - A new trend in emerging nations - Brazil opts for Indian generic drug ignoring US pharmaceutical giant Merck’s patent on AIDS drug Efavirenz
  21. ^ http://www.cipla.com
  22. ^ Patrick Lumumba Osewe; Yvonne Korkoi Nkrumah; Emmanuel K. Sackey (15 June 2008). Improving Access to HIV/AIDS Medicines in Africa: Trade-Related Aspects of Intellectual Property Rights (TRIPS) Flexibilities Utilization. World Bank Publications. pp. 35–39. ISBN 978-0-8213-7544-0. Retrieved 30 June 2012.
  23. ^ http://www.sustiva.com/
  24. ^ http://www.medsafe.govt.nz/consumers/cmi/s/stocrin.pdf
  25. ^ Drugsupdate.com generic brands list: http://www.drugsupdate.com/brand/generic/Efavirenz/87
  26. ^ http://mcneilargusindia.com/
  27. ^ http://www.alkemlabs.com/
  28. ^ "Regast® (efavirenz) film-coated tablets". http://www.pharmasyntez.com (in Russian). Pharmasyntez, 2011. Retrieved 28 June 2015. {{cite web}}: External link in |website= (help)
  29. ^ IOL: Thugs get high on stolen Aids drugs IOL News May 12, 2007
  30. ^ Getting high on HIV drugs in S Africa. BBC News, 8 December 2008.
  31. ^ 'No Turning Back': Teens Abuse HIV Drugs. ABC News, April 6, 2009.
  32. ^ Getting High On HIV Medication Vice 7.04.2014.
  33. ^ Gatch, M. B.; Kozlenkov, A.; Huang, R. Q.; Yang, W.; Nguyen, J. D.; González-Maeso, J.; Rice, K. C.; France, C. P.; Dillon, G. H.; Forster, M. J.; Schetz, J. A. (2013). "The HIV Antiretroviral Drug Efavirenz has LSD-Like Properties". Neuropsychopharmacology. 38 (12): 2373–84. doi:10.1038/npp.2013.135. PMC 3799056. PMID 23702798.
  • Sütterlin, S.; Vögele, C.; Gauggel, S. (2010). "Neuropsychiatric complications of Efavirenz therapy: suggestions for a new research paradigm". The Journal of Neuropsychiatry and Clinical Neurosciences. 22 (4): 361–369. doi:10.1176/jnp.2010.22.4.361.
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