Efavirenz

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Efavirenz
Efavirenz skeletal.svg
Efavirenz 3D balls 1fk9.png
Systematic (IUPAC) name
(4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one
Clinical data
Trade names Sustiva, Stocrin etc.
AHFS/Drugs.com monograph
MedlinePlus a699004
Pregnancy cat. D (U.S.)
Legal status POM (UK), ℞-only (U.S.)
Routes Oral
Pharmacokinetic data
Protein binding 99.5-99.75%
Metabolism Hepatic (CYP2A6 and CYP2B6-mediated)
Half-life 40-55 hours
Excretion Renal and fecal
Identifiers
CAS number 154598-52-4 YesY
ATC code J05AG03
PubChem CID 64139
DrugBank DB00625
ChemSpider 57715 YesY
UNII JE6H2O27P8 YesY
KEGG D00896 YesY
ChEBI CHEBI:119486 YesY
ChEMBL CHEMBL223228 YesY
NIAID ChemDB 032934
PDB ligand ID EFZ (PDBe, RCSB PDB)
Chemical data
Formula C14H9ClF3NO2 
Mol. mass 315.675 g/mol
 YesY (what is this?)  (verify)

Efavirenz (EFV, brand names Sustiva, Stocrin, Efavir etc.) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) discovered at Merck Research Laboratories.[1] It is used as part of highly active antiretroviral therapy (HAART) for the treatment of a human immunodeficiency virus (HIV) type 1.

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.[2]

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

Efavirenz was combined with the popular HIV medication Truvada, which consists of tenofovir and emtricitabine, all of which are reverse transcriptase inhibitors. This combination of three medications approved by the U.S. Food and Drug Administration (FDA) in July 2006 under the brand name Atripla, provides HAART in a single tablet taken once a day. It results in a simplified drug regimen for many patients.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[3]

Medical uses[edit]

Efavirenz is used to treat HIV infection. It is never used alone and is always given in combination with other drugs. The decision on when to start treatment should take into account CD4 count, HIV viral load, treatment history, resistance profiles and patient preference.

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[edit]

  • Psychiatric symptoms, including insomnia, nightmares, confusion, memory loss, and depression, are common,[4] and more serious symptoms such as psychosis may occur in patients with compromised liver or kidney function.[5][6]
  • 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.[7] 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.[8]
  • Safety in children has not been established
  • Use of efavirenz can produce a false positive result in some urine tests for marijuana [9][10]

Drug interactions[edit]

  • 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[edit]

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.[11]

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.[12]

Chemical properties[edit]

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[edit]

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

Society and culture[edit]

Pricing information[edit]

A one month supply of 600 mg tablets cost approximately $550 in April 2008.[13] Merck provides effavirenz in certain developing countries at cost, currently about $0.65 per day.[14] Some emerging countries have opted to purchase Indian generics[15] such as Efavir by Cipla Ltd.[16] 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.[17]

Brand names[edit]

Generic brands India:[20]

Recreational use[edit]

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.[23][24][25][26] 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.[27]

References[edit]

  1. ^ Young, S. D.; Britcher, S. F.; Tran, L. O.; Payne, L. S.; Lumma, W. C.; Lyle, T. A.; Huff, J. R.; Anderson, P. S.; Olsen, D. B.; Carroll, S. S. (1995). "L-743, 726 (DMP-266): A novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase". Antimicrobial agents and chemotherapy 39 (12): 2602–5. PMC 162996. PMID 8592986.  edit
  2. ^ "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents". Retrieved 10 May 2013. 
  3. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  4. ^ 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. 
  5. ^ Hasse, B; Günthard, HF; Bleiber, G; Krause, M (2005). "Efavirenz intoxication due to slow hepatic metabolism". Clinical Infectious Diseases 40 (3): e22–3. doi:10.1086/427031. PMID 15668854. 
  6. ^ Lowenhaupt, EA; Matson, K; Qureishi, B; Saitoh, A; Pugatch, D (2007). "Psychosis in a 12-year-old HIV-positive girl with an increased serum concentration of efavirenz". Clinical Infectious Diseases 45 (10): e128–30. doi:10.1086/522764. PMID 17968817. 
  7. ^ DHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (October 10, 2006). (Available for download from AIDSInfo)
  8. ^ 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.  edit
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ Sustiva (efavirenz) capsules and tablets. Product information (April 2005)
  13. ^ Price listed on http://drugstore.com website, 4/20/2008
  14. ^ "Merck & Co., Inc., Again Reduces Price of Stocrin (efavirenz) for Patients in Least Developed Countries and Countries Hardest Hit by Epidemic - Drugs.com MedNews". 
  15. ^ IndiaDaily - A new trend in emerging nations - Brazil opts for Indian generic drug ignoring US pharmaceutical giant Merck’s patent on AIDS drug Efavirenz
  16. ^ http://www.cipla.com
  17. ^ 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. 
  18. ^ http://www.sustiva.com/
  19. ^ http://www.medsafe.govt.nz/consumers/cmi/s/stocrin.pdf
  20. ^ Drugsupdate.com generic brands list: http://www.drugsupdate.com/brand/generic/Efavirenz/87
  21. ^ http://mcneilargusindia.com/
  22. ^ http://www.alkemlabs.com/
  23. ^ IOL: Thugs get high on stolen Aids drugs IOL News May 12, 2007
  24. ^ Getting high on HIV drugs in S Africa. BBC News, 8 December 2008.
  25. ^ 'No Turning Back': Teens Abuse HIV Drugs. ABC News, April 6, 2009.
  26. ^ Getting High On HIV Medication Vice 7.04.2014.
  27. ^ 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. doi:10.1038/npp.2013.135. PMID 23702798.  edit
  • 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.

External links[edit]