Efavirenz

Efavirenz

Clinical data
Pronunciation	e-FAV-irr-enz
Trade names	Atripla, Sustiva, others[1]
AHFS/Drugs.com	Monograph
MedlinePlus	a699004
Pregnancy category	US: D (Evidence of risk)
Routes of administration	By mouth (capsules, tablets)
ATC code	J05AG03 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	40–45% (under fasting conditions)
Protein binding	99.5–99.75%
Metabolism	Hepatic (CYP2A6 and CYP2B6-mediated)
Onset of action	3–5 hours
Biological half-life	40–55 hours
Excretion	Urine (14–34%) and feces (16–61%)
Identifiers
IUPAC name (4S)-6-Chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one
CAS Number	154598-52-4 Y
PubChem (CID)	64139
DrugBank	DB00625 Y
ChemSpider	57715 Y
UNII	JE6H2O27P8 Y
KEGG	D00896 Y
ChEBI	CHEBI:119486 Y
ChEMBL	CHEMBL223228 Y
NIAID ChemDB	032934
PDB ligand ID	EFZ (PDBe, RCSB PDB)
Chemical and physical data
Formula	C14H9ClF3NO2
Molar mass	315.675 g/mol
3D model (Jmol)	Interactive image
SMILES FC(F)([C@]1(OC(NC2=CC=C(C=C21)Cl)=O)C#CC3CC3)F
InChI 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 an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. It is sold both by itself and in combination as efavirenz/emtricitabine/tenofovir. It is taken by mouth once a day.^[1]

Common side effects include rash, nausea, headache, feeling tired, and trouble sleeping. Some of the rashes may be serious such as Stevens-Johnson syndrome. Other serious side effects include depression, thoughts of suicide, liver problems, and seizures. It is not safe for use during pregnancy. It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and works by blocking the function of reverse transcriptase.^[1]

Efavirenz was approved for medical use in the United States in 1998.^[1] It is on the WHO Model List of Essential Medicines, the most important medication needed in a basic health system.^[2] As of 2015 it is not avaliable as a generic medication.^[3] The wholesale cost in the developing world is about 3.27 to 9.15 USD per month.^[4] As of 2015 the cost for a typical month of medication in the United States is more than 200 USD.^[3]

Medical uses

For HIV infection that has not previously been treated, the United States Department of Health and Human Services Panel on Antiretroviral Guidelines recommends the use of efavirenz in combination with tenofovir/emtricitabine (Truvada) as one of the preferred NNRTI-based regimens in adults and adolescents^[5] and children.^[6]

Efavirenz is also used in combination with other antiretroviral agents as part of an expanded post-exposure 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.).^[7][8]

Pregnancy and breastfeeding

Efavirenz is safe to use during the first trimester of pregnancy.^[9] Efavirenz passes into breast milk and breast-fed infants may be exposed to efavirenz.^[10]

Contraindications

People who have taken this medication before and experienced an allergic reaction should avoid taking further efavirenz dosages. Hypersensitivity reactions include Steven-Johnson syndrome, toxic skin eruptions, and erythema multiforme.^[11]

Adverse effects

Neuropsychiatric effects are the most common adverse effects, and include include disturbed sleep (including nightmares, insomnia, disrupted sleep, and daytime fatigue), dizziness, headaches, vertigo, blurred vision, anxiety, and cognitive impairment (including fatigue, confusion, and memory and concentration problems), and depression, including suicidal thinking.^[12][13] Some people experience euphoria, which makes the drug liable to abuse and diversion.^[12]

Rash and nausea may occur.^[11]

Use of efavirenz can produce a false positive result in some urine tests for marijuana. ^[14][15]

Efavirenz may lengthen the QT interval so should not be used in people with or at risk of Torsades de Pointes.^[16]

Efavirenz may cause convulsions in adult and pediatric populations who have a history of seizures.^[11]

Drug interactions

Efavirenz is broken down in the liver by enzymes that belong to the cytochrome P450 system, which include both CYP2B6 and CYP3A4.^[11] Efavirenz is a substrate of these enzymes and can decrease the metabolism of other drugs that require the same enzymes.^[11] However, efavirenz also induces these enzymes, which means the enzyme activity is enhanced and the metabolism of other drugs broken down by CYP2B6 and CYP3A4 can be increased.^[11] People who are taking both efavirenz and other drugs metabolized by the same enzymes might need the dose of their drugs to be increased or decreased.

One group of drugs that efavirenz affects is protease inhibitors, which are used for HIV/AIDS. Efavirenz will lower the blood levels of most protease inhibitors, including aprenavir, atazanavir, and indinavir.^[11] At lowered levels, protease inhibitors may not be effective in people taking both drugs, which means the virus that causes HIV/AIDS won’t be stopped from replicating and may become resistant to the protease inhibitor.

Efavirenz also affects antifungal drugs, which are used for fungal infections such as urinary tract infections. Similar to the effect seen with protease inhibitors, efavirenz lowers the blood levels of antifungal drugs like voriconazole, itraconazole, ketoconazole, and posaconazole.^[11] As a result of lowered levels, antifungal drugs may not be effective in people taking both drugs, which means that the fungi that cause the infection may become resistant to the antifungal.

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.^[17]

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.^[11] Nucleoside reverse-transcriptase inhibitors (NRTIs) and efavirenz have different binding targets, so cross-resistance is unlikely; the same is true with regard to efavirenz and protease inhibitors.^[1]

Neuropsychiatric effects

As of 2016 the mechanism of efavirenz' neuropsychiatric adverse effects was not clear.^[12][13] Efavirenz appears to have neurotoxicity, possibly by interfering with mitochondrial function, which may in turn possibly be caused by inhibiting creatine kinase but also possibly by disrupting mitochondrial membranes or by interfering with nitric oxide signalling.^[12] Some neuropsychiatric adverse effects may be mediated through cannabinoid receptors, or through activity at the 5-HT_2A receptor, but efavirenz interacts with many CNS receptors, so this is not clear.^[12] The neuropsychiatric adverse effects are dose-dependent.^[12]

Chemical properties

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

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

On February 17, 2016, the FDA approved the generic tablet formulation to be produced by Mylan.^[18]

Society and culture

Pricing information

A one-month supply of 600 mg tablets costs approximately $1,010 in July 2016.^[19] In 2007, Merck provided efavirenz in certain developing countries and countries largely affected by HIV for about $0.65 per day.^[20] Some emerging countries have opted to purchase Indian generics.^[21] In Thailand, one month supply of efavirenz + truvada, as of June 2012, costs THB 2900 ($90), and there is a social program for patients who cannot afford the medication. 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]

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.^{[23][24][25][26]}

Brands

As of 2016, efavirenz was marketed in various jurisdictions under the brand names Adiva, Avifanz, Efamat, Efatec, Efavir, Efavirenz , Efcure, Eferven, Efrin, Erige, Estiva, Evirenz, Filginase, Stocrin, Sulfina V, Sustiva, Virorrever, and Zuletel.^[27]

As of 2016, the combination of efavirenz, tenofovir, and emtricitabine was marketed in various jurisdictions under the brand names Atripla, Atroiza, Citenvir, Oditec, Teevir, Trustiva, Viraday, and Vonavir.^[27]

As of 2016, the combination of efavirenz, tenofovir, and lamivudine was marketed under the brand name Eflaten.^[27]

References