Efavirenz
Encyclopedia
Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and 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 lamivudine
/zidovudine
(Combivir
) or tenofovir/emtricitabine
(Truvada
) as the preferred NNRTI-based regimens in adults and adolescents.
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.).
The usual adult dose is 600 mg once a day. 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 inhibitor
s. 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.
, 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 inhibitor
s. The ACTG 5095 trial showed that the potency of efavirenz is maintained at all CD4 counts and HIV viral loads.
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.
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.
as part of treatment of co-infection with tuberculosis
.
Antiretroviral drug
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
(HAART) for the treatment of a human immunodeficiency virus (HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
) type 1.
For HIV infection that has not previously been treated, the United States Department of Health and Human Services
United States Department of Health and Human Services
The United States Department of Health and Human Services is a Cabinet department of the United States government with the goal of protecting the health of all Americans and providing essential human services. Its motto is "Improving the health, safety, and well-being of America"...
Panel on
Antiretroviral Guidelines currently recommends the use of efavirenz in combination with lamivudine
Lamivudine
Lamivudine is a potent nucleoside analog reverse transcriptase inhibitor .It is marketed by GlaxoSmithKline with the brand names Zeffix, Heptovir, Epivir, and Epivir-HBV.Lamivudine has been used for treatment of chronic hepatitis B at a lower dose than for treatment of HIV...
/zidovudine
Zidovudine
Zidovudine or azidothymidine is a nucleoside analog reverse-transcriptase inhibitor , a type of antiretroviral drug used for the treatment of HIV/AIDS. It is an analog of thymidine....
(Combivir
Combivir
Lamivudine/zidovudine is a pharmaceutical treatment for HIV infection. It is a fixed dose combination of two antiretroviral drugs, lamivudine and zidovudine...
) or tenofovir/emtricitabine
Emtricitabine
Emtricitabine , with trade name Emtriva , is a nucleoside reverse transcriptase inhibitor for the treatment of HIV infection in adults and children....
(Truvada
Truvada
Tenofovir/emtricitabine, trademark Truvada, is a fixed-dose combination of two antiretroviral drugs used for the treatment of HIV. It consists of 300 milligrams of tenofovir and 200 milligrams of emtricitabine. By combining the two agents into one tablet, it reduces the pill burden and increases...
) as the preferred NNRTI-based regimens in adults and adolescents.
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.).
The usual adult dose is 600 mg once a day. It is usually taken on an empty stomach at bedtime to reduce neurological and psychiatric adverse effects.
Efavirenz was combined with the popular HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
medication
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
Truvada
Truvada
Tenofovir/emtricitabine, trademark Truvada, is a fixed-dose combination of two antiretroviral drugs used for the treatment of HIV. It consists of 300 milligrams of tenofovir and 200 milligrams of emtricitabine. By combining the two agents into one tablet, it reduces the pill burden and increases...
, which consists of tenofovir and emtricitabine
Emtricitabine
Emtricitabine , with trade name Emtriva , is a nucleoside reverse transcriptase inhibitor for the treatment of HIV infection in adults and children....
, all of which are reverse transcriptase inhibitor
Reverse transcriptase inhibitor
Reverse-transcriptase inhibitors are a class of antiretroviral drug used to treat HIV infection, tumors, and cancer. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase enzyme that retroviruses need to reproduce.-Mechanism:...
s. This combination of three medications approved by the U.S. Food and Drug Administration (FDA) in July 2006 under the brand name Atripla
Atripla
Emtricitabine/tenofovir/efavirenz is a fixed-dose combination drug for the treatment of HIV infection. It combines Gilead Sciences's tenofovir and emtricitabine with Bristol-Myers Squibb's efavirenz into a fixed-dose pill...
, provides HAART in a single tablet taken once a day. It results in a simplified drug regimen for many patients.
History
Efavirenz was approved by the FDA on September 21, 1998, making it the 14th approved antiretroviral drug.Indications
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 loadViral load
Viral load is a measure of the severity of a viral infection, and can be calculated by estimating the amount of virus in an involved body fluid. For example, it can be given in RNA copies per milliliter of blood plasma...
, 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
Lopinavir
Lopinavir is an antiretroviral of the protease inhibitor class. It is used as a fixed-dose combination with another protease inhibitor, ritonavir, under the trade names Kaletra and Aluvia ....
, efavirenz has been used as first line treatment in preference to the protease inhibitor
Protease inhibitor (pharmacology)
Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...
s. The ACTG 5095 trial showed that the potency of efavirenz is maintained at all CD4 counts and HIV viral loads.
Mode of action
Efavirenz falls in the NNRTI class of antiretrovirals. Both nucleoside and non-nucleoside RTIs inhibit the same target, the reverse transcriptaseReverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
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.
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
Delavirdine
Delavirdine is a non-nucleoside reverse transcriptase inhibitor marketed by ViiV Healthcare. It is used as part of highly active antiretroviral therapy for the treatment of human immunodeficiency virus type 1. It is presented as the mesylate...
. The most common mutation observed after efavirenz treatment is K103N, which is also observed with other NNRTIs.
Dosing
The usual adult dose of efavirenz is 600 mg per day (usually given at bedtime); or 800 mg daily when given concurrently with rifampicinRifampicin
Rifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...
as part of treatment of co-infection with tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
.
Drug interactions
- Efavirenz is metabolized in the liver, and is both a substrate and inducer of the 2B6CYP2B6Cytochrome P450 2B6 is an enzyme that in humans is encoded by the CYP2B6 gene. CYP2B6 is a member of the Cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances.- Function :...
and 3A4CYP3A4Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
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 inhibitorsProtease inhibitor (pharmacology)Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...
. Dosages of amprenavir, atazanavirAtazanavirAtazanavir, marketed under the trade name Reyataz by Bristol Myers, is an antiretroviral drug of the protease inhibitor class...
, or indinavirIndinavirIndinavir is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV infection and AIDS.-History:...
may need to be increased. The blood levels of saquinavirSaquinavirSaquinavir is an antiretroviral drug used in HIV therapy. It falls in the protease inhibitor class. Two formulations have been marketed:*a hard-gel capsule formulation of the mesylate, with trade name Invirase, which requires combination with ritonavir to increase the saquinavir bioavailability;*a...
are dramatically lowered. This can result in incomplete inhibition of viral replication, which can allow multidrug resistant virus to evolve. This condition can potentially be fatal. - St John's wortSt John's wortSt John's wort is the plant species Hypericum perforatum, and is also known as Tipton's Weed, Chase-devil, or Klamath weed....
and garlicGarlicAllium sativum, commonly known as garlic, is a species in the onion genus, Allium. Its close relatives include the onion, shallot, leek, chive, and rakkyo. Dating back over 6,000 years, garlic is native to central Asia, and has long been a staple in the Mediterranean region, as well as a frequent...
supplements may decrease efavirenz blood levels.
Adverse effects
- Psychiatric symptoms, including insomniaInsomniaInsomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, nightmares, confusionConFusionConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...
, memory lossMemory lossMemory loss can be partial or total and it is normal when it comes with aging. Sudden memory loss is usually a result of brain trauma and it may be permanent or temporary. When it is caused by medical conditions such as Alzheimers, the memory loss is gradual and tends to be permanent.Brain trauma...
, and depressionDepression (mood)Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
, are common, and more serious symptoms such as psychosisPsychosisPsychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
may occur in patients with compromised liver or kidney function. - RashRashA rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and...
, nauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, dizzinessDizzinessDizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
and headacheHeadacheA headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
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. 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.
- Safety in children has not been established
- Use of efavirenz can produce a false positive result in some urine tests for marijuanaCannabis (drug)Cannabis, also known as marijuana among many other names, refers to any number of preparations of the Cannabis plant intended for use as a psychoactive drug or for medicinal purposes. The English term marijuana comes from the Mexican Spanish word marihuana...
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 whoongaWhoonga__notoc__Whoonga is a drug that has allegedly come into widespread use in South Africa in 2010, notably in the impoverished townships of Durban. It is claimed to be appearing in other places in South Africa as well....
.