Entecavir (ETV), sold under the brand name Baraclude, is an

antiviral medication Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do ...

used in the treatment of

hepatitis B virus ''Hepatitis B virus'' (HBV) is a partially double-stranded DNA virus, a species of the genus '' Orthohepadnavirus'' and a member of the '' Hepadnaviridae'' family of viruses. This virus causes the disease hepatitis B. Disease Despite there b ...

(HBV) infection. In those with both

HIV/AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...

and HBV

antiretroviral medication Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do n ...

should also be used. Entecavir is taken by mouth as a tablet or solution. Common side effects include headache, nausea,

high blood sugar Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200 mg/dL), but symptoms may not start to become noticeable until even ...

, and decreased kidney function. Severe side effects include enlargement of the liver, high blood lactate levels, and liver inflammation if the medication is stopped. While there appears to be no harm from use during pregnancy, this use has not been well studied. Entecavir is in the

nucleoside reverse transcriptase inhibitors Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replicatio ...

(NRTIs) family of medications. It prevents the hepatitis B virus from multiplying by blocking reverse transcriptase. Entecavir was approved for medical use in 2005. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. Available as a generic medication in the United States.

Medical uses

Entecavir is mainly used to treat chronic hepatitis B infection in adults and children two years and older with active viral replication and evidence of active disease with elevations in liver enzymes. It is also used to prevent HBV reinfection after liver transplant and to treat HIV patients infected with HBV. Entecavir is weakly active against HIV, but is not recommended for use in HIV-HBV co-infected patients without a fully suppressive anti-HIV regimen as it may select for resistance to lamivudine and emtricitabine in HIV. The efficacy of entecavir has been studied in several randomized, double-blind, multicentre trials. Entecavir by mouth is effective and generally well tolerated treatment.

Pregnancy and breastfeeding

No adequate and well-controlled studies exist in pregnant women.

Side effects

The majority of people who use entecavir have little to no side effects. The most common side effects include headache, fatigue, dizziness, and nausea. Less common effects include

trouble sleeping Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

and gastrointestinal symptoms such as sour stomach, diarrhea, and vomiting. Serious side effects from entecavir include lactic acidosis,

liver problems Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Signs and symptoms Some of the s ...

, liver enlargement, and fat in the liver. Laboratory tests may show an increase in

alanine transaminase Alanine transaminase (ALT) is a transaminase enzyme (). It is also called alanine aminotransferase (ALT or ALAT) and was formerly called serum glutamate-pyruvate transaminase or serum glutamic-pyruvic transaminase (SGPT) and was first characte ...

(ALT),

hematuria Hematuria or haematuria is defined as the presence of blood or red blood cells in the urine. “Gross hematuria” occurs when urine appears red, brown, or tea-colored due to the presence of blood. Hematuria may also be subtle and only detectable w ...

glycosuria Glycosuria is the excretion of glucose into the urine. Ordinarily, urine contains no glucose because the kidneys are able to reabsorb all of the filtered glucose from the tubular fluid back into the bloodstream. Glycosuria is nearly always caused ...

, and an increase in lipase. Periodic monitoring of hepatic function and hematology are recommended.

Mechanism of action

Entecavir is a

nucleoside analog Nucleoside analogues are nucleosides which contain a nucleic acid analogue and a sugar. Nucleotide analogs are nucleotides which contain a nucleic acid analogue, a sugar, and a phosphate group with one to three phosphates. Nucleoside and nucl ...

, or more specifically, a

deoxyguanosine Deoxyguanosine is composed of the purine nucleobase guanine linked by its N9 nitrogen to the C1 carbon of deoxyribose. It is similar to guanosine, but with one hydroxyl group removed from the 2' position of the ribose sugar (making it deoxyribo ...

analogue that belongs to a class of

carbocyclic nucleoside Carbocyclic nucleosides (also referred to as carbanucleosides) are nucleoside analogues in which a methylene group has replaced the oxygen atom of the furanose ring. These analogues have the nucleobase attached at a simple alkyl carbon rather tha ...

s and inhibits reverse transcription,

DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...

and

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

in the

viral replication Viral replication is the formation of biological viruses during the infection process in the target host cells. Viruses must first get into the cell before viral replication can occur. Through the generation of abundant copies of its genome an ...

process. Other nucleoside and nucleotide analogues include

lamivudine Lamivudine, commonly called 3TC, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is also used to treat chronic hepatitis B when other options are not possible. It is effective against both HIV-1 and HIV-2. It is typicall ...

telbivudine Telbivudine is an antiviral drug used in the treatment of hepatitis B infection. It is marketed by Swiss pharmaceutical company Novartis under the trade names Sebivo (European Union) and Tyzeka (United States). Clinical trials have shown it to be ...

adefovir dipivoxil Adefovir is a prescription medicine used to treat (chronic) infections with hepatitis B virus. A prodrug form of adefovir was previously called bis-POM PMEA, with trade names Preveon and Hepsera. It is an orally administered nucleotide analog reve ...

, and

tenofovir Tenofovir disoproxil, sold under the trade name Viread among others, is a medication used to treat chronic hepatitis B and to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for preven ...

. Entecavir reduces the amount of HBV in the blood by reducing its ability to multiply and infect new cells.

Administration

Entecavir is taken by mouth as a tablet or solution. Doses are based on a person's weight. The solution is recommended for children more than 2 years old who weigh up to 30 kg. Entecavir is recommended on an empty stomach at least 2 hours before or after a meal, generally at the same time every day. It is not used in children less than 2 years old. Dose adjustments are also recommended for people with decreased kidney function.

History

* 1992: SQ-34676 at Squibb as part of anti-herpes virus program * 1997: BMS 200475 developed at BMS pharmaceutical research institute as antiviral nucleoside analogue à Activity demonstrated against HBV, HSV-1, HCMV, VZV in cell lines & no or little activity against HIV or influenza * Superior activity observed against HBV pushed research towards BMS 200475, its base analogues and its enantiomer against HBV in HepG2.2.15 cell line * Comparison to other NAs, proven more selective potent inhibitor of HBV by virtue of being Guanine NA * 1998: Inhibition of hepadnaviral polymerases was demonstrated in vitro in comparison to a number of NAs-TP * Metabolic studies showed more efficient phosphorylation to triphosphate active form * 3-year treatment of woodchuck model of CHB à sustained antiviral efficacy and prolonged life spans without detectable emergence of resistance * Efficacy # LVD resistant HBV replication in vitro * Superior activity compared to LVD in vivo for both HBeAg+ & HBeAg− patients * Efficacy in LVD refractory CHB patients * Entecavir was approved by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) in March 2005.

Patent information

Bristol-Myers Squibb The Bristol Myers Squibb Company (BMS) is an American multinational pharmaceutical company. Headquartered in New York City, BMS is one of the world's largest pharmaceutical companies and consistently ranks on the ''Fortune'' 500 list of the lar ...

was the original patent holder for Baraclude, the brand name of entecavir in the US and Canada. The drug patent expiration for Baraclude was in 2015. Entecavir patents were a subject of litigation in the US between Bristol Myers Squibb (the patent owner) and

Teva Pharmaceuticals USA Teva Pharmaceutical Industries Ltd. (also known as Teva Pharmaceuticals) is an Israeli multinational pharmaceutical company with headquarters in Tel Aviv, Israel. It specializes primarily in generic drugs, but other business interests include a ...

(a generic manufacturer). The lawsuit resulted in a relatively rare in the pharmaceutical field patent invalidation for obviousness, which was affirmed on 12 June 2014, by the

US Court of Appeals for the Federal Circuit The United States Court of Appeals for the Federal Circuit (in case citations, Fed. Cir. or C.A.F.C.) is a United States court of appeals that has special appellate jurisdiction over certain types of specialized cases in the U.S. federal cour ...

(752 F.32d 967). On August 26, 2014,

gained FDA approval for generic equivalents of Baraclude 0.5 mg and 1 mg tablets; Hetero Labs received such approval on August 21, 2015; and Aurobindo Pharma on August 26, 2015.

References

External links

* {{Portal bar , Medicine , Viruses Bristol Myers Squibb Nucleoside analog reverse transcriptase inhibitors Purines Hepatotoxins World Health Organization essential medicines Wikipedia medicine articles ready to translate Cyclopentanes Alkene derivatives Hydroxymethyl compounds