Abacavir, sold under the brand name Ziagen among others, is a

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

used to treat

HIV/AIDS The HIV, human immunodeficiency virus (HIV) is a retrovirus that attacks the immune system. Without treatment, it can lead to a spectrum of conditions including acquired immunodeficiency syndrome (AIDS). It is a Preventive healthcare, pr ...

. Similar to other nucleoside analog reverse-transcriptase inhibitors (NRTIs), abacavir is used together with other HIV medications, and is not recommended by itself. It is taken by mouth as a tablet or solution and may be used in children over the age of three months. Abacavir is generally well tolerated. Common side effects include vomiting,

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

(trouble sleeping), fever, and feeling tired. Other common side effects include loss of appetite, headache, nausea (feeling sick), diarrhea, rash, and lethargy (lack of energy). More severe side effects include

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) is an abnormal physiological condition in which there is an undesirable and adverse immune response to an antigen. It is an abnormality in the immune system that causes Imm ...

, liver damage, and lactic acidosis.

Genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

can indicate whether a person is at higher risk of developing hypersensitivity. Symptoms of hypersensitivity include rash, vomiting, and shortness of breath. Abacavir is in the NRTI class of medications, which work by blocking

reverse transcriptase A reverse transcriptase (RT) is an enzyme used to convert RNA genome to DNA, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, by retrotransposon mobi ...

, an enzyme needed for HIV virus replication. Within the NRTI class, abacavir is a carbocyclic nucleoside. Abacavir was patented in 1988, and approved for use in the United States in 1998. It is on the World Health Organization's List of Essential Medicines. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

. Abacavir is used together with other HIV medications, such as abacavir/lamivudine/zidovudine, abacavir/dolutegravir/lamivudine, and abacavir/lamivudine. The combination abacavir/lamivudine is an essential medicine.

Medical uses

Abacavir, in combination with other antiretroviral agents, is indicated for the treatment of HIV-1 infection. Abacavir should be used in combination with other antiretroviral agents.

Contraindications

Abacavir is contraindicated for people who have the HLA‑B*5701 allele or who have moderate or severe

liver disease 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. Liver diseases File:Ground gla ...

(hepatic impairment).

Side effects

Common adverse reactions include

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

, Anorexia (symptom) (loss of appetite), and

(trouble sleeping). Rare but serious side effects include

reaction such as

rash A rash is a change of the skin that 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, cracke ...

, elevated AST and ALT, depression,

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

fever Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...

/ chills, URI, lactic acidosis, hypertriglyceridemia, and

lipodystrophy Lipodystrophy syndromes are a group of genetic or acquired disorders in which the body is unable to produce and maintain healthy fat tissue. The medical condition is characterized by abnormal or degenerative conditions of the body's adipose tissu ...

Hypersensitivity syndrome

Hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) is an abnormal physiological condition in which there is an undesirable and adverse immune response to an antigen. It is an abnormality in the immune system that causes Imm ...

to abacavir is strongly associated with a specific allele at the

human leukocyte antigen The human leukocyte antigen (HLA) system is a complex of genes on chromosome 6 in humans that encode cell-surface proteins responsible for regulation of the immune system. The HLA system is also known as the human version of the major histo ...

B locus namely HLA-B*5701. The mechanism for this hypersensitivity reaction is due to abacavir binding in the

antigen In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

-binding cleft of HLA-B*57:01, allowing alternative

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

s to bind, which appear as "non-self" when presented to

T cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...

s. There is an association between the prevalence of HLA-B*5701 and ancestry. The prevalence of the

allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...

is estimated to be 3.4 to 5.8 percent on average in populations of European ancestry, 17.6 percent in

Indian American Indian Americans are Americans whose ancestry originates wholly or partly from India. The terms Asian Indian and East Indian are used to avoid confusion with Native Americans in the United States, Native Americans in the United States, who ar ...

s, 3.0 percent in Hispanic Americans, and 1.2 percent in

Chinese American Chinese Americans are Americans of Chinese ancestry. Chinese Americans constitute a subgroup of East Asian Americans which also constitute a subgroup of Asian Americans. Many Chinese Americans have ancestors from mainland China, Hong Kong ...

s. There is significant variability in the prevalence of HLA-B*5701 among African populations. In

African American African Americans, also known as Black Americans and formerly also called Afro-Americans, are an Race and ethnicity in the United States, American racial and ethnic group that consists of Americans who have total or partial ancestry from an ...

s, the prevalence is estimated to be 1.0 percent on average, 0 percent in the Yoruba from

Nigeria Nigeria, officially the Federal Republic of Nigeria, is a country in West Africa. It is situated between the Sahel to the north and the Gulf of Guinea in the Atlantic Ocean to the south. It covers an area of . With Demographics of Nigeria, ...

, 3.3 percent in the

Luhya Luhya or Abaluyia may refer to: * Luhya people * Luhya language {{disambig Language and nationality disambiguation pages ...

from

Kenya Kenya, officially the Republic of Kenya, is a country located in East Africa. With an estimated population of more than 52.4 million as of mid-2024, Kenya is the 27th-most-populous country in the world and the 7th most populous in Africa. ...

, and 13.6 percent in the Masai from Kenya, although the average values are derived from highly variable frequencies within sample groups. Common symptoms of abacavir hypersensitivity syndrome include

malaise In medicine, malaise is a feeling of general discomfort, uneasiness or lack of wellbeing and often the first sign of an infection or other disease. It is considered a vague termdescribing the state of simply not feeling well. The word has exist ...

, and

. Some patients may also develop a

skin rash A rash is a change of the skin that 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 ...

. Symptoms of AHS typically manifest within six weeks of treatment using abacavir, although they may be confused with symptoms of HIV, immune reconstitution syndrome, hypersensitivity syndromes associated with other drugs, or infection. 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 respo ...

(FDA) released an alert concerning abacavir and abacavir-containing medications on 24 July 2008, and the FDA-approved drug label for abacavir recommends pre-therapy screening for the HLA-B*5701 allele and the use of alternative therapy in subjects with this allele. Additionally, both the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group recommend use of an alternative therapy in individuals with the HLA-B*5701 allele. Epikutanni-test

Skin-patch testing may also be used to determine whether an individual will experience a hypersensitivity reaction to abacavir, although some patients susceptible to developing AHS may not react to the patch test. The development of suspected hypersensitivity reactions to abacavir requires immediate and permanent discontinuation of abacavir therapy in all patients, including patients who do not possess the HLA-B*5701 allele. On 1 March 2011, the FDA informed the public about an ongoing safety review of abacavir and a possible increased risk of heart attack associated with the drug. A

meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

of 26 studies conducted by the FDA, however, did not find any association between abacavir use and heart attack

Immunopathogenesis

The mechanism underlying abacavir hypersensitivity syndrome is related to the change in the HLA-B*5701

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

product. Abacavir binds with high specificity to the HLA-B*5701 protein, changing the shape and chemistry of the antigen-binding cleft. This results in a change in immunological tolerance and the subsequent activation of abacavir-specific

cytotoxic T cell A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular ...

s, which produce a systemic reaction known as abacavir hypersensitivity syndrome.

Interaction

Abacavir, and in general NRTIs, do not undergo hepatic metabolism and therefore have very limited (to none) interaction with the CYP enzymes and drugs that effect these enzymes. That being said there are still few interactions that can affect the absorption or the availability of abacavir. Below are few of the common established drug and food interaction that can take place during abacavir co-administration: * Protease inhibitors such as tipranavir or ritonavir may decrease the serum concentration of abacavir through induction of

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gly ...

. Abacavir is metabolized by both alcohol dehydrogenase and glucuronidation.Prescribing information. Ziagen (abacavir). Research Triangle Park, NC: GlaxoSmithKline, July 2002 *

Ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...

may result in increased levels of abacavir through the inhibition of alcohol dehydrogenase. Abacavir is metabolized by both alcohol dehydrogenase and glucuronidation. * Methadone may diminish the therapeutic effect of Abacavir. Abacavir may decrease the serum concentration of Methadone. * Orlistat may decrease the serum concentration of antiretroviral drugs. The mechanism of this interaction is not fully established but it is suspected that it is due to the decreased absorption of abacavir by orlistat. * Cabozantinib: Drugs from the MRP2 inhibitor (Multidrug resistance-associated protein 2 inhibitors) family such as abacavir could increase the serum concentration of Cabozantinib.

Mechanism of action

Abacavir is a nucleoside reverse transcriptase inhibitor that inhibits

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 ...

. It is a guanosine analogue that is phosphorylated to carbovir triphosphate (CBV-TP). CBV-TP competes with the viral molecules and is incorporated into the viral

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

. Once CBV-TP is integrated into the viral DNA, transcription and HIV

is inhibited.Product Information: ZIAGEN(R) oral tablets, oral solution, abacavir sulfate oral tablets, oral solution. ViiV Healthcare (per Manufacturer), Research Triangle Park, NC, 2015.

Pharmacokinetics

Abacavir is given orally and is rapidly absorbed with a high bioavailability of 83%. Solution and tablet have comparable concentrations and bioavailability. Abacavir can be taken with or without food. Abacavir can cross the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

. Abacavir is metabolized primarily through the enzymes alcohol dehydrogenase and glucuronyl transferase to an inactive carboxylate and glucuronide metabolites. It has a

half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...

of approximately 1.5-2.0 hours. If a person has liver failure, abacavir's half-life is increased by 58%. Abacavir is eliminated via excretion in the urine (83%) and feces (16%). It is unclear whether abacavir can be removed by

hemodialysis Hemodialysis, American and British English spelling differences#ae and oe, also spelled haemodialysis, or simply ''"'dialysis'"'', is a process of filtering the blood of a person whose kidneys are not working normally. This type of Kidney dialys ...

or peritoneal dialysis.

History

Robert Vince and Susan Daluge along with Mei Hua, a visiting scientist from China, developed the medication in the '80s. Abacavir was approved by the US

(FDA) in December 1998 and is the fifteenth approved antiretroviral drug in the United States.Mary Annette Banach.
How HIV Clinicians Acquire Representational Fluency: A Case Study of the HIV Resistance Preceptorship
", ''University of California'', Berkeley, 2003.

Synthesis

References

External links

Abacavir pathway on PharmGKB
{{Portal bar , Medicine , Viruses Acetaldehyde dehydrogenase inhibitors Cyclopentenes Cyclopropyl compounds Hepatotoxins Nucleoside analog reverse transcriptase inhibitors Purines Drugs developed by GSK plc World Health Organization essential medicines Wikipedia medicine articles ready to translate Hydroxymethyl compounds