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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Abacavir

Last Update: January 4, 2016.

OVERVIEW

Introduction

Abacavir sulfate is a nucleoside analogue and reverse transcriptase inhibitor which is used in combination with other agents in the therapy of the human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). Abacavir is a rare cause of clinically apparent drug induced liver injury.

Background

Abacavir (a bak' a vir) (cyclopropylaminopurinylcyclopentene: ABC) is a structural analogue of guanosine and acts by competing with naturally occurring nucleosides for incorporation into the HIV DNA strand during viral replication, causing inhibition of the viral polymerase and chain termination. Abacavir is indicated for the treatment of HIV infection in combination with other HIV medications such as lamivudine and zidovudine. Abacavir is available generically and under the trade name Ziagen in a 20 mg/mL oral solution and a 300 mg oral tablet. Abacavir is also available in fixed combination with lamivudine as Epzicom and Kivexa, with zidovudine and lamivudine as Trizivir and with dolutegravir and lamivudine as Triumeq. The recommended dose of abacavir is 300 mg orally twice daily or 600 mg orally once daily in adults and 8 mg/kg orally twice daily in children larger than 15 kg, with a maximum daily dose of 300 mg. Abacavir was approved for use in the United States in 1998 and is currently used in many antiretroviral regimens. Common side effects include diarrhea, loss of appetite, nausea, headache, and fatigue.

Hepatotoxicity

Elevations in serum aminotransferase levels above 5 times the upper limit of normal occur in up to 6% of patients on abacavir. These elevations are usually mild, transient and do not require dose adjustment. Clinically apparent hepatotoxicity is rare, but isolated cases [usually anicteric] have been published. The liver injury usually arises in the context of abacavir hypersensitivity syndrome and may be overshadowed by the allergic syndromes of fever, rash and fatigue. The onset is usually within 1 to 3 months of starting abacavir. The serum enzyme pattern can be hepatocellular or cholestatic. Patients typically recover rapidly within 4 weeks of stopping therapy.

Likelihood score: C (probable cause of clinically apparent liver injury).

Mechanism of Injury

The cause of the clinically apparent hepatotoxicity from abacavir is hypersensitivity in some cases and is typically associated with the HLA-B*57:01 haplotype. Abacavir binds to the antigen-binding cleft of the HLA-B*57:01 molecule and alters its peptide binding repertoire. Testing for this allele is available in the United States and is recommended before starting abacavir. There are few cases of nonhypersensitivity abacavir induced hepatitis (Case 1) in which the mechanism is unknown.

Outcome and Management

Most cases of liver injury associated with abacavir have been mild and anicteric and resolved rapidly within 4 weeks of discontinuation. There have been no convincing published cases of acute liver failure or vanishing bile duct syndrome due to abacavir. Patients with hepatotoxicity due to abacavir can generally tolerate other antiretroviral agents, rechallenge should be avoided, particularly in cases with features of hypersensitivity.

Drug Class: Antiviral Agents, Antiretroviral Agents

Other Drugs in the Subclass, Nucleoside Analogues: Adefovir, Didanosine, Emtricitabine, Entecavir, Lamivudine, Stavudine, Telbivudine, Tenofovir, Zidovudine

CASE REPORT

Case 1. Abnormal liver function tests occurring in a young HLA B*5701-negative woman shortly after switching to abacavir.

[Modified from: Soni S, Churchill DR, Gilleece Y. Abacavir-induced hepatotoxicity: a report of two cases. AIDS 2008; 22: 2557-8. PubMed Citation]

A 26 year old woman switched from a regimen of zidovudine, lamivudine and nevirapine to abavir/lamivudine/nevirapine and developed nausea six weeks later, but continued on therapy for another month when liver tests were found to be abnormal. Before starting abacavir, she had tested negative for the HLA B*57:01 allele and had normal serum aminotransferase levels. She did not drink alcohol to excess and had no history of liver disease. Serological testing showed no evidence of acute or chronic hepatitis B or C and she tested positive for anti-HAV and anti-HBs, indicative of previous vaccinations. On presentation, serum ALT was 433 U/L. Nevirapine was stopped, but she did not improve and a liver biopsy was done showing severe acute hepatitis with lobular collapse, changes suggestive of drug induced liver injury. Abacavir was discontinued and her symptoms quickly improved. Serum aminotransferases returned to normal 4 weeks later.

Key Points

Medication:Abacavir
Pattern:Hepatocellular
Severity:1+ (no jaundice)
Latency:4 weeks
Recovery:4 weeks
Other medications:Nevirapine, lamivudine, lopinavir

Comment

While liver injury as a part of the hypersensitivity reaction to abacavir is most common in persons with the HLA B*57:01 allele, hepatotoxicity can occur without frank hypersensitivity in other individuals. The injury in this case arose after 6 weeks of therapy, although the presence of liver disease was not suspected until several weeks later. The patient did not become jaundiced (bilirubin levels were not mentioned), but the severity of the illness was shown by liver biopsy findings and manifested by the presence of persistent symptoms. Elevations in serum aminotransferase levels are common during antiretroviral therapy and do not always warrant dose adjustment of drug-continuation. However, the co-occurrence of clinical symptoms and serum aminotransferase elevations is usually indicative of moderate or severe injury and should trigger investigation and alteration in drug regimen.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Abacavir – Ziagen®

DRUG CLASS

Antiviral Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Abacavir 136470-78-5 C14-H18-N6-O
Abacavir Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 04 January 2016

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    (Update and review of HLA associations with serious drug reactions including abacavir hypersensitivity which appears to the T-cell mediated and linked to HLA-B*57:01).
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    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, none were attributed to abacavir).

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