Emtricitabine is a nucleoside analogue and reverse transcriptase inhibitor used in combination with other agents for treatment and prevention of human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). Emtricitabine does not appear to be a significant cause of drug induced liver injury, but may cause flares of disease in patients with underlying chronic hepatitis B virus (HBV) infection.
Emtricitabine (em" trye sye' ta been) is an L-enantiomer and substituted analogue of cytosine (5-fluorothiocytidine: FTC) and is active against both HIV and HBV, being similar in structure and activity to lamivudine. Emtricitabine is intracellularly phosphorylated to emtricitabine 5’-triphosphate which competes with the naturally occurring deoxycytidine 5’-triphosphate for incorporation into HIV DNA by the HIV reverse transcriptase, resulting in chain termination and inhibition of the polymerase activity. Emtricitabine was approved for use in HIV infection in the United States in 2006. Current indications include treatment of HIV infection, the prophylaxis of HIV infection in cases of occupational exposure, nonoccupational exposure, and perinatal transmission. Emtricitabine is also active against HBV, but has not been specifically approved for use in hepatitis B. The combination of emtricitabine with tenofovir is used in many current antiretroviral regimens and is considered the therapy of choice in patients with HBV-HIV coinfection. Emtricitabine is available as 200 mg capsules and in an oral solution as a single agent under the brand name of Emtriva; in 200 mg tablets in combination with tenofovir disoproxil fumarate (300 mg) as Truvada; in tablets in combination with tenofovir (300 mg) and efavirenz (600 mg) as Atripla; and in capsules in combination with tenofovir (300 mg), elvitegravir (150 mg) and cobicistat (150 mg) as Stribild. The recommended dose of emtricitabine in adults is 200 mg orally once daily. The combination formulations of Truvada, Atripla and Stribild are also given orally once daily. Side effects of attributable to emtricitabine are uncommon.
There is little evidence for direct hepatotoxicity of emtricitabine and it has not been specifically implicated in cases of lactic acidosis with steatosis and hepatic failure. However, patients with chronic hepatitis B can experience a flare of the underlying hepatitis during emtricitabine therapy. These flares occur either at the start therapy (treatment flares), with the development of antiviral resistance (breakthrough flares), or when therapy is abruptly stopped (withdrawal flares). Treatment flares occur in 5% to 10% of patients, are usually transient and asymptomatic, and rarely require dose modification or discontinuation of therapy. In contrast, withdrawal flares occur in 15% to 30% of patients, but can be symptomatic and severe, in rare instances (~1%) leading to acute liver failure, death or requirement for emergency liver transplantation. Patients who develop emtricitabine resistance often have relapse of disease activity after the appearance of the mutant HBV strain and rise in HBV DNA levels; this relapse can initially be severe and associated with symptoms and jaundice.
Mechanism of Injury
The apparent absence of significant hepatotoxicity from emtricitabine may be due to its minimal hepatic metabolism (13%) and the fact that it is both an L-enantiomer of cytidine and is blocked at the 3’ position on the deoxyribose component, making it unlikely that emtricitabine would be used by host nuclear or mitochondrial polymerases. The flares of hepatitis B that occur with initiation, antiviral resistance or withdrawal of therapy probably represent activation of immune responses to HBV caused by the sudden change in levels of viral replication.
Outcome and Management
ALT elevations have not been associated with emtricitabine use in patients without hepatitis B. Patients with HBV infection who have a flare of disease during emtricitabine can usually be monitored carefully and continued on therapy. Patients with a flare of hepatitis due to development of antiviral resistance should be switched to or have the addition of another agent with a different profile of resistance. Patients with a withdrawal flare of hepatitis B should be evaluated rapidly and restarted on antiviral therapy, if appropriate. Cases of acute liver failure requiring liver transplantation have been reported in patients with hepatitis B withdrawn from emtricitabine therapy. Due to the correlation between HIV/HBV coinfection and liver dysfunction in a subset of patients who discontinue emtricitabine, all patients with HIV should be tested for HBV before starting therapy with emtricitabine.
Agents used in therapy of HBV infection include adefovir, emtricitabine, entecavir, lamivudine, telbivudine, tenofovir, interferon alfa and peginterferon.
Drug Class: Antiviral Agents, Antiretroviral Agents, Hepatitis B Agents
REPRESENTATIVE TRADE NAMES
Emtricitabine – Emtriva®
Product labeling at DailyMed, National Library of Medicine, NIH
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