Valacyclovir is a nucleoside analogue antiviral agent and prodrug of acyclovir which is used in therapy of herpes and varicella-zoster virus infections. Valacyclovir has been associated with rare instances mild, clinically apparent liver injury.
Valacyclovir (val" ay sye' kloe vir), which is sometimes spelled valaciclovir, is an acyclic purine nucleoside analogue that is rapidly converted to acyclovir once absorbed. Valacyclovir has greater oral bioavailability than acyclovir and has similar activity against herpes viruses, including herpes simplex 1 and 2, cytomegalovirus, Ebstein-Barr virus and varicella-zoster. Once converted to acyclovir, the drug is phosphorylated intracellularly by viral kinases. The resultant triphosphate competes with guanosine for incorporation into viral DNA, blocking viral DNA polymerase activity. Because its activation requires the presence of viral kinases, valacyclovir is only activated in virally infected cells. Valacyclovir is indicated for therapy of mucocutaneous and genital herpes simplex infections, both type 1 and 2 and for herpes zoster. Valacyclovir was approved for use in the United States in 1995 and is widely used in the treatment and prophylaxis of genital and mucocutaneous herpes simplex infection. Valacyclovir is available as capsules of 500 mg and 1000 mg generically and under the brand name of Valtrex. The usually recommended dose in adults is 500 to 1000 mg once or twice daily. Side effects are uncommon, but include headache, dizziness and gastrointestinal upset.
Oral therapy with valacyclovir is associated with a low rate of mild-to-moderate serum aminotransferase elevations, but these abnormalities are usually asymptomatic and self-limited even with continuation of therapy. Complicating the attribution of liver test abnormalities to valacyclovir therapy is the fact that enzyme elevations are not uncommon during the course of varicella-zoster infection (shingles) and can progress to clinically apparent hepatitis and even acute liver failure. Clinically apparent liver disease due to valacyclovir itself is rare, but isolated reports have been published. The time to onset was short (1 to 2 weeks) and the course mild, with few symptoms and rapid resolution (Case 1). The pattern of liver injury described was mixed hepatocellular-cholestatic. Immunoallergic features and autoantibodies were absent.
Mechanism of Injury
After absorption, valacyclovir is converted to acyclovir by the liver, which is metabolized intracellularly in viral infected cells and is excreted largely unchanged by the kidneys. Valacyclovir is not activated in cells without viral kinases, perhaps accounting for the absence or rarity of hepatic injury.
Outcome and Management
No instances of acute liver failure or chronic liver injury have been linked to valacyclovir use. The liver injury associated with valacyclovir is usually mild and resolves rapidly. There is no information on possible cross sensivity of hepatic injury among the various nucleoside analogues used to treat herpes virus infections.
Case 1. Mild acute hepatitis with jaundice after valacyclovir therapy.
[Modified from: Renkes P, Trechot P, Blain H. Valaciclovir-induced hepatitis. Acta Clin Belg 1999; 54: 17-8. PubMed Citation]
A 71 year old woman with shingles was treated with valacyclovir (3 g daily) for 7 days and developed abdominal and back pains by the end of therapy, leading to hospitalization 2 days later. She was also taking acetaminophen for pain in doses up to 3 g daily. She had no history of liver disease, risk factors for hepatitis or alcohol abuse. She was taking thyroid hormone for hypothyroidism, but no other medications. She had a history of cholecystectomy. On admission, she did not have fever or rash and the abdominal pain was attributed to back strain. Laboratory tests showed elevations in serum ALT and alkaline phosphatase with mild hyperbilirubinemia (Table), but no elevations in serum amylase or creatinine. Valacyclovir was stopped. Tests for hepatitis A, B and C were negative as were autoantibodies. An ultrasound showed a prominent common bile duct (9 mm), but subsequent ERCP did not show obstruction or biliary stones. After 5 days, acetaminophen was stopped and other analgesics were substituted. Two weeks after initial presentation, the liver test abnormalities had resolved.
|Medication:||Valacyclovir (3 g daily)|
|Pattern:|| Mixed (R=3.5)|
||3+ (jaundice, hospitalization)|
|Recovery:||Complete in 2 weeks|
|Other medications:||Acetaminophen, thyroid hormone|
|Time After Starting
||Time After Stopping
||Alk P (U/L)
|| Admission:abdominal pain
A mild case of liver injury with a mixed pattern of serum enzyme elevations arising by the end of a one-week course of valacyclovir. While she was also taking acetaminophen in somewhat high doses, the pattern of enzyme elevations and absence of renal dysfunction were atypical for acetaminophen toxicity. The possibility of varicella-zoster induced hepatitis should also be considered.
REPRESENTATIVE TRADE NAMES
Valacyclovir – Generic, Valtrex®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 25 November 2013
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