OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Acyclovir	59277-89-3	C8-H11-N5-O3

ANNOTATED BIBLIOGRAPHY

References updated: 04 February 2016

• Zimmerman HJ. Antiviral agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 621-3.

  (Expert review of antiviral agents and liver injury published in 1999; mentions that acyclovir has not caused "overt hepatic injury").
• Nunez M. Herpesviridae treatment. Hepatic toxicity of antiviral agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 512-3.

  (Review of hepatotoxicity of antiviral agents; mentions that there have been postmarketing reports of ALT elevaitons, hepatitis and jaundice due to acyclovir).
• Acosta EP, Flexner C. Antiviral agents(nonretroviral). In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1593-1622.

  (Textbook of pharmacology and therapeutics).
• Straus SE, Takiff HE, Seidlin M, Bachrach S, Lininger L, Di Giovanna JJ, Western KA, et al. Suppression of frequently recurring genital herpes. A placebo-controlled double-blind trial of oral acyclovir. N Engl J Med 1984; 310: 1545-50. [PubMed: 6328297]

  (Placebo controlled trial of acyclovir in 35 patients with recurrent genital herpes; one patient had ALT elevations [88 U/L] that resolved even during continuation of therapy).
• O'Brien JJ, Campoli-Richards DM. Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1989; 37: 233-309. [PubMed: 2653790]

  (Review of antiviral activity, mechanism of action, pharmacokinetics, clinical efficacy and adverse effects of acyclovir; side effects are usually mild, but high doses intravenously are associated with nausea, vomiting, lightheadedness, neurologic symptoms, and renal dysfunction; no mention of hepatotoxicity or ALT elevations).
• Tilson HH, Engle CR, Andrews EB. Safety of acyclovir: a summary of the first 10 years experience. J Med Virol 1993; Suppl 1: 67-73. [PubMed: 8245895]

  (Between 10-15 million persons have been treated with acyclovir, but the sponsor received only 923 adverse event reports: 129 considered serious, but no specific mention of hepatotoxicity or ALT elevations).
• Styrt B, Freiman JP. Hepatotoxicity of antiviral agents. Gastroenterol Clin North Am 1995; 24: 839-52. [PubMed: 8749901]

  (Review of liver toxicity of antiviral agents; acyclovir may be associated with minor liver test elevations, but there have been no published reports of it causing clinically apparent liver injury).
• Ormrod D, Scott LJ, Perrry CM. Valaciclovir: a review of its long term utility in the management of genital herpes simplex virus and cytomegalovirus infections. Drugs 2000; 59: 839-63. [PubMed: 10804039]

  (Review of efficacy and safety of long term valaciclovir use; rates of side effects are similar in frequency to those in patients on placebo; a single case of hepatitis due to valaciclovir has been reported in abstract form).
• Bodsworth NJ, Crooks RJ, Borelli S, Vejlsgaard G, Paavonen J, Worm A-M, Uexkull N, et al., International Valaciclovir HSV Study Group. Genitourin Med 1997; 73: 110-6. [PMC free article: PMC1195783] [PubMed: 9215092]

  (999 patients randomized at 48 sites to acyclovir or valacyclovir for 5 days for recurrent HSV infection; equivalent efficacy and "no clinically important changes from screening in any clinical chemistry variable").
• Renkes P, Trechot P, Blain H. Valaciclovir-induced hepatitis. Acta Clin Belg 1999; 54: 17-8. [PubMed: 10192972]

  (71 year old woman with shingles developed abdominal pain 7 days after starting valacyclovir and 3 g/day of acetaminophen [bilirubin 3.3 mg/dL, ALT 376 U/L, Alk P 246 U/L], resolving within 2 weeks of stopping).
• Simpson D, Lyseng-Williamson KA. Famciclovir: a review of its use in herpes zoster and genital and orolabial herpes. Drugs 2006; 66: 2397-416. [PubMed: 17181386]

  (Review of famciclovir, oral prodrug of penciclovir, used in herpes zoster and simplex virus infections for limited period as therapy and extended use for suppression; in suppression studies, ALT elevations above twice ULN occurred in 3.2% of famciclovir vs 1.5% of placebo recipients; no hepatic serious adverse events reported).
• Drugs for non-HIV viral infections. Treat Guidel Med Lett 2007; 5: 59-70. [PubMed: 17565338]

  (Review of status of non-antiretroviral antiviral agents for prevention and treatment of herpes, varicella-zoster, cytomegalovirus, influenza A and B, and hepatitis B and C; no mention of liver related side effects for acyclovir).
• Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]

  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, 8 were attributed to antiviral agents including one attributed to valacyclovir, but none to acyclovir).
• Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, 4 of which were due to antiretroviral agents, but none were attributed to an antiherpes virus agent).
• Antiviral drugs. Treat Guidel Med Lett 2013; 11 (127): 19-30. [PubMed: 23459414]

  (Review of safety and efficacy of acyclovir treatment and prophylaxis against varicella and herpes zoster infections; mentions oral acyclovir has been linked to cases of Stevens Johnson syndrome, but does not specifically mention liver injury).
• Gopal MG, Shannoma, Kumar B C S, M R, A S N, Manjunath NC. A comparative study to evaluate the efficacy and safety of acyclovir and famciclovir in the management of herpes zoster. J Clin Diagn Res 2013; 7: 2904-7. [PMC free article: PMC3919380] [PubMed: 24551671]

  (Among 100 patients with herpes zoster treated for 7 days with either acyclovir or famciclovir, there was no "clincally significant difference" in serum biochemistry tests between the two groups).
• Pugi A, Bonaiuti R, Maggini V, Moschini M, Tuccori M, Leone R, Rossi M, et al. Safety profile of antiviral medications: a pharmacovigilance study using the Italian spontaneous-reporting database. Am J Health Syst Pharm 2013; 70: 1039-46. [PubMed: 23719881]

  (Analysis of adverse drug events reported spontaneous during a 22 year period in Italy identified 863 reports involving antivirals, but liver related events were not among the 20 most reported reactions).
• Tachibana T, Nozaki A, Enaka M, Yamamoto E, Kawasaki R, Koharazawa H, Hagihara M, et al. Drug-induced liver injury after allogeneic bone marrow transplantation. Int J Hematol 2013; 98: 499-503. [PubMed: 24037455]

  (23 year old woman with acute leukemia and allogeneic bone marrow transplant developed jaundice [bilirubin 14.0 mg/dL, ALT 1379 U/L, Alk P 1389 U/L] 180 days after transplant, while receiving oral acyclovir [for 104 days], voriconazole [60 days] and rebamipide [97 days], as well as tacrolimus and lansoprazole; a positive lymphocyte stimulation test was found for acyclovir, but not the other agents).
• Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]

  (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none were attributed to acyclovir or any other antiviral agent).
• Kendrick JG, Ensom MH, Steer A, White CT, Kwan E, Carr RR. Standard-dose versus high-dose acyclovir in children treated empirically for encephalitis: a retrospective cohort study of its use and safety. Paediatr Drugs 2014; 16: 229-34. [PubMed: 24497110]

  (Among 61 children with herpes simplex encephalitis treated with high or standard doses of intravenous acyclovir, "elevated liver enzymes" occurred in 4 [6.5%], 2 at each dose level; no mention of outcome, symptoms or jaundice).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-1352. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, one case was attributed to acyclovir but its likelihood was judged to be only possible).