Herpes simplex encephalitis: Lack of clinical benefit of long-term valacyclovir therapy

John W. Gnann, Birgit Sköldenberg, John Hart, Elisabeth Aurelius, Silvia Schliamser, Marie Studahl, Britt Marie Eriksson, Daniel Hanley, Fred Aoki, Alan C. Jackson, Paul Griffiths, Lil Miedzinski, Diane Hanfelt-Goade, Daniel Hinthorn, Clas Ahlm, Allen Aksamit, Salvador Cruz-Flores, Ilet Dale, Gretchen Cloud, Penelope JesterRichard J. Whitley

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


Background. Despite the proven efficacy of acyclovir (ACV) therapy, herpes simplex encephalitis (HSE) continues to cause substantial morbidity and mortality. Among patients with HSE treated with ACV, the mortality rate is approximately 14%-19%. Among survivors, 45%-60% have neuropsychological sequelae at 1 year. Thus, improving therapeutic approaches to HSE remains a high priority. Methods. Following completion of a standard course of intravenous ACV, 87 adult patients with HSE (confirmed by positive polymerase chain reaction [PCR] for herpes simplex virus DNA in cerebrospinal fluid) were randomized to receive either valacyclovir (VACV) 2 g thrice daily (n = 40) or placebo tablets (n = 47) for 90 days (12 tablets of study medication daily). The primary endpoint was survival with no or mild neuropsychological impairment at 12 months, as measured by the Mattis Dementia Rating Scale (MDRS). Logistic regression was utilized to assess factors related to the primary endpoint. Results. The demographic characteristics of the 2 randomization groupswere statistically similar with no significant differences in age, sex, or race. At 12 months, there was no significant difference in theMDRS scoring for VACV-treated vs placebo recipients, with 85.7% and 90.2%, respectively, of patients demonstrating no or mild neuropsychological impairment (P = .72). No significant study-related adverse events were encountered in either treatment group. Conclusions. Following standard treatment with intravenous ACV for PCR-confirmed HSE, an additional 3-month course of oral VACV therapy did not provide added benefit as measured by neuropsychological testing 12 months later in a population of relatively high-functioning survivors.

Original languageEnglish (US)
Pages (from-to)683-691
Number of pages9
JournalClinical Infectious Diseases
Issue number5
StatePublished - Sep 1 2015


  • Acyclovir
  • Antiviral therapy
  • Encephalitis
  • Herpes simplex virus
  • Valacyclovir

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases


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