Editorial Commentary: Failure of Adjunctive Valacyclovir to Improve Outcomes in Herpes Simplex Encephalitis

The majority of cases of acute encephalitis remain of unknown etiology despite extensive diagnostic evaluations [1, 2]. Herpes simplex virus (HSV) is the most common identified cause of acute sporadic encephalitis in the Western world, accounting for approximately 20% of total cases of identified cause [3]. Classic studies by the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group (CASG) established intravenous acyclovir (ACV) as the standard of care for treatment of HSV encephalitis (HSE) [4]. Mortality in patients with brain biopsy–proven HSE dropped from 70% in placebo recipients [5] to 28% in those receiving intravenous ACV (30 mg/kg/day for 10 days) [4]. This impressive effect on mortality was also seen in a randomized multicenter trial in Sweden in which mortality was reduced to 19% in the ACV-treated group [6]. Despite this striking reduction in overall mortality, outcomes in survivors remain suboptimal. In the Swedish study, nearly one-third of ACV-treated survivors had moderate or severe sequelae [6], and in the CASG trial 42% of ACV-treated survivors had moderate or severe sequelae [4]. These results have been confirmed in subsequent studies that extended the duration of therapy to the now-standard 14–21 days and utilized cerebrospinal fluid (CSF) polymerase chain reaction (PCR) tests rather than brain biopsy to confirm the diagnosis of HSE [7]. In a multicenter study from France, mortality in ACVtreated patients was only 15%, although 57% of survivors continued to have moderate or severe disability at 6 months [7]. These studies indicate that there remains significant room for improvement in outcomes of patients with adult HSE. A recent multicenter, randomized, placebocontrolled trial in neonatal HSV central nervous system (CNS) disease has shown that adding oral ACV (300 mg/m three times daily) for 6 months following a standard initial intravenous course of 14– 21 days of ACV dramatically improves outcomes as measured by the Mental Development Index of the Bayley Scales of Infant Development [8]. Although neonatal HSV CNS disease differs from adult HSE in several significant ways, this study raised the possibility that supplemental treatment with an oral antiviral drug after initial intravenous ACV therapy might also improve outcomes in adult HSE. In this issue of Clinical Infectious Diseases, Gnann and colleagues present the results of just such a trial [9]. Following completion of a standard course of 14–21 days of intravenous ACV, patients with CSF PCR–proven HSE were randomized to an additional 90 days of oral valacyclovir (VACV) (2 g three times daily) or placebo. Unfortunately, the addition of oral VACV had no beneficial effect, and in some cases even had a negative effect (not significant) on cognitive function as assessed by either the Mini-MentalStateExamination(MMSE)or the Mattis Dementia Rating Scale (MDRS) at 6, 12, or 24 months post-illness. Although the study result is plausible, the study has a number of significant limitations. Enrollment requirements excluded the most seriously ill patients, and, as noted by the authors, those enrolled were “a relatively high-functioning subset of HSE survivors.” It therefore remains unknown whether more seriously ill patients or those with associated immunocompromising conditionsmight still benefit from supplemental antiviral therapy. Unfortunately, and despite the large number of study sites (N = 15) in North America and Europe, it took 8 years to enroll 91 patients (only 87 were actually randomized). Six US sites only enrolled an average of 1 patient every 3 years per site! This abysmal enrollment rate is not unique to this study. The pediatric trial described earlier [8] required >10 years to enroll 74 patients from 19 institutions. These accrual rates reflect in part the rarity of the disease (HSE has an incidence of about 4 cases per million population per year), but also suggest that the entire Received 1 May 2015; accepted 4 May 2015. Correspondence: Kenneth L. Tyler, MD, Department of Neurology, University of Colorado School of Medicine, 12700 E 19th Ave, MS B-182, Aurora, CO 80045 (ken.tyler@ucdenver. edu). Clinical Infectious Diseases Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. Thiswork iswritten by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/cid/civ373