Adjunctive valacyclovir fails to improve HSE outcomes

An additional 3 months of valacyclovir after standard IV acyclovir therapy for herpes simplex encephalitis did not improve outcomes in adult patients, according to results of a multicenter, randomized, placebo-controlled trial.

“Overall, the proportion of [herpes simplex encephalitis (HSE)] survivors who have no or mild neurological impairment and are able to resume activities of daily living is approximately 40% to 55%,” John W. Gnann Jr., MD, professor of medicine at the Medical University of South Carolina, and colleagues wrote in Clinical Infectious Diseases. “Thus, even with optimal medical management, long-term morbidity among HSE survivors remains unacceptably high.”

After IV acyclovir therapy, persistent low-level herpes simplex virus replication in the central nervous system may result in chronic inflammatory response. Therefore, Gnann and colleagues tested whether extended antiviral therapy with valacyclovir could reduce neuropsychological morbidity and improve outcomes in adult patients.

The trial included 87 HSE patients who received either valacyclovir at 2 g three times daily (n = 40) or placebo (n = 47) for 90 days after the standard 14 to 21 days of IV acyclovir therapy. The study population was a relatively high-functioning subset of HSE survivors who were capable of taking pills at the end of IV acyclovir therapy.

The primary endpoint was survival with no or mild neuropsychological impairment at 12 months following initiation of valacyclovir, measured by the Mattis Dementia Rating Scale, or MDRS. Secondary endpoints included impairment at 90 days and 6, 12 and 24 months.

The researchers observed no benefit on cognitive function with the addition of oral valacyclovir, and in some cases, the antiviral appeared to have a negative effect, although this was not statistically significant. At 12 months, there were no significant differences in MDRS scores between groups, with 86% of HSE patients in the treatment arm demonstrating no or mild neuropsychological impairment vs. 90% of controls, according to Gnann and colleagues. These percentages did not change significantly at 24 months.

However, the researchers noted that the proportion of HSE patients with little or no impairment as measured by MDRS increased from 64% at baseline to 88% at 12 months, with most of the improvement in cognitive function occurring between the time of completion of IV acyclovir and day 90. In addition, there was continued improvement up to 2 years later. This outcome was better than anticipated, they said, given that previous studies have shown fewer HSE patients capable of resuming activities of daily living.

“HSV remains the most common infectious cause of episodic fatal encephalitis,” Gnann told Infectious Disease News. “Clinicians should have a very low threshold for prompt initiation of IV acyclovir for all patients presenting with symptoms and signs suggestive of viral encephalitis. Don’t delay empiric acyclovir therapy while the diagnostic work-up is in progress. The data clearly demonstrate that earlier initiation of therapy translates into improved neuropsychiatric outcomes. As our study showed, prolonged valacyclovir therapy is not helpful — early therapy with high-dose IV acyclovir is the key to optimizing outcomes in patients with HSE.”

In a related editorial, Kenneth L. Tyler, MD, of the University of Colorado School of Medicine, described the results as “discouraging,” and mentioned several new potential HSE therapies in development, including corticosteroids, immunomodulatory therapies, and therapies designed to enhance innate immune responses, although their effectiveness has yet to be established.

Tyler emphasized the need to improve existing HSE therapy in the meantime.

“Perhaps the easiest target of all for improving survival and outcomes is simply to do better with therapy we know works,” he wrote. – by John Schoen

Disclosure: Gnann reports receiving research grants from the NIH and personal fees from BioCryst, GlaxoSmithKline and Merck. Please see the full study for a list of all other authors’ relevant financial disclosures. Tyler reports no relevant financial disclosures.