Exploring the role of oral valacyclovir in the treatment of herpes simplex encephalitis

Herpes simplex encephalitis (HSE) is probably the most serious herpes infection that patients can face. Treatment options for HSE are very limited, with IV acyclovir being the only approved antiviral for this devastating infection.

Given the logistics of prolonged IV therapy, clinicians have expressed interest in oral valacyclovir to simplify treatment in a patient who is clinically improving. With limited data available, the use of oral valacyclovir in EHS warrants further discussion.

Untreated HSE usually fatal

HSE is inflammation of the brain parenchyma resulting from infection with the herpes simplex virus. The annual incidence of HSE is approximately one in every 250,000 to 500,000 people worldwide. Without treatment, the risk of mortality is 70%, but even with timely diagnosis and treatment, the risk is estimated at 20% to 30%.

HSVs are double-stranded DNA viruses belonging to the herpes alpha virus subfamily of the family Herpesviridae. There are two HSVs – HSV-1 and HSV-2 – and both are transmitted from person to person through mucous membranes or damaged skin and establish lifelong infections. HSV-1 is usually spread through direct contact with oral secretions or herpes lesions, while HSV-2 is spread through sexual contact. HSV-1 infections cause encephalitis more frequently than HSV-2 and are responsible for approximately 10-20% of viral encephalitis cases in the United States.

The pathogenesis of HSE is not well understood but may result from primary infection, reactivation of a latent infection, or reinfection of another strain. After central nervous system (CNS) invasion, neuronal destruction is mediated by the immune system or direct viral injury. HSV can enter the brain from a peripheral site or from viremia, resulting in an acute or subacute onset of HSE. Once brain infection is established, early signs and symptoms of fever, malaise, headache, and nausea may appear. More serious clinical presentations include altered mentality, neurological deficit, and seizures. Despite treatment, chronic disability or neurological impairment occurs in more than half of patients with HSE.

Treatment of choice

Treatment of HSE involves rapid initiation of IV acyclovir. Early identification of HSE and initiation of acyclovir are imperative to reduce mortality and improve clinical outcomes; however, identification of HSE is difficult because there are no unique clinical features of HSE. Accordingly, acyclovir is recommended for any patient with suspected or known HSE.

After administration, acyclovir is triphosphorylated intracellularly to produce its active form – acyclovir triphosphate – which competes with deoxyguanosine trisphosphate for viral DNA polymerase and incorporation into viral DNA. Incorporation of acyclovir trisphosphate into viral DNA leads to DNA chain termination, preventing DNA synthesis and viral replication.

Although IV acyclovir is effective against EHS, treatment requires IV access and is expensive. Thus, less invasive treatments available on an outpatient basis are advantageous. This provides the rationale for valacyclovir, the prodrug of acyclovir.

For a drug to be effective in a CNS infection, adequate concentrations must be reached in the cerebrospinal fluid (CSF). The mean 50% inhibitory concentration (IC₅₀) for acyclovir against herpes viruses ranges from 0.07 to 0.97 g/mL. The mean plasma concentration of acyclovir 10 mg/kg every 8 hours is approximately 23 g/mL. Since 50% of plasma concentrations of acyclovir are present in CSF, levels far exceed the IC₅₀ for herpes viruses. Due to the poor oral bioavailability of acyclovir, plasma concentrations are only 15% to 30% of those obtained with IV acyclovir, resulting in levels that would be inadequate for CSF infections. In contrast, high-dose oral valacyclovir (HDVA) can achieve plasma concentrations similar to IV acyclovir because valacyclovir has better bioavailability. In preclinical pharmacokinetic studies in healthy volunteers, valacyclovir 1.5 g to 2 g four times daily achieved an area under the concentration curve similar to that of acyclovir IV 10 mg/kg every 8 hours.

A separate pharmacokinetic study in Vietnam recruited adult patients with the presumptive diagnosis of HSE to initiate treatment with valacyclovir 1000 mg three times daily. Plasma, as well as CSF levels, were analyzed to assess whether adequate levels of acyclovir were achieved in CSF. Nine patients enrolled in the study, but only four patients completed the full 21-day treatment. Of those who did not complete the study, two patients had negative CSF PCR tests for HSV, two patients died, and one patient withdrew. Oral valacyclovir reached adequate concentrations during the study period. However, acyclovir penetration into CSF ​​decreased during treatment. The CSF/plasma concentration ratio decreased from 22.9% on day 2 to 12% on day 20. This was likely due to reduced penetration into CSF ​​as the patient’s condition improved. Of note, the mean CSF acyclovir concentration at day 20 was still above the IC₅₀ for most clinical isolates of HSV. All patients who remained in the study through day 10 had negative HSV PCR tests.

In 2011, a shortage of IV acyclovir forced hospitals to put in place measures to retain its use for those who would benefit most from the therapy. A report from Northwestern Memorial Hospital outlines their experience with how they handled this shortage. Part of their plan was to implement HDVA at a dose of 6g daily to treat suspected viral syndrome in patients who did not meet their strict criteria for IV acyclovir. The authors retrospectively reviewed patients who received HDVA to assess outcomes. Fifteen patients received HDVA during the observation period, including three who had confirmed CNS infection with HSV and one patient with varicella zoster encephalitis. The mean daily dose of valacyclovir was 3 g with a median treatment duration of 11 days. Among those treated with HDVA, two patients had neurological sequelae and one was readmitted within 30 days for bacteremia. The most commonly reported adverse drug event was thrombocytopenia, followed by headache, nausea, and rash. No patient required discontinuation or additional treatment due to adverse drug reactions.

There are a few case reports of successful use of oral valacyclovir for HSE, after initial treatment with IV acyclovir. One report involved a 12-year-old child who developed a rash while receiving IV acyclovir. The patient was switched to valacyclovir 1000 mg three times daily for the last 10 days of treatment, which was well tolerated.

It is clear that more work is needed before there is widespread adoption of oral valacyclovir for the treatment of EHS. Additional studies evaluating oral valacyclovir in EHS could turn the potential into reality, but until then the treatment of choice is IV acyclovir and oral valacyclovir can only be considered on a case-by-case basis.

• For more information:
• James LeFevre is a pharmacy student at Drake University in Des Moines, Iowa, and a 2023 PharmD candidate.
• Jeff Brock, PharmD, MBA, BCPS AQ-ID, is an infectious disease pharmacy specialist at Mercy Medical Center in Des Moines, Iowa. He can be reached at [email protected].