Infectious Disease

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

November 22, 2022

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Brock and LeFevre report no relevant financial disclosures.


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

Given the logistics of providing prolonged IV treatment, clinicians have shown interest in oral valacyclovir to simplify treatment in a clinically improving patient. With limited data available, using oral valacyclovir in HSE begins further discussion.

James LeFevre and Jeff Brock, PharmD, MBA, BCPS AQ-ID

Untreated HSE usually deadly

HSE is inflammation of the brain parenchyma as a result of herpes simplex virus infection. The annual incidence of HSE is about one per 250,000 to 500,000 individuals worldwide. Without treatment, the risk for mortality is 70%, but even with timely diagnosis and treatment, the risk is estimated between 20% and 30%.

HSVs are double-stranded DNA viruses belonging to the alpha-herpes virus subfamily of the Herpesviridae family. There are two HSVs — HSV-1 and HSV-2 — and both transmit person to person through mucous membranes or damaged skin and establish lifelong infections. HSV-1 usually spreads by direct contact with oral secretions or herpes lesions, whereas HSV-2 spreads by sexual contact. HSV-1 infections cause encephalitis more commonly than HSV-2 and are responsible for about 10% to 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 latent infection or reinfection of another strain. After invasion of the central nervous system (CNS), neuronal destruction is mediated by the immune system or direct viral injury. HSV may enter the brain from a peripheral site or viremia, leading to an acute or subacute onset of HSE. Once infection of the brain has established, early signs and symptoms of fever, malaise, headache and nausea may occur. More severe clinical presentations include altered mention, neurologic deficit and seizures. Despite receiving treatment, chronic disability or neurologic impairment occurs in more than half of patients with HSE.

Treatment of choice

Treatment of HSE involves prompt initiation of IV acyclovir. Early identification of HSE and initiation of acyclovir are imperative to reduce mortality and improve clinical outcomes; however, identifying HSE is difficult because there are no unique clinical features of HSE. As a result, acyclovir is recommended in 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 HSE, treatment requires IV access and is expensive. Thus, treatments that are less invasive and available in outpatient settings 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 attained 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. Because 50% of acyclovir plasma concentrations are present in the CSF, levels far exceed the IC50 for herpes viruses. Because of the poor oral bioavailability of acyclovir, plasma concentrations are only 15% to 30% of those achieved with IV acyclovir, resulting in levels that would be inadequate for CSF infections. In contrast, high-dose oral valacyclovir (HDVA) can achieve similar plasma concentrations as IV acyclovir because valacyclovir has better bioavailability. In preclinical pharmacokinetic studies completed in healthy volunteers, valacyclovir 1.5 g to 2 g four times per day achieved a similar area under the concentration curve compared with IV acyclovir 10 mg/kg every 8 hours.

A separate pharmacokinetic study in Vietnam enrolled adult patients with the presumptive diagnosis of HSE to initiate treatment with valacyclovir 1,000 mg three times per day. Plasma, as well as CSF levels, were analyzed to evaluate if adequate acyclovir levels were achieved in the CSF. Nine patients enrolled in the study, but only four patients completed the full treatment course of 21 days. 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 achieved adequate concentrations during the study period. However, acyclovir penetration into the 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 the CSF as the patient’s condition improved. Of note, the day 20 mean CSF acyclovir concentration was still higher than the IC50 for most clinical HSV isolates. All patients who remained in the study until day 10 had negative HSV PCR tests.

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

There are a few case reports of successful use of oral valacyclovir for HSE, after initial treatment with IV acyclovir. One report was in a 12-year-old child who developed a rash while on IV acyclovir. The patient was transitioned to valacyclovir 1,000 mg three times per day for the last 10 days of treatment, which was well tolerated.

Clearly more work is required before there is a widespread adoption of oral valacyclovir for the treatment of HSE. Additional studies assessing oral valacyclovir in HSE could turn potential into a reality, but until then, the treatment of choice is IV acyclovir and oral valacyclovir may be considered only on a case-by-case basis.


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