Background

A thymidine kinase inhibitor, valacyclovir is a prescription drug, and widely available as a generic. Valacyclovir is used to shorten outbreaks of genital herpes or cold sores caused by Herpes simplex virus (HSV) 1 and 2. It is also used to treat outbreaks of varicella zoster, which causes shingles and chickenpox. Taken as oral tablets, valacyclovir inhibits replication of viral DNA. It is most active against HSV-1 and HSV-2. 

The rationale for testing valacyclovir in Alzheimer’s disease stems from the hypothesis that viral infection, particularly with HSV-1, may cause AD or contribute to its progression (reviewed in Itzhaki, 2018; Devanand, 2018; Itzhaki, 2014). Data suggest viruses could act by causing inflammation, seeding amyloid aggregation, or altering expression of AD-related genes (Jun 2018 news; Jun 2018 news; May 2019 news). Epidemiological studies indicate antiviral treatment can reduce the risk of dementia in people with HSV-1 or other viral infections, but the overall evidence is not convergent (Tzeng et al., 2018; Itzhaki and Lathe, 2018, Jan 2021 news).

In a trial to treat cognitive deficits in HSV-1-positive people with schizophrenia, 18 weeks of valacyclovir improved measures of working memory, verbal memory, and visual object memory (Prasad et al., 2013). In people with multiple sclerosis, it produced trends toward clinical improvement, but no change in objective measures of disease (Friedman et al., 2005).

Findings

In May 2013, an open-label pilot study of valacyclovir in 30 HSV-seropositive people with Alzheimer’s disease began at the University of Helsinki. The trial was to treat for 12 weeks, then measure changes in cognition and function on the ADAS-Cog and ADCS-ADL. Results were not published.

In December 2016, VALZ-Pilot, an open-label study in HSV-positive people with early AD, started up at two sites in Sweden, in Umea and Uppsala. The 36 participants had to carry the ApoE4 allele, which is associated with greater susceptibly to neurological effects of HSV infection. They received 1.5 grams valacyclovir daily for one week, then 3 grams daily for another three weeks. The primary outcome was feasibility, tolerability, safety, and change in CSF total tau and neurofilament light levels; additional endpoints included other CSF biomarkers and drug levels, PET measures of HSV replication in the CNS, and MMSE. According to published results, 32 of 33 enrollees completed the full dose regimen, with only mild and temporary adverse events. CSF valacyclovir levels achieved therapeutic range. CSF total tau and NfL levels were unchanged, though CSF sTREM2 rose. A one-point increase in MMSE after treatment was statistically significant. The PET portion of the study failed due to the tracer’s lack of brain penetration (Weidung et al., 2022).

In February 2018, a Phase 2, placebo-controlled trial began at New York University and New York State Psychiatric Institute. It will enroll 130 HSV-seropositive-people who have a clinical diagnosis of Alzheimer’s disease and mild dementia, or of mild cognitive impairment with imaging or CSF biomarker evidence of AD. Half receive 4 grams valacyclovir daily for 18 months, half placebo. Primary outcomes are change in cognition and function as per the ADAS-Cog11 battery and ADCS-ADL; secondary measures are change in brain amyloid and tau accumulation on florbetapir and MK-6240 PET scans; exploratory measures include cortical thinning on MRI, olfactory deficits, and change in antiviral antibody titers from baseline to 78 weeks. A substudy in participants who agree to repeat lumbar puncture will measure CSF Aβ42, total and phosphorylated tau, and levels of valacyclovir. Funded by the NIA, the trial is expected to end in December 2023. The protocol is published (Devanand et al., 2020).

In February 2021, a second Phase 2 trial in New York began recruiting 50 people with mild cognitive impairment, biomarker evidence of AD, and HSV seropositivity. Treatment will be 4 g/day or placebo for one year, against outcomes of change in amyloid PET, the Preclinical Alzheimer’s Cognitive Composite, and the ADCS-ADL-Prevention Instrument. Completion is expected in December 2023.

Valacyclovir is also being evaluated in several types of cancer including gliomas, and for other viral infections. For details on valacyclovir trials, see clinicaltrials.gov.