VALZ‐Pilot: High‐dose valacyclovir treatment in patients with early‐stage Alzheimer's disease

Design

Prospective, multi-center, open-label phase II pilot trial

N= 33

Objective

To evaluate safety, tolerability, feasibility, and efficacy of high‐dose valacyclovir administration to patients with early‐stage Alzheimer's dementia (AD) and anti‐herpes simplex virus (HSV) immunoglobulin (Ig)G and APOE ε4 positivity

Study Groups

Inclusion Criteria

Aged ≥ 65 years old; diagnosis of late‐onset AD or mild cognitive impairment of the AD type; serum or plasma anti‐HSV IgG positivity; APOE ε4 genotype carriership; at least 1 month stability of medication regimens for other conditions

Exclusion Criteria

Allergies to valacyclovir or acyclovir; kidney failure or decreased kidney function (estimated glomerular filtration rate [eGFR] < 30 ml/min/1.73 m²); ongoing anticoagulant treatment, excluding the use of antiplatelet drugs in normal doses; unstable condition or expected survival time < 1 year; major neurocognitive disorder other than AD; current or recent history of substance addiction

Methods

Patients in Sweden were provided valacyclovir (Valtrex; GlaxoSmithKline) 500 mg tablets at the beginning of the study and instructed to take one tablet three times daily on days 1-7, then two tablets three times daily on days 8-28. Clinical information, blood, and CSF were collected from the patients at T0 and day 28.

Duration

Four weeks

Safety: up to 30 days after intervention termination

Outcome Measures

Primary: Intervention's feasibility, tolerability, and safety; changes in the CSF levels of total tau (t‐tau) and neurofilament light chain (NfL) during the intervention

Secondary: Changes in the MMSE score, anti‐HSV IgG titers, and CSF levels of biomarkers; detection, magnitude, and location of replicating herpesvirus in the CNS

Baseline Characteristics

Study cohort (N= 33)

Age, years

Female

APOE genotype

ε2/ε4

ε3/ε4

ε4/ε4

6.1%

72.7%

 21.2%

IgG‐positive

Serum anti‐HSV‐1

Serum anti‐HSV‐2

Serum anti‐CMV

93.9%

27.3%

81.8%

MMSE score (IQR)

23 (19‐26)

Abbreviations: AE, adverse event; APOE, apolipoprotein E; CSF, cerebrospinal fluid; IgG, immunoglobulin G; IQR, interquartile range; MMSE, Mini‐Mental State Examination

Results

Endpoint (IQR)

Before treatment

After treatment

p-value

MMSE score

Serum anti‐HSV IgG, titer

CSF anti‐HSV IgG, titer*

* Three participants had undetectable CSF anti‐HSV IgG concentrations, recorded as 0.

One CSF biomarker, CSF sTREM2, had significantly increased during the intervention (p= 0.028). The CSF levels of t‐tau and NfL (neurodegeneration markers) as well as other biomarkers did not significantly change.

Adverse Events

Common Adverse Events: One patient was on a reduced dosage due to headache. Ten AEs were considered related to the intervention (fatigue, headache [n= 2 each]; thirst, nausea, loose stools, mild depressive symptoms, mild tremor, polyuria [n= 1 each]).

Serious Adverse Events: Two serious AEs were reported, although none were considered related to the intervention.

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

This trial demonstrated that a 4‐week high‐dose oral valacyclovir regimen was feasible, tolerable, and safe for patients with early‐stage AD, HSV, and APOE ε4. These findings may guide the design of RCTs for the assessment of antiviral treatment effectiveness for such patients in terms of AD symptoms, progression, and pathology.

InpharmD Researcher Critique

This study was prematurely terminated due to its low recruitment rate, and thus findings should be interpreted with caution. The open-label and pilot design of the study, the lack of a placebo comparator arm, and the short duration of therapy also limit applicability of findings to a larger patient population. The use of neuroinflammatory biomarkers instead of cognitive scoring systems may not denote clinical benefit with valacyclovir therapy.

Antiherpetic drugs: a potential way to prevent Alzheimer’s disease?

Design

Retrospective observational cohort study

N= 68,291

Objective

To explore whether the protective effect of systemic antiherpetic drugs (AHDs) on the onset of dementia was replicable using a French large medico-administrative database

Study Groups

No systemic AHD (n= 61,649)

Systemic AHD (n= 6,642)

Inclusion Criteria

Aged ≥ 65 years; in the Echantillon Généraliste des Bénéficiaires (EGB)

Exclusion Criteria

Aged < 65 years; not present in the database on January 1, 2007; dementia identified before or on January 1, 2009

Methods

Data was extracted from the EGB, which is a random sample of affiliates to the French Health Insurance System containing information relating to (1) sociodemographic data; (2)  “long-term diseases” (LTDs), a group of chronic diseases for which all medical expenses are fully reimbursed; (3) outpatient healthcare expenditures reimbursements; (4) outpatient drug reimbursements; (5) hospitalizations with the primary, related, and associate diagnoses coded; and (6) dates of death.

Subjects were defined as having dementia, Alzheimer's dementia, or vascular dementia if at least one of the following criteria was present: (1) hospitalization in medical or surgical wards with diagnoses linked to dementia; (2) a declaration of an LTD related to dementia; (3) anti-dementia drugs (i.e., anti-cholinesterase drugs, memantine, or their association) which were considered only for the identification of dementia.

Duration

Followed until exit from primary health care insurance system, dementia onset, death, or December 31, 2017, whichever came first

Outcome Measures

Incident cases of dementia, association between the intake of at least one AHD and onset of dementia

Baseline Characteristics

No systemic AHD (n= 61,649)

Systemic AHD (n= 6,642)

Age, years

Male

Among subjects who have taken systemic AHDs, 88.5% received at least one dose of valacyclovir and 16.6% received at least one dose of acyclovir. Patients who have taken systemic AHDs were more likely to be younger, women, have concomitant lipid-lowering and anti-inflammatory drugs, and have a higher number of different treatment regimens and medical consultations.

Of patients who were hospitalized, 151 (0.22%) had a hospitalization related to HSV infection, 16 (0.02%) to cytomegalovirus (CMV) infection, and 244 (0.36%) to varicella zoster virus (VZV) infection.

A total of 8,883 patients were identified as having incident dementia during follow-up, of which were 5,366 AD diagnoses. The incidence rate of AD was 11.0 cases per 1,000 person-years, with a mean age of 84 ± 6 years at diagnosis of dementia.

Among 509 patients who were treated with systemic AHDs and subsequently diagnosed with dementia, the time interval between first treatment and occurrence of dementia was 2.9 years (IQR 1.2-4.8).

Results

Endpoint

Events

Adjusted hazard ratio* (95% CI)

p-value

Association between intake of at least one systemic AHD and incidence of dementia in all subjects (n= 68,291)

All dementias

Alzheimer's dementia

8,883

5,366

0.90 (0.82-0.99)

0.85 (0.75-0.96)

0.03

0.009

Association after exclusion of immunocompromised subjects, subjects with cancer or with a hospitalization related to herpesviruses (n= 52,254)

All dementias

Alzheimer's dementia

7044

4260

0.84 (0.75-0.94)

0.82 (0.71-0.95)

0.002

0.007

Association after carrying out a lag-time of 1 year (n= 68,291)

All dementias

Alzheimer's dementia

8,883

5,366

0.86 (0.78–0.95)

0.78 (0.68–0.90)

0.004

0.001

Association after exclusion of participants with ≥ 2 deliveries of systemic AHDs per year of follow-up (n= 67,904)

All dementias

Alzheimer's dementia

8,856

5,351

0.91 (0.83-0.997)

0.85 (0.75-0.97)

0.04

0.01

Abbreviations: CI, confidence interval; IQR, interquartile range

* Adjustment for age at inclusion, sex, being beneficiary of a complementary health insurance for low-income people at inclusion, hypertension, diabetes, hypercholesterolemia, heart disease, stroke, intake of nonsteroidal anti-inflammatory drugs, systemic, or inhaled glucocorticoids the year before inclusion, number of different medications the year before inclusion, number of outpatient medical consultations the year before inclusion

Adverse Events

Not disclosed

Study Author Conclusions

Taking at least one systemic AHD during follow-up was significantly associated with a 15% reduced risk of developing AD, even after taking into account several potential methodological biases. Nevertheless, the low frequency of subjects with a regular intake questions the biological plausibility of this association and highlights the limits of epidemiological data to evaluate a potential protective effect of a regular treatment by systemic AHDs on the incidence of dementia.

InpharmD Researcher Critique

Few patients included in analysis were using AHDs regularly, and thus the effect of regular treatment on the incidence of dementia cannot be ascertained. The use of data from a national claims database may bias the results due to potential missing information, misclassification, and inaccuracies. Additionally, as the study was conducted outside of the US, results may not be extrapolatable to a domestic patient population.