A randomized clinical trial of valacyclovir in multiple sclerosis

Friedman, Jacqueline; Zabriskie, J. B.; Plank, Charles R.; Ablashi, Dharam V.; Whitman, James E.; Shahan, Britt; Edgell, Randall C.; Shieh, Ming Jium; Rapalino, Otto; Zimmerman, Robert D.; Ding, Shan

doi:10.1191/1352458505ms1185oa

Cited by 66 publications

(51 citation statements)

References 24 publications

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“…Nevertheless, a significant reduction in the number of new, active, MRI-evident lesions in a subgroup of patients with high disease activity was seen [69]. An American two-year placebo-controlled, doubleblind, clinical trial with valaciclovir has recently been reported to provide positive trends by clinical measures, although these were not statistical significant [70].…”

Section: Controlled Trials Of Antiviral Chemotherapymentioning

confidence: 96%

Multiple sclerosis is linked to Epstein‐Barr virus infection

Haahr

Höllsberg

2006

Reviews in Medical Virology

111

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The aetiology and pathogenesis of MS are unknown, but environmental agents, genetic susceptibility and stochastic events are likely to be involved. In order to evaluate the possibility that MS is linked to EBV infection, we here evaluate studies on MS- and EBV-epidemiology, prospective and retrospective analysis of EBV-serology, investigations of EBV DNA sequences in blood and tissues, specificity of antibodies in oligoclonal bands in MS patients and results from antiviral chemotherapy of MS patients. It could be demonstrated that EBV is complying with the epidemiological observations in MS and that all MS patients are seropositive to EBV in contrast to healthy controls. Importantly, despite difficulties in diagnosing child-MS, the vast majority of these patients are also EBV seropositive. In contrast to control groups, recent EBV infections have never been observed in children or adults with MS. Further prospective studies indicate a 2.8 times higher tendency for development of MS after infectious mononucleosis. In MS patients, unbiased analyses pull out EBV antigens as high-affinity targets for the antibodies in the oligoclonal bands. Humans are the exclusive natural host for EBV, a finding that may explain why MS is unique to humans. Together these unique observations strongly suggest a linkage between MS and EBV infection. Infection by EBV offers numerable mechanisms to perturb the immune system, including mimicry and superantigen induction, which may potentially participate in the disease mechanisms. In contrast, studies demonstrating higher IgG titres and occurrence of viral DNA in serum/plasma are likely to reflect a consequence of the disease. An explanation for a potential role of respiratory diseases in MS is discussed. It is concluded that the ultimate test to the hypothesis of MS and EBV is the development and application of an EBV vaccine, which is predicted to eradicate the disease.

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Section: Controlled Trials Of Antiviral Chemotherapymentioning

confidence: 96%

Multiple sclerosis is linked to Epstein‐Barr virus infection

Haahr

Höllsberg

2006

Reviews in Medical Virology

111

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“…Following oral administration, valacyclovir is rapidly and nearly completely hydrolyzed to acyclovir by first-pass intestinal and hepatic metabolism (13,27). Acyclovir crosses the blood-brain barrier, a desirable quality for the treatment of herpes encephalitis, neonatal herpes simplex virus infections, and, possibly, multiple sclerosis (7,28). Acute, reversible neuropsychiatric symptoms were first associated with acyclovir therapy in the early 1980s (26), and similar adverse effects have been reported for the use of valacyclovir (1,2,10,12,15,21,24).…”

mentioning

confidence: 95%

Pharmacokinetics of Acyclovir and Its Metabolites in Cerebrospinal Fluid and Systemic Circulation after Administration of High-Dose Valacyclovir in Subjects with Normal and Impaired Renal Function

Smith¹,

Weller

Johnson³

et al. 2010

Antimicrob Agents Chemother

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Valacyclovir, the L-valyl ester prodrug of acyclovir (ACV), is widely prescribed to treat infections caused by varicella-zoster virus or herpes simplex virus. Rarely, treatment is complicated by reversible neuropsychiatric symptoms. By mechanisms not fully understood, this occurs more frequently in the setting of renal impairment. We characterized the steady-state pharmacokinetics of ACV and its metabolites 9-[(carboxymethoxy)methyl]-guanine (CMMG) and 8-hydroxy-acyclovir (8-OH-ACV) in cerebrospinal fluid (CSF) and the systemic circulation. We administered multiple doses of high-dose valacyclovir to 6 subjects with normal renal function and 3 subjects with chronic renal impairment (creatinine clearance [CrCl], ϳ15 to 30 ml/min). Dosages were 2,000 mg every 6 h and 1,500 mg every 12 h, respectively. Indwelling intrathecal catheters allowed serial CSF sampling throughout the dosing interval. The average steady-state concentrations of acyclovir, CMMG, and 8-OH-ACV were greater in both the systemic circulation and the CSF among subjects with impaired renal function than among subjects with normal renal function. However, the CSF penetration of each analyte, reflected by the CSF-to-plasma area under the concentration-time curve over the 6-or 12-h dosing interval (AUC ) ratio, did not differ based on renal function. Renal impairment does not alter the propensity for ACV or its metabolites to distribute to the CSF, but the higher concentrations in the systemic circulation, as a result of reduced elimination, are associated with proportionally higher concentrations in CSF.Valacyclovir, the L-valyl ester of the antiviral drug acyclovir (ACV), is widely prescribed for varicella-zoster virus and herpes simplex virus infections. Following oral administration, valacyclovir is rapidly and nearly completely hydrolyzed to acyclovir by first-pass intestinal and hepatic metabolism (13,27). Acyclovir crosses the blood-brain barrier, a desirable quality for the treatment of herpes encephalitis, neonatal herpes simplex virus infections, and, possibly, multiple sclerosis (7, 28). Acute, reversible neuropsychiatric symptoms were first associated with acyclovir therapy in the early 1980s (26), and similar adverse effects have been reported for the use of valacyclovir (1, 2, 10, 12, 15, 21, 24). Symptoms include ataxia, involuntary movements, dysarthria, disturbed consciousness, hyperreflexia, and deranged cerebral functions (hallucinations, confusion, and lethargy). Neuropsychiatric symptoms with valacyclovir are infrequent, but the risk increases with acute or chronic renal dysfunction, concomitant neurotoxic drugs, and advanced age (5, 11). The underlying mechanism for these side effects is unknown, and attempts to relate central nervous system (CNS) symptoms and systemic concentrations of acyclovir have been inconsistent (3,5,6,9), suggesting that a metabolite of acyclovir may be responsible or contributory (11).The major route of acyclovir elimination is the renal excretion of unchanged drug. Urinary recovery data after acyclovir a...

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“…24 Raltegravir had no effect on inflammatory biomarkers and presence of CD 163, a marker of monocytes and macrophages. Three phase II clinical trials of acyclovir or its prodrug valacyclovir have been conducted in patients with MS. [8][9][10] Although they did not meet primary end points, there was a strong trend in the data, with a 34% reduction in ARR in acyclovir-treated patients, and subgroup analysis showed a significant reduction in relapse rate in favour of acyclovir treatment. 10 Moreover, in a predefined subgroup analysis, valacyclovir-treated patients with high disease activity at baseline had significant reduction in new lesions compared to a comparable group of placebo-treated patients.…”

Section: Antiviral Treatment Of Human Endogenous Retrovirus Infectimentioning

confidence: 99%

“…[8][9][10] All were conducted 20-30 years ago, before the era when disease-modifying immunomodulatory therapies were established in RRMS. No magnetic resonance imaging (MRI) was included in this study.…”

Section: Antiherpes Virus Treatment Of Msmentioning

confidence: 99%

Trials of antivirals in the treatment of multiple sclerosis

Lycke

2017

Acta Neurol Scand

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There is increasing evidence that human herpes viruses and human endogenous retroviruses (HERV) are involved in the aetiology and pathogenesis of multiple sclerosis (MS). In order to acquire the ultimate evidence to confirm such a relationship, it is probably required to use specific antiviral drugs in clinical trials of MS. The results of published antiviral clinical trials in patients with MS are summarized in this review.None of them showed statistically significant effects on primary outcomes of disease activity or on disability development. However, given their small sample sizes, the of anti-CD 20 in RRMS is considered to be immunomodulatory, the possibility that the effect could be partly due to EBV suppression has not been eliminated. | ANTIHERPES VIRUS TREATMENT OF MSThere are three published randomized and placebo-controlled phase 2 clinical trials (RCT) of antiherpes treatment in patients with MS. One that investigates acyclovir and two that investigate

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A randomized clinical trial of valacyclovir in multiple sclerosis

Abstract: Although not statistically significant, positive trends were detected for acyclovir by clinical measures, but not by MRI.

Cited by 66 publications

References 24 publications

Multiple sclerosis is linked to Epstein‐Barr virus infection

Multiple sclerosis is linked to Epstein‐Barr virus infection

Pharmacokinetics of Acyclovir and Its Metabolites in Cerebrospinal Fluid and Systemic Circulation after Administration of High-Dose Valacyclovir in Subjects with Normal and Impaired Renal Function

Trials of antivirals in the treatment of multiple sclerosis

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