Acyclovir treatment of relapsing-remitting multiple sclerosis

Abstract

Acyclovir treatment was used in a randomized, double-blind, placebo-controlled clinical trial with parallel groups to test the hypothesis that herpes virus infections are involved in the pathogenesis of multiple sclerosis (MS). Sixty patients with the relapsing-remitting form of MS were randomized to either oral treatment with 800 mg acyclovir or placebo tablets three times daily for 2 years. The clinical effect was investigated by an extensive test battery consisting of neurological examinations, neuro-ophthalmological and neuropsychological tests, and evoked potentials. Results were based on "intent-to-treat" data and the primary outcome measure was the exacerbation rate. In the acyclovir group (n = 30), 62 exacerbations were recorded during the treatment period, yielding an annual exacerbation rate of 1.03. The placebo group (n = 30) had 94 exacerbations and an annual exacerbation rate of 1.57. Thus, 34% fewer exacerbations were encountered during acyclovir treatment. This difference in exacerbation rate between the treatment groups was not significant (P = 0.083). However, this trend to a lower disease activity in acyclovir-treated patients was supported in subsequent data analysis. If the patients were grouped according to exacerbation frequencies, i.e. into low (0-2), medium (3-5) and high (6-8) rate groups, the difference between acyclovir and placebo treatment was significant (P = 0.017). Moreover, in a subgroup of the population with a duration of the disease of at least 2 years providing an exacerbation rate base-line before entry, individual differences in exacerbation rates were compared between the 2-year pre-study period and the study period in acyclovir-treated (n = 19) and placebo (n = 20) patients and acyclovir-treated patients showed a significant reduction of exacerbations (P = 0.024). Otherwise, neurological parameters were essentially unaffected by acyclovir treatment and there were no convincing signs of reduced neurological deterioration in the acyclovir group. This study indicates that acyclovir treatment might inhibit the triggering of MS exacerbations and thus suggests that acyclovir-susceptible viruses might be involved in the pathogenesis of MS. This possibility warrants further investigation.

Increased CD8+ T Cell Response to Epstein-Barr Virus Lytic Antigens in the Active Phase of Multiple Sclerosis

“…The present results do not answer the question of whether EBV dysregulation is consequence or cause of MS but disclose a link between EBV reactivation, antiviral immune response and disease activity during the relapsing-remitting stage of MS. Such a scenario is consistent with the results of randomized, double-blind, placebo-controlled clinical and MRI studies of anti-herpesvirus therapy in relapsing-remitting MS showing that anti-herpesvirus drugs inhibiting viral replication have beneficial effects in subgroups of patients with higher exacerbation rates and more severe disease activity [59], [60]. Further work is needed to better understand whether and how an altered balance between EBV and the host immune system contributes to MS onset and verify the potential benefits of new antiviral drugs in controlling MS [61].…”

The initiation and prevention of multiple sclerosis

“…viral replication, but have limited effects on latent EBV infection, and trials in MS have been inconclusive. 36, 73, 74 Thus at this time the only practical implications may be diagnostic – EBV negativity or low anti-EBNA titers in an individual with CIS would suggest a diagnosis other than MS. 70 …”

Estimating time-varying effects for overdispersed recurrent events data with treatment switching

“…Hence antiviral drugs may be able to reduce the relapse rate in multiple sclerosis patients. The first and largest study to investigate the effect of an antiviral drug, acyclovir, has been reported in Lycke et al (1996). The acyclovir study was a randomized, placebo-controlled, double-blind clinical trial, where 60 multiple sclerosis patients were randomly assigned to acyclovir and placebo, and then followed for two years.…”

“…Similar in spirit are multiple sclerosis clinical trials where information on patient relapses before randomization is available. For example in the randomized placebo-controlled trial described in Lycke et al (1996), relapses that occurred in the two years preceding randomization were recorded. Such settings can also be seen to correspond to a switch of treatment, where before randomization, patients receive standard treatment, and after randomization, some patients are switched to the experimental treatment.…”