acyclovir and Multiple-Sclerosis

Controlled trials suggest that acyclovir/valacyclovir can provide significant clinical benefits when used for prophylaxis in the immunocompromised host. These findings implicate herpesvirus(es) in the pathogenesis of complex medical conditions, including graft rejection and death. However, it is not known which of the 8 herpesviruses are important under particular circumstances. Prime candidates for triggering adverse outcomes are cytomegalovirus (CMV) in solid organ transplant recipients (causing rejection), CMV and human herpesvirus type 6 (HHV-6) in bone marrow transplant patients (causing marrow suppression), and herpes simplex virus, HHV-6, and CMV in AIDS patients (accelerating the rate of human immunodeficiency virus disease progression and death). Other diseases that may have a herpesvirus component or trigger susceptible antiviral agents include atherosclerosis and multiple sclerosis. In the future, clinicians should be alert to novel findings of randomized trials that may provide insight into the pathogenesis of these diseases and the contributions made by clinically silent herpesvirus infections.

Topics: Acquired Immunodeficiency Syndrome; Acyclovir; Antiviral Agents; Arteriosclerosis; Bone Marrow Transplantation; Clinical Trials as Topic; Disease Progression; Herpesviridae; Herpesviridae Infections; Humans; Multiple Sclerosis; Organ Transplantation; Postoperative Complications; Valacyclovir; Valine

In multiple sclerosis (MS), the extensive and long lasting search for viruses or other pathogens has hitherto failed to identify a common etiological agent. However, the beneficial effects by interferon-beta treatment in MS, although suggested to depend mainly on immunomodulation, might lend support to a viral involvement in the pathogenesis. The human herpesviruses have attracted interest since their recurrent modes of infection share some similarity with the relapsing-remitting course of MS, most members are readily detected within the brain, and several of these viruses may induce demyelination within the central nervous system in human hosts as well as in animal models. Accumulated diagnostic and epidemiological data are compatible with a role for the herpesviruses as possible cofactors rather than etiological agents, and recent studies showing early neuronal damage in MS patients focus attention on the neurotropic alpha-herpesviruses. Antiviral treatment trials with safe and effective drugs such as valaciclovir offer a possibility of testing the hypotheses concerning herpesviral involvement in MS.

Topics: Acyclovir; Animals; Antiviral Agents; Herpesviridae; Herpesviridae Infections; Humans; Multiple Sclerosis; Valacyclovir; Valine

To assess the presence of Epstein-Barr virus (EBV) and human herpesvirus 6B (HHV-6B) DNA in saliva and plasma from multiple sclerosis (MS) patients enrolled in a randomized, double-blind, placebo-controlled valacyclovir treatment study.. DNA was prepared following ultracentrifugation of saliva and plasma. EBV and HHV-6B DNAs were determined by real-time polymerase chain reaction.. EBV and HHV-6B DNAs were detected in 41% and 65% of saliva samples, respectively. In patients treated with valacyclovir, the percentage of saliva samples with EBV was significantly reduced (9%; P = 0.000017), whereas the frequency of HHV-6B positive samples was unchanged (57%; P = 0.38). Longitudinal studies demonstrated a time-dependent reduction in the frequency of saliva samples containing EBV following valacyclovir treatment. In contrast, plasma contained EBV and HHV-6B DNAs in 17% and 25% of the samples, respectively, and these numbers were not significantly reduced following valacylovir treatment (13% and 16%, respectively), nor were they different from those of healthy controls (6% and 39%, respectively). Patients with high disease activity had a significantly higher frequency of EBV (P = 0.018) and HHV-6B (P = 0.023) positive samples than did patients with low disease activity. The presence of EBV and HHV-6B was strongly correlated in plasma (P < 0.00000001), but not in saliva (P = 0.41).. MS patients express EBV and HHV-6B in both saliva and plasma, but only the expression of EBV in saliva is significantly reduced following valacyclovir treatment. Although EBV and HHV-6B DNAs can be detected in plasma from healthy individuals, the co-expression of both these viruses in MS patients is highly significant and further associated with clinical activity. The observations of viral DNA in plasma are consistent with an underlying immunologic defect in MS.

Topics: Acyclovir; Adult; Antiviral Agents; Disease Progression; DNA, Viral; Double-Blind Method; Female; Herpesvirus 4, Human; Herpesvirus 6, Human; Humans; Male; Multiple Sclerosis; Saliva; Statistics as Topic; Treatment Outcome; Valacyclovir; Valine; Viral Load

The possible involvement of herpesviruses in the pathogenesis of multiple sclerosis (MS) was recently investigated in a clinical trial of valacyclovir in patients with MS. As an important part of that survey we performed an independent pharmacokinetic study in order to determine the concentration of acyclovir in cerebrospinal fluid (CSF). The concentrations of acyclovir in serum and CSF were measured at steady state after 6 days of oral treatment with 1,000 mg of valacyclovir three times a day. Samples were obtained from 10 patients with MS. All patients had normal renal function, and none had signs of a damaged blood-CSF barrier. The maximum concentration of acyclovir in serum was reached after 1 to 3 h (mean +/- standard deviation [SD], 27.1 +/- 5.6 micro M), and the minimum concentration in serum was 3.1 +/- 1.1 micro M (mean +/- SD). The acyclovir concentrations in CSF at 2 and 8 h were essentially stable, with the mean +/- SD levels being 2.5 +/- 0.9 and 2.3 +/- 0.7 micro M, respectively. Similar levels were recorded in serum and CSF samples from five other MS patients after 6 months of oral treatment with valacyclovir at identical dosages. The area under the concentration-time curve (AUC) for acyclovir in CSF to the AUC for acyclovir in serum (CSF/serum AUC ratio) was approximately 20%. We conclude that the improved bioavailability previously reported for valacyclovir in plasma results in higher concentrations in CSF, while the CSF/serum AUC ratio remains constant.

Topics: Acyclovir; Adult; Antiviral Agents; Area Under Curve; Biological Availability; Female; Half-Life; Herpesviridae Infections; Humans; Male; Middle Aged; Multiple Sclerosis; Nonlinear Dynamics; Valacyclovir; Valine

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.

Topics: Acyclovir; Administration, Oral; Adolescent; Adult; Antibodies, Viral; Antiviral Agents; Double-Blind Method; Female; Herpesviridae; Humans; Male; Middle Aged; Multiple Sclerosis; Placebos; Recurrence; Remission Induction; Tablets

Glial fibrillary acidic protein (GFAp) was analysed in cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) and healthy controls. Patients with relapsing-remitting course (n = 13) were followed with quantitative neurological examinations and lumbar punctures during a 24-month period. The patient group was a subsample from a randomised, double-blind clinical trial of acyclovir on MS: 7 patients were treated with acyclovir and 6 were placebo controls. CSF was also collected from 5 age-matched healthy individuals with normal quantitative neurological examinations. The CSF assays disclosed increased concentrations of GFAp in MS patients compared to controls (p < 0.01). Furthermore, the GFAp levels correlated significantly with the deficit score (p < 0.01) but not with exacerbation frequency. When the group treated with acyclovir was compared with the placebo group, no significant change of CSF GFAp was observed. In the present study we show that GFAp is increased in CSF of patients with MS and that the levels correlate with the neurological dysfunction. Further work is needed to ascertain whether determinations of CSF GFAp can be used to monitor disease progression in MS or whether the assay may be useful to evaluate therapeutic intervention.

Topics: Acyclovir; Adult; Antiviral Agents; Double-Blind Method; Glial Fibrillary Acidic Protein; Herpesviridae Infections; Humans; Multiple Sclerosis; Nervous System Diseases; Spinal Puncture

A long-term clinical trial of acyclovir, 800 mg tid, as a therapeutic agent in multiple sclerosis (MS) is in progress. In three patients paired serum and cerebrospinal fluid (CSF) specimens were sampled after one, four, eight and twelve months of continuous treatment. These samples were collected 1.5 h before or 1.5 h after an oral dose. Acyclovir concentrations were assessed by radioimmunoassay. In the CSF, the acyclovir concentration was relatively stable, with a mean of 0.83 microM, while the serum acyclovir concentration was variable with mean peak and trough concentrations of 4.08 and 2.47 microM, respectively. In two other MS patients the acyclovir concentration time profile in serum and CSF was studied at steady state during the 8 h dose interval. In this study the acyclovir concentration in the CSF was only slightly affected by the fluctuations in serum and the acyclovir CSF/acyclovir serum ratio was apparently not influenced by the blood-brain barrier function. We found no indication of an accumulation of acyclovir in cerebrospinal fluid after one to twelve months of oral treatment.

Topics: Acyclovir; Adolescent; Adult; Double-Blind Method; Female; Humans; Male; Multiple Sclerosis; Serum Albumin

This paper investigates the semiparametric statistical methods for recurrent events. The mean number of the recurrent events are modeled with the generalized semiparametric varying-coefficient model that can flexibly model three types of covariate effects: time-constant effects, time-varying effects, and covariate-varying effects. We assume that the time-varying effects are unspecified functions of time and the covariate-varying effects are parametric functions of an exposure variable specified up to a finite number of unknown parameters. Different link functions can be selected to provide a rich family of models for recurrent events data. The profile estimation methods are developed for the parametric and nonparametric components. The asymptotic properties are established. We also develop some hypothesis testing procedures to test validity of the parametric forms of covariate-varying effects. The simulation study shows that both estimation and hypothesis testing procedures perform well. The proposed method is applied to analyze a data set from an acyclovir study and investigate whether acyclovir treatment reduces the mean relapse recurrences.

Topics: Acyclovir; Data Interpretation, Statistical; Drug Substitution; Humans; Models, Statistical; Multiple Sclerosis; Randomized Controlled Trials as Topic; Recurrence; Regression Analysis; Research Design; Statistics as Topic; Time Factors; Treatment Outcome

Topics: Acyclovir; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fingolimod Hydrochloride; Follow-Up Studies; Herpes Zoster; Humans; Immunosuppressive Agents; Middle Aged; Multiple Sclerosis; Recurrence; Risk Assessment; Treatment Outcome; Valacyclovir; Valine

To highlight diagnostic and management features of auditory neuropathy/auditory dyssynchrony (AN/DS) due to central demyelinating disorder.. A child with AN/DS due to central nervous system pathologic findings.. Audiometry, auditory brainstem response (ABR) test, otoacoustic emission test, magnetic resonance imaging (MRI) with gadolinium contrast, intravenous corticosteroid treatment, antiviral treatment, stereotactic biopsy, and cyclophosphamide immunomodulation.. Pure-tone audiometry, speech discrimination testing, ABR, and MRI.. A 12-year-old girl presented with acute sensorineural hearing loss, abnormal ABR, and normal otoacoustic emissions consistent with AN/DS. The hearing loss demonstrated fluctuation and corticosteroid responsiveness. Magnetic resonance imaging and stereotactic biopsy revealed brainstem demyelination consistent with multiple sclerosis. Definitive treatment consisted of cyclophosphamide immunomodulation.. Although recent focus on pathophysiology of AN/DS has shifted from auditory nerve abnormalities to dyssynchrony within the cochlea, cases associated with fluctuating sensorineural hearing loss and responsiveness to corticosteroid therapy should raise the suspicion of central nervous system pathologic findings. Therefore, it is crucial to obtain brain MRI with contrast enhancement in all patients with AN/DS. This is critical in patients undergoing cochlear implantation because MRI may be contraindicated postoperatively.

Topics: Acyclovir; Adrenal Cortex Hormones; Antiviral Agents; Audiology; Audiometry, Pure-Tone; Central Nervous System Diseases; Child; Cochlear Nerve; Cyclophosphamide; Evoked Potentials, Auditory, Brain Stem; Female; Gadolinium; Hearing Loss, Unilateral; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Multiple Sclerosis; Myelin Sheath; Speech Discrimination Tests; Vestibulocochlear Nerve Diseases

To report two cases of progressive outer retinal necrosis occurring in immunocompetent individuals after treatment with corticosteroids for presumed optic neuropathy.. Observational case report.. University-based tertiary eye hospital.. Retrospective review of existing clinical records.. Two patients were treated empirically with systemic corticosteroids for suspected inflammatory papillopathy. Subsequently, both were diagnosed with necrotizing herpetic retinitis with features of progressive outer retinal necrosis. Anterior chamber paracentesis confirmed varicella-zoster infection. Both patients were human immunodeficiency virus negative; one patient with rheumatoid arthritis was taking etanercept. Both became completely blind in one eye despite intensive treatment with antiviral medication intravenously and intravitreally.. Progressive outer retinal necrosis is not confined to patients with underlying severe immunodeficiency, such as acquired immune deficiency syndrome. Initial treatment of acute, unexplained vision loss with systemic corticosteroids may lead to catastrophic visual loss in patients with evolving necrotizing herpetic retinopathy.

Topics: Acyclovir; Aged; Antiviral Agents; Aqueous Humor; Blindness; DNA, Viral; Drug Therapy, Combination; Female; Foscarnet; Ganciclovir; Glucocorticoids; Herpes Zoster Ophthalmicus; Herpesvirus 3, Human; Humans; Immunocompromised Host; Middle Aged; Multiple Sclerosis; Optic Neuritis; Polymerase Chain Reaction; Prednisone; Pupil Disorders; Retinal Necrosis Syndrome, Acute; Retrospective Studies

Inoue-Melnick virus (IMV) was isolated from the cerebrospinal fluid of patients with chronic neurologic disorders. The effect of acyclovir (ACV), 9-(2-hydroxyethoxymethyl)-guanine, on the growth of IMV was studied in human diploid cell cultures. ACV markedly inhibited the multiplication of all three IMV serotypes in vitro with the same inhibitory effect. By passage of IMV in the presence of ACV in the medium, ACV-resistant mutants of three IMV serotypes were easily isolated.

Topics: Acyclovir; Cell Line; Humans; Multiple Sclerosis; Myelitis; Optic Neuritis; Serotyping; Syndrome; Viruses