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Efficacy of oral antiviral prophylaxis in preventing ocular herpes simplex virus recurrences in patients with and without self-reported atopy.

PURPOSE: To compare the efficacy of oral antiviral prophylactic treatment for herpes simplex virus (HSV) recurrences in patients with and without self-reported atopy. DESIGN: Retrospective cohort comparative study. METHODS: setting: Cornea Service, Wills Eye Hospital. study population: Patients who presented with previously diagnosed ocular HSV between March 2003 and March 2004. From 244 patients invited, 54 patients (58 eyes) were included. One hundred and ninety patients were excluded according to exclusion criteria: no active episode during follow-up, immunosuppression, less than one year of follow-up, or previous history of penetrating keratoplasty. The Questionnaire regarding history of atopic disease, considers: presence of allergic rhinitis, asthma or atopic dermatitis, and chart review of ocular history. main outcome measures: Incidence of all types of HSV recurrences with and without antiviral prophylaxis within each group and between groups. HSV episodes were classified into infectious, inflammatory, and mixed for analysis. RESULTS: Atopic/nonatopic (P value): mean follow-up without prophylaxis 8.1 (+/- 8.2)/7.3 years (+/- 8.6) (P = .71); mean follow-up with prophylaxis 2.9 (+/- 2.3)/2.6 years (+/- 2.2) (P = .51); the effect of prophylaxis significantly reduced the all recurrences in both groups except in the inflammatory recurrences in the atopic group and in the mixed recurrences in both groups. Prophylaxis decreased infectious episodes by 44% in nonatopic and 76% in atopics and decreased inflammatory manifestations by 69% in the nonatopic group and 8% in the atopic group. CONCLUSION: Antiviral prophylaxis for HSV recurrences was more effective in reducing infections in atopics and less effective in reducing inflammatory episodes in atopics versus nonatopics.

2-Aminopurine↗

HSV shedding.

Viral shedding of HSV occurs frequently in infected individuals. HSV is shed asymptomatically from multiple anatomical sites and shedding, like exposure, is a significant risk for transmission. However, the relationship between shedding frequency, viral titer and transmission is unknown. HSV-2 shedding is affected by the site and time since acquisition of infection. The advent of sensitive PCR techniques has shown that the magnitude and frequency of viral shedding is higher than shown previously with viral culture techniques. It has also clearly demonstrated that suppressive (daily) antiviral therapy reduces clinical and subclinical reactivation rates, and has been successfully used in the prevention of recurrent oral and genital HSV infections. A recent study has demonstrated that daily antiviral therapy with valaciclovir can significantly reduce transmission of HSV-2 between discordant heterosexual couples in monogamous relationships.

Acyclovir↗

HSV-2 transmission.

A number of important risk factors for the acquisition of HSV-2 have been established including female gender, black or Hispanic ethnic origin, HIV infection, age, and increased number of sexual partners. Transmission is influenced by a number of biological factors such as sexual behavior, use of condoms, duration of relationships, and knowledge of a partner's serologic status. Vertical transmission (transmission of HSV from mother to neonate) is potentially life-threatening; neonatal HSV infection is associated with significant morbidity and mortality. The valaciclovir transmission study provides evidence that an antiviral agent can interrupt the transmission of a viral sexually transmitted disease between serologically discordant sexual partners. This review explores the importance of the cofactors that affect transmission, and makes recommendations on considerations for the prophylactic use of antiviral agents for the prevention of transmission in other patient populations.

Acyclovir↗

Phase I-II trial evaluating combined intensity-modulated radiotherapy and in situ gene therapy with or without hormonal therapy in treatment of prostate cancer-interim report on PSA response and biopsy data.

PURPOSE: There is an evolving role for combining radiotherapy (RT) with gene therapy in the management of prostate cancer. However, the clinical results of this combined approach are much needed. The preliminary results addressing the safety of this Phase I-II study combining RT and gene therapy (adenovirus/herpes simplex virus-thymidine kinase gene/valacyclovir with or without hormonal therapy) in the treatment of prostate cancer have been previously reported. We now report the prostate-specific antigen (PSA) response and biopsy data. METHODS AND MATERIALS: This trial was composed of three separate arms. Arm A consisted of low-risk patients (Stage T1-T2a, Gleason score <7, pretreatment PSA <10 ng/mL) treated with combined RT-gene therapy. A mean dose of 76 Gy was delivered to the prostate with intensity-modulated RT. They also received adenovirus/herpes simplex virus-thymidine kinase/valacyclovir gene therapy. Arm B consisted of high-risk patients (Stage T2b-T3, Gleason score >6, pretreatment PSA level >10 ng/mL) treated with combined RT-gene therapy and hormonal therapy (luteinizing hormone-releasing hormone agonist [30-mg Lupron, 4-month depot] and an antiandrogen [flutamide, 250 mg t.i.d. for 14 days]). Arm C consisted of patients with Stage D1 (positive pelvic lymph nodes) who received the same regimen as Arm B with the addition of 45 Gy to the pelvic lymphatics. PSA determination and biopsy were performed before, during, and after treatment. The American Society for Therapeutic Radiology and Oncology consensus definition (three consecutive rises in PSA level) was used to denote PSA failure. RESULTS: Fifty-nine patients (29 in Arm A, 26 in Arm B, and 4 in Arm C) completed the trial. The median age was 68 years (range, 39-85 years). The median follow-up for the entire group was 13.5 months (range, 1.4-27.8 months). Only Arm A patients were observed to have an increase in PSA on Day 14. The PSA then declined appropriately. All patients in Arm A (median follow-up, 13.4 months) and Arm B (median follow-up, 13.9 months) had biochemical control at last follow-up. Three patients in Arm C (with pretreatment PSA of 335, 19.6, and 2.5 ng/mL and a combined Gleason score of 8, 9, and 9 involving all biopsy cores) had biochemical failure at 3, 3, and 7.7 months. Two patients had distant failure in bone and 1 patient in the para-aortic lymph nodes outside the RT portal. Six to twelve prostate biopsies performed in these 3 patients revealed no evidence of residual carcinoma. In Arm A, biopsy showed no evidence of carcinoma in 66.7% (18 of 27), 92.3% (24 of 26), 91.7% (11 of 12), 100% (8 of 8), and 100% (6 of 6) at 6 weeks, 4 months, 12 months, 18 months, and 24 months after treatment, respectively. In Arm B, no evidence of carcinoma on biopsy was noted in 96% (24 of 25), 90.5% (19 of 21), 100% (14 of 14), 100% (7 of 7), and 100% (2 of 2), respectively, in the same interval after treatment. CONCLUSION: This is the first reported trial of its kind in the field of prostate cancer that aims to expand the therapeutic index of RT by combining it with in situ gene therapy. The initial transient PSA rise in the Arm A patients may have been a result of local immunologic response or inflammation elicited by in situ gene therapy. Additional investigation to elucidate the mechanisms is needed. Hormonal therapy may have obliterated this rise in Arm B and C patients. The biopsy data were encouraging and appeared to show no evidence of malignancy earlier than historical data. Combined RT, short-course hormonal therapy, and in situ therapy appeared to provide good locoregional control but inadequate systemic control in patients with positive pelvic lymph nodes. Longer term use of hormonal therapy in addition to gene therapy and RT has been adopted for this group of patients to maximize both locoregional and systemic control.

Acyclovir↗

Conjugal transfer vaccinia.

Two cases of conjugal contact transfer vaccinia are described. Each patient had intimate contact after their respective partners, active-duty military personnel, received the smallpox vaccination.

Acyclovir↗

Syntheses, chemical and enzymatic stability of new poly(ethylene glycol)-acyclovir prodrugs.

Two known antiherpetic agents, acyclovir and valaciclovir, were coupled with activated poly(ethylene glycol). In vitro drug release studies demonstrated the conjugates to be stable in buffer solutions at pH 7.4 and 5.5, while only PEG-valacyclovir2 was stable in a buffer solution at pH 1.2. The ability of the macromolecular conjugate to release the free drug was also evaluated in plasma, in which the most stable prodrug also proved to be PEG-valacyclovir2. The derivatives are degraded in the presence of proteolytic enzyme. The rate of hydrolysis was monitored by HPLC-analysis.

Acyclovir↗

[Complete ophthalmoplegia complicating ophthalmic herpes zoster].

We report a case of a 73-year-old patient with complete ophthalmoplegia following an episode of ophthalmic herpes zoster. MRI showed an associated ipsilateral temporal meningioma with cavernous sinus extension. We discuss the possible responsibility of these two conditions in the ocular motor signs.

Acyclovir↗

Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials.

BACKGROUND: Antiviral prophylaxis is commonly used in recipients of solid-organ transplants with the aim of preventing the clinical syndrome associated with cytomegalovirus infection. We undertook a systematic review to investigate whether this approach affects risks of cytomegalovirus disease and death. METHODS: Randomised controlled trials of prophylaxis with antiviral medications for cytomegalovirus disease in solid-organ-transplant recipients were identified. Data were combined in meta-analyses by a random-effects model. FINDINGS: Compared with placebo or no treatment, prophylaxis with aciclovir, ganciclovir, or valaciclovir significantly reduced the risks of cytomegalovirus disease (19 trials, 1981 patients; relative risk 0.42 [95% CI 0.34-0.52]), cytomegalovirus infection (17 trials, 1786 patients; 0.61 [0.48-0.77]), and all-cause mortality (17 trials, 1838 patients; 0.63 [0.43-0.92]), mainly owing to lower mortality from cytomegalovirus disease (seven trials, 1300 patients; 0.26 [0.08-0.78]). Prophylaxis also lowered the risks of disease caused by herpes simplex or zoster virus, bacterial infections, and protozoal infections, but not fungal infection, acute rejection, or graft loss. Meta-regression showed no significant difference in the risk of cytomegalovirus disease or all-cause mortality by organ transplanted or cytomegalovirus serostatus; no conclusions were possible for cytomegalovirus-negative recipients of negative organs. In trials of direct comparisons, ganciclovir was more effective than aciclovir in preventing cytomegalovirus disease. Valganciclovir and intravenous ganciclovir were as effective as oral ganciclovir. INTERPRETATION: Prophylaxis with antiviral medications reduces the risk of cytomegalovirus disease and associated mortality in recipients of solid-organ transplants. This approach should be used routinely in cytomegalovirus-positive recipients and in cytomegalovirus-negative recipients of organs positive for the virus.

Acyclovir↗

Comparison of the efficacy and safety of valaciclovir and acyclovir for the treatment of herpes zoster ophthalmicus.

OBJECTIVE: To compare the efficacy and safety of valaciclovir and acyclovir in immunocompetent patients with herpes zoster ophthalmicus. DESIGN: A multicenter, randomized, double-masked study. PARTICIPANTS: One hundred ten immunocompetent patients with herpes zoster ophthalmicus diagnosed within 72 hours of skin eruption were treated; 56 were allocated to the valaciclovir group and 54 to the acyclovir group. METHODS: Patients randomized to the valaciclovir group received two 500-mg tablets of valaciclovir three times daily and one tablet of placebo twice daily. Patients in the acyclovir group received one 800-mg tablet of acyclovir five times daily and one tablet of placebo three times daily for 7 days. MAIN OUTCOME MEASURES: Main outcome measures included the frequency, severity, and duration of ocular complications, patient reports of zoster-associated pain, and the outcome of skin lesions. Tolerance was also assessed on the incidence and types of adverse effects and changes in laboratory parameters. The analysis was mainly descriptive and performed on an intent-to-treat basis. RESULTS: Ocular complications of herpes zoster ophthalmicus were similar in the valaciclovir and acyclovir treatment groups. The main complications were conjunctivitis (54% and 52%, respectively), superficial keratitis (39% and 48%, respectively for punctate keratitis; 11% in each group for dendritic keratitis), stromal keratitis (13% in each group), and uveitis (13% and 17%, respectively). The long-term outcomes of these ocular complications were favorable and similar in both treatment groups. Pain duration and severity and outcome of skin lesions were similar between groups. Most patients reported prodromal pain. After 1 month, 25% of patients in the valaciclovir group and 31% in the acyclovir group still reported pain. The percentage of patients experiencing postherpetic neuralgia decreased during follow-up. The tolerance to acyclovir and valaciclovir was comparable and considered good. The most frequent adverse events were vomiting and edema of the eyelids or face (3%-5%). Three serious adverse events not linked to the study drugs occurred. CONCLUSIONS: Valaciclovir is as effective as acyclovir in preventing ocular complications of herpes zoster ophthalmicus, including conjunctivitis, superficial and stromal keratitis, and pain. Tolerability of the two drugs is similar, but the dosing schedule of valaciclovir is simpler.

Acyclovir↗

Nonnecrotizing herpetic retinopathies masquerading as severe posterior uveitis.

OBJECTIVE: Aqueous humor analysis can be performed in severe atypical forms of posterior uveitis unresponsive to conventional treatment to exclude a viral infection. DESIGN: Noncomparative interventional case series. PARTICIPANTS: Thirty-seven immunocompetent patients seen with corticosteroid-resistant forms of posterior uveitis underwent extensive evaluation, including anterior chamber paracentesis, to rule out a nonnecrotizing viral retinopathy. INTERVENTION: Aqueous fluid samples were prospectively obtained. Polymerase chain reaction (PCR) and serologic evaluation of intraocular antibody production against herpesviruses were performed by molecular techniques and enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: Polymerase chain reaction and local antibody production for herpes simplex virus types 1 and 2, varicella-zoster virus, cytomegalovirus, and Epstein-Barr virus were determined on aqueous fluid samples. RESULTS: Viral infection was confirmed in 5 cases (13.5%). Clinical presentation included birdshot-like retinochoroidopathy, occlusive bilateral vasculitis, and cystoid macular edema. An antiviral regimen was initiated in all cases. Inflammation was stabilized, and steroid dosage could be significantly reduced. CONCLUSIONS: Identification of a viral agent during severe posterior uveitis can dramatically change therapeutic management.

Acyclovir↗

Temporal pattern of herpes simplex virus type 1 infection and cell death in the mouse brain stem: influence of guanosine nucleoside analogues.

Levels of bystander death occurring in herpes simplex virus type 1 (HSV-1)-infected mouse brain stems were studied, as well as the extent to which bystander death is influenced by guanosine nucleoside analogue treatment. Consecutive sections from brain stems of HSV-1-infected mice were stained alternately for (i) viral infection and (ii) cell death (TUNEL assay). Virus antigen was detectable in brain stems on day 3 of infection, while TUNEL staining was comparatively lower. An increase in the extent of TUNEL staining was observed on day 4 of infection. Despite this increase, however, the ratio of TUNEL-stained to infection marker-stained tissue still indicated that the amount of TUNEL staining remained lower than infection staining at this time point. On days 5 and 6 of infection, TUNEL staining continued to increase and the TUNEL/infection marker ratio switched on day 6 in favour of excess TUNEL staining, which was observed in and around the foci of infection, suggesting bystander death. The excess TUNEL staining on day 6 of infection was further increased on treatment with antivirals. The significance and implications of these results are discussed with respect to the nature and mechanism of action of the TUNEL assay, dynamics of primary HSV-1 infection, immunological influences and potential effects of antiviral treatment. The potential problems of the TUNEL assay are considered in the context of viral infection and the TUNEL assay, in combination with infection marker staining, may potentially provide a model system for quantitative analysis of true bystander death during HSV infection in vivo.

2-Aminopurine↗

Herpesviruses--a rationale for antiviral treatment in multiple sclerosis.

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.

Acyclovir↗

Herpesvirus resistance to antiviral drugs: a review of the mechanisms, clinical importance and therapeutic options.

During the past decade, potent agents against herpes simplex virus (HSV) types 1 and 2, varicella zoster virus (VZV), and cytomegalovirus (CMV) have become available. The increasing clinical use of acyclovir, ganciclovir, and foscarnet has been associated with the emergence of drug-resistant herpesvirus strains. Resistance to acyclovir or ganciclovir most frequently results from deficient intracellular phosphorylation of these agents which is required for drug activation. Resistance to foscarnet is due to viral DNA polymerase mutants that permit viral replication despite the presence of the drug. In immunocompetent patients, herpesvirus resistance is rare and generally does not correlate with clinical outcome. In contrast, in immunocompromised hosts, resistance of HSV, VZV, and CMV is increasingly detected, and may be associated with disease refractory to antiviral therapy. Foscarnet treatment has been used with some clinical benefit in patients with acyclovir-resistant HSV or VZV, or ganciclovir-resistant CMV. For therapy of resistant mucocutaneous HSV disease, topical trifluorothymidine, and topical or intravenous cidofovir (HPMPC) have yielded encouraging results that warrant further investigation. Improved methods for detection of herpesvirus resistance, and validation of alternative therapy for patients with documented resistance are required to reduce the clinical impact of drug-resistant herpesviruses.

2-Aminopurine↗