Combinations of Antiviral and Anti-Inflammatory Preparations for the Topical Treatment of Herpes Simplex Virus Assessed using a Murine Zosteriform Infection Model

Awan, AR; Harmenberg, Johan; Flink, Ola; Field, H. J.

doi:10.1177/095632029800900101

Cited by 16 publications

(17 citation statements)

References 24 publications

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“…A single-day valacyclovir regimen of 2 g (14,16,21). It is presumed, but not proven, that a strong antiviral effect hastens wound resolution by decreasing the extent of keratinocyte destruction, the viral antigen load, and the attendant inflammatory response, which impair reepithelization at the site of infection (1,9,11,22). One-day, two-dose oral valacyclovir constitutes a convenient treatment for herpes labialis in comparison to topical therapies, which typically require frequent applications for multiple days (13,15,19,20,23).…”

Section: Discussionmentioning

confidence: 99%

“…Overall in this study, acyclovir did not affect the duration of the episode, mean maximum lesion size, or the development of lesions, but a subset of early treated patients achieved a 36% mean reduction in pain (P ϭ 0.02) and a 27% mean reduction in time to lesion healing (P ϭ 0.03). Thus, oral acyclovir may provide some benefit, but it has not proven consistently effective.The difficulty in treating cold sore outbreaks has been attributed to the rapid development of lesions and a strong secondary immunological response that limits lesion duration in untreated patients (1,22). However, a window of opportunity for antiviral agents may exist when adequate concentrations are used and treatment is initiated during the time that viral replication dominates temporarily over the host immune response (2, 18).…”

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confidence: 99%

“…The difficulty in treating cold sore outbreaks has been attributed to the rapid development of lesions and a strong secondary immunological response that limits lesion duration in untreated patients (1,22). However, a window of opportunity for antiviral agents may exist when adequate concentrations are used and treatment is initiated during the time that viral replication dominates temporarily over the host immune response (2, 18).…”

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High-Dose, Short-Duration, Early Valacyclovir Therapy for Episodic Treatment of Cold Sores: Results of Two Randomized, Placebo-Controlled, Multicenter Studies

Spruance

Jones

Blatter

et al. 2003

Antimicrob Agents Chemother

102

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Oral valacyclovir is better absorbed than oral acyclovir, increasing acyclovir bioavailability three-to fivefold. This provides the opportunity to explore whether high systemic acyclovir concentrations are effective in the treatment of cold sores (herpes labialis). Two randomized, double-blind, placebo-controlled studies were conducted. Subjects were provided with 2 g of valacyclovir twice daily for 1 day (1-day treatment), 2 g of valacyclovir twice daily for 1 day and then 1 g of valacyclovir twice daily for 1 day (2-day treatment), or a matching placebo and instructed to initiate treatment upon the first symptoms of a cold sore. In study 1, the median duration of the episode (primary endpoint) was reduced by 1.0 day (P ‫؍‬ 0.001) with 1-day treatment and 0.5 days (P ‫؍‬ 0.009) with 2-day treatment compared to placebo. Similarly, the mean duration of the episode was statistically significantly reduced by 1.1 days with 1-day treatment and 0.7 days with 2-day treatment compared to placebo. The proportion of subjects in whom cold sore lesion development was prevented and/or blocked was increased by 6.4% (P ‫؍‬ 0.096) with 1-day treatment and 8.5% (P ‫؍‬ 0.061) with 2-day treatment compared to placebo. The time to lesion healing and time to cessation of pain and/or discomfort were statistically significantly reduced with valacyclovir compared to placebo. In study 2, results similar to those in study 1 were obtained. AEs were similar across treatment groups. These studies provide evidence supporting a simple, 1-day valacyclovir treatment regimen for cold sores that is safe and effective. The 1-day valacyclovir regimen offers patients a unique and convenient dosing alternative compared to available topical therapies.Herpes labialis, or cold sores, are caused by herpes simplex virus type 1 (HSV-1) and can result in significant irritation, pain, discomfort, and worry (18,25). The infection is most often acquired in childhood, but the incidence increases with age (2, 5, 12, 18). Up to 90% of persons over the age of 50, depending on race, sex, and country, would test seropositive for HSV-1, and an estimated 20 to 40% of adults experience cold sore outbreaks (5,12,18,25).Until now, most treatments have consisted of creams that must be applied to affected areas multiple times a day for several days (6,13,15,19,20,23). There have been two previous clinical trials of oral antiviral therapy for episodic treatment of herpes labialis. In a double-blind, placebo-controlled trial involving 210 subjects with recurrent cold sores, it appeared that less time was required for the loss of hard crust for subjects taking 200 mg of oral acyclovir 5 times daily for 5 days (14). This difference as well as other measures of clinical healing was not statistically significant. Spruance et al. evaluated a regimen of 400 mg of oral acyclovir 5 times daily for 5 days in comparison with placebo (21). Overall in this study, acyclovir did not affect the duration of the episode, mean maximum lesion size, or the development of lesions, but a subset o...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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High-Dose, Short-Duration, Early Valacyclovir Therapy for Episodic Treatment of Cold Sores: Results of Two Randomized, Placebo-Controlled, Multicenter Studies

Spruance

Jones

Blatter

et al. 2003

Antimicrob Agents Chemother

102

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“…Although the immune response is quicker and more effective in controlling recurrent disease, it also may be responsible for most of the clinical symptoms, which persist for up to a week after the virus can no longer be isolated (6,9). Thus, a combined modality of therapy aimed at both an antiviral effect and an immunomodulatory effect has been proposed in a number of studies (1,9).…”

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confidence: 99%

Double-Blind, Randomized, Placebo-Controlled Study of Topical 5% Acyclovir-1% Hydrocortisone Cream (ME-609) for Treatment of UV Radiation-Induced Herpes Labialis

Evans

Bernstein²,

Raborn

et al. 2002

Antimicrob Agents Chemother

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Immunopathology is recognized as an important component of infectious disease manifestations, and corticosteroids have been used as an adjunct to antimicrobial therapy for a variety of conditions. Antiviral therapy of herpes labialis has been shown to result in only a small reduction in the time to healing and the duration of pain. To determine if topical application of a combination product containing 5% acyclovir and 1% hydrocortisone (ME-609) could provide benefit to herpes labialis patients, 380 immunocompetent adults with a history of herpes labialis were exposed to experimental UV radiation (UVR) to induce a recurrence. On day 2, just before the appearance of the majority of lesions ("delayed" lesions), subjects were randomized to receive active medication or vehicle control six times per day for 5 days. Overall, 120 of 380 patients developed delayed classical lesions, of whom 50 of 190 (26%) had been treated with ME-609 and 70 of 190 (37%) had received placebo (a reduction of 29% [P ‫؍‬ 0.02]). Healing time, measured as the time to normal skin, was reduced by treatment with ME-609 (9.0 days for treated patients versus 10.1 days for the controls [P ‫؍‬ 0.04]). There was a trend toward a reduction in the maximum lesion size in the ME-609 recipients compared to that in the controls (43 versus 60 mm 2 , respectively [P ‫؍‬ 0.07]). The treatment had no effect on lesion pain, but ME-609 treatment reduced the number of patients with moderate or severe tenderness. Compared to treatment with a placebo, treatment with the combination antiviral-immunomodulatory cream provided benefit to patients with experimental UVR-induced herpes labialis, reducing classical lesion incidence, healing time, lesion size, and lesion tenderness. ME-609 is a novel product that merits further evaluation as a treatment for cold sores.Treatment of herpes simplex virus (HSV) infections with antiviral drugs has been a major challenge for investigators for more than 30 years. The benefits of treatment of recurrent HSV infection have been modest in contrast to the benefits of treatment of primary infection. The main clinical benefit in the treatment of recurrences has been the modest reduction in lesion healing time of approximately 10 to 15% (5, 10). Recurrent disease differs from the primary episode in that the virus is cleared much more rapidly, usually within 3 days or less. Although the immune response is quicker and more effective in controlling recurrent disease, it also may be responsible for most of the clinical symptoms, which persist for up to a week after the virus can no longer be isolated (6, 9). Thus, a combined modality of therapy aimed at both an antiviral effect and an immunomodulatory effect has been proposed in a number of studies (1, 9).The availability of a small-animal model for evaluation of the effects of treatment on the severity of recurrent lesions has been a limiting factor in evaluations of therapy. A novel animal model of recurrent HSV disease was recently developed by the use of zosteriform HSV infection in mic...

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“…Spread requires an intact nerve supply and has been likened to viral reactivation in that the virus must traverse the nervous system to cause disease at a distal site (26)(27)(28). Zosteriform models have been used to determine the effects of antivirals, vaccines, or the immune response on disease (2,8,11,15,17,21,27,28,34).…”

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Herpes Simplex Virus Type 1 Corneal Infection Results in Periocular Disease by Zosteriform Spread

Summers

Margolis

Leib

2001

J Virol

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In humans and animal models of herpes simplex virus infection, zosteriform skin lesions have been described which result from anterograde spread of the virus following invasion of the nervous system. Such routes of viral spread have not been fully examined following corneal infection, and the possible pathologic consequences of such spread are unknown. To investigate this, recombinant viruses expressing reporter genes were generated to quantify and correlate gene expression with replication in eyes, trigeminal ganglia, and periocular tissue. Reporter activity peaked in eyes 24 h postinfection and rapidly fell to background levels by 48 h despite the continued presence of viral titers. Reporter activity rose in the trigeminal ganglia at 60 h and peaked at 72 h, concomitant with the appearance and persistence of infectious virus. Virus was present in the periocular skin from 24 h despite the lack of significant reporter activity until 84 h postinfection. This detection of reporter activity was followed by the onset of periocular disease on day 4. Corneal infection with a thymidine kinase-deleted reporter virus displayed a similar profile of reporter activity and viral titer in the eyes, but little or no detectable activity was observed in trigeminal ganglia or periocular tissue. In addition, no periocular disease symptoms were observed. These findings demonstrate that viral infection of periocular tissue and subsequent disease development occurs by zosteriform spread from the cornea to the periocular tissue via the trigeminal ganglion rather than by direct spread from cornea to the periocular skin. Furthermore, clinical evidence is discussed suggesting that a similar mode of spreading and disease occurs in humans following primary ocular infection.

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Combinations of Antiviral and Anti-Inflammatory Preparations for the Topical Treatment of Herpes Simplex Virus Assessed using a Murine Zosteriform Infection Model

Cited by 16 publications

References 24 publications

High-Dose, Short-Duration, Early Valacyclovir Therapy for Episodic Treatment of Cold Sores: Results of Two Randomized, Placebo-Controlled, Multicenter Studies

High-Dose, Short-Duration, Early Valacyclovir Therapy for Episodic Treatment of Cold Sores: Results of Two Randomized, Placebo-Controlled, Multicenter Studies

Double-Blind, Randomized, Placebo-Controlled Study of Topical 5% Acyclovir-1% Hydrocortisone Cream (ME-609) for Treatment of UV Radiation-Induced Herpes Labialis

Herpes Simplex Virus Type 1 Corneal Infection Results in Periocular Disease by Zosteriform Spread

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