Novel Composite Efficacy Measure To Demonstrate the Rationale and Efficacy of Combination Antiviral–Anti-Inflammatory Treatment for Recurrent Herpes Simplex Labialis

Abstract

c Historically, the primary target for research and treatment of recurrent herpes simplex labialis (HSL) has been limited to inhibiting herpes simplex virus (HSV) replication. Antiviral monotherapy, however, has proven only marginally effective in curtailing the duration and severity of recurrent lesions. Recently, the role of inflammation in the progression and resolution of recurrences has been identified as an additional target. This was evaluated in a randomized study comparing combination topical 5% acyclovir-1% hydrocortisone cream (AHC) with 5% acyclovir alone (AC; in the AHC vehicle) and the vehicle. The efficacy of each topical therapy was evaluated for cumulative lesion size-a novel composite efficacy endpoint incorporating episode duration, lesion area, and proportion of nonulcerative lesions. In that study, cumulative lesion area was significantly decreased with AHC compared with AC (25% decrease; P < 0.05) and the vehicle (50% decrease; P < 0.0001). As research continues in this arena, cumulative lesion area should be included as a measure of efficacy in clinical trials of recurrent HSL therapies.T he seroprevalence of herpes simplex virus 1 (HSV-1), the HSV type most often associated with herpes simplex labialis (HSL) or cold sores, is estimated to be 58% among immunocompetent Americans 14 to 49 years of age (1) and 31% among children 6 to 13 years of age (2). Approximately 15 to 40% of these seropositive individuals will experience a symptomatic HSL recurrence, the frequency of which depends on genetic susceptibility, immune status, age, site of infection, and viral subtype (HSV-1 versus HSV-2) (3, 4). In most cases, patients with recurrent HSL experience minimal discomfort, pain, and disfigurement, but frequent outbreaks (Ͼ5 episodes/year, experienced by approximately 35% of patients with recurrent HSL) are associated with significant impact on physical, emotional, and social well-being (5).Recurrences of HSL differ from the primary/initial infection with respect to the roles that viral replication and inflammation play in the course of a lesion. In primary infection, lesion development, progression, and resolution are closely correlated with viral replication. In recurrent disease, lesion development and progression depend primarily on the proinflammatory host response (6) (Fig. 1). The central role of inflammation in lesion progression in recurrent disease may explain the limited efficacy of current antiviral monotherapy and suggests a new approach for more effective treatment. The value of one such approach, antiviral-anti-inflammatory combination treatment, has been demonstrated via several endpoints, including cumulative lesion area, a new efficacy endpoint. DUAL DISEASE PROCESSES IN HERPES SIMPLEX LABIALIS RECURRENCESRecurrent lesion development: correlations with viral processes. In recurrent HSL, HSV periodically reactivates (by mechanisms that are not completely understood) and moves from the cell body of latently infected sensory neurons toward the epidermis, where the virus begins to r...

Antiherpes evaluation of soybean isoflavonoids

“…Given that herpesvirus infections are always accompanied by an inflammatory process [42], the combination of antiherpes and anti-inflammatory agents in topical pharmaceutical forms is an interesting therapeutic strategy for treatment of HSV infection. In a randomized study, Hull et al [42] showed the efficacy of a topical association of an antiviral drug (acyclovir) and an anti-inflammatory agent (hydrocortisone) for the treatment of HSV infections.…”

“…In a randomized study, Hull et al [42] showed the efficacy of a topical association of an antiviral drug (acyclovir) and an anti-inflammatory agent (hydrocortisone) for the treatment of HSV infections. The efficacy of this combined therapy was observed through a higher reduction in the cumulative lesion area when compared with acyclovir alone.…”

Efficacy of a topical herbal and mineral formulation (Dynamiclear) for the treatment of herpes simplex labialis in the community setting: study protocol for a randomised, double-blind placebo-controlled trial

“…A systematic review by Harmenberg et al ,1 a recent mini review by Hull13 and the most recent Cochrane systematic review protocol20 outline a number of important outcome measures which informed the choices in box 3. Median duration of the episode, as defined by the time to healing either by the loss of the hard crust in participants with ulcerative lesions or the time to normal skin (complete epithelialisation) in those with aborted lesions, either participant or clinician reported is the most common clinically relevant outcome measure.…”

“…C. officinalis has been traditionally used for minor skin infections and inflammation 12. Recent studies have found calendula to be effective in reducing the time to healing in previously non-healing venous leg ulcers 13. This is likely to occur through the upregulation of genes controlling connective tissue growth factor and α-smooth muscle actin14 and the proliferation and migration of fibroblasts 15…”

Immunology of Diseases of the Oral Cavity

“…Viral replication within the keratinocytes activates NF-κB, leading to secretion of CC (β) chemokines and interleukins. These also induce adhesion molecule expression, including endothelial adhesion molecules, and together these attract monocytes, neutrophils, and CD4 + T cells to the site of infection (Hull et al, 2014) and promote inflammation (Patel et al, 2009). Resident dendritic cells take up HSV antigen and migrate to the draining lymph nodes where they present the antigen to circulating antigen-specific memory T cells.…”