Three phase III randomized controlled trials of topical resiquimod 0.01-percent gel to reduce anogenital herpes recurrences.

Resiquimod, a Toll-like receptor 7 and 8 agonist, stimulates production of cytokines that promote an antigen-specific T helper type 1 acquired immune response. Animal and phase II human trials showed posttreatment efficacy in reducing recurrent herpes lesion days and/or time to first recurrence. Three phase III randomized, double-blind, vehicle-controlled trials of topical resiquimod to reduce anogenital herpes recurrences were conducted in healthy adults with ≥4 recurrences within the prior year. Participants applied resiquimod 0.01% gel or vehicle gel 2 times per week for 3 weeks to each recurrence for 12 months. Trials 1 and 2 had 2:1 resiquimod-vehicle randomization. Trial 3 had 1:1:1 randomization for resiquimod and 500 mg valacyclovir orally twice daily for 5 days (RESI-VAL), resiquimod and oral placebo (RESI-PLA), and vehicle and oral placebo (VEH-PLA). The median time to first recurrence was similar for resiquimod and vehicle (trial 1, 60 and 56 days, P=0.7; trial 2, 54 and 48 days, P=0.47; trial 3, 51 [RESI-VAL], 55 [RESI-PLA], and 44 [VEH-PLA] days, P=not significant [NS]). The median time to healing of initial treated recurrence was longer for resiquimod (trial 1, 18 compared to 10 days, P<0.001; trial 2, 19 compared to 13 days, P=0.16; trial 3, 14 [RESI-VAL], 16 [RESI-PLA], and 8 [VEH-PLA] days, P<0.001). In trials 1 and 2, moderate to severe erythema and erosion/ulceration at the application site were more common in resiquimod recipients. In conclusion, no posttreatment efficacy of resiquimod 0.01% gel was observed. Increased application site reactions and initial recurrence healing time are consistent with resiquimod-induced cytokine effects.

Novel composite efficacy measure to demonstrate the rationale and efficacy of combination antiviral-anti-inflammatory treatment for recurrent herpes simplex labialis.

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.

Transcranial Doppler quantification of residual shunt after percutaneous patent foramen ovale closure: correlation of device efficacy with intracardiac anatomic measures.

BACKGROUND: Percutaneous, mechanical closure of defects of the atrial septum fails to completely resolve shunting in up to 20% of cases. Little is known about the factors associated with device failure. METHODS: We measured the left atrial opening (X), right atrial opening (Z), tunnel length (Y), septum secundum, device-septum primum separation, and tunnel compressibility of the patent foramen ovale (PFO) in 301 patients with cryptogenic neurological events, PFO anatomy, and severe Valsalva shunting (Spencer Grade 5-5+). All patients then underwent percutaneous closure with the GORE®HELEX Septal Occluder device and were evaluated at 3 months for residual shunt by transcranial Doppler (TCD). RESULTS: Severe residual Valsalva shunt (TCD Grade 5-5+) was found at 3 months in 21 of 301 (7%) patients. X, Y, and Z were associated with failure with a high degree of statistical significance, whereas the width of the septum secundum, device-septum primum separation, and tunnel compressibility were not. An unanticipated finding was that 14 of 35 (40%) patients sized with a large balloon failed compared with 9 of 280 (3%) sized with a small balloon (P < 0.0001). In the multivariate logistic regression model, X (P = < 0.0001) and balloon size (P < 0.0001) were both strong predictors of failure. CONCLUSIONS: In an intracardiac echocardiography-defined PFO population, characterized by severe baseline Valsalva shunt and a high incidence of persistent (rest) shunting, association of six intracardiac measurements to closure device failure by multivariate logistic regression showed that the width of the left atrial opening was a strong predictor of residual shunting. An unanticipated finding was that use of a large sizing balloon was also strongly associated with failure.

Transcranial doppler quantification of residual shunt after percutaneous patent foramen ovale closure: efficacy of the GORE(®) HELEX septal occluder.

BACKGROUND: Ideally, percutaneous, mechanical closure of defects of the atrial septum should completely resolve shunt. To achieve this goal, more information is needed about the factors associated with device failure. METHODS: Consecutive patients with cryptogenic neurological events who had severe baseline Valsalva shunt (Spencer Grade 5-5+) and intracardiac echocardiography (ICE) defined patent foramen ovale (PFO) who underwent percutaneous PFO closure with the GORE(®) HELEX Septal Occluder device were evaluated for residual 3-month shunt by transcranial Doppler (TCD). RESULTS: We closed 315 PFO patients with the HELEX devices: 15, 20, 25, 30 mm devices in 19, 138, 150, and 8 patients, respectively. Severe residual Valsalva shunt (TCD Grade 5-5+) at 3 months occurred in 23 of 315 (7%) of all patients and in 2 of 108 (2%), 5 of 86(6%), and 16 of 121 (13%) patients with none, Grade 4, and Grade 5-5+ baseline rest shunt, respectively (P = 0.002). At 3 months, rest shunting was essentially abolished by closure. The percent of patients with severe residual Valsalva shunt was also related to device size: 15 mm (0%), 20 mm (4%), 25 mm (10%), and 30 mm (25%) (P = 0.008) and to atrial septal aneurysm. All of these variables were independent predictors of failure by multivariate logistic regression. CONCLUSIONS: In an ICE-defined PFO population characterized by severe baseline Valsalva shunt and a high incidence of persistent (rest) shunting, the GORE(®) HELEX Septal Occluder device effectively reduces both provoked and persistent shunt. The causes of device failure are multifactorial. Larger devices perform less reliably suggesting the need for size-specific modifications to improve closure of more severe defects. (J Interven Cardiol 2011;24:366-372).

Early treatment of cold sores with topical ME-609 decreases the frequency of ulcerative lesions: a randomized, double-blind, placebo-controlled, patient-initiated clinical trial.

BACKGROUND: Prior pilot studies support the use of antiviral medications with topical corticosteroids for herpes simplex labialis (HSL). ME-609 (Xerese, Xerclear) is a combination of 5% acyclovir and 1% hydrocortisone developed for the topical treatment of HSL. OBJECTIVES: The primary study end point was the prevention of ulcerative HSL lesions. METHODS: In all, 2437 patients with a history of HSL were randomized to self-initiate treatment with ME-609, 5% acyclovir in ME-609 vehicle, or ME-609 vehicle (placebo) at the earliest sign of a cold sore recurrence. Cream was applied 5 times/d for 5 days. A total of 1443 patients experienced a recurrence and initiated treatment with ME-609 (n = 601), acyclovir (n = 610), or placebo (n = 232). RESULTS: Of patients receiving ME-609, 42% did not develop an ulcerative lesion compared with 35% of patients receiving acyclovir in ME-609 vehicle (P = .014) and 26% of patients receiving placebo (P < .0001). In patients with ulcerative lesions, healing times were reduced in the ME-609 and acyclovir groups compared with placebo (P < .01 for both). The cumulative lesion area for all lesions was reduced 50% in patients receiving ME-609 compared with the placebo group (P < .0001). There were no differences among groups in the number of patients with positive herpes simplex virus cultures. The side-effect profile was similar among treatments. LIMITATIONS: The study did not contain a group treated with a topical corticosteroid alone. CONCLUSIONS: ME-609 prevented progression of cold sores to ulcerative lesions and significantly reduced the cumulative lesion area compared with acyclovir and placebo. ME-609 treatment offers additional therapeutic benefit compared with therapy with topical acyclovir alone.

Situational antiviral drug prophylaxis for HSV type 1 recurrences.

Recurrent herpes simplex virus type 1 infection is generally associated with mild morbidity. However, frequent recurrences may have a significant psychosocial impact, and reactivation in certain high-risk situations may cause considerable morbidity. Controlled trials demonstrate that antiviral drug prophylaxis can be efficacious in selected circumstances; even for other situations, clinical reports suggest that such antiviral drug prophylaxis remains effective.

An update on short-course intermittent and prevention therapies for herpes labialis.

Infection with herpes simplex virus (HSV) has increased in prevalence worldwide over the past two decades, making it a major public health concern. Approximately 90% of recurrent HSV type 1 (HSV-1) infections manifest as non-genital disease, primarily as orofacial lesions known as herpes labialis. Improvements in our understanding of the natural history of herpes labialis support the rationale for early treatment (during the prodrome or erythema stages) with high doses of antiviral agents in order to maximize drug benefit. When evaluating the efficacy of different antiviral and anti-inflammatory agents in clinical trials, episode duration, lesion healing time, reduction in maximum lesion size and the proportion of aborted lesions should be used as the most reliable measures of therapeutic efficacy. There has also been considerable research into the most beneficial treatment for recurrent episodes of herpes labialis in immunocompetent individuals. Data from clinical studies confirm that short-course, high-dose oral antiviral therapy should be offered to patients with recurrent herpes labialis to accelerate healing, reduce pain and most likely increase treatment adherence. Optimal benefits may be obtained when these oral antiviral agents are combined with topical corticosteroids, but more research is needed with this combination. Patients undergoing facial cosmetic procedures (i.e.facial resurfacing) are at risk of HSV reactivation, but further data are required on the actual risk according to the specific procedure. Aciclovir, valaciclovir and famciclovir all provide effective prophylaxis against HSV-1 reactivation following ablative facial resurfacing. However, no definitive recommendations can be made regarding prophylactic therapy for minimally invasive procedures at present.

Single-dose famciclovir for the treatment of herpes labialis.

BACKGROUND: Approximately 20% to 40% of the population experience recurrent herpes labialis caused by herpes simplex virus type 1 (HSV-1). Since there is no cure, patients typically use antiviral therapy to treat outbreaks as they occur. A large proportion of patients self-administer topical antiviral therapies at the onset of symptoms, but lack of efficacy, frequent dosing, and inconvenient long-term treatment regimens have made the use of oral antiviral therapies more common. Valacyclovir is currently the only oral antiviral approved for the treatment of herpes labialis in immunocompetent individuals. The pharmacokinetic/pharmacodynamic profile of famciclovir suggests that it could be utilized for episodic treatment for immunocompetent individuals as well. FINDINGS: A recent study comparing single-dose vs. single-day bid famciclovir and placebo in the treatment of herpes labialis demonstrated single-dose famciclovir to be as efficacious as single-day bid dosing in time to healing of lesions and more efficacious than single-day bid famciclovir in time to resolution of pain and tenderness. Both were statistically superior to placebo. When results of this study were compared with recently published results of other frequently prescribed treatments, single-dose famciclovir appeared to produce similar or better improvements in healing time and duration of pain. CONCLUSIONS: Single-dose famciclovir appears to be an effective, convenient therapy for recurrent herpes labialis. The convenience of single-dose therapy may lead to better overall management of the condition.

Topical iontophoretic administration of acyclovir for the episodic treatment of herpes labialis: a randomized, double-blind, placebo-controlled, clinic-initiated trial.

BACKGROUND: Multiple studies of the use of acyclovir for the treatment of herpes labialis have suggested that the nominal efficacy of the topical formulation is the result of inadequate penetration of the drug into the target site of infection, the basal epidermis. METHODS: We developed a low-voltage, wireless, hand-held, computer-controlled, iontophoretic applicator to enhance the skin penetration of topical acyclovir in the treatment of herpes labialis. We performed a multicenter, placebo-controlled, clinic-initiated, pilot trial of a single, topical, iontophoretic application of 5% acyclovir cream for the episodic treatment of herpes labialis among 200 patients with an incipient cold sore outbreak at the erythema or papular/edema lesion stage. RESULTS: The median classic lesion healing time (aborted lesions were assigned a value of 0 h) was 1.5 days shorter for the active treatment group than for the vehicle group (113 h vs. 148 h; P = .02). In the subgroup of patients who presented with lesions in the erythema stage, the median classic lesion healing time was 3 days shorter for the acyclovir group, compared with the control group (49 h vs. 120 h; P < .03), and the acyclovir group tended to have more aborted lesions than did the control group (46% vs. 24%; P = .10). CONCLUSIONS: Single-dose topical iontophoresis of acyclovir appears to be a convenient and effective treatment for cold sores and merits further clinical investigation.

Single-dose, patient-initiated famciclovir: a randomized, double-blind, placebo-controlled trial for episodic treatment of herpes labialis.

BACKGROUND: The brief period of viral replication in recurrent herpes labialis lesions suggests shorter therapeutic regimens are a logical episodic treatment strategy. OBJECTIVE: We sought to assess the efficacy and safety of single-dose and single-day famciclovir treatments. METHODS: In all, 701 randomly assigned patients self-initiated therapy with famciclovir (1500 mg once [single dose] or 750 mg twice a day for 1 day [single day]) or placebo within 1 hour of onset of the prodromal symptoms of an episode of herpes labialis. Lesion healing was monitored by diaries and frequent clinic visits. RESULTS: Median healing times of primary (first to appear) vesicular lesions in the famciclovir single-dose, famciclovir single-day, and placebo groups were 4.4, 4.0, and 6.2 days, respectively. There was no significant difference between the famciclovir regimens. Adverse events in the famciclovir groups were similar to placebo. LIMITATIONS: The active arms of this trial were not directly compared to other antiviral regimens. CONCLUSION: Single-dose famciclovir reduced time to healing of herpes labialis lesions by approximately 2 days compared with placebo.

Evaluation of imiquimod 5% cream to modify the natural history of herpes labialis: a pilot study.

BACKGROUND: Imiquimod is currently approved for the treatment of genital warts and has been shown to decrease recurrences of genital herpes in the guinea pig model of genital herpes. Therefore, we evaluated the safety and potential of topical imiquimod to decrease the rate of recurrence in humans with a history of recurrent herpes labialis. METHODS: Forty-seven subjects with recurrent herpes labialis applied imiquimod 5% (n=30) or vehicle cream (n=17) to recurrent lesion(s) on days 1, 3, and 5 of the study (day 1 of observation occurred within 48 h after recurrence of lesion). Subjects were seen at the study centers between each dose and 3 days after application of the final dose or until resolution of the lesion. RESULTS: After application to recurrent lesions, local erythema, edema, scabbing and/or flaking, pain, burning, and maximal lesion size were significantly greater in the imiquimod group than in the vehicle group. The study was terminated early because of severe local adverse events that occurred in 5 recipients of imiquimod. The median time until the next recurrence was, however, increased from 50 days in the vehicle group to 91 days in the imiquimod group (P=.018). CONCLUSIONS: Application of imiquimod 5% cream to herpes labialis lesions was associated with a delay in the time to the first recurrence after treatment, but severe local inflammation occurred in some individuals.

Recurrent antiviral-resistant genital herpes in an immunocompetent patient.

Herpes simplex virus type 2 (HSV-2) resistance to antiviral drugs has been described primarily in immunocompromised patients. We report an apparently immunocompetent, human immunodeficiency virus-negative male patient who has experienced repeated HSV-2 genital outbreaks despite receiving antiviral prophylaxis with several different drugs. Several of the HSV-2 genital isolates from this patient have been confirmed as resistant to acyclovir and penciclovir. Antiviral resistance occurred in the setting of long-term prednisone treatment and intermittent acyclovir prophylaxis at suboptimal doses and persisted despite the cessation of oral steroid treatment. The patient's genital herpes outbreaks were not controlled by high-dose prophylaxis with acyclovir, valacyclovir, and famciclovir. Cessation of antiviral prophylaxis resulted in reversion of this patient's HSV-2 isolates to acyclovir and penciclovir sensitivity, although resistant virus reappeared when antiviral prophylaxis was resumed. Transmission of a sensitive HSV-2 strain from this patient to a female sex partner was observed. These observations confirm previous reports that resistance to acyclovir may develop during prophylactic therapy in an otherwise well, immunocompetent patient. These findings support the conclusion that both drug-sensitive and drug-resistant HSV-2 strains established latency in this patient and that both strains are capable of frequent reactivation.

Clinical significance of antiviral therapy for episodic treatment of herpes labialis: exploratory analyses of the combined data from two valaciclovir trials.

Valaciclovir (Valtrex) 2 g twice daily for 1 day was recently approved in the United States for treatment of cold sores. In order to apply more clinically relevant assumptions to the analysis, we examined the effect of different missing data and endpoint assumptions on apparent valaciclovir efficacy. Results of each analysis demonstrate statistically significant increases in the proportion of subjects whose cold sores were aborted with valaciclovir compared with placebo, and significant decreases in healing times for subjects with cold sore lesions who were treated with valaciclovir compared with placebo. These exploratory analyses provide evidence of the robustness of the results to differing missing data assumptions and show that use of more clinically relevant endpoint assumptions increases the magnitude of some therapeutic responses. We also introduce a new measure that combines the two observed drug effects (reduced lesion duration, increased aborted lesions) into a single endpoint that captures the global benefit of the drug to the patient.

Susceptibility of herpes simplex virus isolates to nucleoside analogues and the proportion of nucleoside-resistant variants after repeated topical application of penciclovir to recurrent herpes labialis.

Subjects received topical penciclovir for 4 days during successive episodes of recurrent herpes labialis. Isolation of herpes simplex virus (HSV) was attempted from lesions obtained before initiation of treatment and on each day of therapy. Isolates remained sensitive to penciclovir when tested by a plaque reduction assay, and there was no significant change in sensitivity during any treatment course or between successive treatments. The proportion of nucleoside-resistant variants present within a subset of these isolates was further investigated using a more-sensitive plating efficiency assay. Although the proportion of antiviral-resistant HSV variants increased on successive days, it invariably remained a minor subpopulation. Moreover, isolates from successive episodes obtained before treatment showed no change in the proportion of resistant HSV variants. We conclude that antiviral-resistant variants, which are readily detected in HSV isolates from peripheral lesions, do not accumulate in the sensory ganglia of immunocompetent patients receiving multiple courses of nucleoside analogues.

High-dose, short-duration, early valacyclovir therapy for episodic treatment of cold sores: results of two randomized, placebo-controlled, multicenter studies.

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.

Treatment of herpes simplex labialis.

Recurrent herpes simplex labialis is associated with mild morbidity, but remains a significant problem for people with frequent and/or severe recurrences. Both topical and peroral episodic antiviral treatments of recurrences are modestly effective at reducing the duration of signs and symptoms. Recent studies with high-dose, short-course valaciclovir suggest that maximum benefit from antiviral therapy may be achieved with as little as 1 day of treatment. Topical steroids may be useful in combination with an antiviral agent, but more needs to be learnt about the appropriate strength and duration of steroid therapy before a general recommendation can be made. Selected subgroups of patients are candidates for prophylactic treatment with perorally administered nucleoside antiviral agents. Prophylaxis with topical agents is not effective.

Glycoprotein-D-adjuvant vaccine to prevent genital herpes.

BACKGROUND: An effective prophylactic vaccine would help control the spread of genital herpes. METHODS: We conducted two double-blind, randomized trials of a herpes simplex virus type 2 (HSV-2) glycoprotein-D-subunit vaccine with alum and 3-O-deacylated-monophosphoryl lipid A in subjects whose regular sexual partners had a history of genital herpes. In Study 1, subjects were seronegative for herpes simplex virus type 1 (HSV-1) and HSV-2; in Study 2, subjects were of any HSV serologic status. At months 0, 1, and 6, subjects received either vaccine or a control injection and were evaluated for 19 months. The primary end point was the occurrence of genital herpes disease in all subjects in Study 1 and in HSV-2-seronegative female subjects in Study 2. RESULTS: A total of 847 subjects who were seronegative for both HSV-1 and HSV-2 (268 of them women, in Study 1) and 1867 subjects who were seronegative for HSV-2 (710 of them women, in Study 2) underwent randomization and received injections. Vaccination was well tolerated and elicited humoral and cellular responses. Overall, the efficacy of the vaccine was 38 percent in Study 1 (95 percent confidence interval, -18 to 68 percent; 15 cases occurred in the vaccine group and 24 in the control group), and efficacy in female subjects was 42 percent in Study 2 (95 percent confidence interval, -31 to 74 percent; 9 cases occurred in the vaccine group and 16 in the control group). In both studies, further analysis showed that the vaccine was efficacious in women who were seronegative for both HSV-1 and HSV-2: efficacy in Study 1 was 73 percent (95 percent confidence interval, 19 to 91 percent; P=0.01), and efficacy in Study 2 was 74 percent (95 percent confidence interval, 9 to 93 percent; P=0.02). It was not efficacious in women who were seropositive for HSV-1 and seronegative for HSV-2 at base line or in men. CONCLUSIONS: These studies suggest that the glycoprotein D vaccine has efficacy against genital herpes in women who are seronegative for both HSV-1 and HSV-2 at base line but not in those who are seropositive for HSV-1 and seronegative for HSV-2. It had no efficacy in men, regardless of their HSV serologic status.