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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. (J Interven Cardiol 2012;25:304–312)

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)

There are substantial difficulties involved in carrying out clinical studies of recurrent herpes labialis, since the disease has a rapid onset, short-lasting viral shedding period and is rapidly self-healing. The aim of this paper was to critically assess published reports of episodic treatment of herpes labialis and to review biological and methodological problems involved in such studies. Limited, but statistically significant, results have been shown with topical antivirals, such as acyclovir and penciclovir, improving healing times by approximately 10%. Orally administrated antivirals, such as valaciclovir and famciclovir, have subsequently found clinical use. However, these two oral medications have different profiles in phase 3 studies. Famciclovir showed additional improvement of efficacy in terms of lesion healing time, but no effect on prevention of ulcerative lesions, while valaciclovir appeared to have similar efficacy to that of acyclovir cream on lesion healing, but some additional efficacy with respect to prevention of ulcerative lesions. A formulation of acyclovir/hydrocortisone showed further improvement in prevention of ulcerative lesions, while retaining efficacy with respect to lesion healing.

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.

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% ( ) or vehicle cream n p 30 ( ) to recurrent lesion(s) on days 1, 3, and 5 of the study (day 1 of observation occurred within 48 h after n p 17 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 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.

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.

Time-to-event curves analyzed by Cox proportional hazards regression are commonly used to describe the outcome of drug studies. This methodology has the advantage of using all available information, including patients who fail to complete the trial, such as in cancer chemotherapy or human immunodeficiency virus antiviral treatment studies. The goal of treatment in such studies may be to prevent the development of a complication, for example, Pneumocystis carinii pneumonia, and to describe the likelihood of this complication's developing in the treatment group compared to the control group. The hazard ratio describes the relative risk of the complication based on comparison of event rates.

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 differ- ent 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.

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.

Acyclovir cream has been available for the treatment of herpes labialis in numerous countries outside the United States for over a decade. Evidence for its efficacy comes from a few small clinical trials conducted in the 1980s. To examine more comprehensively the efficacy and safety of this formulation, we conducted two independent, identical, parallel, randomized, double-blind, vehicle-controlled, large-scale multicenter clinical trials. Healthy adults with a history of frequent herpes labialis were recruited from the general population, screened for eligibility, randomized equally to 5% acyclovir cream or vehicle control, given study medication, and told to self-initiate treatment five times daily for 4 days beginning within 1 h of the onset of a recurrent episode. The number of patients who treated a lesion was 686 in study 1 and 699 in study 2. In study 1, the mean duration of episodes was 4.3 days for patients treated with acyclovir cream and 4.8 days for those treated with the vehicle control (hazards ratio [HR] = 1.23; 95% confidence interval [CI], 1.06 to 1.44; P = 0.007). In study 2, the mean duration of episodes was 4.6 days for patients treated with acyclovir cream and 5.2 days for those treated with the vehicle control (HR = 1.24; 95% CI, 1.06 to 1.44; P = 0.006). Efficacy was apparent whether therapy was initiated “early” (prodrome or erythema lesion stage) or “late” (papule or vesicle stage). There was a statistically significant reduction in the duration of lesion pain in both studies. Acyclovir cream did not prevent the development of classical lesions (progression to vesicles, ulcers, and/or crusts). Adverse events were mild and infrequent.

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.

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.

We studied signal transducers and activators of transcription (Stat) expression in mouse trigeminal ganglia (TG) to gain an understanding of herpes simplex virus (HSV) infection and reactivation. Mouse TG were harvested and were either frozen for Western blot analysis or preserved in 4% paraformaldehyde for subsequent immunohistochemistry study. The thawed specimens were homogenized, and nuclear/cytoplasmic extractions were performed for Western blots and immunoprecipitation. Immunohistochemistry showed that Stat1, Stat3, Stat4, Stat5b, and phosphotyrosine Stat3 localized to TG neurons, not surrounding satellite cells. Western blot of TG nuclear and cytoplasmic extracts confirmed the presence of these Stat at the appropriate molecular weights. Stat2 was undetectable in TG by these methods. Immunoprecipitation of TG nuclear extracts did not confirm the presence of Stat-Stat dimers in these specimens. These studies show that several Stat, including phosphotyrosine Stat3, are present in TG neurons, the site of HSV latency, where they could act upon latent viral DNA to effect reactivation.

Herpes simplex viruses (HSVs) can cause a variety of infections, including genital herpes. Despite effective antiviral therapy, HSV infections remain a significant worldwide public health problem. Vaccines offer the best hope for controlling spread and limiting HSV disease. This article discusses the pathogenesis and immunobiology of mucocutaneous HSV infections, summarizes the spectrum of diseases caused by HSV, and provides a review of the field of HSV vaccine research. This article also discusses what might be realistically expected of a vaccine intended for control of genital herpes and explores the question of whether a vaccine that is effective in controlling genital HSV disease might also be effective in controlling nongenital HSV disease. The efficacy of such vaccines for the full spectrum of HSV disease will eventually determine the timing and targeting of immunization, ranging from selective immunization in preadolescence to universal childhood immunization as part of the routine childhood regimen.

Three doses of famciclovir were tested for treatment of experimental ultraviolet radiation (UVR)-induced herpes labialis. Patients received 125, 250, or 500 mg of famciclovir or placebo 3 times a day for 5 days beginning 48 h after UVR exposure, a model of early episodic intervention. Of 248 patients irradiated, 102 developed lesions while on treatment. There were no significant differences between groups in the number of lesions. The mean maximal lesion size was reduced in a dose-proportional manner: 139, 105, 77, and 55 mm2 for the placebo and 125-, 250-, and 500-mg famciclovir groups, respectively (P=.040, linear regression). Median time to healing was faster in the 500-mg famciclovir group than in the placebo group, both by investigator (4 vs. 6 days, 33% reduction, P=.010) and patient assessment (3.0 vs. 5.8 days, 48% reduction, P=.008) analyses. These findings suggest that evaluation of higher drug doses for herpes labialis treatment is warranted.