Immunotherapy of Recurrent Herpes Labialis With Squaric Acid

Abstract

This randomized placebo-controlled study examines the results of squaric acid dibutyl ester for the treatment of herpes labialis in adults.

Herpes labialis is a common condition caused by a double-stranded DNA virus belonging to the human herpesvirus family characterized by blisters or erosions on the lips and skin around the mouth and nose. Currently, there are no US Food and Drug Administration–approved medications for preventing herpes labialis outbreaks or prolonging the interval between outbreaks.

Squaric acid dibutyl ester (SADBE) is a topical immunosensitizer that induces a delayed-type hypersensitivity response and is commonly used in the treatment of verruca vulgaris and alopecia areata. When applied to warts, SADBE is believed to incite a T-cell response and to induce the killing of virally infected cells by cytotoxic lymphocytes. This influx of lymphocytes into lesional tissue may also enhance the recognition and processing of viral antigens, leading to clonal expansion of effector cells. It is hoped that SADBE will reduce the frequency and severity of herpes labialis outbreaks through these mechanisms.

Methods

This exploratory, double-blind, randomized placebo-controlled study was conducted between November 2013 and September 2015 at Massachusetts General Hospital. Healthy adults, ages 18 to 69 years, who self-reported having 6 or more episodes of herpes labialis in the previous 12 months received a topical sensitization dose on the arm at the initial visit, and then received a topical treatment dose applied to a lesion during the first 2 herpes labialis episodes occurring at least 2 weeks after the sensitization dose. Participants were randomized 1:1:1 to receive dimethyl sulfoxide alone (placebo), 2.0% SADBE sensitization and 0.5% SADBE treatment doses, or 2.0% SADBE sensitization, 0.2% SADBE treatment doses. The study was approved by Partners Human Research Committee institutional review board, and all participants provided their written informed consent (clinicaltrials.gov identification No. NCT01971385; trial protocol is available in the Supplement).

Results

Fifty-four patients were enrolled into the study; 43 patients had at least 1 form of contact (either in person or by phone) with research staff following the sensitizing dose and were included in the efficacy data analysis (Table). The data analyzed involves 9 males and 34 females.

Table. Baseline Demographics of All Subjects by Treatment Arm.

Characteristic	SADBE		Placebo
	0.50%	0.20%
Patients, No.	14	14	15
Age (range), y	47.21 (25-62)	44.86 (18-69)	44.13 (23-61)
Age, mean (SD), y	47.21 (9.37)	44.86 (13.68)	44.13 (10.88)
Male, %	21.43	21.43	20.00
Race, No. (%)
White	13 (92.86)	11 (78.57)	14 (93.33)
Asian	NA	1 (7.14)	NA
African American	NA	2 (14.29)	NA
Hispanic	1 (7.14)	NA	1 (6.67)
Mean outbreaks/y, No.	7.82	7.21	8.23
Mean days from sensitization to last contact, No. (range)	251.21 (111-566)	212.5 (91-383)	257.4 (39-497)

Abbreviations: NA, not applicable; SADBE, squaric acid dibutyl ester.

One planned primary end point was days to the next herpes labialis outbreak after the last treatment dose. However, 16 of 28 patients who received 2.0% SADBE for sensitization did not experience another outbreak and did not receive a subsequent treatment dose after sensitization. Thus, we analyzed time to next outbreak after the sensitization dose. Data from patients who never experienced a first outbreak following sensitization were censored on the last available follow-up date and Kaplan-Meier time-to-event curves were estimated and graphed (Figure). The median time to event for the placebo group was 40 days vs more than 122 days for the 2.0% SADBE group, which difference was highly significant (P = .009).

Figure. Days to First New Herpes Labialis Outbreak Following the Sensitization Dose.

This Kaplan-Meier graph shows the time-to-event curve of percent of subjects without a new herpes labialis outbreaks for the indicated number of days after the sensitization dose. Circles along the curves represent censored observations. DMSO indicates dimethyl sulfoxide; SADBE, squaric acid dibutyl ester.

Aside from autosensitization dermatitis that occurred in 1 patient after being exposed to the SADBE sensitization dose for 24 hours, the only other adverse events noted were itching and redness at the sensitization site, which was seen in 13 patients who received 2.0% SADBE and 2 patients who received placebo.

Discussion

This study suggests that sensitization of patients with SADBE may be useful in preventing herpes simplex virus outbreaks. Our initial hypothesis was that treatment of an active lesion would be necessary to achieve the appropriate immunologic response, but our results suggest this additional step may not be necessary for many patients. Overall, SADBE was well tolerated by our patients.

Limitations of our study include small sample size, few recurrences of herpes labialis lesions after sensitization (limiting subsequent in-person evaluation), relatively short follow-up time, and recall bias of patient-reported number of previous outbreaks per year for subject inclusion.

Supplement.

Trial Protocol.