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Effectiveness of topical corticosteroids in addition to antiviral therapy in the management of recurrent herpes labialis: a systematic review and meta-analysis

Arain et al. BMC Infectious Diseases (2015) 15:82 DOI 10.1186/s12879-015-0824-0 Effectiveness of topical corticosteroids inaddition to antiviral therapy in the managementof recurrent herpes labialis: a systematic reviewand meta-analysis Nasira Arain1, Sharath CV Paravastu1 and Mubashir A Arain2* Background: Recurrent herpes labialis (RHL) is one of the most common viral infections worldwide. The availabletreatments have limited efficacy in preventing the recurrence of ulcerative lesions and reducing the duration ofillness. The objective of this review was to identify the effectiveness of topical corticosteroids in addition to antiviraltherapy in the treatment of RHL infection.
Methods: A systematic review of randomized clinical trials comparing the efficacy of combined therapy (topicalcorticosteroids with antiviral) with placebo or antiviral alone in the management of RHL was conducted. MEDLINE,EMBASE, CINAHL, Web of Science, the Cochrane library, and Google Scholar databases were searched. We usedRevMan software to conduct the meta-analysis. A fixed-effects model was used for mild to moderate heterogeneity,whereas a random-effects model was used for significant heterogeneity. Heterogeneity among trials was establishedusing I2 and chi-square test for heterogeneity.
Results: Four studies that fulfilled the selection criteria were included in this review. The total number ofparticipants across included studies was 1,891 (range, 29 to 1,443). The antiviral drugs used were acyclovir,famciclovir, and valacyclovir. Corticosteroids used were 1% hydrocortisone and 0.05% fluocinonide. Pooled resultsshowed that patients receiving combined therapy had a significantly lower recurrence rate of ulcerative lesionscompared to those in both the placebo group (OR, 0.50; 95% CI, 0.39-0.66; P < .001) and the antiviral treatmentalone group (OR, 0.73, 95% CI, 0.58–0.92; P = .007). The healing time was also significantly shorter in combinedtherapy in comparison to placebo (P < .001). However, there were no significant differences in healing timebetween combined therapy and antiviral alone. The adverse reactions in combined therapy were not significantlydifferent than the placebo group (OR, 1.09; 95% C, 0.75-1.59; P = .85).
Conclusion: Treatment with combined therapy is safe and more effective than placebo or antiviral alone forpreventing the recurrence of ulcerative lesions in RHL infection.
Keywords: Herpes labialis, Recurrent herpes infection, Cold sores, Corticosteroids and Herpes infection,Meta-analysis * Correspondence: 2Faculty of Nursing, University of Calgary, 2500 University Drive NW, T2N1 N4 Calgary, AB, CanadaFull list of author information is available at the end of the article 2015 Arain et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver applies to the data made available in this article,unless otherwise stated.
Arain et al. BMC Infectious Diseases (2015) 15:82 yet in other countries such as the UK. Therefore, it is im- Herpes labialis infection is a global public health prob- portant to understand the role of topical corticosteroid lem, with 15 to 40% of the population who experience therapy plus anti-viral agent in the management of RHL symptomatic outbreak Infection rates are high infection. The purpose of this review was to determine the among HIV positive patients; about 95% of patients are effectiveness of topical corticosteroids in addition to anti- seropositive to herpes simplex type I antigen [In de- viral therapy (combined therapy) compared to antiviral veloped countries, one third of the population suffer therapy alone or placebo in the management of RHL infec- from recurrent herpes labialis. (RHL) Between 20 to 40% tion using a systematic review and meta-analysis.
of adults become infected with herpes simplex infectionat some point during their lifetime Detectable serum antibodies against herpes simplex virus are more preva- Search methods for identification of studies lent in lower socioeconomic groups Over the last We searched electronic databases including MEDLINE 20 years, prevalence has increased globally and the pre- via ovid, EMBASE, CINAHL, Web of Science, and vention of RHL poses a big challenge for the 21st cen- Cochrane Library. Searches were limited to English- tury. The infection is difficult to eradicate and treatment language reports of human studies from 2000, which has minimal impact on reduction and prevention of marked the first clinical trial conducted on topical corti- herpes infection. To date, no vaccination has been suc- costeroids and antiviral therapy on humans, to 2013.
cessful so far in humans to prevent the primary infection A combination of medical subject headings (MeSH) and key word searches were used to retrieve the relevant Herpes simplex labialis (HSL) is a contagious infection literature in this review. All keywords were entered ei- that appears as a rash of the skin, usually involving the ther with "OR" and "AND" boolean operators and were lips but can affect oral membranes, and is characterized used with $/* where appropriate.
by blisters with pain and occasional itching There The following MeSH search terms were used: are different sequential stages of lesion including pro- "herpes simplex"; "herpes simplex virus"; "herpes labia- drome, redness, papule, vesicular, ulcer, hard crust, dry lis"; herpes labialis viruses"; "recurrences"; "recurrent flaking, and normal skin (complete epithelisation). Ul- herpes"; "topical administration"; "anti-infective agents"; cerative lesions take longer time to heal, which can "topical drug administration"; "corticosteroids"; "steroid"; adversely impact quality of life The diagnosis is typ- "antiviral agents"; antiviral drugs".
ically based on clinical history and examination; in some The following key words were used: cases, however, specific laboratory tests may be required herpes simplex; herpes labialis; herpes virus; recurrent The condition is usually mild, but some patients herpes labialis; prevention of herpes; treatment of herpes may have severe disease that may affect internal organs labialis; antiviral for herpes; antiviral + corticosteroid + or lead to secondary bacterial infections [ herpes; topical antiviral for herpes; topical treatment + her- Current treatment options for HSL include oral anti- pes; herpes labialis treatment + antiviral + corticosteroid.
viral drugs, antiviral ointment or other topical applica- Additional studies were sought through a review of tions (e.g., zinc oxide, zinc sulphate), and anesthetic the reference lists of obtained reports and other relevant creams for symptomatic improvement Treatment reviews on the topic. Grey literature was also searched needs to be initiated promptly to achieve favorable re- using Google Scholar and the ClinicalTrials.gov website sults. Despite the above mentioned available treatment options, antivirals are commonly used and can slightlyreduce the duration of herpes lesions by restraining the Inclusion and exclusion criteria multiplication of the virus However, treatment with Original research articles of randomized controlled clin- antiviral alone is not very effective and in most cases ical trials (RCTs) or controlled clinical trials comparing only has a minor effect on the duration of illness. There- the effectiveness of topical corticosteriods in addition to fore, researchers have suggested adding corticosteroids antiviral (combined therapy) versus antiviral alone or to antiviral agents to increase the responsiveness of le- placebo for the treatment of RHL were eligible for inclu- sions because herpes infection also triggers im- sion. Pilot clinical trial studies with similar interventions mune response. However, some controversy exists about and outcomes were also included. We excluded observa- the addition of corticosteroids, as steroidal contents may tional studies and studies that evaluated the treatment worsen the infection by reducing the natural defense for primary herpes labialis, as well as case reports, con- system against the infection ference presentations, and editorials. Studies of healthy Several countries such as US, Germany, and Netherlands (12–17 years) and have approved antiviral with topical corticosteroids for the adults (≥18 years) with a history of RHL were included, treatment of HSL However, it has not been licensed irrespective of gender, socioeconomic status, and race.
Arain et al. BMC Infectious Diseases (2015) 15:82 Two types of interventions were considered for the in- with 95% confidence intervals (CI). P < .05 was con- clusion: (1) combined therapy versus antiviral therapy sidered significant. For continuous outcomes, mean alone; or (2) combined therapy versus placebo. The pri- differences between the groups along with 95% CIs mary outcomes of interest were the development of clas- were measured.
sical lesions and reduction in pain. Secondary outcomes The meta-analysis of continuous data requires means were healing time, adverse events, and reduction in size with variance (or SD) to pool data. Outcomes of con- of the lesions.
tinuous variables were transformed from medians with All authors were involved in determining inclusion.
interquartile ranges (IQR) to means with SD, using thefollowing formulas Data collection and analysisData collection and analysis was performed using Review 1. Conversion of median into mean: χ ≈ a + 2m + b/4 Manager (RevMan Version 5.2, Copenhagen: The Nordic 2. Conversion of range into variance: S = b-a/4 = R/4 Cochrane Centre, the Cochrane Collaboration, 2012).
Data from the studies were extracted using data extrac- [X = mean, a = smallest value, b = largest value, m = me- tion form. Risk of bias was assessed using the following dian, S = variance, R = range].
key domains: randomization, allocation concealment, A fixed-effects model was used for mild to moderate sample size, blinding (single, double or triple), and attri- heterogeneity, whereas random-effects model was used tion rate ].
for those outcomes when the chi-square test for het- Odd ratios (ORs) were used for dichotomous out- erogeneity was significant (P < .10) and I2 was higher comes to measure the strength of association along Records identified through Additional records identified database searching through other sources Records after duplicates removed Record titles screened Title not according to inclusion criteria: not human subjects, other infections, not focusing on treatment Record abstracts screened -Not an original article-Abstracts were not fulfilling our inclusion criteria -Treatment not combined with hydrocortisone - Inappropriate study design Full-text articles assessed Full-text articles excluded -Study with children <12 -Study with unhealthy population(n = 1) Studies included in - No comparison condition quantitative synthesis -Other interventions (n = 2) - Unpublished study with unavailable data (n = 1) Figure 1 PRISMA flow diagram.
Arain et al. BMC Infectious Diseases (2015) 15:82 studies was 1,892 (range, 29 to 1,443). All four selected Description of the selected studies studies appropriately reported the process of random- A total of 9,450 studies were originally identified, and 4 isation. Most of the randomisation achieved 1:1 treat- were included in the final review (see Figure for ment to control ratios whilst Hull et al. (2010) PRISMA flow diagram). All 4 selected studies performed 2.7:1 for the treatment and placebo group were RCTs (see Table for study characteristics). Hull respectively Allocation concealment was also re- et al. 2010 was a RCT and topical corticosteroids ported in all four selected studies. Therefore, a mini- plus antiviral in the management of RHL was evaluated.
mum risk of selection bias was expected in the selected A total of 89 patients were recruited. There were cross- studies as a result of allocation concealment. The par- overs and there were no losses to follow up. Evans et al.
ticipants as well as personnel involved in providing care 2002 conducted a trial on 380 participants to evalu- (medication) were blinded in all four selected studies.
ate the effect of ME-609 (topical corticosteroid with All studies reported the use of identical looking sub- antiviral) in comparison to placebo. Hull et al. 2009 stances in both group in similar packing and labels.
was a small trial on 39 participants in which valacyclovir Two studies clearly reported the blinding of personnel and clobetasol gel were compared with placebo. Spruance assessing the outcome On the other hand, it et al. 2000 conducted a trial on 29 participants where was unclear in two studies ]. The intention to topical corticosteroid with valacyclovir 2gm was compared treat analysis was used in all four studies and risk of with antiviral alone. The antiviral used was acyclovir in 2 bias was minimal in relation to drop outs and loss to studies [famciclovir and valacyclovir in each of the follow up patients' data.
other 2 studies ]. The average number of episodes ofthe RHL in the participants ranged from 4.5 to 5.6 Effects of interventions episodes per year.
The development of the ulcerative lesions The risk of bias was assessed in the selected studies.
Three studies reported on this outcome -]. There The total number of participants included in the was no significant heterogeneity (I2 = 20%) found amongst Table 1 Characteristics of randomized controlled trials included in the review Participants (n) Groups (n) Male, n (%) Frequency of RHL (mean episodes/year) Hull et al. 2010 51 sites in the United States and 4 sites in 1. ME-609 cream (5% Acyclovir, 1% Canada (July 2006 to Hydrocortisone) (n = 601) 1. Acyclovir (5% in ME-609 vehicle) 2. Placebo (vehicle) (n = 232) Evans et al.
4 major university clinics 380 1. ME-609 cream (5% Acyclovir, 1% Hydrocortisone) (n = 190) 1. Placebo (n = 190) Hull et al. 2009 University of Utah (August 2004 to March 1. Oral Valacyclovir (2 g 2×/day for 1 day) plus topical Clobetasol gel (0.05% 2×/dayfor 3 days) (n = 20) 1. Placebo (n = 19) Spruance et al.
University of Utah Health Sciences Center, 1. Oral Famciclovir (Famvir, 500 mg 3×/day for 5 days) plus topical Fluocinonide (0.05%Lidex Gel 3×/day for 5 days) (n = 17) 1. Famciclovir and topical vehicle control

Arain et al. BMC Infectious Diseases (2015) 15:82 trials (Figure . The chi-square test for heterogeneity was magnitude was observed for reduction in pain and ten- not significant (P = .29). Meta-analysis showed a statisti- derness when the combine therapy was compared with cally significant reduction in the development of ulcerative antiviral alone. There was a significant heterogeneity lesions, demonstrating that the odds of the occurrence of (I2 = 67%) between the 2 studies in this analysis. The ulcerative lesions were 50% less likely in the intervention overall effect using the pooled data of 618 participants group as compared to placebo (OR, 0.50; 95% CI, 0.39- showed no significant difference in pain between topical 0.66; P < .001).
corticosteroid plus antiviral group compared to antiviral Similarly, the comparison of combined therapy with alone (OR, 0.32; 95%CI, 0.03- 3.76; P = .37).
antiviral alone also showed a significant reduction in thedevelopment of ulcerative lesions in the intervention Adverse reactions arm as compared to the control (Figure (OR, 0.73; The most common adverse reactions appeared were dry- 95% CI, 0.58-0.92; P = .007). There was moderate hetero- ness, irritation, and stinging symptoms, which were re- geneity among trials (I2 = 56%). Chi-square test for het- lated to topical application and not specifically due to erogeneity was insignificant (P = .13).
the corticosteroid component. Studies showed no signifi-cant difference in proportion of adverse reaction ob- Healing time for ulcerative lesions (complete epithelisation) served between the intervention and the placebo group.
The meta-analysis of 407 patients showed a significant There was no heterogeneity between the selected studies reduction of 1.49 days in the healing time for ulcerative (I2 = 0%). The overall effect also showed no significant lesions in the combine therapy group in compared to difference between the intervention and the placebo the placebo group (Figure (95% CI, −1.99 to −0.98; group (OR, 1.09; 95% CI, 0.75-1.59; P = .65).
P < .001). This outcome was observed on the based of The odds of the occurrence of adverse reactions were the healing time from the first sign of lesion until 37% more likely in the antiviral alone as compared to complete epithelisation. All studies showed significant the combine therapy group; however, the effect was not reduction in healing time in the intervention group statistically significant (OR, 1.37; 95% CI, 0.97-1.95, compared to placebo and there was a moderate hetero- P = .08). Heterogeneity between the two groups was not geneity between the studies (I2 = 53%).
statistically significant (I2 = 28%).
No significant difference was found in the healing time for ulcerative lesions between the combined therapy and the treatment with antiviral alone (mean difference = −1.68; To date, this is the first meta-analysis to determine the 95% CI, −4.52 to 1.16) in the pooled data of 357 patients effect of adding topical corticosteroids in the treatment (Figure ). There was a highly significant heterogeneity be- of RHL. The results of this review show that addition of tween the selected studies (I2 = 93%), so the random effect topical corticosteroids to antiviral therapy has significant model was used.
benefit compared to either antiviral therapy alone or pla-cebo. The review was conducted on RCTs only, which The effect of treatment on pain or tenderness in the lesion helped in producing rigorous findings about the effect- In the comparison of topical corticosteroid plus antiviral iveness of adding topical corticosteroids in the treatment with placebo, two of the three studies did not show any significant reduction in pain or tenderness in the inter- This review indicates that the chance of developing ul- vention group as compared to the placebo. However, the cerative lesions is reduced in patients who receive topical overall effect revealed a significant reduction (OR, 0.59; corticosteroids in addition to antiviral treatment in com- 95% CI, 0.45-0.77; P < .001). An effect of a smaller parison to placebo or antiviral treatment alone. Evidence Figure 2 Forest plot of comparison: topical corticosteroid plus antiviral group versus placebo, outcome: Pooled odds ratio of developmentof ulcerative lesions.
Arain et al. BMC Infectious Diseases (2015) 15:82 Figure 3 Forest plot of comparison: topical corticosteroid plus antiviral group versus antiviral alone, outcome: Pooled odds ratio fordevelopment of ulcerative lesions.
shows that the treatment with antiviral alone decreases ranging from 0.5 to 2 days ]. Treatment with topical the duration of ulcerative lesions in herpes labialis ,].
penciclovir alone reduced healing time by 0.5 days in However, in most cases antiviral treatment alone does not two clinical trials of 3,057 and 1,573 patients prevent the development of ulcerative lesion ].
Oral antiviral treatment with famciclovir has shown a re- Pain is another important determinant of the morbid- duction of approximately 2 days in healing time ity in RHL A 24% reduction in the development of Another trial with valacyclovir 2 grams on 1,524 patients pain in the lesion was an important outcome observed.
found a median reduction in healing time by 1.5 days One study reported a 26% faster improvement in pain which is comparable to the reduction in the healing among those patients who received topical penciclovir time with topical corticosteroids plus antiviral demon- than those who received a placebo However, a re- strated in this review.
view of 10 antiviral studies showed that none of them There are a number of limitations of this study. First, had any significant effect on pain reduction Fur- the meta-analysis in this study was conducted on a small thermore, topical anesthetic treatment alone also did not number of studies, which is likely attributable to the lim- show any significant impact on pain reduction ited availability of topical corticosteroid plus antiviral Photodynamic therapy is effective in relieving pain in treatment. The statistical tests to identify publication bias could not be performed due to the small number of The adverse reactions were lower in corticosteroids studies in the review. Second, the selected studies used group than those appeared in the antiviral group alone.
different form and type of antivirals (oral and topical).
A non-randomized clinical trial to determine the safety The topical antiviral agents that are most commonly rec- and tolerance of topical corticosteroids plus antiviral in ommended to treat RHL include acyclovir 5% cream, adolescents found that the treatment was well tolerated penciclovir 1% cream and docosanol 10% cream. Most and safe Studies on animals have also shown that of these preparations need to be applied every 2 hours the treatment with acyclovir with hydrocortisone is su- from the time of prodrome until complete healing perior to antiviral alone without any significant adverse Unlike topical agents, systemic medications enable greater drug exposure, rapid access to site of viral repli- The healing time was significantly reduced (around cation, better biocompatibility, less frequent dosing, and 1.5 days) in the treatment group in comparison to pla- improved compliance. Systemic antiviral agents may be cebo. A review on topical acyclovir revealed that 9 of 13 administered orally or intravenously. Acyclovir has a studies did not show any significant effect on healing short half-life and multiple doses are required to main- time, while 4 studies demonstrated significant reductions tain an optimum drug levels in serum. Famciclovir and Figure 4 The comparison of effect of corticosteroid plus antiviral and placebo on the healing time for ulcerative lesions from the firstsign until complete epithelisation.
Arain et al. BMC Infectious Diseases (2015) 15:82 Figure 5 The comparison of effect of corticosteroid plus antiviral and antiviral alone on the healing time for ulcerative lesions fromthe first sign until complete epithelisation.
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short-duration, early valacyclovir therapy for episodic treatment of coldsores: results of two randomized, placebo-controlled, multicenter studies.
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