Efficacy of Topical 5% Acyclovir-1% Hydrocortisone Cream (ME-609) for Treatment of Herpes Labialis: a systematic review.

We performed a systematic review with the objective of verifying the efficacy of topical use 5% Acyclovir-1% Hydrocortisone cream compared to the placebo group for herpes simplex labialis treatment. We performed a literature search using MEDLINE, Embase, BIOSIS, LILACS, Scopus, Grey literature, the Cochrane Central Register of Controlled Trials, the ISI Web of Science and IBECS from 1990 to June 2014. We reported the outcomes using relative risk (RR) with 95% confidence intervals. The literature search yielded 180 potentially relevant publications. Reviews of the reference lists yielded two further citations. Among these papers, two were considered eligible for inclusion in this review. Both trials included 1,213 patients. A meta-analysis of these studies showed a RR = 0.77, (95% CI 0.70-0.86; p<0.001).This result suggests that an early episodic treatment with the combination of an antiviral and a steroid is beneficial for herpes simplex labialis treatment.


inTroduCTion
Herpes simplex labialis (HSL) occurs in 20% to 40% of the general population.Approximately onethird of all infected patients suffer relapses (Embil et al. 1975).
Two strains of herpes simplex viruses have been identified, including HSV-1 and HSV-2.HSV-1 is mainly implicated in orofacial infections, whereas HSV-2 is predominantly associated with genital lesions (Wald et al. 2004).
Following the primary infection in the oral cavity, often occurring at an early age, the virus establishes a chronic, latent and life-long infection in the sensory ganglia, predominantly in the trigeminal ganglion (Whitley and Roizman 2001).
Despite many advances in antiviral therapy for recurrent herpes labialis in immunocompetent patients, the treatment remains controversial.The development of novel strategies to eradicate herpes simplex virus is a global public health priority.
We have performed a systematic review including all randomized controlled trials which used topical 5% Acyclovir-1% Hydrocortisone cream compared to the placebo group for herpes simplex labialis treatment.

MATEriALs And METHods
The PRISMA guidelines were followed for this metaanalysis of randomized trials (Liberati et al. 2009).

InclusIon and ExclusIon crItErIa
To be eligible for inclusion in our systematic review, studies had to examine specific treatments with Topical 5% Acyclovir-1% Hydrocortisone Cream (ME-609) for Herpes Labialis in comparison with the topical placebo group.Only randomized trials were included.

sEarch stratEgy
We performed a literature search using MEDLINE, Embase, BIOSIS, LILACS, Scopus, Grey literature, the Cochrane Central Register of Controlled Trials, the ISI Web of Science and IBECS from 1990 to June 2014).We first derived 3 themes that were combined with the Boolean operator "AND".Each theme was created with the Boolean operator "OR" to search for terms appearing as either exploded medical headings (MeSH) or text words.The first theme was "randomized control trial"; the second theme was "Herpes Labialis" and the third was "5% Acyclovir-1% Hydrocortisone Cream" "ME-609".We then manually scanned the reference lists of all the identified articles.There were no restrictions placed on the language of the publications.

data ExtractIon
Multiple teams of two reviewers (M.I.R and P.D.P) independently screened the title, abstract, and key words of each reference identified by the search and applied the inclusion and exclusion criteria.The same procedure was applied to full text articles and potentially eligible references.Differences in the reviewers' opinions were resolved by discussion or by a third reviewer.Data on quality, patient characteristics, interventions, and relevant outcomes were independently abstracted by two reviewers (S.L.S. and B.F.F).
Bias risk was assessed by considering the adequacy of randomization and allocation concealment, and the comparability of the women in the different study groups.The main outcome was the development of ulcerative lesions.

statIstIcal analysIs
We measured the inter-rater agreement for study inclusion and methodological quality assessment (weighted κ) (DerSimonian and Laird 1986).We reported the outcomes using relative risk (RR) with 95% confidence intervals (CIs).Pooled-effect estimates were derived using a random-effects model with Mantel-Haenszel statistics.Study heterogeneity was determined using the I 2 statistic, in which numbers greater than 75% suggest considerable heterogeneity (DerSimonian and Laird 1986), and P values from the χ 2 test.In cases of considerable heterogeneity, no pooled estimate was provided.A sensitivity analysis was planned a priori to compare the results, the designs and to report the quality of the studies; we focused on studies that were defined as "good quality" (Deeks et al. 2008).

rEsuLTs
The literature search yielded 180 potentially relevant publications.Reviews of the reference lists yielded two further citations.Among these papers, two were considered eligible for inclusion in this review (Fig. 1).The inter-rater reliability for study selection was good (κ = 0.9).
Both trials included 1,213 patients (791 in the experimental group and 422 in the control group).
The studies included were published in English.Table I shows the details of the studied populations, interventions, outcome assessments, and data reporting.The assessment of quality studies are presented in Figure 2, showing low risk of bias.
The heterogeneity was checked by Chi² test, which produced P value of 0.57 and I 2 =0%.No heterogeneity was detected in either?studies.The funnel plot was not shown because only two studies were included in the meta-analysis.

disCussion
This review compared the effectiveness of Acyclovir/hydrocortisone topical in reducing clinical   recurrence of herpes simplex labialis.Only two studies which met the criteria of the research were found.The results showed a statistically significant difference between Acyclovir/hydrocortisone topical versus placebo in the development decrease of the ulcerative lesions of herpes simplex labialis.
Acyclovir (9-[2-hydroxyethoxymethyl] is an acyclic nucleoside analogue of guanosine.The drug was synthesized by Howard Schaeffer, and found to have potent in vitro antiviral activity against herpes simplex virus type 1 (Balfour Jr et al. 1983).
The selective activity of acyclovir for cells infected with herpes viruses is due to the production of two unique herpes-specific enzymes, an isofunctional deoxynucleoside kinase (usually referred to as the herpes-specific thymidine kinase) and a herpes-specific DNA polymerase (Elion 1982).Acyclovir inhibits viral replication in two ways.First, acyclovir triphosphate inhibits the incorporation of deoxynucleotide triphosphates into herpes virus DNA.Second, the triphosphorylated drug is incorporated into newly formed herpes virus DNA (Elion 1982, Laskin 1983).
Hydrocortisone is the main glucocorticoid secreted by the adrenal cortex.It is used topically for its anti-inflammatory effects which suppress the clinical manifestations of the disease in a wide range of disorders where inflammation is a prominent feature (Brazzini and Pimpinelli 2002).
The use of a mild corticosteroid, such as hydrocortisone, in combination with acyclovir, appears to alter the clinical course of herpes labialis for a sizeable proportion of the patients.This naturally opens the way for further improvements in the future, when more potent corticosteroids, as well as corticosteroids with different properties could be tested (Harmenberg et al. 2010).
A study in animal models of HSV infection showed that topical treatment with ME-609 (which contains 5% acyclovir and 1% hydrocortisone) in the ATI mouse model was substantially more efficacious than 5% Zovirax® cream, 1% hydrocortisone or no treatment, respectively.The beneficial properties of ME-609 were also found to be superior to those of Zovirax® cream when tested in the standard guinea pig model, representing a primary HSV infection (Harmenberg et al. 2003).
In the Hull and co-workers study, patients receiving ME-609, 42% did not develop an ulcerative lesion compared with 26% of patients receiving placebo (P\.0001).In Evans and co-workers, the main result of double blind randomized study was that 29% fewer patients in the combination treatment group developed ulcerative lesions compared with placebo patients.
This meta-analysis complied with the criteria for performing a rigorous systematic review planed a priori.This included the use of study quality assessment and investigation of results by random effect models to test the robustness of the results.The potential limitations of this systematic review were the small number of studies included.

Figure 2 -
Figure 2 -Forest Plot showing the meta-analysis of uses of Topical 5% Acyclovir-1% Hydrocortisone Cream (ME-609) versus placebo for the treatment of Herpes Labialis.

Figure 3 -
Figure 3 -Assessment of study quality.