Interventions for prevention of herpes simplex labialis (cold sores on the lips)

Ching‐Chi Chi; Shu‐Hui Wang; Finola M Delamere; Fenella Wojnarowska; Mathilde C Peters; Preetha P Kanjirath

doi:10.1002/14651858.CD010095.pub2

. 2015 Aug 7;2015(8):CD010095. doi: 10.1002/14651858.CD010095.pub2

Interventions for prevention of herpes simplex labialis (cold sores on the lips)

Ching‐Chi Chi ^1,^2,^✉, Shu‐Hui Wang ³, Finola M Delamere ⁴, Fenella Wojnarowska ⁵, Mathilde C Peters ⁶, Preetha P Kanjirath ⁷

Editor: Cochrane Skin Group

PMCID: PMC6461191 PMID: 26252373

Abstract

Background

Herpes simplex labialis (HSL), also known as cold sores, is a common disease of the lips caused by the herpes simplex virus, which is found throughout the world. It presents as a painful vesicular eruption, forming unsightly crusts, which cause cosmetic disfigurement and psychosocial distress. There is no cure available, and it recurs periodically.

Objectives

To assess the effects of interventions for the prevention of HSL in people of all ages.

Search methods

We searched the following databases up to 19 May 2015: the Cochrane Skin Group Specialised Register, the Oral Health Group Specialised Register, CENTRAL in the Cochrane Library (Issue 4, 2015), MEDLINE (from 1946), EMBASE (from 1974), LILACS (from 1982), the China National Knowledge Infrastructure (CNKI) database, Airiti Library, and 5 trial registers. To identify further references to relevant randomised controlled trials, we scanned the bibliographies of included studies and published reviews, and we also contacted the original researchers of our included studies.

Selection criteria

Randomised controlled trials (RCTs) of interventions for preventing HSL in immunocompetent people.

Data collection and analysis

Two authors independently selected trials, extracted data, and assessed the risk of bias. A third author was available for resolving differences of opinion.

Main results

This review included 32 RCTs, with a total of 2640 immunocompetent participants, covering 19 treatments. The quality of the body of evidence was low to moderate for most outcomes, but was very low for a few outcomes. Our primary outcomes were 'Incidence of HSL' and 'Adverse effects during use of the preventative intervention'.

The evidence for short‐term (≤ 1 month) use of oral aciclovir in preventing recurrent HSL was inconsistent across the doses used in the studies: 2 RCTs showed low quality evidence for a reduced recurrence of HSL with aciclovir 400 mg twice daily (risk ratio (RR) 0.26, 95% confidence interval (CI) 0.13 to 0.51; n = 177), while 1 RCT testing aciclovir 800 mg twice daily and 2 RCTs testing 200 mg 5 times daily found no similar preventive effects (RR 1.08, 95% CI 0.62 to 1.87; n = 237; moderate quality evidence and RR 0.46, 95% CI 0.20 to 1.07; n = 66; low quality evidence, respectively). The direction of intervention effect was unrelated to the risk of bias. The evidence from 1 RCT for the effect of short‐term use of valaciclovir in reducing recurrence of HSL by clinical evaluation was uncertain (RR 0.55, 95% CI 0.23 to 1.28; n = 125; moderate quality evidence), as was the evidence from 1 RCT testing short‐term use of famciclovir.

Long‐term (> 1 month) use of oral antiviral agents reduced the recurrence of HSL. There was low quality evidence from 1 RCT that long‐term use of oral aciclovir reduced clinical recurrences (1.80 versus 0.85 episodes per participant per a 4‐month period, P = 0.009) and virological recurrence (1.40 versus 0.40 episodes per participant per a 4‐month period, P = 0.003). One RCT found long‐term use of valaciclovir effective in reducing the incidence of HSL (with a decrease of 0.09 episodes per participant per month; n = 95). One RCT found that a long‐term suppressive regimen of valaciclovir had a lower incidence of HSL than an episodic regimen of valciclovir (difference in means (MD) ‐0.10 episodes per participant per month, 95% CI ‐0.16 to ‐0.05; n = 120).

These trials found no increase in adverse events associated with the use of oral antiviral agents (moderate quality evidence).

There was no evidence to show that short‐term use of topical antiviral agents prevented recurrent HSL. There was moderate quality evidence from 2 RCTs that topical aciclovir 5% cream probably has little effect on preventing recurrence of HSL (pooled RR 0.91, 95% CI 0.48 to 1.72; n = 271). There was moderate quality evidence from a single RCT that topical foscarnet 3% cream has little effect in preventing HSL (RR 1.08, 95% CI 0.82 to 1.40; n = 295).

The efficacy of long‐term use of topical aciclovir cream was uncertain. One RCT found significantly fewer research‐diagnosed recurrences of HSL when on aciclovir cream treatment than on placebo (P < 0.05), but found no significant differences in the mean number of participant‐reported recurrences between the 2 groups (P ≥ 0.05). One RCT found no preventive effect of topical application of 1,5‐pentanediol gel for 26 weeks (P > 0.05). Another RCT found that the group who used 2‐hydroxypropyl‐β‐cyclo dextrin 20% gel for 6 months had significantly more recurrences than the placebo group (P = 0.003).

These studies found no increase in adverse events related to the use of topical antiviral agents.

Two RCTs found that the application of sunscreen significantly prevented recurrent HSL induced by experimental ultraviolet light (pooled RR 0.07, 95% CI 0.01 to 0.33; n = 111), but another RCT found that sunscreen did not prevent HSL induced by sunlight (RR 1.13, 95% CI 0.25 to 5.06; n = 51). These RCTs did not report adverse events.

There were very few data suggesting that thymopentin, low‐level laser therapy, and hypnotherapy are effective in preventing recurrent HSL, with one to two RCTs for each intervention. We failed to find any evidence of efficacy for lysine, LongoVital® supplementation, gamma globulin, herpes simplex virus (HSV) type I subunit vaccine, and yellow fever vaccine in preventing HSL. There were no consistent data supporting the efficacy of levamisole and interferon, which were also associated with an increased risk of adverse effects such as fever.

Authors' conclusions

The current evidence demonstrates that long‐term use of oral antiviral agents can prevent HSL, but the clinical benefit is small. We did not find evidence of an increased risk of adverse events. On the other hand, the evidence on topical antiviral agents and other interventions either showed no efficacy or could not confirm their efficacy in preventing HSL.

Plain language summary

Measures for preventing cold sores

Review question

What measures are effective in preventing recurrence of cold sores?

Background

A cold sore is an irritating recurrent viral infection with no proven cure. It gives rise to painful vesicles on the lips that form unsightly crusts, causing an unpleasant look and mental distress. We aimed to examine the effects of available measures for preventing recurrence of cold sores in people with normal immunity.

Study characteristics

We examined the research published up to 19 May 2015. We wanted to include studies only if receiving one preventative measure or another was decided by chance. This research method, termed randomised controlled trial (RCT), is the best way to test that a preventive effect is caused by the measure being tested. We found 32 RCTs that included 2640 people and examined 19 preventative measures. The drug manufacturer funded a total of 18 out of 32 studies, non‐profit organisations funded 4, and we do not know how the other 10 were funded.

Key results

Long‐term use of antiviral drugs taken by mouth prevented cold sores, though with a very small decrease of 0.09 episodes per person per month. The preventative effect of long‐term use of aciclovir cream applied to the lips was uncertain. Long‐term use of 1,5‐pentanediol gel and 2‐hydroxypropyl‐β‐cyclo dextrin 20% gel applied to the lips did not prevent cold sores.

Short‐term use of either antiviral drugs or creams did not prevent cold sores. Neither short‐term nor long‐term use of these antiviral drugs or creams appeared to cause side‐effects.

The preventative effects of sunscreen were uncertain. Application of sunscreen prevented cold sores induced by experimental ultraviolet light, but did not prevent cold sores induced by sunlight.

We found very little evidence about the preventative effects of thymopentin, low‐energy laser, and hypnotherapy for cold sores. The available evidence found no preventative effects of lysine, LongoVital® supplementation, gamma globulin, herpes virus vaccine, and yellow fever vaccine. There were no consistent data to confirm that levamisole and interferon do prevent cold sores.

These studies found no increase in adverse events related to the use of topical antiviral agents.

Quality of the evidence

The quality of the evidence was low to moderate for most outcomes, but was very low for some outcomes.

Summary of findings

Background

Description of the condition

A virus that resides in the skin of the lips causes herpes simplex labialis (HSL) (Higgins 1993). Its manifestation on the skin is also known as a 'cold sore' or 'fever blister'. The initial infection with the virus, which is called herpes simplex virus (HSV), is by direct contact between the mucous membranes or abraded skin of the lips or mouth and the saliva or other secretions of a person with active primary or recurrent infection (Higgins 1993). Primary infection with HSV typically occurs in early childhood, often with no symptoms, but primary HSV infection may also present as herpetic gingivostomatitis, which is characterised by oral and perioral vesicles (tiny blisters) and ulcers (Higgins 1993). It has been reported that when clinical disease is not present, the virus spreads through respiratory droplets or through interaction with the mucocutaneous releases of an asymptomatic person shedding the virus (Fatahzadeh 2007). Following the primary infection, the virus resides in the sensory ganglia (nerve endings) in a latent form (Higgins 1993). After reactivation, HSV migrates from these sensory ganglia to the outer layer of the skin of the lips or mouth to cause recurrent HSL (Fatahzadeh 2007). Herpes simplex virus type 1 (HSV‐1) causes recurrent HSL. Although herpes simplex virus type 2 (HSV‐2) may occasionally cause primary oral infection, it rarely causes recurrent HSL (Fatahzadeh 2007).

Herpes simplex labialis affects the lips, with the outer third of the lower lip being most frequently affected (Marques 2003). In up to 60% of affected people, HSL is preceded by warning signs, which are known as 'prodromal symptoms'; these are feelings of pain, burning, itching, or tingling at the site of subsequent vesicle development. Headache may also occur in the prodromal stage (Joseph 1985). Within 24 hours of the prodrome, multiple grouped vesicles appear and then weep until they finally form crusts (Fatahzadeh 2007). Such crusts can often bleed quite easily, forming unsightly blackish crusts due to dried blood, which can bleed again when the skin is stretched, e.g., when smiling (Fatahzadeh 2007). These usually heal without scarring within 5 to 15 days (Marques 2003). Herpes simplex labialis may cause pain, discomfort, inconvenience, and some amount of psychological and social distress as a result of cosmetic disfigurement (Fatahzadeh 2007).

Herpes simplex labialis occurs worldwide and is a very common disease (Higgins 1993). The lifetime prevalence of recurrent herpes labialis is 20% to 52.5% (Celik 2013; Higgins 1993). It has been estimated that there are 98 million cases of HSL each year in the US alone (Higgins 1993). Most people with recurrent HSL have fewer than 2 episodes per year, but 5% to 10% of affected people have a minimum of 6 recurrences per annum (Celik 2013; Rooney 1993). Recurrences of HSL seem to be precipitated by a number of factors, including ultraviolet light (UVL); illness; stress; premenstrual tension; severe drug eruptions; and surgical procedures, such as dental surgery, neural surgery, and dermabrasion (a cosmetic procedure used to smooth scars) (Celik 2013; Higgins 1993; Shiohara 2013). People with atopic dermatitis who carry filaggrin mutations are prone to recurrent HSL, which may be attributed to their deficient antiviral immune response (Leung 2014; Rystedt 1986).

Description of the intervention

To date, there has been no proven way of eradicating HSV from the body completely. A number of interventions have been proposed for the prevention of recurrent HSL, including oral antivirals, topical antivirals, and sunscreens (Worrall 2009).

Antiviral agents, including aciclovir, famciclovir, penciclovir, and valaciclovir, inhibit DNA polymerase and viral replications. Before converting to the active antiviral triphosphate form, these drugs need to be phosphorylated by enzymes, such as viral thymidine kinase (TK) or host cellular kinases. Compared with aciclovir, famciclovir and valaciclovir have greater bioavailability and need less frequent dosing. Foscarnet inhibits viral DNA polymerase independent of phosphorylation and is thus used in aciclovir‐resistant HSV infections (Fatahzadeh 2007).

The active ingredients of sunscreens are generally classified into inorganic and organic UVL filters. Inorganic filters, such as titanium oxide, reflect or scatter UVL, while organic filters absorb UVL and convert the energy into heat. The most frequently‐used efficacy index of sunscreen in preventing sunburns is the sun protection factor (SPF), which is measured after application of 2 mg/cm² of product (Kullavanijaya 2005).

How the intervention might work

Long‐term prophylactic administration of oral antivirals (e.g., aciclovir, famciclovir, and valaciclovir) is expected to prevent reactivation of HSV (Worrall 2009). However, continuous daily intake of antivirals is not only costly but also requires the person to adhere to such a programme consistently (Fatahzadeh 2007). Therefore, it is important to design an optimal regimen, balancing known effectiveness of any preventative intervention with the inconvenience and possible side‐effects of continuous medication.

When topical aciclovir cream is used as a treatment for HSL, the frequency of application is five times daily (four hours apart except for sleep) (GSK 2008). However, the efficacy and frequency of application when used as a preventative intervention is unclear.

Based on the fact that ultraviolet light induces the recurrence of HSL (Higgins 1993), sunscreens, theoretically, can prevent recurrence of HSL. However, commercially available sunscreens vary greatly in their active ingredients and the effectiveness of their photoprotection. The effectiveness of photoprotection also depends on the appropriate application of sunscreens; frequency of re‐application after sweating or water sports (Kullavanijaya 2005); and in the case of lips, eating or drinking (Rooney 1991). In actual use, most people apply less than the amounts used in testing SPF, which compromises the efficacy of the sunscreen (Kullavanijaya 2005). Photoprotective lipscreens often contain less UVL‐absorbing ingredients than skin sunscreens (Wahie 2007).

Why it is important to do this review

There has been a Cochrane review on the effects of systemic aciclovir for primary herpetic gingivostomatitis (Nasser 2008) and another on the interventions for the prevention and treatment of HSV in people being treated for cancer (Glenny 2009). However, a systematic review on interventions for preventing HSL in those who are immunocompetent is lacking. We aimed to conduct such a review in order to find out the best evidence on the effects of those interventions currently available for the prevention of recurrent HSL.

The plans for this review were published as a protocol 'Interventions for prevention of herpes simplex labialis (cold sores on the lips)' (Chi 2012).

Objectives

To assess the effects of interventions for the prevention of HSL in people of all ages.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) of systemic, topical, and physical interventions for the prevention of herpes simplex labialis (HSL).

Types of participants

Anyone who was immunocompetent and had been initially diagnosed with recurrent HSL by a healthcare professional or trained researcher.

Types of interventions

Any systemic, topical, or physical intervention used for the prevention of HSL. The interventions could be either a single intervention or a combination of interventions. When there were different lengths of use of the intervention, we regarded those of ≤ 1 month as short‐term use and those of > 1 month as long‐term use. The controls might be a placebo, no intervention, or another active intervention.

Types of outcome measures

Primary outcomes

Incidence of HSL during use of the preventative intervention. We accepted both researcher‐diagnosed and participant‐reported recurrences.
Adverse effects during use of the preventative intervention.

Secondary outcomes

Duration of attack of recurrent HSL during use of the preventative intervention.
Severity (lesion area, stage, pain) of attack of recurrent HSL during use of the preventative intervention.
Viral load in saliva.
Rate of adherence to the regimen of the preventative intervention.
Incidence of HSL after use of the preventative intervention. We accepted both researcher‐diagnosed and participant‐reported recurrences.
Duration of attack of recurrent HSL after use of the preventative intervention.
Severity (lesion area, stage, pain) of attack of recurrent HSL after use of the preventative intervention.

Search methods for identification of studies

We aimed to identify all relevant RCTs regardless of language or publication status (published, unpublished, in press, or in progress).

Electronic searches

We searched the following databases up to 19 May 2015:

the Cochrane Skin Group Specialised Register using the search strategy in Appendix 1;
the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (Issue 4, 2015) using the strategy in Appendix 2;
MEDLINE via Ovid (from 1946) using the strategy in Appendix 3;
EMBASE via Ovid (from 1974) using the strategy in Appendix 4; and
LILACS (Latin American and Caribbean Health Science Information database, from 1982) using the strategy in Appendix 5.

We searched the Cochrane Oral Health Group Specialised Register using the search strategy in Appendix 1 up to 19 May 2015.

On 22 May 2015, we searched the China National Knowledge Infrastructure (CKNI) database (from 1994) using the strategy in Appendix 6 and Airiti Library (publications and theses from Taiwan, from 1991) using the strategy in Appendix 7.

Trials registers

We searched the following trials databases on 25 May 2015 using the strategy in Appendix 8.

The US National Institutes of Health Ongoing Trials Register (www.clinicaltrials.gov).
The Australian New Zealand Clinical Trials Registry (www.anzctr.org.au).
The World Health Organization International Clinical Trials Registry platform (www.who.int/trialsearch).
The EU Clinical Trials Register (www.clinicaltrialsregister.eu).

We searched the metaRegister of Controlled Trials (www.controlled‐trials.com) on 13 June 2014, but this was closed and under review when we updated our search on 25 May 2015.

Searching other resources

Reference lists

We scanned the bibliographies of the included studies and published reviews for further references to relevant trials.

Unpublished literature

We tried to identify further unpublished trials through correspondence with the original researchers of the included studies.

Adverse effects

We did not run separate searches for adverse effects of the target interventions. However, we did extract relevant data from the included trials that we identified.

Data collection and analysis

Some parts of this section uses text that was originally published in another Cochrane review (Chi 2011). We included 'Summary of findings' tables where we used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of the evidence for the primary outcomes for the treatment comparisons.

Selection of studies

Two authors (CC and SW) independently checked titles and abstracts identified from the searches. The authors were not blinded to the names of the original researchers, journals, or institutions. If it was clear from the abstract that the study did not refer to a RCT on interventions for prevention of HSL, we excluded it. The same two authors independently assessed the full text version of each remaining study to determine whether it met the predefined selection criteria. We resolved any disagreement by discussion with referral to a third author (FW), if necessary. We listed the studies that we could only exclude after reading the full text and reasons for exclusion in the 'Characteristics of excluded studies' tables.

Data extraction and management

Two authors (CC and SW) independently extracted the data using a specialised data extraction form. We resolved discrepancies by discussion with a third author (FW). One author (CC) entered the data into Review Manager (RevMan) (Review Manager 2014).

Assessment of risk of bias in included studies

We evaluated the following components since there is some evidence that these are associated with biased estimates of intervention effect (Higgins 2011):

random sequence generation ‐ adequacy of the method of random sequence generation to produce comparable groups in every aspect except for the intervention;
allocation concealment ‐ adequacy of the method used to conceal the allocation sequence to prevent anyone foreseeing the allocation sequence in advance of, or during, enrolment;
blinding of participants and personnel ‐ adequacy of blinding study participants and researchers from knowledge of the allocated interventions;
blinding of outcome assessment ‐ adequacy of blinding outcome assessors from knowledge of the allocated interventions;
incomplete outcome data ‐ the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis, whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomised participants), reasons for attrition/exclusions where reported, and any re‐inclusions in our analyses;
selective reporting ‐ whether all prespecified outcomes were reported when the trial protocol was available; and
other sources of bias ‐ any other important concerns about bias.

Measures of treatment effect

For dichotomous outcomes, we expressed the results as risk ratios (RR) with 95% confidence intervals (CI) and where appropriate as number needed to treat to benefit (NNTB) with 95% CI and the baseline risk to which it applies. For continuous outcomes, we expressed the results as difference in means (MD) with 95% CI or where different outcome scales were pooled as standardised mean differences (SMD) with 95% CI. For time‐to‐event outcomes, we expressed the results as hazard ratios (HRs). If Kaplan‐Meier curves were presented, we would have extracted the data from the graphs and calculated HRs according to the methods given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). However, time‐to‐event outcomes were treated as continuous data in a few included trials. We therefore could only present the original data reported.

With regard to our primary outcome 'Adverse effects during use of the preventative intervention', we measured this by assessing the proportion of participants who experienced adverse events.

With regard to our secondary outcome 'Rate of adherence to the regimen of the preventative intervention', we measured this by assessing either the proportion of participants who adhered to the interventions or the mean proportion of interventions participants received.

Unit of analysis issues

All randomised participants in the control and intervention groups were the unit of analysis. We did not pool the following types of studies with studies of other designs.

Cluster‐randomised trials

For cluster‐randomised trials, we would have used appropriate techniques described in section 16.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Cross‐over trials

For cross‐over trials, we used appropriate techniques described in section 16.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Studies with multiple treatment groups

Where there were multiple intervention groups within a trial, we made pair‐wise comparisons of an intervention versus no intervention, placebo, or another active intervention.

Dealing with missing data

We contacted the original researchers of studies less than 15 years old for missing data (Table 21). When the missing data were not available, we initially assumed those data were missing at random. If the missing data were caused by participants' dropout, we conducted intention‐to‐treat analyses. For dichotomous outcomes, we would have regarded participants with missing outcome data as treatment failures and included them in the analyses. For continuous outcomes, we would have carried forward the last recorded value for participants with missing outcome data. Where high levels of missing data were seen within the analyses, we would have conducted sensitivity analyses to assess the robustness of the results from the approach described above by comparing the results with those that exclude the missing data from the analyses. However, we failed to conduct the planned analyses because of lacking adequate data, for example, the respective number of randomised participants and those who were lost to follow up in each group.

1. Trialists contacted for missing or unpublished data.

Study	Enquiries	Reply
Baker 2003	We sent the following request on 13 February 2015: (1) How did you randomise the participants? (2) Did you do any measures for allocation concealment? (3) Could you please offer the details of how you achieved double blindness? (4) Did you use a person other than the physician to assess the outcomes?	No reply
de Carvalho 2010	We sent the following request on 23 June 2014: (1) How did you randomise the participants? (2) Did you do any measures for allocation concealment? (3) Did you use a person other than the physician to assess the outcomes? (4) The number of dropouts or withdrawals in this trial (5) Did you assess any outcomes regarding adverse events? If you did, what were the results?	4 August 2014 (1) Randomisation was down through sortition (2) No (3) No (4) 01 (5) Adverse events were evaluated, but there were no adverse events detected
Gilbert 2007	We sent the following request on 13 February 2015: (1) How did you randomise the participants? (2) Did you do any measures for allocation concealment?	No reply
Pfitzer 2005	We sent the following request on 23 June 2014: (1) How did you randomise the participants? (2) Did you do any measures for allocation concealment? (3) The number of dropouts or withdrawals in this trial (4) Did you assess any outcomes regarding adverse events? If you did, what were the results?	No reply
Senti 2013	This trial was identified from searching trial registers (NCT00914745). We sent the following request on 27 December 2013: "Dear Prof Kündig, I am conducting a Cochrane review on interventions for prevention of herpes simplex labialis (see http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010095/abstract). I have noticed that you have completed a trial (http://clinicaltrials.gov/show/NCT00914745) that assessed a topical ointment for prevention of herpes simplex labialis, and was wondering if you would like to share your results with us, thus we could include your trial in our review. Your assistance would be appreciated"	The trialists provided us with the full published article
ISRCTN03397663	We sent the following request on 27 December 2013: "Dear Dr Cheras, I am conducting a Cochrane review on interventions for prevention of herpes simplex labialis (see http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010095/abstract). I have noticed that you completed a trial that used Sheabutter extract BSP110 for prevention of herpes simplex labialis (http://www.controlled‐trials.com/ISRCTN03397663#?close=1). I was wondering if you would like to share your results with us. Thus, we could include your trial in our review. Your assistance would be appreciated"	No reply
NCT01225341	We sent the following request on 27 December 2013: "Dear Dr Dayan, I am conducting a Cochrane review on interventions for prevention of herpes simplex labialis (see http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010095/abstract). I have noticed that you are conducting a trial that uses botulinum toxin A injections for prevention of herpes simplex labialis (http://clinicaltrials.gov/show/NCT01225341). I was wondering if you have completed the trial and would like to share your results with us. Thus, we could include your trial in our review. Your assistance would be appreciated"	No reply
NCT01971385	We sent the following request on 19 January 2014: "Dear Dr Kimball, I am conducting a Cochrane review on interventions for prevention of herpes simplex labialis (see http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010095/abstract). I have noticed that you are doing a trial (http://www.clinicaltrials.gov/ct2/show/NCT01971385) that assessed a topical ointment for prevention of herpes simplex labialis, and was wondering if you would like to share your results with us if you have completed the trial, thus we could include your trial in our review. Your assistance would be greatly appreciated"	No reply

Oral aciclovir (short‐term) compared with placebo for prevention of herpes simplex labialis
Patient or population: participants with recurrent herpes simplex labialis (cold sores on the lips)  Settings: ski sites and university hospitals  Intervention: oral aciclovir (short‐term)  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Oral aciclovir (short‐term)
Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ aciclovir 800 mg twice daily	Study population		RR 1.08   (0.62 to 1.87)	237  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
	171 per 1000	184 per 1000   (106 to 319)
	Moderate
	171 per 1000	185 per 1000   (106 to 320)
Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ aciclovir 400 mg twice daily	Study population		RR 0.26   (0.13 to 0.51)	177  (2 studies)	⊕⊕⊝⊝  Low²	‐
	364 per 1000	95 per 1000   (47 to 185)
	Moderate
	538 per 1000	140 per 1000   (70 to 274)
Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ aciclovir 200 mg 5 times/day	Study population		RR 0.46   (0.2 to 1.07)	66  (1 study)	⊕⊕⊝⊝  Low³	‐
	394 per 1000	181 per 1000   (79 to 422)
	Moderate
	394 per 1000	181 per 1000   (79 to 422)
Incidence of herpes labialis during use of the preventative intervention (by culture) ‐ aciclovir 400 mg twice daily	Study population		RR 0.05   (0 to 0.7)	30  (1 study)	⊕⊕⊝⊝  Low³	‐
	750 per 1000	38 per 1000   (0 to 525)
	Moderate
	750 per 1000	38 per 1000   (0 to 525)
Adverse effects during use of the preventative intervention ‐ aciclovir 800 mg twice daily	Study population		RR 0.98   (0.7 to 1.38)	239  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
	363 per 1000	356 per 1000   (254 to 501)
	Moderate
	363 per 1000	356 per 1000   (254 to 501)
Adverse effects during use of the preventative intervention ‐ aciclovir 400 mg twice daily	Study population		RR 2.3   (0.62 to 8.58)	183  (2 studies)	⊕⊕⊝⊝  Low²	‐
	33 per 1000	75 per 1000   (20 to 280)
	Moderate
	20 per 1000	46 per 1000   (12 to 172)
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; RR: risk ratio.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Oral aciclovir (long‐term) compared with placebo for prevention of herpes simplex labialis
Patient or population: participants with recurrent herpes simplex labialis  Settings: a medical centre  Intervention: oral aciclovir (long‐term)  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo	Oral aciclovir (long‐term)
Incidence of herpes labialis during use of the preventative intervention (by culture)	1.40 episodes per participant per a 4‐month period	0.40 episodes per participant per a 4‐month period	Not estimable	40  (1 study)	⊕⊕⊝⊝  Low¹	‐
Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation)	1.80 episodes per participant per a 4‐month period	0.85 episodes per participant per a 4‐month period	Not estimable	40  (1 study)	⊕⊕⊝⊝  Low¹	‐
Duration of attack of herpes labialis during use of the preventative intervention	‐	The mean duration of attack of herpes labialis during use of the preventative intervention in the intervention groups was 3.6 lower (7.2 lower to 0 higher)	‐	40  (1 study)	⊕⊕⊝⊝  Low¹	‐
Rate of adherence to the regimen of the preventative intervention	99% of the prescribed study medication	99% of the prescribed study medication	‐	40  (1 study)	⊕⊕⊝⊝  Low¹	‐
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; RR: risk ratio.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Valaciclovir (short‐term) compared with placebo for prevention of herpes simplex labialis
Patient or population: participants with recurrent herpes simplex labialis  Settings: a university hospital  Intervention: valaciclovir (short‐term)  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Valaciclovir (short‐term)
Incidence of HSL during use of the preventative intervention (by clinical evaluation)	Study population		RR 0.55   (0.23 to 1.28)	125  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
	206 per 1000	113 per 1000   (47 to 264)
	Moderate
	206 per 1000	113 per 1000   (47 to 264)
Incidence of HSL during use of the preventative intervention (by culture)	Study population		RR 0.47   (0.21 to 1.08)	125  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
	238 per 1000	112 per 1000   (50 to 257)
	Moderate
	238 per 1000	112 per 1000   (50 to 257)
Adverse effects during use of the preventative intervention	Study population		RR 1.33   (0.71 to 2.5)	125  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
	206 per 1000	274 per 1000   (147 to 516)
	Moderate
	206 per 1000	274 per 1000   (146 to 515)
Viral load (shedding) in saliva	Study population		RR 0.16   (0.02 to 1.26)	120  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
	103 per 1000	17 per 1000   (2 to 130)
	Moderate
	103 per 1000	16 per 1000   (2 to 130)
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; HSL: herpes simplex labialis; RR: risk ratio.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Valaciclovir (long‐term) compared with placebo for prevention of herpes labialis
Patient or population: participants with recurrent herpes labialis  Settings: a university hospital  Intervention: valaciclovir (long‐term)  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Valaciclovir (long‐term)
Incidence of herpes labialis during use of the preventative intervention	0.21 episodes per participant per month	0.12 episodes per participant per month	Not estimable	95  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
Adverse effects during use of the preventative intervention	Study population		RR 0.86   (0.51 to 1.46)	95  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
	396 per 1000	340 per 1000   (202 to 578)
	Moderate
	396 per 1000	341 per 1000   (202 to 578)
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; RR: risk ratio.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Valaciclovir (suppressive regimen compared with episodic regimen) for prevention of herpes labialis
Patient or population: participants with recurrent herpes labialis  Settings: a university hospital  Intervention: suppressive regimen  Comparison: episodic regimen
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Episodic regimen	Suppressive regimen
Incidence of herpes labialis during use of the preventative intervention (number of recurrences per participant per month)	0.1775 ± 0.1975	0.075 ± 0.1025	The mean incidence of herpes labialis during use of the preventative intervention in the intervention groups was 0.1 lower (0.16 to 0.05 lower)	120  (1 study)	⊕⊝⊝⊝  Very low¹	‐
Adverse effects during use of the preventative intervention	Study population		RR 1.21 (0.78 to 1.87)	152  (1 study)	⊕⊝⊝⊝  Very low¹	‐
	316 per 1000	382 per 1000   (246 to 591)
	Moderate
	316 per 1000	382 per 1000   (246 to 591)
Duration of attack of recurrent herpes labialis during use of the preventative intervention	2.86 ± 3.10 days	1.78 ± 2.92 days	The mean duration of attack of recurrent herpes labialis during use of the preventative intervention in the intervention groups was 1.08 days shorter (2.16 lower to 0 higher)	120  (1 study)	⊕⊝⊝⊝  Very low¹	‐
Severity (pain) of attack of recurrent herpes labialis during use of the preventative intervention	0.23 ± 0.32	0.14 ± 0.27	The mean severity (pain) of attack of recurrent herpes labialis during use of the preventative intervention in the intervention groups was 0.09 lower (0.2 lower to 0.02 higher)	120  (1 study)	⊕⊝⊝⊝  Very low¹	‐
Severity (maximum total lesion area) of attack of recurrent herpes labialis during use of the preventative intervention	10.52 ± 19.45 mm²	5.14 ± 9.98 mm²	The mean severity (maximum total lesion area) of attack of recurrent herpes labialis during use of the preventative intervention in the intervention groups was 5.38 smaller (10.91 lower to 0.15 higher)	120  (1 study)	⊕⊝⊝⊝  Very low¹	‐
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; RR: risk ratio.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Famciclovir compared with placebo for prevention of herpes labialis
Patient or population: participants with recurrent herpes labialis  Settings: multicentre  Intervention: famciclovir  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Famciclovir
Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ famciclovir 125 mg	Study population		RR 0.74   (0.5 to 1.11)	120  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
	517 per 1000	382 per 1000   (258 to 574)
	Moderate
	517 per 1000	383 per 1000   (259 to 574)
Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ famciclovir 250 mg	Study population		RR 0.69   (0.45 to 1.04)	122  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
	517 per 1000	357 per 1000   (232 to 537)
	Moderate
	517 per 1000	357 per 1000   (233 to 538)
Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ famciclovir 500 mg	Study population		RR 0.82   (0.56 to 1.21)	121  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
	517 per 1000	424 per 1000   (289 to 625)
	Moderate
	517 per 1000	424 per 1000   (290 to 626)
Duration of attack of recurrent herpes labialis during use of the preventative intervention ‐ famciclovir 125 mg	Study population		HR 1.63   (0.84 to 3.15)	47  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
	See comment²	See comment²
Duration of attack of recurrent herpes labialis during use of the preventative intervention ‐ famciclovir 250 mg	Study population		HR 1.59   (0.79 to 3.2)	45  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
	See comment²	See comment²
Duration of attack of recurrent herpes labialis during use of the preventative intervention ‐ famciclovir 500 mg	Study population		HR 2.39   (1.23 to 4.63)	51  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
	See comment²	Shortened by 2.8 days
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; HR: hazard ratio; RR: risk ratio.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Levamisole compared with placebo for prevention of herpes labialis
Patient or population: participants with recurrent herpes labialis  Settings: a university hospital  Intervention: levamisole  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Levamisole
Incidence of herpes labialis during use of the preventative intervention	2.7 ± 2.3 recurrences during a 6‐month period	The mean incidence of herpes labialis during use of the preventative intervention in the intervention groups was 2 lower (2.24 to 1.76 lower) during a 6‐month period	‐	72  (1 study)	⊕⊝⊝⊝  Very low¹	Of the 99 participants randomised, 27 (27.2%) did not complete the trial and were excluded from the analysis, with 19 (39.6%) in the levamisole group and 8 (15.7%) in the placebo group
Adverse effects during use of the preventative intervention (leading to withdrawal)	Study population		See comment	99  (1 study)	⊕⊝⊝⊝  Very low¹	Risks were calculated from pooled risk differences
	157 per 1000	395 per 1000   (227 to 566)
	Moderate
	157 per 1000	396 per 1000   (228 to 567)
Duration of attack of recurrent herpes labialis during use of the preventative intervention	8.2 ± 2.8 days	The mean duration of attack of recurrent herpes labialis during use of the preventative intervention in the intervention groups was 0.7 days longer (0.22 to 1.18 longer)	‐	72  (1 study)	⊕⊝⊝⊝  Very low¹	‐
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Lysine compared with placebo for prevention of herpes labialis
Patient or population: participants with recurrent herpes simplex labialis (cold sores on the lips)  Settings: a university hospital  Intervention: lysine  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Lysine
Incidence of herpes labialis during use of the preventative intervention (number of recurrences per participant per month)	‐	The mean incidence of herpes labialis during use of the preventative intervention in the intervention groups was 0.04 lower (0.37 lower to 0.29 higher)	‐	26  (1 study)	⊕⊝⊝⊝  Very low¹	‐
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Topical aciclovir (short‐term) compared with placebo for prevention of herpes labialis
Patient or population: participants with recurrent herpes labialis  Settings: ski sites and university hospitals  Intervention: topical aciclovir (short‐term)  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Topical aciclovir (short‐term)
Incidence of herpes labialis during use of the preventative intervention	Study population		RR 0.91   (0.48 to 1.72)	271  (2 studies)	⊕⊕⊕⊝  Moderate¹	‐
	304 per 1000	276 per 1000   (146 to 522)
	Moderate
	328 per 1000	298 per 1000   (157 to 564)
Adverse effects during use of the preventative intervention	Study population		RR 1.17   (0.59 to 2.32)	191  (1 study)	⊕⊕⊝⊝  Low²	‐
	135 per 1000	158 per 1000   (80 to 314)
	Moderate
	135 per 1000	158 per 1000   (80 to 313)
Severity (aborted lesions) of attack of recurrent herpes labialis during use of the preventative intervention	Study population		RR 1.02   (0.19 to 5.57)	52  (1 study)	⊕⊕⊝⊝  Low²	‐
	95 per 1000	97 per 1000   (18 to 530)
	Moderate
	95 per 1000	97 per 1000   (18 to 529)
Incidence of herpes labialis after use of the preventative intervention	Study population		RR 0.35   (0.13 to 0.94)	181  (1 study)	⊕⊕⊝⊝  Low²	‐
	156 per 1000	54 per 1000   (20 to 146)
	Moderate
	156 per 1000	55 per 1000   (20 to 147)
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; RR: risk ratio.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Topical aciclovir and 348U87 cream (short‐term) compared with placebo for prevention of herpes labialis
Patient or population: participants with recurrent herpes labialis  Settings: research institutes  Intervention: topical aciclovir and 348U87 cream (short‐term)  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Topical aciclovir and 348U87 cream (short‐term)
Incidence of herpes labialis during use of the preventative intervention (by culture)	Study population		RR 0.78   (0.19 to 3.14)	51  (1 study)	⊕⊝⊝⊝  Very low¹	‐
	154 per 1000	120 per 1000   (29 to 483)
	Moderate
	154 per 1000	120 per 1000   (29 to 484)
Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation)	Study population		RR 1.46   (0.53 to 3.99)	51  (1 study)	⊕⊝⊝⊝  Very low¹	‐
	192 per 1000	281 per 1000   (102 to 767)
	Moderate
	192 per 1000	280 per 1000   (102 to 766)
Duration of attack of recurrent herpes labialis during use of the preventative intervention	‐	The mean duration of attack of recurrent herpes labialis during use of the preventative intervention in the intervention groups was 2.5 days longer (1.39 shorter to 6.39 longer)	‐	9  (1 study)	⊕⊝⊝⊝  Very low¹	‐
Severity of attack of recurrent herpes labialis during use of the preventative intervention (maximum lesion area)	‐	The mean severity of attack of recurrent herpes labialis during use of the preventative intervention (maximum lesion area) in the intervention groups was 73 larger (42.22 smaller to 188.22 larger)	‐	9  (1 study)	⊕⊝⊝⊝  Very low¹	‐
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; RR: risk ratio.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of HSL during use of the preventative intervention (by clinical evaluation)	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.1 Aciclovir 800 mg twice daily	1	237	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.62, 1.87]
1.2 Aciclovir 400 mg twice daily	2	177	Risk Ratio (M‐H, Random, 95% CI)	0.26 [0.13, 0.51]
1.3 Aciclovir 200 mg 5 times/day	1	66	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.20, 1.07]
2 Incidence of HSL during use of the preventative intervention (by culture)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Adverse effects during use of the preventative intervention	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.1 Aciclovir 800 mg twice daily	1	239	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.70, 1.38]
3.2 Aciclovir 400 mg twice daily	2	183	Risk Ratio (M‐H, Fixed, 95% CI)	2.30 [0.62, 8.58]
4 Severity (lesion size) of attack of herpes labialis during use of the preventative intervention	2		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.1 Length	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Width	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Area	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Severity (stage) of attack of recurrent HSL during use of the preventative intervention	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5.1 Prodrome	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 Erythema	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.3 Papule	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Severity (pain) of attack of recurrent HSL during use of the preventative intervention	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7 Incidence of HSL after use of the preventative intervention	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Incidence of HSL during use of the preventative intervention (by clinical evaluation)	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.1 Famciclovir 125 mg	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Famciclovir 250 mg	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.3 Famciclovir 500 mg	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Duration of attack of recurrent HSL during use of the preventative intervention	1	Hazard Ratio (Random, 95% CI)	Totals not selected
2.1 Famciclovir 125 mg	1	Hazard Ratio (Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Famciclovir 250 mg	1	Hazard Ratio (Random, 95% CI)	0.0 [0.0, 0.0]
2.3 Famciclovir 500 mg	1	Hazard Ratio (Random, 95% CI)	0.0 [0.0, 0.0]
3 Severity (pain) of attack of recurrent HSL during use of the preventative intervention	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.1 Famciclovir 125 mg	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Famciclovir 250 mg	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.3 Famciclovir 500 mg	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of HSL during use of the preventative intervention (by clinical evaluation)	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.1 Solar radiation	1	51	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.25, 5.06]
1.2 Experimental ultraviolet light	2	111	Risk Ratio (M‐H, Random, 95% CI)	0.07 [0.01, 0.33]
2 Incidence of HSL during use of the preventative intervention (by culture)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of HSL during use of the preventative intervention	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.1 Presurgical	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Postsurgical	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.3 Pre‐ & postsurgical	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Adverse effects during use of the preventative intervention (fever)	2	114	Risk Ratio (M‐H, Random, 95% CI)	2.30 [1.44, 3.67]
2.1 Presurgical	1	32	Risk Ratio (M‐H, Random, 95% CI)	2.45 [1.26, 4.78]
2.2 Postsurgical	1	44	Risk Ratio (M‐H, Random, 95% CI)	1.96 [1.00, 3.84]
2.3 Pre‐ & postsurgical	1	38	Risk Ratio (M‐H, Random, 95% CI)	11.76 [0.71, 195.11]
3 Adverse effects during use of the preventative intervention (other)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.1 Pain & tenderness at injection site	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Malaise, nausea or vomiting	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Topical foscarnet compared with placebo for prevention of herpes labialis
Patient or population: participants with recurrent herpes labialis  Settings: medical centres  Intervention: topical foscarnet  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Topical foscarnet
Incidence of herpes labialis during use of the preventative intervention	Study population		RR 1.08   (0.82 to 1.4)	295  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
	408 per 1000	441 per 1000   (335 to 571)
	Moderate
	408 per 1000	441 per 1000   (335 to 571)
Adverse effects during use of the preventative intervention (leading to discontinuation)	Study population		RR 2.96   (0.12 to 72.11)	302  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
	0 per 1000	0 per 1000   (0 to 0)
	Moderate
	0 per 1000	0 per 1000   (0 to 0)
Adverse effects during use of the preventative intervention (application site reactions)	Study population		RR 2.47   (0.79 to 7.69)	302  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
	27 per 1000	66 per 1000   (21 to 205)
	Moderate
	27 per 1000	67 per 1000   (21 to 208)
Duration of attack of recurrent herpes labialis during use of the preventative intervention (healing time)	‐	The mean duration of attack of recurrent herpes labialis during use of the preventative intervention (healing time) in the intervention groups was 0.21 days shorter (1.68 shorter to 1.26 longer)	‐	125  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
Severity of attack of recurrent herpes labialis during use of the preventative intervention (mean lesion area)	‐	The mean severity of attack of recurrent herpes labialis during use of the preventative intervention (mean lesion area) in the intervention groups was 16 lower (38.96 lower to 6.96 higher)	‐	124  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
Severity of attack of recurrent herpes labialis during use of the preventative intervention (maximum lesion area)	‐	The mean severity of attack of recurrent herpes labialis during use of the preventative intervention (maximum lesion area) in the intervention groups was 30 lower (72.64 lower to 12.64 higher)	‐	124  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
Severity of attack of recurrent herpes labialis during use of the preventative intervention (duration of pain)	‐	The mean severity of attack of recurrent herpes labialis during use of the preventative intervention (duration of pain) in the intervention groups was 0.1 higher (1.11 lower to 1.31 higher)	‐	113  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; RR: risk ratio.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Topical 1,5‐pentanediol compared with placebo for prevention of herpes labialis
Patient or population: participants with recurrent herpes labialis  Settings: study centres  Intervention: topical 1,5‐pentanediol  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Topical 1,5‐pentanediol
Incidence of herpes labialis during use of the preventative intervention	Study population		Not estimable	102  (1 study)	⊕⊕⊕⊝  Moderate¹	P > 0.05 calculated using the Mann‐Whitney test by the trialists
	109 episodes out of 50	120 episodes out of 52
	Moderate
	‐	‐
Adverse effects during use of the preventative intervention	Study population		Not estimable	102  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
	See comment	See comment
	Moderate
	‐	‐
Severity (blistering, swelling, or pain) of recurrence	Study population		RR 1.05   (0.91 to 1.2)	224  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
	756 per 1000	794 per 1000   (688 to 908)
	Moderate
	756 per 1000	794 per 1000   (688 to 907)
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; RR: risk ratio.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sunscreen compared with placebo for prevention of herpes labialis
Patient or population: participants with recurrent herpes labialis  Settings: single centre and multicentre  Intervention: sunscreen  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Sunscreen
Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ solar radiation	Study population		RR 1.12   (0.25 to 5.06)	51  (1 study)	⊕⊕⊝⊝  Low¹	‐
	111 per 1000	124 per 1000   (28 to 562)
	Moderate
	111 per 1000	124 per 1000   (28 to 562)
Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ experimental ultraviolet light	Study population		RR 0.07   (0.01 to 0.33)	111  (2 studies)	⊕⊝⊝⊝  Very low²	‐
	456 per 1000	32 per 1000   (5 to 151)
	Moderate
	487 per 1000	34 per 1000   (5 to 161)
Incidence of herpes labialis during use of the preventative intervention (by culture)	Study population		See comment	73  (1 study)	⊕⊝⊝⊝  Very low³	Risks were calculated from pooled risk differences
	658 per 1000	26 per 1000   (0 to 191)
	Moderate
	658 per 1000	26 per 1000   (0 to 191)
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; RR: risk ratio.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Interferon compared with placebo for prevention of herpes labialis
Patient or population: participants with recurrent herpes labialis  Settings: hospitals  Intervention: interferon  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Interferon
Incidence of herpes labialis during use of the preventative intervention ‐ presurgical	Study population		RR 1.59   (1.05 to 2.41)	32  (1 study)	⊕⊕⊝⊝  Low¹^, ²	‐
	571 per 1000	909 per 1000   (600 to 1000)
	Moderate
	571 per 1000	908 per 1000   (600 to 1000)
Incidence of herpes labialis during use of the preventative intervention ‐ postsurgical	Study population		RR 0.99   (0.59 to 1.66)	44  (1 study)	⊕⊕⊝⊝  Low¹^, ²	‐
	571 per 1000	566 per 1000   (337 to 949)
	Moderate
	571 per 1000	565 per 1000   (337 to 948)
Incidence of herpes labialis during use of the preventative intervention ‐ pre‐ and postsurgical	Study population		RR 0.57   (0.34 to 0.95)	37  (1 study)	⊕⊕⊝⊝  Low¹^, ²	‐
	833 per 1000	475 per 1000   (283 to 792)
	Moderate
	833 per 1000	475 per 1000   (283 to 791)
Adverse effects during use of the preventative intervention (fever) ‐ presurgical	Study population		RR 2.45   (1.26 to 4.78)	32  (1 study)	⊕⊕⊕⊝  Moderate²	‐
	333 per 1000	817 per 1000   (420 to 1000)
	Moderate
	333 per 1000	816 per 1000   (420 to 1000)
Adverse effects during use of the preventative intervention (fever) ‐ postsurgical	Study population		RR 1.96   (1 to 3.84)	44  (1 study)	⊕⊕⊕⊝  Moderate²	‐
	333 per 1000	653 per 1000   (333 to 1000)
	Moderate
	333 per 1000	653 per 1000   (333 to 1000)
Adverse effects during use of the preventative intervention (fever) ‐ pre‐ and postsurgical	Study population		RR 11.76   (0.71 to 195.11)	38  (1 study)	⊕⊕⊕⊝  Moderate²	‐
	0 per 1000	0 per 1000   (0 to 0)
	Moderate
	0 per 1000	0 per 1000   (0 to 0)
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; RR: risk ratio.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Gamma globulin compared with histamine (control) for prevention of herpes labialis
Patient or population: participants with recurrent herpes labialis  Settings: single centre  Intervention: gamma globulin  Comparison: histamine (control)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Histamine (control)	Gamma globulin
Duration of attack of recurrent herpes labialis during use of the preventative intervention	‐	The mean duration of attack of recurrent herpes labialis during use of the preventative intervention in the intervention groups was 0.7 higher (0.55 lower to 1.95 higher)	‐	72  (1 study)	⊕⊕⊝⊝  Low¹	‐
Severity of attack of recurrent herpes labialis during use of the preventative intervention (less severe recurrences than usual)	Study population		RR 0.97   (0.74 to 1.28)	73  (1 study)	⊕⊕⊝⊝  Low¹	‐
	750 per 1000	728 per 1000   (555 to 960)
	Moderate
	750 per 1000	728 per 1000   (555 to 960)
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; RR: risk ratio.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Thymopentin compared with placebo for prevention of herpes labialis
Patient or population: participants with recurrent herpes labialis  Settings: medical centres  Intervention: thymopentin  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Thymopentin
Incidence of herpes labialis during use of the preventative intervention	0.9 (range 0.1 to 2.0)	Median 0.2 (range 0.0 to 2.7)	‐	36  (1 study)	⊕⊕⊕⊝  Moderate¹	P = 0.0027 using the Mann‐Whitney test by the trialists
Adverse effects during use of the preventative intervention	111 per 1000	222 per 1000   (47 to 1000)	RR 2   (0.42 to 9.58)	36  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; RR: risk ratio.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

HSV vaccination compared with placebo for prevention of herpes labialis
Patient or population: participants with recurrent herpes labialis  Settings: university hospitals  Intervention: HSV vaccination  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	HSV vaccination
Incidence of herpes labialis during use of the preventative intervention	1.3 recurrences in a 4‐month period	1.6 recurrences in a 4‐month period	P = 0.10 calculated by the trialists	64  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
Adverse effects during use of the preventative intervention	13 adverse events per 100 injections	22 adverse events per 100 injections	RR 0.33   (0.01 to 7.45)	64  (1 study)	⊕⊕⊕⊝  Moderate¹	Several adverse events might have occurred in the same participant; no statistical tests were conducted by the trialists
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; HSV: herpes simplex virus; RR: risk ratio.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Yellow fever vaccination compared with placebo for prevention of herpes labialis
Patient or population: participants with recurrent herpes labialis  Settings: hospital  Intervention: yellow fever vaccination  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Yellow fever vaccination
Incidence of herpes labialis during use of the preventative intervention	See comment	See comment	‐	1  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
Adverse effects during use of the preventative intervention	83 per 1000	28 per 1000   (1 to 621)	RR 0.33   (0.01 to 7.45)	24  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; RR: risk ratio.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Laser compared with no interventions for prevention of herpes labialis
Patient or population: participants with recurrent herpes labialis  Settings: university hospitals  Intervention: laser  Comparison: no interventions
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	No interventions	Laser
Incidence of herpes labialis during use of the preventative intervention	0.116 recurrences per month	0.076 recurrences per month	Not estimable	71  (1 study)	⊕⊝⊝⊝  Very low¹	P = 0.076, calculated using the Mann‐Whitney U test by the trialists
Adverse effects during use of the preventative intervention	0	0	Not estimable	119  (2 studies)	⊕⊕⊝⊝  Low²	No adverse events were observed in either group
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; RR: risk ratio.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Hypnotherapy compared with control for prevention of herpes labialis
Patient or population: participants with recurrent herpes labialis  Settings: psychological institute  Intervention: hypnotherapy  Comparison: control
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Hypnotherapy
Incidence of herpes labialis during use of the preventative intervention (change in frequency of recurrence)	‐	The mean incidence of herpes labialis during use of the preventative intervention (change in frequency of recurrence) in the intervention groups was 6.5 lower (8.76 to 4.24 lower)	‐	21  (1 study)	⊕⊝⊝⊝  Very low¹	‐
Severity of attack of recurrent herpes labialis during use of the preventative intervention (change in intensity)	‐	The mean severity of attack of recurrent herpes labialis during use of the preventative intervention (change in intensity) in the intervention groups was 9.7 lower (12.46 to 6.94 lower)	‐	21  (1 study)	⊕⊝⊝⊝  Very low¹	‐
Change in severity (pain) of herpes labialis	‐	The mean change in severity (pain) of herpes labialis in the intervention groups was 2.2 lower (3.14 to 1.26 lower)	‐	21  (1 study)	⊕⊝⊝⊝  Very low¹	‐
Change in severity (impairment of appearance) of herpes labialis	‐	The mean change in severity (impairment of appearance) of herpes labialis in the intervention groups was 1.6 lower (2.5 to 0.7 lower)	‐	21  (1 study)	⊕⊝⊝⊝  Very low¹	‐
The basis for the assumed risk* (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

PERMALINK

Interventions for prevention of herpes simplex labialis (cold sores on the lips)

Ching‐Chi Chi

Shu‐Hui Wang

Finola M Delamere

Fenella Wojnarowska

Mathilde C Peters

Preetha P Kanjirath

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Trials registers

Searching other resources

Reference lists

Unpublished literature

Adverse effects

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Cluster‐randomised trials

Cross‐over trials

Studies with multiple treatment groups

Dealing with missing data

1. Trialists contacted for missing or unpublished data.

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Other

Results

Description of studies

Results of the search

1.

Included studies

Design

Sample sizes

Setting

Participants

Interventions

Outcomes

Funding source

Excluded studies

Ongoing Studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. Oral aciclovir (short‐term) compared with placebo for prevention of herpes simplex labialis.

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Incidence of herpes labialis during use of the preventative intervention (by culture)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Adverse effects during use of the preventative intervention	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Viral load (shedding) in saliva	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Incidence of herpes labialis during use of the preventative intervention (number of recurrences per participant per month)	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
2 Adverse effects during use of the preventative intervention	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3 Duration of attack of recurrent HSL during use of the preventative intervention	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
4 Severity (pain) of attack of recurrent HSL during use of the preventative intervention	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
5 Severity (maximum total lesion area) of attack of recurrent HSL during use of the preventative intervention	1	Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of HSL during use of the preventative intervention	2	271	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.48, 1.72]
2 Adverse effects during use of the preventative intervention	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3 Severity (aborted lesions) of attack of recurrent HSL during use of the preventative intervention	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4 Incidence of HSL after use of the preventative intervention	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Duration of attack of recurrent HSL during use of the preventative intervention	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
2 Severity of attack of recurrent HSL during use of the preventative intervention (less severe recurrences than usual)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Methods	This was a multicentre, randomised, double‐blind study
Participants	Inclusion criteria Detection of herpes simplex virus type I in the herpes lesions Occurrence of at least 4 episodes of herpes eruptions within the last 4 months before the start of the study A herpes episode or a recurrence of herpes had to meet the following clinical criteria: small grouped vesicles on gerӧ‐coated background with discomfort, such as burning or stinging Exclusion criteria Had acute or chronic infections needing therapy, malignancies, and disease associated with immunosuppression Age under 18 years and over 50 years Application of antivirals after the start of the study Pregnancy A total of 64 participants were randomised, with 35 in the vaccine group and 29 in the placebo group
Interventions	A: HSV type I subunit vaccine B: placebo The participants were followed up for a 4‐month 'pilot phase' without treatments. Then in the first main phase of 4 months' duration, the assigned treatment was given weekly for 3 times on days 120, 127, and 134. In the second main phase of another 4 months' duration, the assigned treatment was repeated for another 3 times on days 240, 247, and 254
Outcomes	Number of HSL recurrences in the first main phase and the total main phase (compared with that in the pilot phase) Adverse events
Notes	Setting: university hospitals Country: Germany Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The methods of random sequence generation were not reported
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not mentioned
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	The vaccine and placebo preparations were identical in appearance and labelling except for the consecutive number of the labelling
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	The vaccine and placebo preparations were identical in appearance and labelling except for the consecutive number of the labelling
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	1 participant dropped out immediately after allocation to the vaccine group. 1 participant in the vaccine group and 1 in the placebo group withdrew before treatments started. 1 in the vaccine group withdrew after completing the vaccination due to an adverse event. 1 in the vaccine group and 1 in the placebo group withdrew in the second main phase. Thus, a total of 4 (11.4%) and 2 (6.9%) participants in the vaccine and placebo group, respectively, did not complete the study
Selective reporting (reporting bias)	Low risk	Both efficacy and adverse outcomes were reported
Other bias	Unclear risk	There was insufficient information to assess whether an important risk of bias existed

Methods	This was a pooled analysis of 2 randomised, double‐blind, placebo‐controlled, single‐centre studies
Participants	Inclusion criteria Men or women aged 18 years or older who tested seropositive for herpes simplex virus type 1 by Western blot test and had a history of at least 4 herpes simplex virus type 1 herpes labialis lesions in the previous year Exclusion criteria People were excluded if they (1) had used any antiherpes medication in the month prior to enrolment; (2) showed evidence of active herpes labialis reactivation; (3) were immunosuppressed or taking immunosuppressant medication; or (4) were women who were breast‐feeding or had a positive pregnancy test A total of 98 participants were randomised, with 49 in each group
Interventions	A: oral valaciclovir 500 mg once daily for 4 months B: oral placebo once daily for 4 months If there was clinical evidence of recurrent herpes labialis, participants received open‐label oral valaciclovir 500 mg twice daily for 5 days. Participants resumed their assigned study medication at the end of the 5‐day open‐label regimen
Outcomes	Incidence of HSL during use of the preventative intervention (researcher‐diagnosed): participants were instructed to contact their clinician within 8 hours of any sign of a recurrence of a herpes labialis lesion occurring at any time during the 4‐month treatment period. Participants were to be examined at the clinic within 12 hours of onset of a suspected recurrent lesion Adverse effects during use of the preventative intervention
Notes	Setting: a university hospital Country: US Funding source: supported in part by GlaxoSmithKline
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The methods of random sequence generation were not reported
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not mentioned
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "double‐blind" Comment: probably done
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "double‐blind" Comment: probably done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "All patients randomized to treatment who attended at least 1 of the monthly clinic visits were included in the efficacy analyses." "Two patients (1 in the valaciclovir group and 1 in the placebo group) who were lost to follow‐up and 1 patient in the valaciclovir group who withdrew prior to the first clinic visit were not included in the efficacy analyses" Comment: only 3 (3.1%) out of 98 participants were lost to follow up
Selective reporting (reporting bias)	Low risk	The number of participants with recurrences, number of recurrences per participant per month, and incidence of adverse events during the treatment period were reported
Other bias	Unclear risk	There was insufficient information to assess whether an important risk of bias existed

Methods	This was a double‐blind, randomised, placebo‐controlled trial
Participants	Inclusion criteria Healthy adults with a history of sunlight‐induced herpes labialis and at least 2 episodes of herpes labialis in the preceding year Exclusion criteria Use of anti‐inflammatory medication within 1 week was not permitted Use of immunomodulatory drugs or antiviral mediation within 30 days was not permitted Use of lip balm, cosmetics, soaps, fragrances, or medication known to produce abnormal response to sunlight were also prohibited A total of 51 participants were randomised, with 25 and 26 in the aciclovir and 348U87 group and placebo group, respectively
Interventions	A: topical aciclovir and 348U87 cream (consisted of aciclovir 5% and 348U87 3% in a 40% propylene glycol base) B: placebo cream Immediately after UV exposure, participants began treatment by application of the study medication to the UV‐exposed quadrant. The cream was applied every 2 hours while awake (maximum 8 applications/day), for 7 days. If herpetic lesions developed, treatment was continued until the lesions healed up to a maximum of 5 additional days
Outcomes	Incidence of HSL during use of the preventative intervention (researcher‐diagnosed): number of participants developing HSV culture‐positive or any lesions consistent with herpes labialis Severity of attack of recurrent HSL during use of the preventative intervention: number of HSV culture‐positive lesions and number of lesions consistent with herpes labialis
Notes	Setting: research institutes (James N. Gamble Institute of Medical Research and Hilltop Research) Country: US Funding source: Burroughs Wellcome & Co.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomly assigned according to a code supplied by the sponsor" Comment: probably done
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not mentioned
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "A subsequent double blind evaluation was performed...on 51 subjects to assess the effects of a combination of topical aciclovir and 348U87 compared to placebo on lesion development and severity"
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "A subsequent double blind evaluation was performed...on 51 subjects to assess the effects of a combination of topical aciclovir and 348U87 compared to placebo on lesion development and severity"
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	No dropouts or withdrawals were reported
Selective reporting (reporting bias)	High risk	The adverse effects during use of the preventative intervention were not reported
Other bias	High risk	Quote: "The sample size for the drug evaluation was estimated to be 50 patients per group to achieve a power of 80% and a significance level of 0.05 if the drug decreased recurrences by 60%. An interim analysis after 50 subjects was planned." "Because there was no trend for the benefit of the drug treatment the study was discontinued after the interim analyses" Comment: this was an early‐stopped trial. Therefore, a small benefit of the study drug could not be ruled out

Methods	This was a randomised, double‐blind, multicentre trial
Participants	Inclusion criteria Healthy adults with a history of sunlight‐induced herpes labialis Exclusion criteria None reported A total of 310 participants were enrolled at the 4 centres, but 8 did not receive the study drug. Of the 302 treated participants, 152 received foscarnet 3% and 150 received placebo cream. 7 participants (4 for foscarnet and 3 for placebo) were excluded from the efficacy analysis because of major predefined protocol violations
Interventions	A: topical foscarnet 3% (trisodium phosphonoformate) in an oil‐in‐water cream B: vehicle alone Beginning immediately after ultraviolet radiation (UVR) exposure of the lips, participants applied the cream on the UVR‐exposed area and surrounding skin 8 times daily (at least every 2 hours while awake) for 7 days, but if a herpetic lesion developed, dosing was extended as necessary to treat the lesion for at least 4 days. The time of each application was recorded in a participant diary
Outcomes	Recurrence of HSL (researcher‐diagnosed): following UVR exposure of the lips, participants returned on days 2, 3, 5, 8 ± 1, and 14 ± 1 and were examined for the development of herpes labialis Adverse events Healing time (from appearance of vesicle to loss of crust) Mean lesion area Maximum lesion area Duration of pain
Notes	Setting: 4 medical centres Country: US Funding source: Astra Arcus AB, Sweden
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The methods of randomisation were not reported
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not mentioned
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "This was a randomized, double‐blind investigation" Comment: probably done
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "This was a randomized, double‐blind investigation" Comment: probably done
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Quote: "A total of 310 subjects were enrolled at the four centers, but 8 did not receive the study drug." "Seven subjects (four for foscarnet and three for placebo) were excluded from the efficacy analysis because of major predefined protocol violations" Comment: there were 15 (4.8%) dropouts/withdrawals out of 310 enrolled participants
Selective reporting (reporting bias)	Low risk	The efficacy outcomes and adverse effects were reported
Other bias	Unclear risk	There was insufficient information to assess whether an important risk of bias existed

Methods	This was a placebo‐controlled, double‐blind, randomised, multicentre study
Participants	Inclusion criteria Frequent recurrences of herpes infections (on average not less than 12 per year, i.e., 1 per month) Viral culture was desired but not obligatory Duration of the disease should have been longer than 6 months Exclusion criteria People with significant renal, haematologic, hepatic, or other acute/chronic disease (severe congestive heart failure, uncontrolled diabetes mellitus, etc.) that might have jeopardised their ability to participate in the study were excluded, as well as females with childbearing potential using no adequate contraception A total of 36 participants older than 16 years and suffering from frequent recurrences (≥ 12 relapses/year) of herpes labialis infections, with 18 in each group, entered this study
Interventions	A: thymopentin B: placebo Thymopentin was provided in a concentration of 100 mg/ml. A 6‐week treatment with 0.5 ml of the test drug (50 mg thymopentin or placebo), administered by the subcutaneous route 3 times weekly, was performed
Outcomes	After the double‐blind course of treatment, a follow‐up period of 18 weeks without any treatment was proposed. After 6 weeks' treatment and at the end of the follow‐up period, the outcomes below were assessed: Incidence of herpes labialis after use of the preventative intervention Adverse effects during use of the preventative intervention Duration of attack of herpes labialis after use of the preventative intervention
Notes	Setting: 14 medical centres Country: Europe Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The methods of randomisation were not reported
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not mentioned
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "Thymopentin and placebo (vehicle) were supplied in coded, unidentifiable 5‐ml multidose vials"
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "double blind"
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	No dropouts or withdrawals were reported
Selective reporting (reporting bias)	Low risk	Both the efficacy outcomes and adverse effects were reported
Other bias	Unclear risk	There was insufficient information to permit judgement

Methods	This was a randomised, double‐blind, placebo‐controlled trial
Participants	Inclusion criteria Participants should have had at least 6 episodes of recurrent herpes during the preceding 12‐month period Exclusion criteria None reported A total of 105 participants were randomised to either 1,5‐pentanediol (PD) (53 participants) or placebo (52 participants)
Interventions	A: topical PD gel B: placebo The clinical trial consisted of a prophylactic period of 26 weeks, during which at least 2 examinations (at the start of the trial and after 25 to 27 weeks) were performed. During the prophylactic phase, the participants applied PD or placebo gel twice daily to both lips. Upon occurrence of a herpes episode, the participant started immediately with the therapy phase and presented herself/himself promptly to the participating investigator for confirmation of the herpes symptoms. During the 5‐day therapy phase, the gel was applied 8 times daily. On day 6 after the start of the therapy, the participant visited the investigator again for examination and evaluation of the healing process and started prophylactic treatment twice daily again until the next herpes episode
Outcomes	Incidence of HSL during use of the preventative intervention Adverse effects during use of the preventative intervention Severity (blistering, swelling, and pain) of attack of recurrent HSL during use of the preventative intervention
Notes	Setting: 4 study centres in Berlin Country: Germany Funding source: Natumin Pharma AB
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomization for this clinical trial was undertaken with the help of randomization plan NP/RL/060407/132"
Allocation concealment (selection bias)	Low risk	Quote: "The gel supplied to the patients had a consecutive random number on the label. This number was previously assigned to the PD gel and to the placebo gel externally. Neither the investigator nor the patients had any knowledge of what kind of treatment was given"
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "The PD and the placebo gel were packed in 4 g tubes and labelled for the clinical trial. The gels were not distinguishable by color or smell." "Neither the investigator nor the patients had any knowledge of what kind of treatment was given"
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "The gel supplied to the patients had a consecutive random number on the label. This number was previously assigned to the PD gel and to the placebo gel externally. Neither the investigator nor the patients had any knowledge of what kind of treatment was given." "The randomization code remained with the study sponsor until the final closure of the database"
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Of the 105 participants recruited, 3 (2.9%) participants who had been assigned to the PD group dropped out of the study
Selective reporting (reporting bias)	Low risk	The efficacy outcomes and adverse events were reported
Other bias	Unclear risk	There was insufficient information to permit judgement