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Meta-Analysis
. 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 , Shu-Hui Wang, Finola M Delamere, Fenella Wojnarowska, Mathilde C Peters, Preetha P Kanjirath
Affiliations
Meta-Analysis

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

Ching-Chi Chi et al. Cochrane Database Syst Rev. .

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.

PubMed Disclaimer

Conflict of interest statement

Ching‐Chi Chi: nothing to declare. Shu‐Hui Wang: nothing to declare. Finola M Delamere: nothing to declare. Fenella Wojnarowska: nothing to declare. Mathilde C Peters: nothing to declare. Preetha P Kanjirath: nothing to declare.

Oliver Chosidow, who refereed this protocol, has acted as a consultant for BioAlliance Pharma, a company developing a long‐acting aciclovir formulation in the management of episodic therapy of cold sores.

Figures

1
1
Study flow diagram.
2
2
'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.
3
3
'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.
1.1
1.1. Analysis
Comparison 1 Oral aciclovir (short‐term) versus placebo, Outcome 1 Incidence of HSL during use of the preventative intervention (by clinical evaluation).
1.2
1.2. Analysis
Comparison 1 Oral aciclovir (short‐term) versus placebo, Outcome 2 Incidence of HSL during use of the preventative intervention (by culture).
1.3
1.3. Analysis
Comparison 1 Oral aciclovir (short‐term) versus placebo, Outcome 3 Adverse effects during use of the preventative intervention.
1.4
1.4. Analysis
Comparison 1 Oral aciclovir (short‐term) versus placebo, Outcome 4 Severity (lesion size) of attack of herpes labialis during use of the preventative intervention.
1.5
1.5. Analysis
Comparison 1 Oral aciclovir (short‐term) versus placebo, Outcome 5 Severity (stage) of attack of recurrent HSL during use of the preventative intervention.
1.6
1.6. Analysis
Comparison 1 Oral aciclovir (short‐term) versus placebo, Outcome 6 Severity (pain) of attack of recurrent HSL during use of the preventative intervention.
1.7
1.7. Analysis
Comparison 1 Oral aciclovir (short‐term) versus placebo, Outcome 7 Incidence of HSL after use of the preventative intervention.
2.1
2.1. Analysis
Comparison 2 Oral aciclovir (long‐term) versus placebo, Outcome 1 Duration of attack of herpes labialis during use of the preventative intervention.
3.1
3.1. Analysis
Comparison 3 Valaciclovir (short‐term) versus placebo, Outcome 1 Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation).
3.2
3.2. Analysis
Comparison 3 Valaciclovir (short‐term) versus placebo, Outcome 2 Incidence of herpes labialis during use of the preventative intervention (by culture).
3.3
3.3. Analysis
Comparison 3 Valaciclovir (short‐term) versus placebo, Outcome 3 Adverse effects during use of the preventative intervention.
3.4
3.4. Analysis
Comparison 3 Valaciclovir (short‐term) versus placebo, Outcome 4 Viral load (shedding) in saliva.
4.1
4.1. Analysis
Comparison 4 Valaciclovir (long‐term) versus placebo, Outcome 1 Adverse effects during use of the preventative intervention.
5.1
5.1. Analysis
Comparison 5 Valaciclovir (suppressive regimen versus episodic regimen), Outcome 1 Incidence of herpes labialis during use of the preventative intervention (number of recurrences per participant per month).
5.2
5.2. Analysis
Comparison 5 Valaciclovir (suppressive regimen versus episodic regimen), Outcome 2 Adverse effects during use of the preventative intervention.
5.3
5.3. Analysis
Comparison 5 Valaciclovir (suppressive regimen versus episodic regimen), Outcome 3 Duration of attack of recurrent HSL during use of the preventative intervention.
5.4
5.4. Analysis
Comparison 5 Valaciclovir (suppressive regimen versus episodic regimen), Outcome 4 Severity (pain) of attack of recurrent HSL during use of the preventative intervention.
5.5
5.5. Analysis
Comparison 5 Valaciclovir (suppressive regimen versus episodic regimen), Outcome 5 Severity (maximum total lesion area) of attack of recurrent HSL during use of the preventative intervention.
6.1
6.1. Analysis
Comparison 6 Famciclovir versus placebo, Outcome 1 Incidence of HSL during use of the preventative intervention (by clinical evaluation).
6.2
6.2. Analysis
Comparison 6 Famciclovir versus placebo, Outcome 2 Duration of attack of recurrent HSL during use of the preventative intervention.
6.3
6.3. Analysis
Comparison 6 Famciclovir versus placebo, Outcome 3 Severity (pain) of attack of recurrent HSL during use of the preventative intervention.
7.1
7.1. Analysis
Comparison 7 Levamisole versus placebo, Outcome 1 Incidence of HSL during use of the preventative intervention.
7.2
7.2. Analysis
Comparison 7 Levamisole versus placebo, Outcome 2 Adverse effects during use of the preventative intervention (leading to withdrawal).
7.3
7.3. Analysis
Comparison 7 Levamisole versus placebo, Outcome 3 Duration of attack of recurrent HSL during use of the preventative intervention.
8.1
8.1. Analysis
Comparison 8 Lysine versus placebo, Outcome 1 Incidence of HSL during use of the preventative intervention (number of recurrences per participant per month).
9.1
9.1. Analysis
Comparison 9 Topical aciclovir (short‐term) versus placebo, Outcome 1 Incidence of HSL during use of the preventative intervention.
9.2
9.2. Analysis
Comparison 9 Topical aciclovir (short‐term) versus placebo, Outcome 2 Adverse effects during use of the preventative intervention.
9.3
9.3. Analysis
Comparison 9 Topical aciclovir (short‐term) versus placebo, Outcome 3 Severity (aborted lesions) of attack of recurrent HSL during use of the preventative intervention.
9.4
9.4. Analysis
Comparison 9 Topical aciclovir (short‐term) versus placebo, Outcome 4 Incidence of HSL after use of the preventative intervention.
10.1
10.1. Analysis
Comparison 10 Topical aciclovir and 348U87 cream (short‐term) versus placebo, Outcome 1 Incidence of HSL during use of the preventative intervention (by culture).
10.2
10.2. Analysis
Comparison 10 Topical aciclovir and 348U87 cream (short‐term) versus placebo, Outcome 2 Incidence of HSL during use of the preventative intervention (by clinical evaluation).
10.3
10.3. Analysis
Comparison 10 Topical aciclovir and 348U87 cream (short‐term) versus placebo, Outcome 3 Duration of attack of recurrent HSL during use of the preventative intervention.
10.4
10.4. Analysis
Comparison 10 Topical aciclovir and 348U87 cream (short‐term) versus placebo, Outcome 4 Severity of attack of recurrent HSL during use of the preventative intervention (maximum lesion area).
11.1
11.1. Analysis
Comparison 11 Topical foscarnet versus placebo, Outcome 1 Incidence of HSL during use of the preventative intervention.
11.2
11.2. Analysis
Comparison 11 Topical foscarnet versus placebo, Outcome 2 Adverse effects during use of the preventative intervention (leading to discontinuation).
11.3
11.3. Analysis
Comparison 11 Topical foscarnet versus placebo, Outcome 3 Adverse effects during use of the preventative intervention (application site reactions).
11.4
11.4. Analysis
Comparison 11 Topical foscarnet versus placebo, Outcome 4 Duration of attack of recurrent HSL during use of the preventative intervention (healing time).
11.5
11.5. Analysis
Comparison 11 Topical foscarnet versus placebo, Outcome 5 Severity of attack of recurrent HSL during use of the preventative intervention (mean lesion area).
11.6
11.6. Analysis
Comparison 11 Topical foscarnet versus placebo, Outcome 6 Severity of attack of recurrent HSL during use of the preventative intervention (maximum lesion area).
11.7
11.7. Analysis
Comparison 11 Topical foscarnet versus placebo, Outcome 7 Severity of attack of recurrent HSL during use of the preventative intervention (duration of pain).
12.1
12.1. Analysis
Comparison 12 Topical 1,5‐pentanediol versus placebo, Outcome 1 Severity (blistering, swelling, or pain) of recurrence.
13.1
13.1. Analysis
Comparison 13 Sunscreen versus placebo, Outcome 1 Incidence of HSL during use of the preventative intervention (by clinical evaluation).
13.2
13.2. Analysis
Comparison 13 Sunscreen versus placebo, Outcome 2 Incidence of HSL during use of the preventative intervention (by culture).
14.1
14.1. Analysis
Comparison 14 Interferon versus placebo, Outcome 1 Incidence of HSL during use of the preventative intervention.
14.2
14.2. Analysis
Comparison 14 Interferon versus placebo, Outcome 2 Adverse effects during use of the preventative intervention (fever).
14.3
14.3. Analysis
Comparison 14 Interferon versus placebo, Outcome 3 Adverse effects during use of the preventative intervention (other).
15.1
15.1. Analysis
Comparison 15 Gamma globulin versus histamine (control), Outcome 1 Duration of attack of recurrent HSL during use of the preventative intervention.
15.2
15.2. Analysis
Comparison 15 Gamma globulin versus histamine (control), Outcome 2 Severity of attack of recurrent HSL during use of the preventative intervention (less severe recurrences than usual).
16.1
16.1. Analysis
Comparison 16 Thymopentin versus placebo, Outcome 1 Adverse effects during use of the preventative intervention.
17.1
17.1. Analysis
Comparison 17 Yellow fever vaccination versus placebo, Outcome 1 Adverse effects during use of the preventative intervention.
18.1
18.1. Analysis
Comparison 18 Laser versus no interventions, Outcome 1 Time to first recurrence.
19.1
19.1. Analysis
Comparison 19 Hypnotherapy versus control, Outcome 1 Incidence of HSL during use of the preventative intervention (change in frequency of recurrence).
19.2
19.2. Analysis
Comparison 19 Hypnotherapy versus control, Outcome 2 Severity of attack of recurrent HSL during use of the preventative intervention.
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Update of

  • doi: 10.1002/14651858.CD010095

References

References to studies included in this review

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Pfitzer 2005 {published data only}
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    1. Fawcett HA, Wansbrough‐Jones MH, Clark AE, Leigh IM. Prophylactic topical acyclovir for frequent recurrent herpes simplex infection with and without erythema multiforme. British Medical Journal 1983;287(6395):798‐9. [MEDLINE: ] - PMC - PubMed
Hellgren 1983 {published data only}
    1. Hellgren L Hermann LS. Tromantadine hydrochloride in the treatment of herpes simplex. Results of a double‐blind therapeutic trial and an open prophylactic investigation. Dermatologica 1983;167(5):267‐72. [MEDLINE: ] - PubMed
Jose 1980 {published data only}
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Kalimo 1983 {published data only}
    1. Kalimo KO, Joronen IA, Havu VK. Failure of oral inosiplex treatment of recurrent herpes simplex virus infections. Archives of Dermatology 1983;119(6):463‐7. [MEDLINE: ] - PubMed
Lacour 2000 {published data only}
    1. Lacour J. Low‐power laser and recurrent labial herpes [Laser de basse intensite et herpes labial recurrent]. Annales de Dermatologie et de Venereologie 2000;127(6‐7):652‐6. [MEDLINE: ] - PubMed
Lamey 2000 {published data only}
    1. Lamey PJ, Biagioni PA. Evaluation of Zovirax 5% cream in subjects with recurrent herpes labialis (Abstract no: 2690). IADR abstracts. Journal of Dental Research 2000;79(Spec Iss):480. [CENTRAL: CN‐00793708]
Lamura 1997 {published data only}
    1. Lamura A, Castro A, Lamura G, Garriga EE, Castro YK. Effects of sunscreens on an emplient base used in 100 cases of recurrent herpes labialis. Journal of Dental Research 1997;76(1 Suppl):236.
Likar 1968 {published data only}
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Milman 1980 {published data only}
    1. Milman N, Scheibel J, Jessen O. Lysine prevention in recurrent labial herpes simplex [Lysinprofylakse af recidiverende herpes simplex labialis]. Ugeskrift for Laeger 1980;142(19):1202‐3. [MEDLINE: ] - PubMed
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Mindel 1985 {published data only}
    1. Mindel A. Inosine pranobex for mucocutaneous herpes. Lancet 1985;1(8429):631‐2. [MEDLINE: ] - PubMed
Munoz 2012 {published data only}
    1. Muñoz Sanchez PJ, Capote Femenías JL, Díaz Tejeda A, Tuner J. The effect of 670‐nm low laser therapy on herpes simplex type 1. Photomedicine & Laser Surgery 2012;30(1):37‐40. [MEDLINE: ] - PubMed
Myers 1975 {published data only}
    1. Myers MG, Oxman MN, Clark JE, Arndt KA. Failure of neutral‐red photodynamic inactivation in recurrent herpes simplex virus infections. New England Journal of Medicine 1975;293(19):945‐9. [MEDLINE: ] - PubMed
NCT00913692 {unpublished data only}
    1. NCT00913692. A randomized double‐blind control‐comparison crossover trial of oral glutamine to suppress frequently recurrent herpes labialis. clinicaltrials.gov/show/NCT00913692 (accessed 8 October 2014).
Pedrazini 2007 {published data only}
    1. Pedrazini MC, Cury PR, Araujo VC, Wassall T. The effect of lysine in the incidence and period of healing of recurrent herpes labialis [Efeito da lisina na incidência e duração das lesões de herpes labial recorrente]. Revista Gaúcha de Odontologia 2007;55(1):7‐10.
Qadripur 1976 {published data only}
    1. Qadripur SA. Controlled clinical trial of the herpes antigen 'lupidon' against placebo [ERGEBNISSE EINER KONTROLLIERTEN KLINISCHEN STUDIE MIT DEM HERPES ANTIGEN LUPIDON GEGEN PLACEBO]. Aktuelle Dermatologie 1976;2(3):131‐6. [EMBASE: 0977155159]
Queiroz Carvalho 1976 {published data only}
    1. Queiroz Carvalho CA, Kinue Otuki T, Elizabeth Poli M, Nogueira JL, Guerrero J. Recurrent herpes infections and levamisole. Revista Latinoamericana de Microbiologia 1976;18(4):225‐6. [MEDLINE: ] - PubMed
Rosenthal 1992 {published data only}
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Rowe 1978 {published data only}
    1. Rowe NH, Brooks SL, Young SK. A clinical trial of topically applied 3% vidarabine against recurrent herpes labialis. Journal of Dental Research 1978;57(spec. A):No. 482. [EMBASE: 0978331762] - PubMed
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Siegel 1990 {published data only}
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Simon 1985 {published data only}
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    1. Spruance SL, Crumpacker CS, Haines H, Bader C, Mehr K, MacCalman J, et al. Ineffectiveness of topical adenine arabinoside 5'‐monophosphate in the treatment of recurrent herpes simplex labialis. New England Journal of Medicine 1979;300(21):1180‐4. [MEDLINE: ] - PubMed
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    1. Strand A. Once‐daily valaciclovir for the prevention of recurrent herpes labialis (cold sores) (Abstract FC2‐4). The 12th Congress of the European Academy of Dermatology and Venereology. Barcelona, Spain 15‐18th October 2003. Journal of the European Academy of Dermatology & Venereology 2003;17(Suppl 3):105‐6.
Thomas 1985 {published data only}
    1. Meyrick Thomas RH, Dodd HJ, Yeo JM, Kirby JD. Oral acyclovir in the suppression of recurrent non‐genital herpes simplex virus infection. British Journal of Dermatology 1985;113(6):731‐5. [MEDLINE: ] - PubMed
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References to ongoing studies

ISRCTN03397663 {unpublished data only}
    1. ISRCTN03397663. Evaluation of the efficacy and safety of a Sheabutter extract on cold sores (herpes simplex labialis). www.controlled‐trials.com/ISRCTN03397663 (accessed 8 October 2014).
NCT01225341 {unpublished data only}
    1. NCT01225341. Botulinum toxin A for herpes labialis. clinicaltrials.gov/show/NCT01225341 (accessed 8 October 2014).
NCT01902303 {unpublished data only}
    1. NCT01902303. Evaluation of cold sore treatments on UV induced cold sores. clinicaltrials.gov/show/NCT01902303 (accessed 8 October 2014).
NCT01971385 {unpublished data only}
    1. NCT01971385. Safety and efficacy of squaric acid dibutyl ester for the treatment of herpes labialis (Squarex). clinicaltrials.gov/show/NCT01971385 (accessed 8 October 2014).

Additional references

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