Supplementary Material

SUPPLEMENTARY MATERIAL

Appendix; Search strategy

MEDLINE 1. Herpes Labialis/ 2. Stomatitis, Herpetic/ 3. ((herpe* adj3 (labial* or stomatiti* or gingivostomatiti*)) or cold-sore* or fever-blister*).tw,kf. 4. 1 or 2 or 3 5. Herpes Simplex/ 6. Simplexvirus/ or herpesvirus 1, human/ or herpesvirus 2, human/ 7. (hsv-1 or hsv1 or hsv-2 or hsv2 or simplexvirus or simplex-virus or herpes-simplex or herpe*).tw,kf. 8. exp Mouth/ 9. (lip*1 or mouth or labial* or orolabial* or oro-labial* or perioral or peri-oral or extraoral or extra-oral or intraoral or intra-oral or gingiva* or gingivo*).tw,kf. 10. (5 or 6 or 7) and (8 or 9) 11. 4 or 10 12. Secondary Prevention/ 13. exp Recurrence/ 14. (prevention or recurren* or prophyla*).tw,kf. 15. pc.fs. 16. 12 or 13 or 14 or 15 17. 11 and 16 18. exp animals/ not human*.sh. 19. 17 not 18

EMBASE 1. herpes labialis/ 2. herpetic stomatitis/ 3. ((herpe* adj3 (labial* or stomatiti* or gingivostomatiti*)) or cold-sore* or fever-blister*).tw,kw,dq. 4. 1 or 2 or 3 5. herpes simplex/ 6. simplexvirus/ or exp human alphaherpesvirus 1/ or exp herpes simplex virus 2/ 7. (hsv-1 or hsv1 or hsv-2 or hsv2 or simplexvirus or simplex-virus or herpes-simplex or herpe*).tw,kw,dq. 8. mouth/ or exp cheek/ or exp lip/ or exp mouth cavity/ or exp mouth floor/ or exp mouth mucosa/ or exp palate/ or oral blister/ 9. (lip*1 or mouth or labial* or orolabial* or oro-labial* or perioral or peri-oral or extraoral or extra-oral or intraoral or intra-oral or gingiva* or gingivo*).tw,kw,dq. 10. (5 or 6 or 7) and (8 or 9) 11. 4 or 10 12. prevention/ or exp prophylaxis/ or secondary prevention/ 13. reccurent disease/ or relapse/ or reccurent infection/ 14. (prevention or recurren* or prophyla*).tw,kw,dq. 15. pc.fs. 16. 12 or 13 or 14 or 15 17. 11 and 16 18. exp animal/ not human*.sh. 19. 17 not 18

PUBMED (((herpe* AND (labial* OR stomatiti* OR gingivostomatiti*)) OR cold-sore* OR fever-blister*) OR ((hsv-1 OR hsv1 OR hsv-2 OR hsv2 OR simplexvirus OR simplex-virus OR herpes-simplex OR herpe* OR human-alphaherpesvirus OR human-alpha-herpesvirus OR human-alpha-herpes-virus OR herpesvirus OR herpes-virus) AND (lip OR lips OR mouth OR labial* OR orolabial* OR oro-labial* OR perioral OR peri-oral OR extraoral OR extra-oral OR intraoral OR intraoral OR gingiva* OR gingivo* OR cheek OR palate OR oro-blister OR oral-blister))) AND (prevention OR recurren* OR prophyla* OR relapse) AND (NOTNLM OR publisher[sb] OR inprocess[sb] OR pubmednotmedline[sb] OR indatareview[sb] OR pubstatusaheadofprint)

1 Table: Other long-term interventions for reducing the recurrence and severity of herpes labialis

Intervention Number Number Patients’ Dose Effect during intervention / conclusion of RCT of patient mean age (range or SD) Oral Levamisole 1 [1] 48 35.9 years-old 2.5 mg/kg (usually 150 mg) once a day for 2-fold decrease in HL recurrence rate (range 11-56) 2 consecutive days each week for 6 No difference in HL episode duration months High withdrawal rate of 40% in the levamisole group because of either adverse events (such as nausea and fever) or lack of efficacy Lysine 2 [2, 3] 91 29 and 36 1000 mg daily for 6 months 2.1 to 2.8-fold increase in recurrence-free patients years-old No difference in HL episode duration or severity (range 8-73) Data suggest that serum lysine concentration over 165 nmol/ml induce a significant decrease in HL recurrence rate and below 165 nmol/ml induce a significant increase.[2] Inosiplex 1 [4] 23 25 years-old 70 mg/kg once a day for a week and 1.3-fold decrease in HL recurrence rate (SD 7) during the subsequent 5th, 9th, and 12th 30% patient recurrence-free at 6 months (compared to 0% in the weeks placebo group) LongoVital® 1 [5] 27 36 years-old 3 tablets once a day for 4 months No difference in HL recurrence rate, episode duration or severity (a vitamin and (range 19–57) herbs supplement) Topical Lipstick 1 [6] 20 43.5 years-old 2 applications (double protective layer) 10-fold increase in recurrence-free patients sunscreen (SPF (range 30-54) before going out, repeated every 2 hours, 10-fold decrease in HL recurrence rate 30) and after eating, drinking, smoking, or swimming for 30 days Acyclovir 1 [7] 23 31.7 years-old 1 application 4 times per day for 16 weeks 2.2-fold decrease in HL recurrence rate (range 19-68) 1.3-fold decrease in patients’ total days with HL 1,5-pentanediol 1 [8] 50 48 years-old 0.04 g/day consisting in 1 application two No difference in HL recurrence rate, episode duration or severity (range not times a day for 26 weeks available) 2-hydroxypropyl- 1[9] 18 32.6 years-old 1 application two times a day for 6 months Significantly more recurrence than in the placebo group β-cyclo dextrin (SD 9.1) No difference in HL episode duration Slight diminution in HL episode severity Continued

2 Intervention Number Number Patients’ Dose Effect during intervention / conclusion of RCT of patient mean age (continued) (range or SD) Laser Low-energy 1 [10] 41 28.8 years-old 3-4.5J/cm2 once a week during 10 weeks No difference in HL recurrence rate gallium- (range NA) Slight diminution in HL episode severity aluminium- arsenide laser Low-intensity 1 [11] 24 31.3 years-old 48 J/cm² once a day for 2 weeks 12.5-fold prolongation of relapse-free time before first recurrence diode laser (SD 12.1) therapy Injection Thymopentine 1 [12] 18 30.8 years-old 50 mg subcutaneous injections thrice a 5-fold prolongation of relapse-free time before first recurrence (range 19-51) week for 6 weeks 4.5-fold decrease in HL recurrence rate 2-fold increase in adverse events Gamma globulin 1 [13] 43 NA 0.2 ml intradermal injection No difference in HL recurrence rate, episode duration or severity HSV type I 1 [14] 35 Mean age NA 0.5 ml intramuscular injection (200 µg No difference in HL recurrence rate subunit vaccine (range 18-50) HSV-1 surface protein antigen and 1.5 mg aluminium) thrice at day 0, 7, and 14 Yellow fever 1 [15] 12 31.1 years-old 0.5 ml subcutaneous injection No difference in HL recurrence rate vaccine (range NA) Other Hypnotherapy 1 [16] 10 41.4 years-old Individual therapy session once a week 1.6-fold decrease in HL recurrence rate (range NA) during 5 weeks Slight diminution in HL episode severity HL: herpes labialis; HSV: herpes simplex virus; NA: not available; RCT: randomized controlled trial; SD: standard deviation.

3 REFERENCES

1. Russell AS, Brisson E, Grace M. A double-blind, controlled trial of levamisole in the treatment of recurrent herpes labialis. J Infect Dis 1978;137(5):597-600. 2. Thein DJ, Hurt WC. Lysine as a prophylactic agent in the treatment of recurrent herpes simplex labialis. Oral Surg Oral Med Oral Pathol 1984;58(6):659-66. 3. Milman N, Scheibel J, Jessen O. Lysine prophylaxis in recurrent herpes simplex labialis: a double-blind, controlled crossover study. Acta Derm Venereol 1980;60(1):85-7. 4. Galli M, Lazzarin A, Moroni M, et al. Inosiplex in recurrent herpes simplex infections. Lancet 1982;2(8293):331-2. 5. Pedersen A. LongoVital and herpes labialis: a randomised, double-blind, placebo- controlled study. Oral Dis 2001;7(4):221-5. 6. Mazzarello V, Ferrari M, Piu G, et al. Do sunscreen prevent recurrent Herpes labialis in summer? J Dermatolog Treat 2018:1-4. [Epub ahead of print] 7. Gibson JR, Klaber MR, Harvey SG, et al. Prophylaxis against herpes labialis with acyclovir cream--a placebo-controlled study. Dermatologica 1986;172(2):104-7. 8. Busch R, Graubaum HJ, Gruenwald J, et al. Therapeutic effect of 1,5-pentanediol for herpes simplex labialis: A randomized, double-blind, placebo-controlled clinical trial. Adv Ther 2009;26(7):719-27. 9. Senti G, Iannaccone R, Graf N, et al. A randomized, double-blind, placebo-controlled study to test the efficacy of topical 2-hydroxypropyl-beta-cyclodextrin in the prophylaxis of recurrent herpes labialis. Dermatology 2013;226(3):247-52. 10. de Carvalho RR, de Paula Eduardo F, Ramalho KM, et al. Effect of laser phototherapy on recurring herpes labialis prevention: an in vivo study. Lasers Med Sci 2010;25(3):397- 402. 11. Schindl A, Neumann R. Low-intensity laser therapy is an effective treatment for recurrent herpes simplex infection. Results from a randomized double-blind placebo-controlled study. J Invest Dermatol 1999;113(2):221-3. 12. Bolla K, Djawari D, Kokoschka EM, et al. Prevention of recurrences in frequently relapsing herpes labialis with thymopentin. A randomized double-blind placebo- controlled multicenter study. Surv Immunol Res 1985;4 Suppl 1:37-47. 13. Redman JC, Davis LE, McLaren LC, et al. Intradermal gamma globulin for herpes labialis? Results of a double-blind study. Postgrad Med 1986;79(8):315-8. 14. Altmeyer P, Wehrenberg O, Holzmann H, et al. [Treatment of recurrent herpes labialis using a herpes simplex Type-I subunit vaccine. A prospective randomized double-blind multicenter study]. Hautarzt 1991;42(12):759-63. 15. Moller A, Andersen PL, Korsager B, et al. [Yellow fever vaccination as prophylaxis of herpes labialis]. Ugeskr Laeger 1997;159(15):2228-9. 16. Pfitzer BE, Clark K, Revenstorf D. [Medical hypnosis in cases of herpes labialis improves resistance for recurrence. A pilot study]. Hautarzt 2005;56(6):562-8.