Research Letter
doi:10.2196/38322
Keywords
In 2016, the World Health Organization estimated that 67% of the global population is infected with herpes simplex virus type 1 (HSV-1), which causes herpes simplex labialis (HSL) [].The lifetime prevalence of recurrent HSL is 20% to 52.5% [].It is highly contagious and mainly transmitted through oral-to-oral contact []. HSL is a lifelong, often asymptomatic infection that lays dormant in the trigeminal nerve. Common symptoms include prodromal tingling or burning sensation around the mouth and eruption of painful, self-limiting vesicles (“cold sores”) progressing to unsightly crusts [,]. HSV-1 recurrence can be triggered by ultraviolet light, stress, premenstrual changes, and surgical procedures; its highly visible nature can lead to embarrassment and psychological distress []. Antiviral medications are the standard treatment but have adverse effects such as rash, headache, and gastrointestinal upset [].
A 2015 Cochrane review [] assessed the effects of preventative interventions for HSL in immunocompetent people of all ages, analyzing evidence from 32 randomized controlled trials on 19 preventative measures. Primary outcomes and key findings are summarized in .
| Comparison | Measurement (primary outcome) | Result | Statistical results | Quality of evidence |
| Oral acyclovir vs placebo (short term ≤1 month): (1) 800 mg 2×/day; (2) 400 mg 2×/day; (3) 200 mg 5×/day | Incidence of HSL during use of the preventive intervention | Unclear. No preventative effect; not currently recommended |
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| Oral acyclovir vs placebo (long term >1 month): 400 mg 2×/day | Incidence of HSL during use of the preventive intervention (clinical recurrences) | Acyclovir was slightly superior. Recommended (small effect) |
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| Oral valaciclovir vs placebo (short term ≤1 month): 2 g 2×/day for the first day, 1 g 2×/day for the second day | Incidence of HSL during use of the preventive intervention | No significant difference. No preventative effect; not currently recommended |
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| Oral valacyclovir vs placebo (long term >1 month): 500 mg 1×/day | Incidence of HSL during use of the preventive intervention | Valacyclovir was slightly superior. Recommended (small effect) |
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| Oral famciclovir vs placebo (short term ≤1 month): (1) 125 mg 3×/day; (2) 250 mg 3×/day; (3) 500 mg 3×/day | Incidence of HSL during use of the preventive intervention | No significant difference. No preventative effect; not currently recommended |
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| Oral levamisole vs placebo (long term >1 month): 2.5 mg/kg 2×/week | Incidence of HSL during use of the preventive intervention | No consistent data. No preventative effect; not currently recommended |
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| Oral lysine vs placebo (long term >1 month): 1000 mg 1×/day | Incidence of HSL during use of the preventive intervention | No significant difference. No preventative effect; not currently recommended |
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| Topical acyclovir 5% cream vs placebo (short term ≤1 month): 5×/day | Incidence of HSL during use of the preventive intervention | No significant difference. No preventative effect; not currently recommended |
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| Topical acyclovir 5% and 348U87 3% cream vs placebo (short term ≤1 month): 1×/2 hours during awake hours | Incidence of HSL during use of the preventive intervention (by culture) | No significant difference. No preventative effect; not currently recommended |
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| Topical foscarnet 3% vs placebo (short term ≤1 month): 8×/day | Incidence of HSL during use of the preventive intervention | No significant difference. No preventative effect; not currently recommended |
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| Topical 1,5 pentanediol vs placebo (long term >1 month): 2×/day | Incidence of HSL during use of the preventive intervention | No significant difference. No preventative effect; not currently recommended |
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| Sunscreen vs placebo (short term ≤1 month); 1× prior to immediate exposure to (1) solar radiation and (2) experimental ultraviolet light | Incidence of HSL during use of the preventive intervention | Unclear. Not currently recommended; further research warranted |
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| Interferon injection (70,000 U/kg) vs placebo (short term ≤1 month): (1) presurgical 2×/day; (2) postsurgical 2×/day; (3) pre- and postsurgical 2×/day | Incidence of HSL during use of the preventive intervention | Unclear. No preventative effect; not currently recommended |
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| Gamma globin injection vs histamine (control, dilute 1:5000) (short term ≤1 month): 0.2 ml 1× dose | Duration of HSL outbreak | No significant difference. No preventative effect; not currently recommended |
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| Thymopentin injection vs placebo (long term >1 month): 50 mg 3×/week | Incidence of HSL during use of the preventive intervention | Thymopentin was superior. Not currently recommended; further research warranted |
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| Herpes simplex virus type I vaccine injection vs placebo (short term ≤1 month): 1× dose | Incidence of HSL during use of the preventive intervention | No significant difference. No preventative effect; not currently recommended |
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| Laser (low intensity, 690 nm, 80 mW/cm2, 48 J/cm2) vs no intervention (short term ≤1 month): 1×/day | Time to first occurrence | Low-intensity diode laser was superior but low-energy gallium-aluminum-arsenide laser was not. Not currently recommended; further research warranted |
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| Hypnotherapy vs control (long term >1 month): 1×/week | Change in the frequency of recurrence | Hypnotherapy was superior. Not currently recommended; further research warranted |
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Compared to the placebo, long-term oral acyclovir and valaciclovir reduced recurrences, although clinical benefit is limited. Limited data suggest thymopentin, low-level laser therapy (LLLT), and hypnotherapy may be effective, but further research is required. There was no evidence supporting the efficacy of lysine, LongoVital supplementation, gamma globulin, the HSV vaccine, the yellow fever vaccine, levamisole, or interferon. Compared to the placebo, there was no significant increase in adverse effects for any of the interventions assessed.
Further research is needed to establish the safety and efficacy of other preventive methods, such as HSV-1 subunit and dendritic cell–based vaccines, LLLT, and topical corticosteroids []. A dendritic cell vaccine pilot study (n=14) reported a 3-fold reduction in recurrence during the posttreatment period []. Laser therapy relies on analgesic, anti-inflammatory, anti-infective, and biostimulating effects, promoting tissue regeneration and immune response. Although LLLT is promising, caution is warranted due to heterogenicity in study methods and laser parameters [].
This Cochrane review [] confirms the preventative efficacy of long-term oral antivirals, highlights the need for further research on sunscreen and natural sunlight, and emphasizes the importance of defining core outcome sets for future studies to adopt. Establishing additional preventative options for HSL remains of paramount importance, considering its significant disease burden and growing antiviral resistance.
Conflicts of Interest
RD is a joint coordinating editor for Cochrane Skin, editor-in-chief of JMIR Dermatology, a dermatology section editor for UpToDate, a social media editor for the Journal of the American Academy of Dermatology, and a podcast editor for the Journal of Investigative Dermatology. He is a coordinating editor representative on Cochrane Council. RD receives editorial stipends (JMIR Dermatology, Journal of Investigative Dermatology), royalties (UpToDate), and expense reimbursement from Cochrane Skin. TS is an editorial board member-at-large for JMIR Dermatology. TS receives fellowship funding from Pfizer Inc. C-CC is a Skin and Methods editor at Cochrane Skin, an associate editor of the British Journal of Dermatology, editor-in-chief of Dermatologica Sinica, and an academic editor of Evidence-Based Complementary and Alternative Medicine. C-CC is an honorary director of the Taiwan Evidence-Based Medicine Association. JV and LZ have no disclosures to report.
Editorial Notice
The views expressed in this paper are those of the author(s) and in no way represent the Cochrane Library or Wiley. This article is based on a Cochrane Review previously published in the Cochrane Database of Systematic Reviews 2015, Issue 8, DOI: 10.1002/14651858.CD010095.pub2 (see www.cochranelibrary.com for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and Cochrane Database of Systematic Reviews should be consulted for the most recent version of the review.
References
- Herpes simplex virus. World Health Organization. 2020 May 01. URL: https://www.who.int/news-room/fact-sheets/detail/herpes-simplex-virus [accessed 2021-10-06]
- Chi C, Wang SH, Delamere FM, Wojnarowska F, Peters MC, Kanjirath PP. Interventions for prevention of herpes simplex labialis (cold sores on the lips). Cochrane Database Syst Rev 2015 Aug 07(8):CD010095 [FREE Full text] [CrossRef] [Medline]
- Leplina O, Starostina N, Zheltova O, Ostanin A, Shevela E, Chernykh E. Dendritic cell-based vaccines in treating recurrent herpes labialis: Results of pilot clinical study. Hum Vaccin Immunother 2016 Dec;12(12):3029-3035 [FREE Full text] [CrossRef] [Medline]
- Al-Maweri S, Kalakonda B, AlAizari NA, Al-Soneidar WA, Ashraf S, Abdulrab S, et al. Efficacy of low-level laser therapy in management of recurrent herpes labialis: a systematic review. Lasers Med Sci 2018 Sep;33(7):1423-1430. [CrossRef] [Medline]
Abbreviations
| HSL: herpes simplex labialis |
| HSV-1: herpes simplex virus type 1 |
| LLLT: low-level laser therapy |
Edited by R Alhusayen; submitted 28.03.22; peer-reviewed by A Ortega, B Chu; comments to author 20.04.22; revised version received 18.05.22; accepted 19.05.22; published 14.06.22
Copyright©Torunn Sivesind, Jennifer Viola, Linda Zhang, Robert Dellavalle, Ching-Chi Chi. Originally published in JMIR Dermatology (http://derma.jmir.org), 14.06.2022.
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