Abstract / Summary
Herpes labialis (also known as cold sores or fever blisters) is a highly prevalent recurrent infection caused by the herpes simplex virus. Recurrences arise from varied triggers. Standard treatments usually involve nucleoside antivirals. Several studies have investigated alternative treatments such as zinc, honey, and photodynamic therapy for their potential to shorten lesion duration and relieve symptoms, but most reviews exclude these therapies. We wished to address this evidence gap by evaluating both conventional and alternative approaches, synthesising evidence on efficacy and safety to inform clinical practice and guide patient decisions.
To assess the benefits and harms of interventions for treating herpes labialis in immunocompetent people.
We searched CENTRAL, MEDLINE, and Embase on 23 September 2025, and we searched two clinical trial registries (ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform) on 1 October 2025.
We included randomised controlled trials (RCTs) enrolling immunocompetent people with herpes labialis. Eligible interventions included topical, oral, and physical therapies (e.g. nucleoside antivirals, anti-inflammatory agents, phototherapy, photodynamic therapy). Eligible comparators were placebo, no treatment, or another active intervention. We applied no restrictions related to publication language or status (published, unpublished, in press, or in progress).
Our critical outcomes were healing time (with healing defined as loss of crusts or all symptoms), rated by participants or investigators; and any adverse events leading to treatment cessation. Our important outcomes were participant-rated improvement of signs and symptoms (e.g. global rate of change scales), change from baseline in clinical episode severity (e.g. lesion size), change from baseline in pain severity, and any mild or moderate adverse events not leading to treatment cessation.
We assessed the risk of bias using the Cochrane RoB 2 tool.
We synthesised outcomes descriptively and pooled data with a random-effects meta-analysis using the inverse-variance method where appropriate. We reported dichotomous outcomes as risk ratios (RRs), continuous outcomes as mean differences (MDs), and time-to-event data as hazard ratios (HRs), all with 95% confidence intervals (CIs). For rare outcomes, we calculated the Peto odds ratio (OR). We assessed heterogeneity using the I² statistic and performed subgroup analyses by intervention or dose. We also conducted sensitivity analyses, excluding trials with high risk of bias. We rated the certainty of evidence using the GRADE approach.