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A 13-year-old girl presents with recurrent herpes labialis (HL) on her face. She gives a history of painful episodes occurring approximately monthly since the age of 9 years. Since becoming a teenager, she has missed a lot of school due to her worry about the cosmetic appearance of recurrences. Her parents ask whether long-term antiviral medication will prevent recurrences.
Structured clinical question
In an otherwise healthy child or adolescent with recurrent HL (patient), is oral antiviral suppressive therapy (intervention) effective in reducing the frequency of recurrences of HL (outcome).
Medline, Pubmed and EMBASE were searched in January 2019 with no language restriction. The search strategy is detailed in the online supplementary material.
Of 2032 unique articles, after exclusion of studies investigating immunocompromised patients, pre-emptive treatment or short-term (<4 weeks) interventions, four were relevant (table 1). Only one study addressed recurrences in children or adolescents (a retrospective study in four patients).1 The remaining three articles described randomised controlled trials (RCTs) in adults,2–4 also reported in a Cochrane meta-analysis.5 The references of all relevant publications were reviewed and no further articles were identified.
HL is caused by herpes simplex virus (HSV), a ubiquitous double-stranded DNA virus that primarily infects through contact or respiratory droplets, subsequently establishing lifelong latent infection in regional nerve ganglia. Reactivation can be triggered by physical or emotional stress, fever, menstruation or exposure to sun. Reactivation leads to asymptomatic shedding or lesions around the initial point of entry. Infections can occur anywhere but are more frequent around the oral or genital mucosa.6 The highest incidence of primary infection occurs in the first 4 years of life.7 The worldwide global seroprevalence of HSV is >70% in those over 15 years of age with geographical and socioeconomic variations in prevalence.7 8 Between 14% and 40% of the population have frequent recurrent HL (RHL).9–11 Discomfort and cosmetic appearance can have a significant impact on quality of life, especially in adolescents. In younger children, pain can limit fluid intake. Long-term oral antiviral suppressive therapy is frequently suggested for patients with severe and/or frequent recurrences. However, recommendations for patient selection, choice of antiviral, dosage and duration vary (table 2).
The retrospective study in children included four teenagers 12–14 years of age in Spain with six or more HL episodes per year. A 4-month course of oral valacyclovir (500 mg once daily) induced a 3.9-fold reduction in HL episodes and a significant increase in quality of life.1 Two patients reported adverse events (not detailed) but treatment was not discontinued. The three RCTs included 196 adults in the USA with RHL, defined as between three and six or more episodes per year.2–4 All studies had two arms and two had a cross-over design. The studies compared a 4-month course of acyclovir (400 mg twice daily) or valacyclovir (500 mg or 1 g once daily) to placebo or to pre-emptive treatment (valacyclovir 2 g twice daily for 1 day at first sign of prodrome). Methodological differences precluded pooling of the data in the Cochrane review.5 Overall, the results showed that oral antiviral suppressive therapy increased the number of recurrence-free patients (1.6 to 3.3-fold), prolonged the time to first HL recurrence (1.4 to 2.6-fold), decreased the recurrence rate (1.8 to 2.4-fold) and decreased the duration of HL episodes (1.8-fold). In one of the studies, the reduction in HL episodes was greater (3.5-fold) when including only culture-positive recurrences, suggesting lower viral shedding in patients receiving long-term acyclovir.2 Interestingly, another of the studies found that a suppressive approach was superior to a pre-emptive approach.4 There were no safety concerns, with no difference in adverse events between the groups in all three studies.
Although only four studies have addressed the efficacy of oral long-term suppressive therapy with acyclovir or valacyclovir in patients with RHL, all reported a reduction in frequency, severity and duration of episodes. Suppressive therapy also decreased viral shedding, which reduces the risk of secondary inoculation, a particular risk in children. However, these findings are based primarily on studies in adults.
No study has directly compared the efficacy of different antiviral drugs in preventing RHL, and no study has investigated long-term suppressive therapy with famciclovir. Valacyclovir and famciclovir have superior bioavailability than acyclovir, enabling a once daily or twice daily administration.12–14 However, although frequently used in children, valacyclovir and famciclovir are not approved for use in this age group in many countries, and are generally more costly.12
Adverse effects of these antivirals include myelosuppression (mostly neutropenia), and, rarely, renal toxicity and liver toxicity. However, these adverse effects have mainly been reported in neonates receiving intravenous acyclovir for HSV encephalitis. The low rate of adverse effects is likely explained by the fact that the activity of these drugs depends on phosphorylation by virally-induced thymidine kinase, and are therefore only active in infected cells, with no effect on uninfected cells.13 In immunocompetent patients, selection of antiviral-resistant mutants (which in any case have impaired replicative ability, and decreased ability to establish latency and to reactivate) has not been reported.15 16
Other treatment options for RHL have been studied in individual RCTs, mainly in adults (table in online supplementary material).5 Among them, the greatest benefit has been reported for repeated application of sunscreen in patients with sun-induced RHL. In one study, the double application of sunscreen lipstick repeated at least 2-hourly induced a 10-fold decrease in HL recurrence rate, and a 10-fold increase in recurrence-free patients throughout the month of intervention.17
Clinical bottom lines
Oral long-term suppressive therapy with acyclovir or valacyclovir reduces the frequency, severity and duration of episodes in adults with recurrent herpes labialis (RHL) (grade A) but has not been the subject of a trial in children.
Oral valacyclovir reduces the frequency of episodes and increases quality of life in teenagers with RHL (grade C).
The optimal indication to start, choice of antiviral, as well as dosage and duration of long-term antiviral therapy is unknown.
Contributors LFP drafted the initial manuscript. NC critically revised the manuscript and both authors approved the final version as submitted.
Funding LFP is supported by the Swiss National Science Foundation (Early Postdoc.Mobility grant number P2GEP3_178155).
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.
Patient consent for publication Not required.
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