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Three Part Question

In [an immunocompetent child presenting with primary herpes simplex gingivostomatitis], does [oral aciclovir] reduce [the duration of symptoms]?

Clinical Scenario

A 3-year-old previously well boy presents with a fever of 38.6°C and several ulcers and erosions extending from his lips, along the tongue and cheek, to the back of the throat. The lesions have all appeared within the last 2 days. He has been crying inconsolably over the past 24 h and is refusing food and drink. Considering the current evidence we question whether the use of oral aciclovir is indicated for primary herpes gingivostomatitis in children.

Search Strategy

Cochrane Library: using "herpes AND gingivostomatitis AND aciclovir/acyclovir", "herpes AND gingivostomatitis", "herpes AND aciclovir", "aciclovir AND gingivostomatitis": one relevant result – "Acyclovir for treating primary herpetic gingivostomatitis" – currently in title stage (registered 23 May 2007). PubMed: with no limits set using "herpes AND gingivostomatitis AND aciclovir", and "gingivostomatitis AND aciclovir" 24 publications were found. Fifteen were not relevant or unavailable in English. Two were letters. Two studies were relevant. Five publications were review articles. These five articles were scrutinised for relevant primary research citations which were not elicited directly by the PubMed search. Three such articles were found
Medline using OVID interface (1950 to August week 5 2007): with no limits set using "herpes AND gingivostomatitis AND aciclovir", and "gingivostomatitis AND aciclovir" 17 publications were found. Ten were not relevant or unavailable in English. Two articles were letters. Five articles were relevant; four of these articles had been identified in previous searches. One new review article was identified which contained no new relevant primary research citations

Search Outcome

5 articles

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Amir et al, 1997,	61 children aged 1–6 years with clinical manifestations of gingivostomatitis (within 72 h of onset) and positive HSV cultures	Randomised double blind placebo controlled trial (level Ib, Jadad = 5)	Duration of oral lesions Fever Eating and drinking difficulties Viral shedding	Treatment group showed significantly reduced median duration of all symptoms (i: oral lesions 4 vs 6 days; ii: eating difficulties 4 vs 7 days; iii: drinking difficulties 3 vs 6 days; iv: extra-oral lesions 0 vs 5.5 days) and completion of viral shedding (1 vs 5 days). (p<0.05)	High proportion of subjects presenting with mild disease (<20 oral lesions)
Cataldo et al, 1993,	162 immunocompetent children with herpetic gingivostomatitis (peak age of incidence 9–28 months)	Retrospective clinical and epidemiological study (level IIc)	Time to symptom regression Epidemiological aspects of HSV gingivostomatitis	More rapid symptom regression in children treated with 5–6-day course of aciclovir	Non-blind/random selection of treatment group combined with epidemiological study design means limited data on intervention can be elicited from this study in isolation
Ducoulombier et al, 1988,	20 children (mean age 2 years) presenting within 96 h of symptom onset with positive isolation of HSV in cell culture	Randomised double blind placebo controlled trial (level Ic, Jadad = 4)	Duration of pain Hypersalivation Fever Duration of oral lesions	Significant improvement in pain and hypersalivation in treatment group. Mean duration of pain 4.3 days in aciclovir group vs 5.0 days in placebo group (p<0.05)	Study may be too small for valid comparison between groups
Aoki et al, 1993,	68 children presenting within 96 h of symptom onset	Randomised double blind placebo controlled trial (level Ic, Jadad = 4)	Duration of oral lesions Gum swelling Hypersalivation Completion of viral shedding	Treatment group showed a significant reduction in median symptom duration of 20–50% (i: oral lesions 6 vs 8 days; ii: gum swelling 5 vs 7 days; iii: drooling 4 vs 8 days) and in completion of viral shedding (4 vs 10 days). (p<0.05)	Results presented but not published as an article Duration of treatment 10 days. Results thus not directly comparable to similar studies
Mueller et al, 1988,	41 children with herpetic gingivostomatitis treated with aciclovir	Non-blind, uncontrolled, open study (level IIc)	Duration of oral lesions Duration of pain	90% free of pain and oral lesions after 6 days of treatment and afebrile after 3 days of treatment. Treatment considered "good or very good" in 85% of children	Subjective outcome measures limit validity of findings

Comment(s)

Primary herpes simplex gingivostomatitis is a self-limiting condition and affected individuals may experience significant mouth pain, fever, and difficulty eating and drinking, as well as being highly infectious (Amir). Although an approved treatment, retrospective data suggest that aciclovir is used infrequently in the management of this condition (Faden).

Aciclovir may cause a range of adverse effects including nausea, vomiting, diarrhoea and headaches, and is also a relatively expensive drug requiring administration five times a day (although cost has dropped substantially since its patent expired; for a 7-day course the cost is currently £9.21)(Murph, BNF).Concerns have been expressed regarding the possible selection of resistant strains of herpes with aciclovir being used for such common disorders. This is thought to be unlikely as, in a study of immunocompetent children receiving aciclovir for over 6 years, no resistant strains were identified (Fife). Earlier and more severe recurrences of genital herpes have been demonstrated in subjects who received aciclovir during their primary illness. This is thought to be as a result of a decreased antibody response to herpes simplex viral proteins in such patients (Bernstein, Ashley). Nevertheless, no study identified has demonstrated this phenomenon in patients treated with a short course of aciclovir, as would be the case for primary herpes simplex gingivostomatitis.

No class I evidence was found in regard to the treatment of children presenting later than 96 h from symptom onset. In subjects presenting early (within 72 or 96 h), three small randomised controlled trials have demonstrated reduced symptom duration and faster lesion healing in patients treated with a course of oral aciclovir as compared to subjects treated with placebo (Amir, Ducoulombier, Aoki) findings which are broadly supported by two non-blinded retrospective studies (Cataldo, Mueller).

There is no consensus as to the optimum length of treatment and dose of aciclovir. None of the studies have examined the side-effect profile in relation to concomitant therapeutic gain, so evidence based risk-benefit analysis remains difficult. Concern has also been expressed about the lack of data supporting the use of oral aciclovir in younger children(Ardunio). Two population analyses have found aciclovir to be well tolerated in children under 2 years of age in dosing regimens consistent with those used in the three randomised controlled trials discussed (Tod, Sullender).

Despite there being no consensus as to the treatment of immunocompetent children with primary herpes gingivostomatitis, the limited data available suggest that, while being moderately expensive, oral aciclovir given early on, reduces the duration of symptoms and infectivity of affected individuals, without causing unacceptably severe or frequently occurring side effects or long term sequelae.

Clinical Bottom Line

Oral aciclovir given early in primary herpes gingivostomatitis has been shown to reduce duration of symptoms, improve healing of oral lesions and reduce infectivity of affected individuals. (Grade B)

Current evidence supports the use of oral aciclovir (15 mg/kg/five times a day for 7 days) in cases of primary herpes gingivostomatitis in immunocompetent children presenting within 72 h of symptom onset. (Grade B)

References

1. Amir J, Harel L, Smetana Z, et al. Treatment of herpes simplex gingivostomatitis in children: a randomised double-blind placebo controlled study. BMJ 1997;314:1800–3.
2. Cataldo F, Violante M, Maltese I, et al. Herpetic gingivostomatitis in children: the clinico-epidemiological aspects and findings with acyclovir treatment. A report of the cases of 162 patients. Pediatr Med Chir 1993;15:193–5.
3. Ardunio PG, Porter SR. Oral and perioral herpes simplex virus type 1 (HSV-1) infection: review of its management. Oral Dis 2006;12:254–70.
4. Blevins J. Primary herpetic gingivostomatitis in young children. Pediatr Nurs 2003;29:199–202.
5. Amir J. Clinical aspects and antiviral therapy in primary herpetic gingivostomatitis. Paediatr Drugs 2001;3:593–7.
6. Leigh IM. Management of non-genital herpes simplex virus infections in immunocompetent patients. Am J Med 1988;85:34–8.
7. Faden H. Management of primary herpetic gingivostomatitis in young children. Pediatr Emerg Care 2006;22:268–9.
8. Ducoulombier H, Cousin J, Dewilde A, et al. Herpetic stomatitis-gingivitis in children: controlled trial of aciclovir versus placebo. Ann Pediatr (Paris) 1988;35:212–16.
9. Aoki FY, Law BJ, Hammond GW, et al.. Acyclovir suspension for treatment of acute herpes simplex virus gingivostomatitis in children: a placebo controlled double blind trial. Abstract no. 1530. In: Program and abstracts of the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy New Orleans, LA. Washington, DC: American Society for Microbiology, 1993:399.
10. Mueller R, Weigand KH. The treatment of herpetic gingivostomatitis with aciclovir suspension. Der Kinderarzt 1988;19:1189–92.
11. Murph JR, Grose C. Routine acyclovir therapy: isn’t it time? Contemp Pediatr 1999;16:79–99.
12. BMJ Publishing Group, RPS Publishing, RCPCH Publications. Herpesvirus infections. In: British National Formulary for children . Section 5.3.2. London: BMJ Publishing Group 2006:369.
13. Fife KH, Cru M, Packer SC, et al. Recurrence and resistance patterns of herpes simplex virus following cessation of >6 years of chronic suppression with acyclovir. J Infect Dis 1994;169:133–4.
14. Bernstein DI, Lovett MA, Bryson YJ. The effects of acyclovir on antibody response to herpes simplex virus in primary genital hermetic infections. J Infect Dis 1984;150:7–13.
15. Ashley R, Mack K, Critchlow C, et al. Differential effect of systemic acyclovir treatment of genital HSV-2 infections on antibody responses to individual HSV-2 proteins. J Med Virol 1988;24:309–20.
16. Tod M, Lokiec F, Bidault R, et al. Pharmacokinetics of oral acyclovir in neonates and in infants: a population analysis. Antimicrob Agents Chemother 2001;45:150–7.
17. Sullender WM, Arvin AM, Diaz PS, et al. Pharmacokinetics of acyclovir suspension in infants and children. Antimicrob Agents Chemother 1987;31:1722–6.
18. Curry SS. Cutaneous herpes simplex infections and their treatment. Cutis 1980;26:41–58.