Current issues of ACP Journal Club are published in Annals of Internal Medicine


Oral acyclovir reduced recurrent herpes labialis in otherwise healthy patients with frequently recurrent disease

ACP J Club. 1993 July-Aug;119:14. doi:10.7326/ACPJC-1993-119-1-014

Source Citation

Rooney JF, Straus SE, Mannix ML, et al. Oral acyclovir to suppress frequently recurrent herpes labialis. A double-blind, placebo-controlled trial. Ann Intern Med. 1993 Feb 15;118:268-72.



To evaluate the effectiveness of oral acyclovir in reducing the incidence of recurrent herpes labialis in otherwise healthy patients with frequently recurrent disease.


Randomized, double-blind, placebo-controlled, crossover trial.


Outpatient facilities of the Clinical Center of the National Institutes of Health.


22 otherwise healthy adults (mean age 39 y, 14 women) who reported histories of ≥ 6 episodes of herpes labialis per year and had ≥ 2 recurrences during a 4-month observation period. Pregnant women were excluded. 20 patients (91%) completed the study.


Patients were randomized to receive either oral acyclovir, 400 mg twice daily, or placebo for 4 months and then were switched to the opposite therapy for another 4 months. Study medication was then discontinued.

Main outcome measure

Recurrent outbreaks of herpes labialis determined by physical examination and by viral culture of suspected lesions.

Main results

17 patients had a total of 36 clinically confirmed recurrences of herpes labialis while receiving placebo treatment, whereas 10 patients receiving acyclovir treatment had a total of 17 recurrences { P = 0.02}* (Table). The mean number of clinically documented recurrences per 4-month treatment period was 1.80 episodes per patient during placebo compared with 0.85 episodes per patient during acyclovir (difference 0.95, 95% CI 0.26 to 1.64, P = 0.009). More patients receiving placebo had virologically confirmed recurrences than those who received acyclovir { P = 0.002}* (Table). The mean number of culture-positive recurrences per patient was 1.40 with placebo treatment compared with 0.40 with acyclovir (difference 1.00, CI 0.31 to 1.64, P = 0.003). The median time to the first clinically determined recurrence of herpes labialis was 46 days for patients receiving placebo compared with 118 days for patients receiving acyclovir (P = 0.05). The median time to first virologically determined recurrence was 46 days for patients receiving placebo compared with > 118 days for patients receiving acyclovir (P = 0.002).


Oral acyclovir, 400 mg twice daily, reduced the number of recurrent episodes and prolonged the median time to first recurrence of herpes labialis in otherwise healthy patients with proven, frequently recurrent disease.

Source of funding: In part, Burroughs Wellcome Company.

For article reprint: Dr. J.F. Rooney, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA. FAX 650-573-4854.

* P values calculated from data in article.

Table. Acyclovir vs placebo in otherwise healthy patients with frequently recurrent disease after 2 crossover treatment periods of 4 months†

Outcomes Acyclovir Placebo RRR (95% CI) NNT (CI)
Clinically confirmed recurrence 50% 85% 41% (9 to 66) 3 (2 to 17)
Virologically confirmed recurrence 30% 80% 63% (30 to 82) 2 (2 to 6)

†Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


In this carefully planned trial, Rooney and colleagues showed that long-term prophylaxis with acyclovir reduced the incidence of recurrent herpes labialis in immunocompetent patients. In the study of a chronic disease with possible spontaneous remissions, the objective documentation of recurrences during a pretrial observation period, the crossover design, and the long duration of the trial give us confidence. A drawback of the study is the small number of patients (n = 20). The presentation of the actual results for each patient, in addition to the descriptive statistics reported in the article, would probably have served the reader better. Nevertheless, judged in the context of successful use of acyclovir for prophylaxis of herpes infections in immunocompromised patients and long-term suppression of herpes genitalis (1), the study supports its use for prevention of recurrent herpes labialis in immunocompetent patients.

Should this recommendation be implemented in clinical practice? It probably should be in the small percentage of patients with frequent and incapacitating attacks, both perceived and objective. Before advising on more frequent use of acyclovir as prophylaxis of herpes labialis, several issues need to be addressed. The results of the study must be corroborated by other clinical trials, preferably including more patients and longer duration. The clinical improvement as perceived by the patient must be assessed by him or her and compared with the cost of the drug and the need for daily medication. The dosage used in the present study may not be the optimal one. Although no teratogenic effects of acyclovir are reported, low-frequency events cannot be ruled out (1). This may be a major drawback of the treatment in young women. The frequency of appearance of acyclovir-resistant strains during long-term treatment has not been established. This is a major consideration against the use of a potentially life-saving drug for a minor affliction.


A relevant alternative to continuous treatment with an anti-herpes drug is patient-initiated early treatment of episodes. Penciclovir cream was shown to achieve a modest effect on pain, healing of lesions, and lesion virus-shedding (for all measures, the improvement was faster by a median interval of < 1 day) (2). It is of interest to note that patients are accurate in diagnosing early stages of herpes labialis (3).

Leonard Leibovici, MD
Rabin Medical CenterPetah-Tiqva University, Israel


1. Whitley RJ, Grann JW. Acyclovir: a decade later. N Engl J Med. 1992;327:782-9.

2. Spruance SL, Rea TL, Thoming C, et al., for the Topical Penciclovir Collaborative Study Group. Penciclovir cream for the treatment of herpes simplex labialis. A randomized, multicenter, double-blind, placebo-controlled trial. JAMA. 1997;277:1374-9.

3. Lamey PJ, Biagioni PA. Patient recognition of recrudescent herpes labialis: a clinical and virological assessment. J Dent. 1996;24:325-7.