EVIDENCE-BASED ANSWER
When herpes simplex virus (HSV) type 1 lesions are in the papule or vesicle stage, there is no benefit to starting oral acyclovir (strength of recommendation [SOR]: C, based on expert opinion). However, topical acyclovir 5% cream applied 5 times a day decreases pain and the duration of hard crust (SOR: B, extrapolated from randomized controlled trials [RCTs]).
If started at the onset of symptoms (during the prodrome stage), acyclovir (400 mg 5 times daily for 5 days) decreases pain and healing time to loss of crust and valacyclovir (2 g twice daily for 1 day) reduces the lesion duration and time to healing and may prevent lesion development (SOR: A, based on RCTs).
Evidence summary
Cold sores, or herpes labialis, are caused by HSV. Recurrent lesions progress quickly through several stages (prodrome, erythema, papule, vesicle, ulcer, crust, residual swelling, healed).1 Because of the rapid development of the vesicle stage (<12 hours) and the rapid decrease in detectable virus after 48 hours, studies of antiviral therapy empirically require early treatment within the first several hours of signs or symptoms of a recurrence. For this reason, there are no controlled trials of oral medications given later than 12 hours after the onset of recurrent symptoms.
Although limited, the clearest indication of appropriate timing for HSV 1 treatment with acyclovir comes from a well-designed, double-blinded RCT of 174 adults with a history of culture confirmed HSV labialis who initiated self-treatment with acyclovir 400 mg or placebo 5 times a day for 5 days. Patients were asked to defer treatment until the next episode if they awoke with the lesion or first noticed them in the vesicle or ulcer stage. Ninety-seven percent of the patients started treatment within 1 hour of signs/symptoms of a recurrence. Of the 174 patients, 90 had lesions in the prodrome or erythema stage at the start of treatment and 84 had lesions in the papule or vesicle stage.
Overall, acyclovir did not effect lesion progression, size, or healing time to loss of hard crust or normal skin. However, the mean duration of pain for all patients significantly decreased (2.5 days vs 3.8 days for placebo, P=.01). For the subgroup of patients who started acyclovir treatment in the prodrome or erythema stage, the mean duration of pain significantly decreased (2.5 days vs 3.9 days for placebo, P=.02), as did healing time to loss of crust (5.8 days vs 7.9 days for placebo, P=.03). Among those who started acyclovir in the papular stage, the trend was toward drug benefit, but this was not statistically significant (mean pain duration: 2.5 vs. 3.6, P=.36; mean healing time to loss of crust: 8.0 vs. 7.2, P=.52).2 This evidence supports early (prodrome or erythema stage) but not late (macule, papule, vesicle, or crusted stage) treatment of HSV 1 with oral acyclovir.
Topical application of 5% acyclovir cream significantly decreases clinician-assessed duration of the episode and duration of patient-reported pain, based on 2 double-blind, multicenter RCTs that used a vehicle control. In these trials, 686 and 699 patients self-initiated treatment 5 times a day for 4 days beginning within 1 hour of the onset of a recurrent lesion. In the first study, the mean clinician-assessed duration of the episode with topical acyclovir was 4.3 vs 4.8 days for placebo (hazard ratio [HR]=1.23; 95% confidence interval [CI], 1.06–1.44), and the mean duration of patient-assessed pain was 2.9 vs 3.2 days (HR=1.20; 95% CI, 1.03–1.40). The second study showed a mean clinician-assessed duration with topical acyclovir of 4.6 vs 5.2 days for control (HR=1.24; 95% CI, 1.06–1.44), and the mean duration of patient-assessed pain was 3.1 vs 3.5 days (HR=1.21; 95% CI, 1.04–1.40). Benefits were seen regardless of whether treatment was initiated early (prodrome or erythema stage) or late (macule, papule, vesicle or crusted stage).3