Applied Evidence

Short-course therapy for recurrent genital herpes and herpes labialis

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Entering an era of greater convenience, better treatment adherence, and reduced cost.



Practice recommendation
  • Consider giving patients an oral antiviral (OAV) medication to self-administer when HSV prodromal symptoms occur.
  • Patient-initiated, short-course, high-dose OAV treatment of recurrent HSV outbreaks may be as effective as the traditional, longer-course regimens.

Hit early, hit hard. That expression arose during the evolution of treatment for human immunodeficiency virus (HIV).1 While this approach has not lived up to expectations for HIV treatment, it may have found its place in the treatment of recurrent herpes simplex virus (HSV) infections.

Our review focuses on episodic treatment of acute recurrent HSV outbreaks for immunocompetent persons. We do not discuss suppressive therapy, which may be indicated for frequent or severe recurrences (6 or more per year) in immunocompetent persons, for immunocompromised patients, or as an adjunctive measure to reduce genital herpes transmission.2

As we will describe in detail, the efficacy of the new short-course therapy is, at minimum, comparable to that seen with the older, longer-course trials of topical and oral antiviral therapy. In one head-to-head comparison, Leone et al compared a short-course regimen (3 days) of valacyclovir with 5 days of treatment; they found no difference in results.3 If the efficacy of short-course treatment is the same as that of longer courses, the increased convenience and expected improvement in patient adherence with these new regimens argue strongly in their favor. (See Scope of the problem.)

The strategy: Take advantage of a brief therapeutic window

The innate and acquired immune responses of chronically infected, immunocompetent persons rapidly limit cutaneous viral replication, thereby truncating the duration of recurrent HSV outbreaks.13,14 In both recurrent herpes labialis and genital herpes, HSV viral titers peak in the first 24 hours following lesion onset (FIGURE 1A).13-15

Herpes labialis lesion size and pain are also greatest in the first 24 hours.13,16 Most herpes labialis lesions progress from the vesicle stage to the ulcer/soft crust stage within 48 hours, with a hard crust forming by day 2 or 3 (FIGURE 1B).17

With genital lesions, crust formation depends on whether the skin area is dry (3–4 days) or moist (8–9 days).14

The likely events are a burst of virus replication in the first 24 hours of outbreak that lyses basal keratinocytes in a discreet area of epidermis innervated by the infected neuron(s), followed by a vigorous immune response that curtails the infection and creates, in part, the clinical disease (erythema, swelling, vesiculation, and ulceration). The subsequent elements of the illness, which are the majority of the lesion course, are related to wound healing

Recognizing the window. Given the brief period of viral replication and the rapid evolution of lesions, the therapeutic window for treating HSV outbreaks with antiviral drugs is both early and short, making it problematic to effectively treat HSV recurrences. Patients often have mature lesions by the time they consult a physician, rendering subsequent anti-viral treatment less effective.18 However, before lesions appear, many patients experience prodromal symptoms such as pain, burning, or itching.13,18 These symptoms can be a prompt to start treatment early, thereby taking advantage of the transient therapeutic window.

If a patient is able to self-administer therapy when prodromal symptoms occur, there may be a greater benefit to treatment. Giving patients drugs for self-administration is therefore an important strategy in managing HSV recurrences.

Traditionally, patient-initiated episodic therapy for recurrent genital herpes and herpes labialis has involved multiple daily doses of topical or oral antiviral agents for 4 to 5 days.19-26 Studies of the pathogenesis of HSV recurrences, however, indicate—as said earlier—that the period of virus replication is early and brief, such that a shorter duration of treatment might be more appropriate and equally effective. Other recent clinical studies have indicated that patient-initiated, short-course, high-dose OAV treatment of recurrent HSV infections may be as effective as the traditional therapies.3,27-30 In the section that follows, we examine and compare the results of these trials. (See The agents and how they work.)

Lesion HSV-1 titer peaks within 24 hours of onset of herpes labialis lesions

Source: Krueger et al, J Clin Epidemiol Derm 1978.15 Reproduced with permission from GG Krueger.

Hard crust formation occurs by 48 to 72 hours of onset of herpes labialis lesions

Source: Spruance, Sem Dermatol 1992.17 With permission from Elsevier.

Clinical trials: Short-course, high-dose, patient-initiated episodic OAV therapy for recurrent genital herpes

Three-day vs 5-day valacyclovir therapy. The efficacy of 3-day treatment with oral valacyclovir was compared with that of 5-day treatment in immunocompetent adults with a history of ≥4 episodes of recurrent genital herpes and confirmed HSV infection.3 Eight hundred participants were randomized to receive 500 mg twice daily valacyclovir for 3 days (and placebo for the remaining 2 days) or 500 mg twice daily for 5 days, and were required to self-administer therapy no later than 24 hours after the onset of symptoms.


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