Short-course therapy for recurrent genital herpes and herpes labialis

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Applied Evidence

Short-course therapy for recurrent genital herpes and herpes labialis

J Fam Pract. 2007 January;56(1):30-36

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References

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TABLE 1
Short-course, patient-initiated OAV therapy is effective for treating episodic genital herpes

DRUG	TREATMENT DURATION	TREATMENT DOSE	CONTROL	MEDIAN TIME (DAYS) TO LESION HEALING (TREATMENT VS CONTROL)	MEDIAN EP ISODE DURATION (DAYS) (TREATMENT VS CONTROL)	PATIENTS WITH ABORTED EPISODES (%) (TREATMENT VS CONTROL)
Valacyclovir³	3 days	500 mg 2×daily	valacyclovir 500 mg 2×/day for 5 days	4.4 vs 4.7 (P=NS)	4.3 vs 4.4 (P=NS)	25 vs 27 (P=NS)
Acyclovir²⁸	2 days	800 mg 3×daily	Placebo	4.0 vs 6.0 (P=.001)	4.0 vs 6.0 (P=.001)	27 vs 11 (P=.029)
Famciclovir²⁹	1 day	1000 mg 2×daily	Placebo	4.3 vs 6.1 (P<.001)	3.5 vs 5.0 (P<.001)	23 vs 13 (P=.003)
Lesion healing time measures the duration of a subset of severe or classical herpetic outbreaks, characterized by the formation of vesicles, ulcers, or crusts (also papules in some studies^28,29). The endpoint is lesion reepithelialization/loss of crust. Episodes where there were only prodromal symptoms, erythema, and/or papule formation (or only symptoms and/or erythema in some studies^28,29) were considered “aborted” or prevented lesions. The occurrence of these favorable episode outcomes is described as a percentage of all episodes. Episode duration, sometimes called healing time of all lesions or time to return to normal skin, is the time to resolution of all episodes, regardless of lesion severity. The definition of normal skin varies among the different studies.
NS=not significant.

Short-course, high-dose, patient-initiated episodic OAV therapy for recurrent herpes labialis

Placebo-controlled trial of single-day and 2-day valacyclovir therapy. Spruance and coworkers studied the efficacy of single-day and 2-day valacyclovir treatments in comparison with placebo for an episode of herpes labialis.²⁷ Two identical studies were performed on individuals who were at least 12 years old, had a clinical history of recurrent cold sores, and had experienced ≥3 episodes in the preceding year. Participants in both studies (study 1, N=1524; study 2, N=1627) were required to self-administer 2 g valacyclovir twice daily for 1 day (valacyclovir 1 day), 2 g valacyclovir twice daily for 1 day followed by 1 g twice daily for 1 day (valacyclovir 2 days), or matching placebo at the earliest onset of prodromal symptoms and before the appearance of lesions. Patients were asked to return to the clinic within 24 hours of initiation of therapy.

The primary endpoint in study 1 was clinician-observed duration of all herpes labialis lesions and the secondary endpoint was the percentage of subjects who had herpes labialis lesions that did not progress beyond the papule stage. In study 2, the endpoints were reversed: the primary endpoint was the percentage of patients with lesions that did not progress and the secondary endpoint was the duration of lesions. Other efficacy endpoints were time to healing of vesicular (classical) lesions and duration of pain and discomfort.

FAST TRACK

Three-, two-, and even single-day treatments of oral antivirals may be as effective as traditional longer treatments for genital herpes

Both studies demonstrated that single-day valacyclovir treatment significantly decreased lesion healing time and the duration of herpes labialis episodes by 0.5 to 1.0 days compared with placebo (TABLE 2). A statistically significant decrease in the duration of pain and other symptoms was also seen with single-day valacyclovir compared with placebo (data not shown). In both studies, a higher percentage of patients in the valacyclovir group did not progress to full outbreak compared with placebo, but these differences were not statistically significant. The results with 2 days of valacyclovir treatment were similar. Adverse events were similar between the treatment groups and the placebo group.

Placebo-controlled trial of single-dose and single-day famciclovir therapy. Spruance and coworkers assessed patient-initiated famciclovir 1500 mg (single-dose) and 750 mg twice daily (single-day) in immunocompetent adults with recurrent cold sores.³⁰ Subjects (N=1376) were at least 18 years of age and had experienced ≥3 episodes of cold sores over the previous 12 months. Subjects were instructed to administer 1500 mg (single-dose), 750 mg twice daily (single-day), or matching placebo within 1 hour of the onset of prodromal symptoms and before the onset of lesions, and were asked to return to the clinic within 24 hours of initiating medication.

The agents and how they work

Topical antiviral drug formulations were the first treatments approved for recurrent HSV-1 and HSV-2 outbreaks, but these were only marginally efficacious.^19-21,31 orally-administered antiviral agents appear to be more effective, possibly because of better delivery of the drug to the site of infection. Three oral antiviral agents (OAVs) are currently approved for the treatment of recurrent genital herpes: acyclovir, an acyclic nucleoside analog; valacyclovir, the prodrug of acyclovir; and famciclovir, the prodrug of penciclovir, another acyclic nucleoside analog. one OAV (valacyclovir) is currently approved for the treatment of herpes labialis in immunocompetent patients.²⁷ The prodrugs of acyclovir and penciclovir, valacyclovir and famciclovir, respectively, were synthesized to provide high oral bioavailability and thus permit less frequent administration and potentially greater efficacy compared to the parent compounds.

Following oral administration, valacyclovir and famciclovir undergo first-pass metabolism to acyclovir and penciclovir, respectively.^4,32 acyclovir and penciclovir are selectively phosphorylated by the viral thymidine kinase of infected cells and then converted to the active triphosphate by cellular enzymes. The triphosphate forms (which have different half-lives depending upon the compound)³³ inhibit viral DNA polymerase and interfere with DNA chain extension,³⁴ thereby halting viral DNA synthesis. The drugs cannot prevent the death of a cell once it is infected, but they can reduce, in a dose-dependent manner, the quantity of virions produced by an infected cell. The mechanism of action of HSV-selective antiviral drugs suggests that the most logical strategy for episodic treatment is to maximally inhibit HSV replication using high doses.^18,35