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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

Based on the following published articles: Current Medical Research and Opinion 2006;22(7):1307-10 and 2006;22(9):1699-702

Approximately 25% of American adults have genital herpes caused by herpes simplex virus 2 (HSV-2), and the incidence of genital herpes infection caused by HSV-1 is increasing, presumably because of increased prevalence of oral-genital sexual behaviour. An estimated 40% of Americans have become infected by HSV-1 by adolescence, and as many as 90% of older adults worldwide are seropositive for the virus. In herpes labialis, HSV-1 establishes latency in sensory nerve ganglia, and when reactivated, the virus descends through sensory nerve fibres to the perioral epithelium.

Recurrent genital herpes typically produces prodromal symptoms that include pain, burning, tingling and itching, and vesicles typically form 12 to 24 hours after the onset of symptoms. Maximum viral replication occurs within 24 hours after appearance of prodromal symptoms, presenting a narrow window of opportunity to reduce viral replication and minimize tissue damage. Patients with frequent, severe recurrences of HSV-2 infection may receive long-term suppressive therapy with an oral antiviral agent. Commonly used regimens typically require three to five days of treatment. However, many patients prefer episodic treatment with an oral antiviral. Given the nature of HSV-2 replication, a short course of an oral antiviral administered at the first sign of prodromal symptoms might be a more effective, efficient and convenient approach to treatment.

Episodic antiviral therapy is the most common approach to treatment of recurrent herpes labialis. However, the agents do not prevent cell lysis by HSV and thus only slow the spread of infection between cells by reducing the number of infectious virions generated. The best approach to minimize the duration of infection may be patient-initiated episodic therapy, which involves making medication available to patients so they can start self-treatment at the first sign of recurrence. Patient-initiated therapy for recurrent herpes labialis historically has involved topical antiviral agents. However, long treatment duration, poor drug penetration, and lack of evidence that the topical agents decrease healing time have led to increased use of oral antivirals (Hull et al. Curr Med Res Opin 2006;22(9):1699-702).

As with recurrent genital herpes, peak viral replication during an episode of recurrent herpes labialis occurs during the first 24 hours after symptom onset. Inhibition of viral replication at its peak might reduce lesion severity and tissue damage.

Short-course Therapy for Genital Herpes

Two recent clinical studies evaluated short-course oral antiviral therapy for treatment of recurrent HSV infection: one involved patients with genital herpes, and the other focused on recurrent herpes labialis (Aoki et al. Clin Infect Dis 2006;42:8-13, Spruance et al. J Am Acad Dermatol 2006;55(1):47-53). Subsequently, each of the investigations was examined and discussed in detail in separate published reviews presently discussed.

Investigators in a multicentre, randomized, placebo-controlled clinical trial evaluated a one-day treatment regimen utilizing oral famciclovir 1000 mg b.i.d. (Aoki et al.). The study involved 270 immunocompetent patients with recurrent genital herpes. Patients were randomized to active treatment or placebo and instructed to take the assigned treatment within six hours of the onset of prodromal symptoms or lesions. The primary end points were lesion healing, time to resolution of pain and other symptoms, percentage of patients who did not progress to a full outbreak, and the safety and tolerability of the study medication.

Single-day treatment significantly decreased healing time and time to resolution of all symptoms at two days compared to placebo. Additionally, it prevented progression to full outbreak in 25% of patients. The frequency and severity of adverse events were similar between the active treatment and placebo groups.

In the published review of the study, the authors noted that the reduction in healing time and resolution of symptoms with single-day therapy were as good or better than the results achieved in previous studies of longer courses of antiviral therapy for recurrent genital herpes. A full course of antiviral therapy administered in one day instead of three to five days offers the potential to inhibit viral replication at the time of maximal viral concentration. The results make famciclovir the first oral antiviral agent to demonstrate the ability to prevent progression to a full herpes outbreak with single-day treatment. Patient-initiated episodic therapy with single-day oral treatment may help increase patient satisfaction and adherence, which in turn could help decrease the severity of a recurrence or prevent a full outbreak from occurring, the authors stated.

Single-dose Treatment for Recurrent Herpes Labialis

Oral valacyclovir already is indicated for single-day treatment of recurrent herpes labialis. Famciclovir has a high bioavailability, and its active metabolite has a significantly longer intracellular half-life compared to acyclovir and a 100-fold greater affinity for viral thymidine kinase than acyclovir does. These characteristics suggest oral famciclovir also can be used as short-course therapy for recurrent herpes labialis.

A randomized, placebo-controlled, multicentre clinical trial examined the efficacy of single-dose and single-day oral famciclovir for treatment of recurrent herpes labialis (Spruance et al.). The study involved 701 patients with a history of recurrent herpes labialis. Patients received famciclovir 1500 mg q.d., 750 mg b.i.d. or placebo and were instructed to initiate therapy within one hour of the onset of prodromal symptoms of herpes labialis.

The active regimens reduced the time to healing of primary vesicular lesions by 1.2 to 2.2 days vs. placebo and primary plus secondary lesions (lesions that develop after the primary lesions and are located at least 1 cm from primary lesions) by 2.1 to 2.5 days vs. placebo. The two regimens did not differ from each other with respect to the healing time of primary lesions. Compared to placebo, single-dose treatment significantly improved the time to return to normal skin of primary and secondary lesions (P<0.001) and significantly reduced the time to resolution of pain and tenderness (P<0.001). The single-dose regimen also appeared to be more effective than the two-dose regimen in resolving pain and tenderness (P=0.046).

The authors of the review of the herpes labialis study noted that the magnitude of the benefit conferred by single-dose active therapy compared favourably with results observed in previous studies of other treatment regimens. They also pointed out that the study is the first demonstration of single-dose efficacy in patient-initiated antiviral therapy for recurrent herpes labialis.

Summary

Short-course antiviral therapy with famciclovir is feasible, safe and effective for treatment of recurrent herpes infection, including genital herpes and herpes labialis. The short-course, self-administered regimens offer a more convenient approach to treatment that can improve patient adherence and lead to better clinical outcomes for conditions affecting millions of patients.

The following question-and-answer session was conducted with Dr. Francisco Díaz-Mitoma, Professor of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario.

Q: In your opinion, are these abbreviated regimens ready for routine use in clinical practice?

A: The indication for single-day episodic treatment of genital herpes with famciclovir will very likely become clinical practice in Canada as physicians become aware of this treatment modality, which offers a simplified option for patients to control their symptoms during an outbreak of herpes. It may [also] increase adherence and compliance because of its simplicity.

Q: Does a short course of antiviral therapy increase the likelihood of incomplete or inadequate control, or more frequent recurrence?

A: There is no evidence that a short course of therapy may result in incomplete control of virus replication in an outbreak of genital herpes. The clinical trial suggests that a one-day course of famciclovir is as effective in the control of symptoms as five days of the medication. On the other hand, episodic treatment of genital herpes does not have an effect on the frequency of outbreaks. To suppress future episodes, patients need to be on daily antiviral treatment with famciclovir, valacyclovir or acyclovir.

Q. What is the rationale for a single dose of famciclovir for herpes labialis vs. a single day of treatment for genital herpes?

A: In general, HSV-1 is more susceptible to antivirals than HSV-2. In one study, a single dose of famciclovir was able to control symptoms as well as a two-dose course (one day) of treatment. However, to my knowledge, single-dose regimens for the treatment of genital herpes have not been tested in clinical trials.