Reports

Despite extensive public health campaigns, the incidence of infection with herpes simplex virus (HSV) continues to increase in many parts of the world. In the US, for example, 20% of the population has cold sores associated with HSV-1, and 90% of people older than 50 years have HSV-1 antibodies, noted Dr. Raj Patel, Consultant Genitourinary Physician, Southampton University Hospitals, UK. The rate of HSV-2 seropositivity is 20%, and 90% of infected individuals are unaware they are infected. An estimated 45 million people in the US have genital herpes, and the number of new cases is increasing by 1 million annually.

“The virus establishes a chronic, lifelong, latent infection of sensory neurons,” Dr. Patel told the audience. “During latency, the virus cannot be detected on the skin. The virus exists as extrachromosomal plasmids. Viral DNA and RNA can be detected in the ganglia. Reactivation of the infection occurs episodically by unknown mechanisms, and the virus descends in nerve axons and reinfects the skin.”

HSV neuronal transport proceeds at a rate of 3 to 4 mm/hr, consistent with fast axonal transport. Viral assembly likely occurs in the axon terminus just prior to egress, leading to multifocal inoculation of the epidermis (Holland et al. J Virol 1999;73:8503-11).

The epidemiology of HSV infection is changing, remarked Dr. Patel. Fewer children are acquiring HSV-1, which is becoming a more prominent cause of genital herpes in adults. However, the incidence of HSV-2 infection continues to increase in many parts of the world.

Narrow Therapeutic Window

Viral replication and crust formation associated with HSV occur within the first 48 hours, and viral replication in herpes labialis peaks within 24 hours after onset of lesions. Viral shedding and the time to healing in genital herpes also proceeds at a brisk pace, as wound formation appears to occur within 12 hours after viral reactivation.

“Few patients are getting worse after 12 hours,” stated Dr. Patel. “Healing has already started, as reflected in clinical studies of late treatment initiation showing little or no benefit.”

Knowledge of the time course of lesion development has several implications for treatment. Multiple studies have shown that early therapy leads to better outcomes, observed Dr. Patel. Clinical trials have demonstrated that patient-initiated, high-dose, short-course therapy is efficacious.

Current HSV Management

Current options for reducing the risk of acquisition or transmission of HSV consist of sexual abstinence, regular use of condoms and daily antiviral therapy to suppress HSV, explained Dr. Lawrence Stanberry, Chairman of Pediatrics, and Director, Center for Vaccine Development, University of Texas Medical Branch, Galveston. All three strategies are effective among adherent patients. For example, condom use during more than 25% of sex acts can reduce the risk of HSV transmission in women by more than 90% (Wald et al. JAMA 2001;285:3100-6). A randomized trial of daily suppressive antiviral therapy reduced the risk of symptomatic genital herpes infection by 75% and the risk of HSV-2 infection at any time by 48% in susceptible sexual partners (Corey et al. N Engl J Med 2004;350(1):11-20).

“The problem with each of these strategies is adherence,” Dr. Stanberry told the audience. “In the case of suppressive therapy, the risk of acquiring infection is decreased but not eliminated.” The long-term solution to the health problems posed by HSV infection lies in the development of a successful vaccine, he continued. In the meantime, patient-initiated episodic antiviral therapy has demonstrated the ability to reduce the duration of recurrent episodes of HSV infection and to abort some episodes.

As opposed to daily suppressive therapy, episodic treatment of recurrent HSV infection may be more convenient and acceptable to patients, leading to better adherence. In addition, episodic antiviral therapy might offer the potential to abort some episodes before they become full-blown recurrent infections, noted Dr. Stanberry.

Short-course Therapy

Two recent prospective multicentre studies reflect the potential of episodic patient-initiated, high-dose, short-course antiviral therapy. One of the studies involved 329 patients with a history of recurrent genital herpes (Aoki et al. Clin Infect Dis 2006;42:8-13). Patients were randomized to single-day treatment with famciclovir 1000 mg b.i.d. or placebo and instructed to begin treatment within six hours of the onset of prodromal symptoms.

The patient-initiated single-day regimen significantly reduced the median time to healing for non-aborted lesions from 6.1 days with placebo to 4.3 days and for aborted and non-aborted healing from five days to 3.5 days (P<0.001). Almost twice as many patients in the famciclovir group had aborted lesions (23.3% vs. 12.7%, P=0.003). Adverse events in the active treatment group were infrequent and similar to those seen in the placebo group.

A second study in 701 patients with recurrent herpes labialis compared the safety and efficacy of famciclovir in single-dose (1500 mg), single-day (750 mg b.i.d.) or placebo (Spruance et al. J Am Acad Dermatol 2006;55:47-53). Patients were instructed to initiate treatment within an hour of the onset of symptoms.

The median healing times for primary vesicular lesions were 4.4 days and 4.0 days with the single-dose and single-day regimens, respectively, compared to 6.0 days with placebo. The healing times between the two active treatment groups did not differ significantly.

Both studies yielded evidence of famciclovir’s ability to reduce viral shedding. Treatment reduced the relative risk of genital shedding by 65% overall and the risk of subclinical shedding by 50% compared to placebo (P<0.001). Active treatment reduced the risk of oral shedding by 40% overall and subclinical shedding by 38% compared to placebo, although the differences did not achieve statistical significance.

“These studies showed that HSV-2 seropositive individuals often experience asymptomatic shedding,” stated Dr. Stanberry, adding that treatment “was effective in decreasing the rate of total, subclinical, and clinical HSV shedding. This is the first famciclovir study to evaluate genital HSV shedding in HSV-2 seropositive individuals who do not have a history of genital herpes. The data demonstrated that these patients have frequent subclinical shedding.”

FaST Results

Results with the single-dose and once-daily regimens build on other evidence that episodic, patient-initiated, short-course antiviral therapy is safe and effective for treatment of recurrent HSV infections. The FaST (Famciclovir Short Course Herpes Therapy) study demonstrated that famciclovir 500 mg taken immediately, then 250 mg b.i.d. for two days was at least equivalent to standard therapy of 125 mg b.i.d. for five days for treatment of recurrent genital herpes, reported Dr. Mark Bloch, Holdsworth House Medical Practice, Sydney, Australia, and Dr. Stella Heley, Melbourne Sexual Health Centre, Australia.

The probability of a lesion being present at 132 hours was 25% with the short course and 29% with the standard course in an intent-to-treat analysis involving 1038 recurrences in 873 patients. Similar differences were observed in analyses of per-patient recurrences.

The time to second recurrence averaged 72 days with the short course and 71 days with standard therapy. The proportion of recurrences aborted 8% with the short course and 10% with the standard course, which was not statistically different. “All sensitivity analyses favoured the short course of therapy,” Dr. Bloch reported.