Antiviral therapy for genital herpes simplex virus type 2 is clinically effective, but even high-dose therapy did not substantially alter the frequency of viral shedding episodes in a series of three separate, but complementary, open-label crossover studies.
Suppressive therapies with greater potency are needed to prevent HSV-2 transmission and HIV-1 acquisition and transmission, Dr. Christine Johnston of the University of Washington, Seattle, and her colleagues, concluded in the Jan. 5 edition of the Lancet.
The studies – which together included 90 HSV-2-seropositive, HIV-negative adults with a median age of 43 years – evaluated within-person viral shedding in patients receiving no medication vs. standard-dose aciclovir (400 mg twice daily), those receiving high-dose aciclovir (800 mg three times daily) vs. standard-dose valaciclovir (500 mg daily), and those receiving standard-dose valaciclovir vs. high-dose valaciclovir (1 g three times daily).
Based on 23,605 swabs collected during the course of the studies, shedding frequency was reduced by all treatments, compared with no treatment.
The most significant difference occurred in the study comparing no medication vs. standard-dose acyclovir, in which 18% and 1% of the swabs indicated shedding in those groups, respectively (incidence rate ratio, 0.05), the investigators found.
However, breakthrough reactivation occurred at all drug doses. The number of episodes per person-year was highest in the no-treatment group at 28.7, and ranged from 10.0 to 22.6, with the difference reaching statistical significance only in the no-treatment vs. standard-dose aciclovir groups (28.7 vs. 10.0), the investigators said (Lancet 2011 Jan. 5 [doi:10.1016/S0140-6736(11)61750-9]).
Most of the shedding episodes during active treatment were subclinical, and the duration of episodes was shorter in the treatment groups vs. the no-treatment group (7-10 hours vs. 13 hours).
Although the available therapies for HSV have increased in use over the past 2 decades and have been successful for reducing genital lesions, treatment with daily valaciclovir has been associated with only a 48% reduction in the risk of sexual transmission of genital herpes.
"Moreover, aciclovir does not effectively reduce the risk of HIV transmission or acquisition in HSV-2 seropositive people," the investigators noted, adding that this discrepancy between potent suppression of symptoms and failure to prevent transmission has not been well understood.
Mathematical models suggest that short bursts of shedding occur frequently, and may be the cause of up to 85% of all HSV-2 reactivations, but whether treatment suppresses such short reactivation events was unknown.
To assess whether standard and/or high doses of aciclovir and valaciclovir affect these subclinical periods of HSV reactivation, they enrolled participants between November 2006 and July 2010 into the three studies, each with a 4- to 7-week initial treatment period, followed by a 1-week washout period, followed by crossover to the other treatment for an additional 4-7 weeks. Swabs were collected four times daily.
The "data suggest that anti-HSV therapy, although clinically effective, does not substantially alter the underlying pathobiology of frequent, subclinical HSV-2 reactivation. That we could not eliminate or even alter the frequency of shedding episodes with high-dose valaciclovir suggests that the maximum benefit of shedding reduction has probably been reached for currently available antiviral drugs," the investigators said.
The study was funded by the National Institutes of Health. Valaciclovir was provided for free for the third trial by GlaxoSmithKline. Dr. Johnston disclosed that she is a research investigator for AiCuris and GmbH. Two other study authors disclosed that they are consultants for those companies. These and other authors also disclosed financial relationships with Immune Design Corp., Sanofi-Pasteur, Agenus, Coridon, Vical, and/or PATH. Additionally Dr. Lawrence Corey and Dr. David M. Koelle are coinventors in several patents describing antigens and epitopes to which T-cell responses to HSV-2 are directed.