Vaccine and Infectious Disease Division

Can high-dose antiherpes therapy eliminate genital HSV-2 shedding?

Figure 2. HSV detection in genital swabs from three clinical trials.

Despite the efficacy of acyclovir and valacyclovir in reducing herpes genital lesions, antiviral therapy decreases the risk of transmission by only 48%. The high prevalence of HSV-2 continues to be a worldwide public health issue, and it has recently come to light that most reactivation, or “shedding,” episodes of the chronic infection caused by HSV-2 occur much more frequently than once thought. Recent studies have shown that only ~20 percent of all shedding episodes result in characteristic genital lesions; approximately 80 percent of shedding episodes are asymptomatic and of short duration (<12 hours). This constant, subclinical shedding pattern of HSV-2 could partially explain the discrepancy between efficacious antiviral therapy in reducing lesions but not eliminating the risk of sexual transmission.

VIDD scientists wondered if increasing the dosage of antiherpes medications would be efficacious in inhibiting HSV-2 short shedding episodes, ergo reducing risk of transmission to sexual partners. The team, led by VIDD Affiliate Investigator Dr. Christine Johnston and including Associate Member Dr. Amalia Magaret, Affiliate Staff Scientist Dr. Meei-li Huang, Associate Dr. Joshua Schiffer, Affiliate Investigator Dr. David Koelle, Member Dr. Anna Wald, and Center President and Director Larry Corey, set up three randomized, open-labeled, cross-over clinical trials that tested the potency of various doses of acyclovir and valacyclovir in reducing genital HSV-2 shedding frequency in HSV-2 seropositive persons from the Seattle area. The arms of the three clinical trials included: no medication versus standard-dose acyclovir; standard-dose valcayclovir versus high-dose acyclovir; and standard-dose valacyclovir versus high-dose valacyclovir. The cohort included 90 participants who took a genital swab every 6 hours (4 swabs daily) for 9-15 weeks for a total of 23,605 swabs; 1,272 were HSV-positive. HSV shedding frequency was significantly higher in the no medication group (18%) compared to the standard-dose acyclovir group (1%); and in standard-dose valacyclovir (6%) compared to high-dose valcayclovir (3%). Mean episode duration was also higher in the no medication group compared to standard-dose acyclovir (13 hours vs 7 hours, respectively) and for standard-dose valcayclovir compared to high-dose valacyclovir (10 h vs 7 h, respectively). However, they found that the number of episodes per year was not significantly different on standard-dose and high-dose valacyclovir. There was no difference between standard-dose valacyclovir and high-dose acyclovir in shedding frequency, episode duration or episodes per year. The authors did find that 80% of the episodes were subclinical in all three trial groups, irrespective of the drug treatment. This study shows that short, frequent shedding episodes occur during chronic HSV-2 infection despite high-dose antiviral therapy, suggesting more efficacious drugs are required to thwart herpes transmission.

Johnston C, Saracino M, Kuntz S, Magaret A, Selke S, Huang ML, Schiffer JT, Koelle DM, Corey L and Wald A. Standard-dose and high-dose daily antiviral therapy for short episodes of genital HSV-2 reactivation: three randomized, open-label, cross-over trials. The Lancet. 2012 Jan 5.

Comment on article:

Van de Perre P and Nagot N. Herpes simplex virus: a new era? The Lancet. 2012 Jan 5.