January 4, 2012 — Even high-dose antiviral suppressive therapy for herpes simplex virus type 2 (HSV2) does not appear to prevent subclinical shedding of virus, new research suggests, and this finding may explain why HSV2 continues to be transmitted even when HSV2-positive individuals take suppressive antiviral therapy.

Christine Johnston, MD, MPH, from the Department of Medicine at the University of Washington, and from the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center, both in Seattle, and colleagues published their findings online January 5 in the Lancet.

According to the researchers, antisuppressive therapy for HSV2 can suppress clinical symptoms, but studies suggest that suppressive therapy with acyclovir and valacyclovir reduces the risk for transmission only by 48%. "The discrepancy between potent suppression of clinical symptoms and failure of antiviral agents to fully prevent HSV transmission is not well understood," the authors note.

Dr. Johnston and colleagues also point out that short bursts of shedding, lasting less than 12 hours, are even more frequent than can be detected by current sampling methods and account for about 70% to 85% of all reactivations. If suppressive therapy fails to suppress these short reactivation events, then this could "account for the lower than expected effectiveness of antiviral drugs in clinical studies of HSV-2 transmission," they write.

The current report describes 3 complementary crossover clinical studies that assessed whether either standard or high doses of suppressive acyclovir or valacyclovir could affect the frequency of short, subclinical periods of HSV genital reactivation.

One study evaluated no medication vs acyclovir 400 mg twice daily (standard-dose acyclovir); another study compared valacyclovir 500 mg daily (standard-dose valacyclovir) vs acyclovir 800 mg, 3 times daily (high-dose acyclovir); and a third study evaluated standard-dose valacyclovir vs valacyclovir 1 g, 3 times daily (high-dose valacyclovir).

Each of the test periods lasted 4 to 7 weeks, and each was separated by a 1-week wash-out phase, after which each patient switched to the other study treatment. Genital swabs were collected 4 times daily for quantitative HSV DNA polymerase chain reaction.

Of the 113 randomized participants, 90 were eligible for analysis of within-person shedding rate, which was the primary endpoint. A total of 23,605 swabs were collected, of which 1272 (5.4%) were HSV-positive.

HSV shedding rate was significantly higher in the no-medication group (18.1% of swabs) than in the standard-dose acyclovir group (1.2%; incidence rate ratio [IRR] 0.05; 95% confidence interval [CI], 0.03 - 0.08). High-dose acyclovir was associated with less shedding than was standard-dose valacyclovir (4.2% vs 4.5%; IRR, 0.79; 95% CI, 0.63 - 1.00). In addition, shedding was less frequent in the high-dose valacyclovir group than in the standard-dose valacyclovir group (3.3% vs 5.8%; IRR, 0.54; 95% CI, 0.44 - 0.66).

The number of episodes per person per year did not differ between standard- and high-dose valacyclovir (14.9 vs 16.5; P = .34), nor did it differ between standard-dose valacyclovir and high-dose acyclovir (22.6 vs 20.2; P = .54), but the number of episodes per person per year was lower in those taking standard-dose acyclovir than in those taking no medication (10 vs 28.7 episodes/year; P = .001). Median episode duration was longer when no medication was used (13 hours) compared with standard-dose acyclovir (7 hours; P = .01), as well as when standard-dose valacyclovir was used (10 hours) compared with high-dose valacyclovir (7 hours; P = .03), but it did not differ between standard-dose valacyclovir (8 hours) and high-dose acyclovir (8 hours; P = .23).

Similar results were found for the maximum log10 copies of HSV detected per milliliter, which was higher for no medication than for standard-dose acyclovir (3.3 vs 2.9; P = .02), and for standard-dose valacyclovir than for high-dose valacyclovir (2.5 vs 3.0; P = .001), but no different for standard-dose valacyclovir than for high-dose acyclovir (2.7 vs 2.8; P = .66).

Eighty percent of episodes in all study groups were subclinical. About 30% of patients receiving high-dose valacyclovir experienced headaches; otherwise, treatments were well tolerated.

The authors conclude that "short episodes of genital HSV shedding occur frequently with antiviral therapy, even for high-dose regimens."

According to the researchers, the findings suggest that "suppressive therapies with greater potency, including antiviral drugs or immunotherapy in the form of therapeutic vaccines, are needed to provide substantial public health benefits, such as prevention of HSV-2 transmission and HIV-1 acquisition and transmission."

In a related editorial, Philippe Van de Perre, MD, and Nicolas Nagot, MD, both from the Université Montpellier in France, point out that these findings "should encourage patients to use condoms and adopt safe sex practices, especially since increase of the treatment dose would not further reduce the risk of transmission to patients' partners."

"The development of new antiherpetic drugs such as helicase–primase inhibitors is important," they add. "Alternative control tools, such as immunotherapeutic strategies (therapeutic vaccines), are in preclinical development, but they are hampered by the absence of an adequate animal model and the lack of commitment from pharmaceutical companies and the public sector."

The study was supported by the National Institutes of Health. In 1 of the studies, GlaxoSmithKline provided valacyclovir at no cost. Several of the study authors have relevant financial associations with companies developing anti-HSV approaches. Dr. Johnson is a research investigator for AiCuris, GmbH. The editorialists have disclosed no relevant financial relationships.

By Emma Hitt, PhD

Lancet. Published online January 5, 2012.