Brief Reports

Transmission of Herpes Simplex Virus — Despite Antivirals

By Carol A. Kemper, MD, FACP, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases, Santa Clara Valley Medical Center.

Sources: Johnston C, et al. Standard-dose and high-dose daily antiviral therapy for short episodes of genital HSV-2 reactivation: Three randomized open-label, cross-over trials. Lancet 2012;379:641-647. Van DePerre P, Nagot N. Herpes simplex virus: A new era? Lancet 2012;379:598-599.

I just had a patient present for consultation, concerned he’d transmitted herpes simplex virus (HSV) to two new sexual partners, despite a lack of symptoms or obvious lesions, and expressing concern about the adequacy of suppressive acyclovir therapy. He had tried to convince both new partners it was not him! I had to disappoint him.

These investigators conducted three open-label, crossover treatment trials of suppressive antiviral therapy in 113 participants with known active HSV, examining genital swabs collected four times daily during treatment for quantitative HSV DNA by PCR. Patients were given no treatment vs oral acyclovir standard dose 400 mg twice daily; standard dose acyclovir 400 mg twice daily vs 800 mg three times daily; or standard dose valcyclovir 500 mg daily vs 1 g three times daily. Treatment duration ranged from 4-7 weeks, with a 1-week washout. While the treatment was provided in an open-label manner for the patients, the study monitors were blinded to the treatment group.

A total of 23,603 swabs were collected, 1272 (5.4%) of which were positive for HSV DNA. Eighty percent of all episodes detected were subclinical. Not unexpectedly, 18.1% of the swabs collected from patients on no treatment were HSV positive compared with 1.2% of the swabs from patients receiving standard-dose acyclovir. But an even more important finding was the frequency of HSV detection in patients receiving high-dose treatment. The frequency of HSV detection was 4.5% vs 4.2% in persons receiving standard dose ACV vs high-dose valcyclovir; and, 5.8% vs 3.3 % in persons receiving standard dose valcyclovir vs high-dose valcyclovir.

While no statistically significant difference in the number of episodes of shedding per person-years was observed for any of the treatment groups, there was an observed difference in the duration of viral shedding during episodes. The median duration of an episode was longer for patients on no treatment vs standard ACV treatment (13 hrs vs 7 hrs, P = 0.01), and, similarly, for standard vs high dose valcyclovir treatment (10 hrs vs 7 hrs, P = 0.03). A small but statistically significant difference was also observed in the maximum copy number of HSV particles detected in persons receiving no treatment vs standard ACV, and standard ACV vs higher-dose valcyclovir.

Overall, HSV was detected on 3% of the days during standard dose ACV treatment, 7% of the days on high-dose valcyclovir, and 9% of the days during treatment with either standard dose valcyclovir or high-dose acyclovir. While on no treatment, genital swabs were positive for HSV DNA 24% of the days. That’s one-fourth of the time!

The accompanying editorial suggests that we are functioning under a mistaken impression of genital HSV as a latent infection, punctuated by short but self-limited “bursts” of viral replication, some of which is symptomatic. A more accurate model may (unfortunately) be one of constant low-grade viral replication, with ongoing production of small numbers of viral particles (40-90 virions) from infected neurons every day. Propagation of HSV then occurs, with more rapid spread of virions to the skin surface — which is only controlled in situ by CD8 cells. Data suggest that low-level replication may actually be harder to suppress with antiviral therapies, and therefore increases the risk of transmission. In other words, people with recognized outbreaks of symptomatic infection may be easier to suppress and at lower risk than those with low-level replication and subclinical infection.

Patients are often under the mistaken impression that viral shedding is a rare event if they take long-term suppressive therapy. Clearly these data speak otherwise. Patients should be counseled that, while suppressive antiviral therapy may reduce viral shedding, it may still occur — and with surprising frequency. Use of condoms may further reduce the risk of viral shedding, but also does not prevent sexual transmission.