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Anti-herpetic agents reduce recurrence of herpes simplex-2 (HSV-2) symptoms but do not completely block subclinical shedding of virus, even at high doses, researchers reported.

In three complementary crossover trials, short episodes of genital shedding occurred despite daily therapy, according to Christine Johnston, MD, of the University of Washington in Seattle, and colleagues.

The finding may explain why even high doses of anti-herpetic drugs do not prevent transmission of the virus, Johnston and colleagues suggested online in The Lancet.

The researchers enrolled 113 patients with confirmed HSV-2 infection for the three trials, which tested:

• No medication against a standard 400-milligram dose of acyclovir (Zovirax) twice a day
• A standard 500-milligram dose of valacyclovir (Valtrex) once a day, against 800 milligrams of acyclovir three times daily
• Standard-dose valacyclovir against 1 gram of valacyclovir three times daily

Participants in each trial were assigned to one of the arms for four through seven weeks, had a week without any treatment, and then were crossed over to the other arm.

They took genital swabs four times a day and all told collected 23,605 swabs, of which 1,272 (or 5.4%) were positive for HSV-2.

Johnston and colleagues reported that 23 participants took 2,123 swabs while receiving no medication, and the virus was found in 384 (or 18%) of them.

In comparison, all of the drug regimens reduced the frequency of detection of the virus on swabs to between 1% (for standard-dose acyclovir) and 6% (for standard-dose valacyclovir).

Despite that, the researchers reported, "breakthrough reactivation occurred at all drug doses."

The number of such episodes per person year – the annualized episode rate – ranged from a high of 28.7 for no medication to a low of 10 for standard-dose acyclovir, while in the other four treatment groups the rates ranged from 14.9 to 22.6.

The number of episodes per person-year did not differ significantly for standard-dose valacyclovir versus high-dose acyclovir (22.6 versus 20.2, P=0.54), and standard-dose valacyclovir versus high-dose valacyclovir (14.9 versus 16.5; P=0.34), but did for no medication and standard-dose aciclovir (28.7 versus 10, P=0.001).

The researchers noted that the drugs benefit patients by reducing clinical recurrences.

But, they added, the outcome "suggests that the maximum benefit of shedding reduction has probably been reached for currently available antiviral drugs."

The findings "should encourage patients to use condoms and adopt safe sex practices," commented Philippe Van de Perre, MD, PhD, and Nicolas Nagot, MD, both of Université Montpellier in Montpellier, France.

In an accompanying commentary, they argued that new drugs would help, as long as they had good coverage and long-term adherence.

But those needs "are unlikely to be met," they noted, because about 20% of people in the U.S. and Europe are infected with HSV-2, "most of whom have no clinical need for anti-herpetic therapy."

In the absence of new drugs, other tools, such as vaccines, will be needed, but their development has been hampered by the lack of both a good animal model and pharmaceutical company commitment, they concluded.