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More potent antiviral therapies needed to prevent HSV-2 shedding
Johnston C. Lancet. 2012;doi:10.1016/S0140-6736(11)61750-9.
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Short episodes of breakthrough genital herpes simplex virus type 2 shedding persisted on very high doses of acyclovir and valacyclovir, suggesting that these drugs are not potent enough to completely prevent reactivation and potential transmission, according to Christine Johnston, MD, MPH, and colleagues.
“Our trials were motivated by the fact that suppressive antiviral therapy decreases the risk of HSV-2 transmission by only about 50%, despite about 70-80% reduction in viral shedding,” Johnston said.
“We hypothesized that breakthrough shedding may occur in short bursts which could be captured with frequent genital sampling, and that we could suppress theses short bursts with higher doses of antiviral therapy. We found that athough [herpes simplex virus type 2 (HSV-2)] shedding was reduced by 50% with the highest doses of valacyclovir (1 g, three-times daily; Valtrex, GlaxoSmithKline), the rate of breakthrough shedding episodes — about 16 to 20 episodes per year did not change,” the researchers wrote. “These data suggest that novel therapies are needed to completely prevent HSV reactivation.”
Researchers led by Johnston, of the University of Washington in Seattle, conducted three randomized, open-label, crossover trials comparing no medication with standard-dose acyclovir (Zovirax, GlaxoSmithKline) 400 mg twice daily; standard-dose valacyclovir 500 mg once daily with high-dose acyclovir 800 mg three-times daily; and standard-dose valacyclovir with high-dose valacyclovir 1 g three-times daily.
Participants were HSV-2-seropositive, HIV-seronegative healthy adults aged 18 years and older enrolled at the University of Washington Virology Research Clinic between November 2006 and July 2010. Genital swabs were collected four-times daily throughout the study period.
Of 23,605 genital swabs gathered, 5.4% tested positive for HSV. The frequency of HSV shedding was significantly higher in the no medication group (18.1% of swabs) compared with the standard-dose acyclovir group (1.2%; incidence rate ratio [IRR]=0.05; 95% CI, 0.03-0.08).
HSV shedding was less frequent in the high-dose acyclovir group (4.2%) vs. the standard-dose valacyclovir (4.5%; IRR=0.79; 95% CI, 0.63-1.00); as well as the high-dose valacyclovir group (3.3%) vs. the standard-dose valacyclovir group (5.8%; IRR=0.54; 95% CI, 0.44-0.66). While the duration of shedding episodes was shorter on high-dose valayclcovir, the number of episodes of breakthrough shedding per person-year did not differ significantly between standard-dose valaciclovir (14-9) and high dose valaciclovir (!6-5; p=0.34), suggesting that even very high doses of valacyclovir cannot suppress viral reactivation.
Despite a higher frequency of headaches reported among 13 patients on high-dose valacyclovir, all regimens were generally well tolerated, according to the researchers.
In an accompanying editorial, Philippe Van de Perre, MD, PhD, and Nicolas Nagot, MD, both of Université Montpellier in France, wrote: “The development of new antiherpetic drugs such as helicase–primase inhibitors is important. However, even if such antiviral drugs could stop HSV shedding, and thereby transmission, their use would need good coverage and satisfactory long-term adherence to affect HSV dynamics substantially. These needs are unlikely to be met because about 20% of the general population is infected with HSV-2 in the United States and Europe, most of whom have no clinical need for antiherpetic therapy.”
Disclosure: This research was funded by the NIH. Valacyclovir was provided for free for the third trial by GlaxoSmithKline. Dr. Johnston reports being a research investigator for AiCuris GmbH.
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