New approaches eyed to herpes simplex virus
New research points to the need for more potent approaches to containing the genital herpes simplex virus (HSV). In three separate but complementary open-label crossover studies examining standard and high-dose therapies, scientists found short bursts of subclinical reactivation are frequent, even during high-dose antiherpes therapy, and probably account for continued transmission of HSV during suppressive antiviral therapy.1
The Centers for Disease Control and Prevention estimates about one out of six people ages 14-49 have genital type 2 (HSV-2) infection.2 While there is no treatment available to cure herpes, clinicians have looked to antiviral medications to shorten and prevent outbreaks and daily suppressive therapy to reduce transmission to partners.2
To perform the studies, scientists designed the trials to compare no medication versus aciclovir 400 mg (the standard dose for the drug) twice daily, valaciclovir (the standard dose for the drug) 500 mg daily versus aciclovir 800 mg (high-dose aciclovir) three times daily, and standard-dose valaciclovir versus valaciclovir 1 g (high-dose valaciclovir) three times daily. Patients enrolled in the study were HSV-2-seropositive, HIV-seronegative healthy adults age 18 and older who were enrolled at the University of Washington Virology Research Clinic in Seattle between November 2006 and July 2010. Investigators collected genital swabs four times daily throughout the study period; study periods lasted 4-7 weeks, separated by one week wash-out.
Research findings indicate that frequency of HSV shedding was significantly higher in the no medication group (n = 384, 18.1% of swabs) than in the standard-dose aciclovir group (25, 1.2%; incidence rate ratio [IRR] 0.05, 95% confidence interval [CI] 0.03-0.08). High-dose aciclovir was associated with less shedding than standard-dose valaciclovir (198 [4.2%] versus 209 [4.5%]; IRR 0.79, 95% CI 0.63-1.00). Shedding was less frequent in the high-dose valaciclovir group than in the standard-dose valaciclovir group (164 [3.3%] versus 292 [5.8%]; 0.54, 0.44-0.66). The number of episodes per person-year did not differ significantly for standard-dose valaciclovir (22.6) versus high-dose aciclovir (20.2; p = 0.54), and standard-dose valaciclovir (14.9) versus high-dose valaciclovir (16.5; p = 0.34), but it did differ for no medication (28.7) and standard-dose aciclovir (10.0; p = 0.001). Median episode duration was longer for no medication than for standard-dose aciclovir (13 hours versus seven q hours; p = 0.01) and for standard-dose valaciclovir than for high-dose valaciclovir (10 hours versus seven hours; p = 0.03), but did not differ significantly between standard-dose valaciclovir and high-dose aciclovir (eight hours versus eight hours; p = 0.23).1
What is the next step in research in determining alternative suppressive therapies for HSV-2?
"We need new antiviral drugs with novel mechanisms of action against HSV-2," says Christine Johnston, MD, MPH, acting assistant professor in the University of Washington School of Medicine in Seattle and lead author of the current research. "These drugs would ideally potently inhibit HSV-2 shedding and have a high threshold for development of resistance."
Johnston points to recent research in which a tenofovir microbicide intravaginal gel was unexpectedly shown to decrease HSV-2 acquisition in HSV-2 seronegative women in the CAPRISA 004 HIV prevention trial.3
The effect of oral tenofovir and intravaginal tenofovir gel on HSV-2 shedding among HSV-2 seropositive women will be studied in an upcoming clinical trial, says Johnston. "Helicase-primase inhibitors are another example of a promising new antiviral which is being studied for HSV-2 infection," Johnston observes. "In addition, further research into interactions between HSV-2 and the human host are needed to identify protective immune responses, which could potentially be stimulated with a therapeutic HSV-2 vaccine."
Vaccines in development
Science is moving forward on vaccine development against HSV. In a just-published Phase III study, data indicates an investigational vaccine protected some women against infection from one of the two types of herpes simplex viruses that cause genital herpes. While the vaccine was partially effective at preventing HSV-1, data indicate it did not protect women from HSV-2.4
More than 8,000 women between ages 18-30 who did not have HSV-1 or HSV-2 infection at the start of the study were enrolled in the study; participants were randomly assigned to receive three doses of an investigational HSV vaccine (Simplirix)that was developed by GlaxoSmithKline Biologicals of London or a hepatitis A vaccine, which served as the control. Participants were followed for 20 months and evaluated for occurrence of genital herpes disease. Findings suggest that two or three doses of the investigational vaccine offered significant protection against genital herpes disease caused by HSV-1; however the vaccine did not protect women from genital disease caused by HSV-2. The company has decided not to pursue further worldwide development of the vaccine, based on the trial results.
What is the next step in research? Robert Beishe, MD, professor of medicine, pediatrics and molecular microbiology at Saint Louis University, says data from the current study offers some direction: A simple vaccine such as the one tested has very modest efficacy, and a more complex vaccine is needed to protect against herpes. Beishe, who served as lead author of the current paper, says his own bias lies in research of a live attenuated vaccine.
"Chickenpox is the only herpes virus for which we have a vaccine," Beishe observes. "We use a live attenuated virus there, and it's very effective. And so for all the other human herpes viruses, I think a live attenuated vaccine, or a vaccine that mimics the benefits of live attenuated vaccine, would be the way to go."
References
- Johnston C, Saracino M, Kuntz S, et al. Standard-dose and high-dose daily antiviral therapy for short episodes of genital HSV-2 reactivation: three randomised, open-label, cross-over trials. Lancet 2012. Doi: 10.1016/S0140-6736(11)61750-9.
- Centers for Disease Control and Prevention. Genital herpes. Fact sheet. 2010; Atlanta. Accessed at http://www.cdc.gov/std/Herpes/STDFact-Herpes.htm.
- Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al; CAPRISA 004 Trial Group. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010; 329:1,168-1,174.
- Belshe RB, Leone PA, Bernstein DI, et al. Efficacy results of a trial of a herpes simplex vaccine. N Engl J Med 2012; 366:34-43.
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