In the development of new antivirals and therapeutic vaccines for genital HSV-2 infection, the rate of genital herpes recurrences has been used as an outcome to assess disease severity and response to therapy. However, this outcome may not be observed in all participants. We tested whether genital HSV shedding is an appropriate intermediate endpoint for clinical genital herpes infection as it is more consistent, common, and in the causal pathway to recurrences.
We analyzed prospective data from HSV-2 studies at the University of Washington Virology Research Clinic 1990-2014. All participants provided 30 days of daily self-collected anogenital swabs. Viral shedding was quantified by HSV DNA PCR. Genital recurrences were self-reported.
Genital shedding rate was assessed on 674 HSV-2 seropositive persons. HSV shedding was detected in 465 (69%) participants, and recurrences were reported in 283 (42%) participants. The annualized recurrence rate increased 28% for each 10% increase in shedding rate (95%CI 23% to 33%, p<0.001) on a relative scale from 3.9 per year at 0% shedding to 10.5 per year at 40% shedding. For each additional reported recurrence in the preceding year, the predicted shedding rate increased by 6% (95% CI 4% to 8%, p<0.0001) on a relative scale from 13% at 0 recurrences, to 26% with 12 recurrences. Ninety persons contributed two shedding sessions. Shedding rates in the first session strongly predicted shedding (r=0.39, p<0.0001) but were less associated with recurrence rates at subsequent sampling periods (r=0.20, p=0.062). In studies of antiviral agents, the relative reduction in recurrence rate was 72% (p=0.041) on pritelivir compared to placebo, but decreased to 21% (p=0.75) when the model included shedding rate. Similarly, acyclovir reduced recurrence rates by 82% (p-value <0.0001) compared to placebo, but only decreased recurrence rates by 63% (p-value= 0.002) after adjusting for shedding rate. Similar relative reductions were seen when lesion rate was used as the outcome.
HSV genital shedding measured by PCR is an appropriate surrogate for disease severity and clinical response to antiviral therapy because it is consistent, objective, and in the causal pathway to recurrences.
S. Selke, None
C. Johnston, Aicuris: Investigator , Research support
Genocea: Sub-Investigator , Research support
Vical: Sub-Investigator , Research support
Agenus: Sub-Investigator , Research support
Gilead: Sub-Investigator , Research support
L. Corey, Immune Design Corp: Scientific Advisor and Shareholder , Salary
HSV Vaccine Trials: Coinventor and listed on several patents involving HSV vaccine development , Salary
A. Wald, Agenus: Investigator , Research support
Genocea: Investigator , Research support
Vical: Investigator , Research grant and Research support
Gilead: Investigator , Research support
Aicuris: Consultant , Consulting fee