Effect of Pritelivir Compared With Valacyclovir on Genital HSV-2 Shedding in Patients With Frequent Recurrences
Authors: Anna Wald, Burkhard Timmler, Amalia Magaret, Terri Warren, Stephen Tyring, Christine Johnston, Kenneth Fife, Stacy Selke, Meei-Li Huang, Hans-Peter Stobernack, Holger Zimmermann, Lawrence Corey, Alexander Birkmann, Helga Ruebsamen-Schaeff
Journal: JAMA (2016)

<h3>Importance</h3> Current therapy of herpes infections relies on nucleoside analogues. Pritelivir is a well-tolerated novel herpes simplex virus (HSV) helicase-primase inhibitor that reduced genital shedding and lesions. <h3>Objective</h3> To compare the efficacy of pritelivir with valacyclovir for suppression of genital HSV-2 infection. <h3>Design, Setting, and Participants</h3> A phase 2, randomized, double-blind, crossover clinical trial at clinical research centers in 4 US cities (October 2012-July 2013) compared daily oral doses of 100 mg of pritelivir with 500 mg of valacyclovir. The planned sample size was 98 adults, allowing for detection of a 50% reduction in viral shedding between the study treatments. Healthy adults with 4 to 9 annual genital HSV-2 recurrences were eligible. Ninety-one participants were randomized: 45 to receive pritelivir and 46 to receive valacyclovir first when the US Food and Drug Administration placed the trial on clinical hold based on findings in a concurrent nonclinical toxicity study, and the sponsor terminated the study. <h3>Interventions</h3> Participants took the first drug for 28 days followed by 28 days of washout before taking the second drug for 28 days. Throughout treatment, the participants collected genital swabs 4 times daily for testing by HSV polymerase chain reaction assays. <h3>Main Outcomes and Measures</h3> The primary end point was within-participant genital HSV shedding while receiving pritelivir compared with valacyclovir. Secondary end points included the quantity of HSV in positive swabs and the frequency of genital lesions and shedding episodes. <h3>Results</h3> Of the 91 randomized participants (median age, 48 years; 57 women [63%]), 56 had completed both treatment periods at the time of the study's termination. In intent-to-treat analyses, HSV shedding was detected in 2.4% (173 of 7276 ) of swabs during pritelivir treatment compared with 5.3% (392 of 7453) during valacyclovir treatment (relative risk [RR], 0.42; 95% CI, 0.21 to 0.82;<i>P</i> = .01). In swabs with HSV, the mean quantity of HSV was 3.2 log<sub>10</sub>copies/mL during pritelivir treatment vs 3.7 log<sub>10</sub>copies/mL during valacyclovir treatment (difference, −0.1; 95% CI, −0.6 to 0.5;<i>P</i> = .83). Genital lesions were present on 1.9% of days in the pritelivir group vs 3.9% in the valacyclovir group (RR, 0.40; 95% CI, 0.17-0.96;<i>P</i> = .04). The frequency of shedding episodes did not differ by group, with 1.3 per person-month for pritelivir and 1.6 per person-month for valacyclovir (RR, 0.80; 95% CI, 0.52 to 1.22;<i>P</i> = .29). Treatment-emergent adverse events occurred in 62.3% of participants in the pritelivir group and 69.2% of participants in the valacyclovir group. <h3>Conclusions and Relevance</h3> Among adults with frequently recurring genital HSV-2, the use of pritelivir compared with valacyclovir resulted in a lower percentage of swabs with HSV detection over 28 days. Further research is needed to assess longer-term efficacy and safety. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT01658826