Vaccine and Infectious Disease Division
Thirty years ago, Seattle scientists were instrumental in demonstrating that the drug acyclovir was efficacious for curbing HSV-2 symptoms and promoting genital ulcer healing. Since that time, acyclovir and related drugs valacyclovir and famciclovir have been widely used to treat HSV-1 and HSV-2 infections. These drugs are nucleoside analogs, which inhibit viral DNA replication. However, they do not completely eliminate HSV reactivation and shedding, and there is a need for more potent medications. In addition, acyclovir-resistant disease occasionally develops and there are no good treatment options for those patients. Thus, the hunt for alternative drugs continues.
Pritelivir is a novel helicase-primase inhibitor that targets viral replication at a different stage of the viral DNA replication cycle than nucleoside analogues. The authors, including VIDD’s Affiliate Senior Research Scientist Meei-Li Huang, Affiliate Assistant Professor Christine Johnston, Associate Member Amalia Magaret, Member Larry Corey and Member Anna Wald, conducted a randomized, double-blind, placebo controlled phase 2 trial that demonstrated, for the first time, the antiviral as well as clinical benefits of pritelivir in persons infected with HSV-2. In the trial, conduced between April and December 2010, participants were randomized to receive one of the following treatments: placebo; pritelivir in the dose 5 mg, 25 mg or 75 mg daily; or pritelivir 400 mg weekly. The 155 HSV-2 infected participants who were enrolled across 7 sites in the United States kept a diary of symptoms and swabbed their genital area daily for a month. The swabs were then tested for HSV in the molecular virology laboratory at FHCRC. You cannot use swabs to test for clinical symptoms.
Compared to placebo, the relative risk of viral shedding (figure, left graph) at a daily dose of 5 mg was 1.11 (P=0.70); at a daily dose of 25 mg, 0.57 (P=0.06); at a daily dose of 75 mg, 0.13 (P<0.001); and at a weekly dose of 400 mg, 0.32 (P<0.001). In addition to reducing the rate of genital viral shedding, when HSV was detected the drug reduced viral load in a dose-dependent manner (figure, right graph). Pritelivir also successfully reduced clinical disease, with 75 mg daily and 400 mg weekly of drug showing the highest efficacy in lowering the frequency of genital lesions (figure, left graph). This study demonstrated that pritelivir had dose-dependent antiviral activity against genital HSV-2 infection and established the dose that can be used for future studies. While the main message from the study was the description of the safety and potential effectiveness of a new class of HSV-2 antivirals (helicase-primase inhibitors), the study design is both novel and efficient, and demonstrates how one can develop dose-response data in humans for HSV-2 infections in an objective and cost-effective fashion.
Wald, A., Corey, L., Timmler, B., Magaret, A., Warren, T., Tyring, S., Johnston, C., Kriesel, J., Fife, K., Galitz, L., Stoelben, S., Huang, M.-L., Selke, S., Stobernack, H.-P., Ruebsamen-Schaeff, H., Birkmann, A. Helicase-primase inhibitor pritelivir for HSV-2 infection. N Engl J Med. 2014 Jan 16;370(3):201-10.
Full-text Article: http://scholars.fhcrc.org/2789/
PubMed Record: http://www.ncbi.nlm.nih.gov/pubmed/24428466?otool=fhcrclib
Whitley RJ, Prichard M. A novel potential therapy for HSV. N Engl J Med. 2014 Jan 16;370(3):273-4.