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Helicase–Primase Inhibitor Pritelivir for HSV-2 Infection

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Helicase–Primase Inhibitor Pritelivir for HSV-2 Infection The new england journal of medicine established in 1812 january 16, 2014 vol. 370 no. 3 Helicase–Primase Inhibitor Pritelivir for HSV-2 Infection Anna Wald, M.D., M.P.H., Lawrence Corey, M.D., Burkhard Timmler, M.D., Amalia Magaret, Ph.D., Terri Warren, M.N., Stephen Tyring, M.D., Ph.D., Christine Johnston, M.D., M.P.H., John Kriesel, M.D., Kenneth Fife, M.D., Ph.D., Lawrence Galitz, M.D., Susanne Stoelben, M.D., M.P.H., Meei-Li Huang, Ph.D., Stacy Selke, M.A., Hans-Peter Stobernack, D.V.M., Helga Ruebsamen-Schaeff, Ph.D., and Alexander Birkmann, Ph.D. Abstract Background Pritelivir, an inhibitor of the viral helicase–primase complex, exhibits antiviral From the University of Washington and Fred Hutchinson Cancer Research Center, activity in vitro and in animal models of herpes simplex virus (HSV) infection. We Seattle (A.W., L.C., A.M., C.J., M.-L.H., tested the efficacy and safety of pritelivir in otherwise healthy persons with genital S. Selke); AiCuris, Wuppertal, Germany HSV-2 infection. (B.T., S. Stoelben, H.-P.S., H.R.-S., A.B.); Westover Heights Clinic, Portland, OR Methods (T.W.); University of Texas, Houston (S.T.); University of Utah, Salt Lake City We randomly assigned 156 HSV-2–positive persons with a history of genital herpes (J.K.); Indiana University School of Med- to receive one of four doses of oral pritelivir (5, 25, or 75 mg daily, or 400 mg weekly) icine, Indianapolis (K.F.); and Cetero Re- or placebo for 28 days. Participants obtained daily swabs from the genital area for search, Miami (L.G.). Address reprint requests to Dr. Wald at the University HSV-2 testing, which was performed with a polymerase-chain-reaction assay. Partici- of Washington Virology Research Clinic, pants also maintained a diary of genital signs and symptoms. The primary end point Box 359928, 325 9th Ave., Seattle, WA was the rate of genital HSV shedding. 98104, or at [email protected]. Drs. Ruebsamen-Schaeff and Birkmann Results contributed equally to this article. HSV shedding among placebo recipients was detected on 16.6% of days; shedding among pritelivir recipients was detected on 18.2% of days among those receiving N Engl J Med 2014;370:201-10. DOI: 10.1056/NEJMoa1301150 5 mg daily, 9.3% of days among those receiving 25 mg daily, 2.1% of days among Copyright © 2014 Massachusetts Medical Society. those receiving 75 mg daily, and 5.3% of days among those receiving 400 mg weekly. The relative risk of viral shedding with pritelivir, as compared with placebo, was 1.11 (95% confidence interval [CI], 0.65 to 1.87) with the 5-mg daily dose, 0.57 (95% CI, 0.31 to 1.03) with the 25-mg daily dose, 0.13 (95% CI, 0.04 to 0.38) with the 75-mg daily dose, and 0.32 (95% CI, 0.17 to 0.59) with the 400-mg weekly dose. The percentage of days with genital lesions was also significantly reduced, from 9.0% in the placebo group to 1.2% in both the group receiving 75 mg of pritelivir daily (relative risk, 0.13; 95% CI, 0.02 to 0.70) and the group receiving 400 mg weekly (relative risk, 0.13; 95% CI, 0.03 to 0.52). The rate of adverse events was similar in all groups. Conclusions Pritelivir reduced the rates of genital HSV shedding and days with lesions in a dose- dependent manner in otherwise healthy men and women with genital herpes. (Funded by AiCuris; ClinicalTrials.gov number, NCT01047540.) n engl j med 370;3 nejm.org january 16, 2014 201 The New England Journal of Medicine Downloaded from nejm.org at UNIV OF UTAH ECCLES on March 18, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. The new england journal of medicine reatment of genital infections immunosuppression, treatment with medica- with the herpes simplex virus (HSV) relies tions that induce drug-metabolizing enzymes or T on nucleoside analogues that inhibit the transporters (e.g., carbamazepine or phenytoin) HSV DNA polymerase after phosphorylation by were exclusion criteria. Receipt of other anti-HSV the viral thymidine kinase.1 These compounds, therapy, consumption of grapefruit, and intake which were developed three decades ago and are of quinine or products containing quinidine were in widespread use today, ameliorate clinical dis- not permitted during the study. All participants ease. However, they do not abrogate viral shedding provided written informed consent. and only partially reduce the risk of transmission to sexual partners.2-4 In immunocompromised Study Design and Oversight persons, resistance to nucleoside analogues de- The study was designed as a randomized, paral- velops occasionally, and treatment options for lel, double-blind, placebo-controlled study by in- acyclovir-resistant HSV are limited.5,6 vestigators at the University of Washington and The thiazolylamide pritelivir (BAY 57-1293; by the sponsor, AiCuris, and was managed by AIC316) is the first in a new class of antiviral FHI 360. The statistical analyses were performed agents that inhibit HSV replication by targeting by authors at the University of Washington, ac- the viral helicase–primase enzyme complex. cording to a statistical plan previously developed Pritelivir binds to the complex composed of the by the academic and industry investigators. Both gene products of UL5, UL8 and UL52.7 Unlike the academic and industry authors contributed to the nucleoside analogues, pritelivir does not re- all drafts of the manuscript and approved the quire activation by phosphorylation, and it is submission of the final manuscript for publica- active in uninfected cells. Pritelivir exhibits po- tion. All authors had full access to all data, veri- tent in vitro activity against HSV-1 and HSV-2 fied the accuracy of the data, and vouch for the isolates, including strains resistant to nucleoside fidelity of the study to the protocol and for the analogues, and has shown efficacy in studies in completeness of the data presented. The study animals, including a study of genital infection in was approved by the institutional review board at guinea pigs.8-10 In phase 1 studies of pritelivir, each study center. For full details of the design no safety concerns were identified, and the ter- and conduct of the study, see the protocol, avail- minal half-life reported was up to 80 hours.11 able with the full text of this article at NEJM.org. To investigate the efficacy and safety of pri- telivir in the treatment of genital infection with Study Drug HSV-2 and to determine the most effective, safe The four dosing regimens for pritelivir were a dose, we conducted a proof-of-concept study to loading dose of 20 mg followed by a daily dose of evaluate the effect of four different doses of oral 5 mg, a loading dose of 100 mg followed by a pritelivir on mucocutaneous viral shedding in daily dose of 25 mg, a loading dose of 300 mg adults with genital HSV-2 infection. followed by a daily dose of 75 mg, and a weekly dose of 400 mg. The regimen for the administra- Methods tion of placebo was the same as it was for the administration of pritelivir. The study drug was Study Participants taken for a period of 28 days. We enrolled otherwise healthy adults (≥18 years of age) who were seropositive for HSV-2 and had Study Procedures a history of genital herpes. Eligible participants Eligible participants were randomly assigned to had a history of one to nine recurrences of geni- one of the five study groups in a 1:1:1:1:1 ratio. tal herpes per year. Other inclusion criteria were A statistician who was not involved in the con- a body-mass index (the weight in kilograms di- duct of the study generated the randomization vided by the square of the height in meters) be- schema using the permuted-blocks method, with tween 18 and 35, the use of effective contracep- stratification according to sex and study site. tion, and normal results on laboratory tests, Throughout the study period, participants including electrocardiography and urinalysis. obtained daily swabs of genital skin and mucosa Infection with the human immunodeficiency vi- and delivered them to the study site weekly for rus or with hepatitis B or C virus, pregnancy, the purpose of HSV detection.3,4,12 Participants 202 n engl j med 370;3 nejm.org january 16, 2014 The New England Journal of Medicine Downloaded from nejm.org at UNIV OF UTAH ECCLES on March 18, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. Pritelivir for HSV-2 Infection also maintained a diary of genital signs and symp- were obtained. The primary end point was the toms. If a lesion developed that was consistent reduction in the HSV shedding rate among par- with genital herpes, an additional swab was ob- ticipants receiving pritelivir relative to the shed- tained from the lesion. Participants who had a re- ding rate among participants receiving placebo. currence (i.e., papules, vesicles or pustules, ulcers, Secondary end points included the rate of genital or crusts) during the study were asked to return lesions, the reduction of HSV DNA copies, the to the clinic for an examination within 24 hours. frequency of herpes recurrence, and the rate of subclinical shedding. Laboratory Studies The intention-to-treat analysis included all pa- Western blot analysis was used to confirm HSV-2 tients who took at least one dose of study medica- serostatus.13 Samples of genital secretions were tion and obtained at least one swab of genital analyzed for HSV DNA with a real-time, quantita- secretions.
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