Effect of pritelivir compared with valacyclovir on genital HSV-2 shedding in patients with frequent recurrences: A randomized clinical trial

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

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

IMPORTANCE 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. OBJECTIVE To compare the efficacy of pritelivir with valacyclovir for suppression of genital HSV-2 infection. DESIGN, SETTING, AND PARTICIPANTS 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 100mg of pritelivir with 500mg 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 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. INTERVENTIONS 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. MAIN OUTCOMES AND MEASURES The primary end pointwas 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. RESULTS 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], 42; 95%CI, 0.21 to 0.82; P = .01). In swabs with HSV, the mean quantity of HSV was 3.2 log10 copies/mL during pritelivir treatment vs 3.7 log10 copies/mL during valacyclovir treatment (difference, -0.1; 95%CI, -0.6 to 0.5; P = .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; P = .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; P = .29). Treatment-emergent adverse events occurred in 62.3%of participants in the pritelivir group and 69.2%of participants in the valacyclovir group. CONCLUSIONS AND RELEVANCE 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.

Original languageEnglish (US)
Pages (from-to)2495-2503
Number of pages9
JournalJAMA - Journal of the American Medical Association
Volume316
Issue number23
DOIs
StatePublished - Dec 20 2016

Fingerprint

valacyclovir
Virus Shedding
Herpes Genitalis
Human Herpesvirus 2
Randomized Controlled Trials
Simplexvirus
Recurrence
Therapeutics
BAY 57-1293
Clinical Trials
DNA Primase

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Effect of pritelivir compared with valacyclovir on genital HSV-2 shedding in patients with frequent recurrences : A randomized clinical trial. / Wald, Anna; Timmler, Burkhard; Magaret, Amalia; Warren, Terri; Tyring, Stephen; Johnston, Christine; Fife, Kenneth; Selke, Stacy; Huang, Meei Li; Stobernack, Hans Peter; Zimmermann, Holger; Corey, Lawrence; Birkmann, Alexander; Ruebsamen-Schaeff, Helga.

In: JAMA - Journal of the American Medical Association, Vol. 316, No. 23, 20.12.2016, p. 2495-2503.

Research output: Contribution to journalArticle

Wald, A, Timmler, B, Magaret, A, Warren, T, Tyring, S, Johnston, C, Fife, K, Selke, S, Huang, ML, Stobernack, HP, Zimmermann, H, Corey, L, Birkmann, A & Ruebsamen-Schaeff, H 2016, 'Effect of pritelivir compared with valacyclovir on genital HSV-2 shedding in patients with frequent recurrences: A randomized clinical trial', JAMA - Journal of the American Medical Association, vol. 316, no. 23, pp. 2495-2503. https://doi.org/10.1001/jama.2016.18189
Wald, Anna ; Timmler, Burkhard ; Magaret, Amalia ; Warren, Terri ; Tyring, Stephen ; Johnston, Christine ; Fife, Kenneth ; Selke, Stacy ; Huang, Meei Li ; Stobernack, Hans Peter ; Zimmermann, Holger ; Corey, Lawrence ; Birkmann, Alexander ; Ruebsamen-Schaeff, Helga. / Effect of pritelivir compared with valacyclovir on genital HSV-2 shedding in patients with frequent recurrences : A randomized clinical trial. In: JAMA - Journal of the American Medical Association. 2016 ; Vol. 316, No. 23. pp. 2495-2503.
@article{dfb3e9c795954e8e8cba38e9f04e92c2,
title = "Effect of pritelivir compared with valacyclovir on genital HSV-2 shedding in patients with frequent recurrences: A randomized clinical trial",
abstract = "IMPORTANCE 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. OBJECTIVE To compare the efficacy of pritelivir with valacyclovir for suppression of genital HSV-2 infection. DESIGN, SETTING, AND PARTICIPANTS 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 100mg of pritelivir with 500mg 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 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. INTERVENTIONS 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. MAIN OUTCOMES AND MEASURES The primary end pointwas 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. RESULTS 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], 42; 95{\%}CI, 0.21 to 0.82; P = .01). In swabs with HSV, the mean quantity of HSV was 3.2 log10 copies/mL during pritelivir treatment vs 3.7 log10 copies/mL during valacyclovir treatment (difference, -0.1; 95{\%}CI, -0.6 to 0.5; P = .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; P = .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; P = .29). Treatment-emergent adverse events occurred in 62.3{\%}of participants in the pritelivir group and 69.2{\%}of participants in the valacyclovir group. CONCLUSIONS AND RELEVANCE 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.",
author = "Anna Wald and Burkhard Timmler and Amalia Magaret and Terri Warren and Stephen Tyring and Christine Johnston and Kenneth Fife and Stacy Selke and Huang, {Meei Li} and Stobernack, {Hans Peter} and Holger Zimmermann and Lawrence Corey and Alexander Birkmann and Helga Ruebsamen-Schaeff",
year = "2016",
month = "12",
day = "20",
doi = "10.1001/jama.2016.18189",
language = "English (US)",
volume = "316",
pages = "2495--2503",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
number = "23",

}

TY - JOUR

T1 - Effect of pritelivir compared with valacyclovir on genital HSV-2 shedding in patients with frequent recurrences

T2 - A randomized clinical trial

AU - Wald, Anna

AU - Timmler, Burkhard

AU - Magaret, Amalia

AU - Warren, Terri

AU - Tyring, Stephen

AU - Johnston, Christine

AU - Fife, Kenneth

AU - Selke, Stacy

AU - Huang, Meei Li

AU - Stobernack, Hans Peter

AU - Zimmermann, Holger

AU - Corey, Lawrence

AU - Birkmann, Alexander

AU - Ruebsamen-Schaeff, Helga

PY - 2016/12/20

Y1 - 2016/12/20

N2 - IMPORTANCE 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. OBJECTIVE To compare the efficacy of pritelivir with valacyclovir for suppression of genital HSV-2 infection. DESIGN, SETTING, AND PARTICIPANTS 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 100mg of pritelivir with 500mg 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 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. INTERVENTIONS 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. MAIN OUTCOMES AND MEASURES The primary end pointwas 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. RESULTS 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], 42; 95%CI, 0.21 to 0.82; P = .01). In swabs with HSV, the mean quantity of HSV was 3.2 log10 copies/mL during pritelivir treatment vs 3.7 log10 copies/mL during valacyclovir treatment (difference, -0.1; 95%CI, -0.6 to 0.5; P = .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; P = .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; P = .29). Treatment-emergent adverse events occurred in 62.3%of participants in the pritelivir group and 69.2%of participants in the valacyclovir group. CONCLUSIONS AND RELEVANCE 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.

AB - IMPORTANCE 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. OBJECTIVE To compare the efficacy of pritelivir with valacyclovir for suppression of genital HSV-2 infection. DESIGN, SETTING, AND PARTICIPANTS 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 100mg of pritelivir with 500mg 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 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. INTERVENTIONS 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. MAIN OUTCOMES AND MEASURES The primary end pointwas 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. RESULTS 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], 42; 95%CI, 0.21 to 0.82; P = .01). In swabs with HSV, the mean quantity of HSV was 3.2 log10 copies/mL during pritelivir treatment vs 3.7 log10 copies/mL during valacyclovir treatment (difference, -0.1; 95%CI, -0.6 to 0.5; P = .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; P = .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; P = .29). Treatment-emergent adverse events occurred in 62.3%of participants in the pritelivir group and 69.2%of participants in the valacyclovir group. CONCLUSIONS AND RELEVANCE 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.

UR - http://www.scopus.com/inward/record.url?scp=85008225359&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85008225359&partnerID=8YFLogxK

U2 - 10.1001/jama.2016.18189

DO - 10.1001/jama.2016.18189

M3 - Article

C2 - 27997653

AN - SCOPUS:85008225359

VL - 316

SP - 2495

EP - 2503

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

IS - 23

ER -