Standard-dose and high-dose daily antiviral therapy for short episodes of genital HSV-2 reactivation: three randomised, open-label, cross-over trials

Abstract

Background: Skin and mucosal herpes simplex virus type 2 (HSV-2) shedding predominantly occurs in short subclinical episodes. We assessed whether standard-dose or high-dose antiviral therapy reduces the frequency of such shedding.

Methods: HSV-2-seropositive, HIV-seronegative people were enrolled at the University of Washington Virology Research Clinic (WA, USA). We did three separate but complementary open-label cross-over studies comparing no medication with aciclovir 400 mg twice daily (standard-dose aciclovir), valaciclovir 500 mg daily (standard-dose valaciclovir) with aciclovir 800 mg three times daily (high-dose aciclovir), and standard-dose valaciclovir with valaciclovir 1 g three times daily (high-dose valaciclovir). The allocation sequence was generated by a random number generator. Study drugs were supplied in identical, numbered, sealed boxes. Study periods lasted 4-7 weeks, separated by 1 week wash-out. Participants collected genital swabs four times daily for quantitative HSV DNA PCR. Clinical data were masked from laboratory personnel. The primary endpoint was within-person comparison of shedding rate in each study group. Analysis was per protocol. The trials are registered at ClinicalTrials.gov (NCT00362297, NCT00723229, NCT01346475).

Results: Of 113 participants randomised, 90 were eligible for analysis of the primary endpoint. Participants collected 23 605 swabs; 1272 (5·4%) were HSV-positive. The frequency of HSV shedding was significantly higher in the no medication group (n=384, 18·1% of swabs) than in the standard-dose aciclovir group (25, 1·2%; incidence rate ratio [IRR] 0·05, 95% CI 0·03-0·08). High-dose aciclovir was associated with less shedding than standard-dose valaciclovir (198 [4·2%] vs 209 [4·5%]; IRR 0·79, 95% CI 0·63-1·00). Shedding was less frequent in the high-dose valaciclovir group than in the standard-dose valaciclovir group (164 [3·3%] vs 292 [5·8%]; 0·54, 0·44-0·66). The number of episodes per person-year did not differ significantly for standard-dose valaciclovir (22·6) versus high-dose aciclovir (20·2; p=0·54), and standard-dose valaciclovir (14·9) versus high-dose valaciclovir (16·5; p=0·34), but did for no medication (28·7) and standard-dose aciclovir (10·0; p=0·001). Median episode duration was longer for no medication than for standard-dose aciclovir (13 h vs 7 h; p=0·01) and for standard-dose valaciclovir than for high-dose valaciclovir (10 h vs 7 h; p=0·03), but did not differ significantly between standard-dose valaciclovir and high-dose aciclovir (8 h vs 8 h; p=0·23). Likewise, maximum log(10) copies of HSV detected per mL was higher for no medication than for standard dose aciclovir (3·3 vs 2·9; p=0·02), and for standard-dose valaciclovir than for high-dose valaciclovir (2·5 vs 3·0; p=0·001), but no significant difference was recorded for standard-dose valaciclovir versus high-dose aciclovir (2·7 vs 2·8; p=0·66). 80% of episodes were subclinical in all study groups. Except for a higher frequency of headaches with high-dose valaciclovir (n=13, 30%) than with other regimens, all regimens were well tolerated.

Interpretation: Short bursts of subclinical genital HSV reactivation are frequent, even during high-dose antiherpes therapy, and probably account for continued transmission of HSV during suppressive antiviral therapy. More potent antiviral therapy is needed to eliminate HSV transmission.

Funding: NIH. Valaciclovir was provided for trial 3 for free by GlaxoSmithKline.

Conflict of interest statement

Conflicts of Interest:

CJ is a research investigator for AiCuris, GmbH. AW and LC are consultants for AiCuris GmbH, which is developing treatments for HSV. LC is the head of the scientific advisory board for and holds stock (<1% of company) in Immune Design Corp. LC and DMK are listed as coinventors on several patents describing antigens and epitopes to which T-cell responses to HSV-2 are directed.

AM and DMK are consultants for Immune Design Corp.

DMK is a consultant to Sanofi-Pasteur and Agenus Inc, for HSV-2 vaccines, and is contracted by Coridon Pty Ltd, Vical, Inc, and PATH for preclinical evaluation of a candidate HSV-2 vaccine. MS, SK, SS, MLH, JTS no conflicts.

Copyright © 2012 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Enrollment, randomization and follow-up of participants. R=Randomized, NM=no medication, SD-ACV=aciclovir 400 mg twice daily, SD-VAL=valaciclovir 500 mg daily, HD-ACV=aciclovir 800 mg three times daily, HD-VAL=valaciclovir 1 gm three times daily, LTFU=Lost to follow up

Figure 2

Rate of HSV detection in genital swabs by antiviral dose. IRR=Incidence risk ratio, CI=confidence interval, BID=twice daily, QD=once daily, TID=three times daily AUC=area under the curve (μg.h/ml).

Figure 3

Distribution of HSV quantity (log10 copies/ml) in swabs with HSV DNA detected by PCR, during no medication (black), aciclovir 400 mg twice daily and valaciclovir 500 mg daily (SD-antiviral, gray), aciclovir 800 mg three times daily (HD-ACV) (light gray) and valaciclovir 1 gm three times daily (HD-VAL) (cross-hatched). N=number of swabs

Figure 4

Distribution of HSV episode duration in the 260 episodes of known duration, during no medication (black), aciclovir 400 mg twice daily and valaciclovir 500 mg daily (SD-antiviral, gray), aciclovir 800 mg three times daily (HD-ACV) (light gray) and valaciclovir 1 gm three times daily (HD-VAL) (cross-hatched). N=number of episodes. Supplemental Figure 1. Quantity of HSV detected per swab in participant in Trial 2 which HSV was detected on 84 (49%) of 172 swabs during arm 1 (HD-ACV) and 70 (37%) of 189 swabs during arm 2 (SD-VAL).