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Sexually Transmitted Diseases:
doi: 10.1097/OLQ.0b013e31815407d7
Article

Does Frequency of Genital Herpes Recurrences Predict Risk of Transmission? Further Analysis of the Valacyclovir Transmission Study

Kim, H Nina MD, MS*; Wald, Anna MD, MPH*†‡; Harris, Julia MA§; Almekinder, Jennifer BS§; Heitman, Cathy PhD§; Corey, Lawrence MD*‡∥

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From the *Department of Medicine, Division of Allergy and Infectious Diseases; †Department of Epidemiology; ‡Department of Laboratory Medicine, University of Washington, Seattle, Washington; §GlaxoSmithKline, Triangle Park, North Carolina; and ∥Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington

Supported by GlaxoSmithKline, National Institutes of Health Herpes Program Project grant AI-030731 and K24 AI-071113. The University of Washington Virology Division has received grant funding from GlaxoSmithKline and Novartis pharmaceuticals to perform HSV testing.

Presented in part at the 2006 National STD Prevention Conference, Centers for Disease Control and Prevention Meeting; May 10, 2006; Jacksonville, FL. Abstract 227.

A.W. is a consultant for Novartis, Powdermed, and Medigene and a speaker for Merck Vaccines. A.W. has received grant support from National Institutes of Health, GlaxoSmithKline, Antigenics, 3M, Roche, and Vical. J.H., J.A. and C.H. receive salaries from GlaxoSmithKline. L.C. directs the Division but receives no direct salary support for these activities. He has been a consultant to Antigenics in their program to develop an HSV vaccine.

Correspondence: H. Nina Kim, MD, MS, 901 Boren Avenue, Suite 1300, Seattle, WA 98104. E-mail: hyangkim@u.washington.edu.

Received for publication March 21, 2007, and accepted July 12, 2007.

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Abstract

Background: The benefit of suppressive antiviral therapy for reducing the risk of herpes simplex virus (HSV)-2 transmission to sex partners may be enhanced if persons at high risk for transmission can be identified.

Objective: To determine whether frequency of genital herpes recurrences is associated with increased risk of HSV-2 transmission.

Methods: Analysis of recurrence frequency and shedding frequency (subset) among participants in a randomized controlled trial of valacyclovir 500 mg qd versus placebo for reducing the risk of HSV-2 transmission.

Results: Overall, 1484 monogamous HSV-2-serodiscordant couples participated and 41 HSV-2 transmissions occurred during the 8-month trial; 40 were able to provide a history of recurrence frequency. The rate of recurrences per year before study entry did not differ between source partners who transmitted and those who did not, 4.8 versus 5.1, respectively. Similarly, the mean frequency of recurrences observed during the study also did not differ among those who transmitted versus those who did not for placebo recipients (4.4 vs. 4.8) or valacyclovir recipients (1.4 vs. 1.3). Among the 40 source partners who transmitted HSV-2, 8 of 27 placebo recipients and 7 of 13 valacyclovir recipients had no recurrences during the study.

Conclusion: Clinical assessment of HSV-2 disease severity as defined by the frequency of genital herpes recurrences does not predict the risk of transmission to sexual partners. Though patients with frequent recurrences are most likely to benefit clinically from suppressive therapy, frequency of recurrences is not helpful in identifying persons who are most likely to transmit HSV-2.

HERPES SIMPLEX VIRUS type-2 (HSV-2) causes a mucocutaneous infection that has become the most common etiology for genital ulcer disease worldwide.1–5 Potential risk factors, both behavioral and biological, that influence the acquisition of HSV-2 infection have been identified from observational studies. Seroepidemiologic investigations have largely focused on susceptible persons who acquired genital HSV-2 infection rather than on source partners at risk of transmitting infection.6,7 Transmission of HSV-2 infection to others is a primary concern of persons with known genital herpes,8 but little data are available to identify factors related to the source patient that influence the risk of transmitting HSV-2 infection.

Daily valacyclovir therapy and condom use in the source partner have been shown to reduce the risk of HSV-2 transmission to susceptible partners.9–11 However, the risk of HSV-2 transmission among HSV-2-discordant couples is low. The absolute risk reduction with valacyclovir over an 8-month follow-up was 1.7% (3.6% vs. 1.9% of susceptible partners acquired HSV-2 infection, placebo vs. valacyclovir recipients). Thus an estimated 88 partners would need to take the drug daily for 1 year to prevent a single case of new HSV-2 infection.

The benefit of suppressive antiviral therapy for reducing the risk of HSV-2 transmission to sex partners may be enhanced if persons at high risk for transmission can be identified. We conducted further analysis of the Valacyclovir HSV Transmission Study to identify potential clinical risk factors for transmission.

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Methods

Population

The participants were enrolled in a randomized trial that compared the effect of valacyclovir versus placebo on HSV-2 transmission in 1484 immunocompetent, heterosexual couples in monogamous relationships who were serodiscordant for HSV-2. Details of the study design and outcomes have been published.9 In brief, inclusion criteria for the HSV-2-seropositive source partner were: age of 18 years or older, history of recurrent genital herpes with fewer than 10 episodes per year, and nonuse of any daily antiviral therapy. Inclusion criteria for the susceptible partner were age of 18 years or older and HSV-2 seronegative status on Western blot analysis.12 The institutional review board or ethics committee of each center approved the protocol, and all partners signed separate informed consents. Enrollment occurred from February 1998 to July 2001 in 96 sites in North America, Latin America, Europe, and Australia.

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Measurements and Definitions

HSV-2 seropositive potential source partners were asked the number of genital herpes recurrences in the past year, unless they received chronic suppressive therapy for HSV within the previous year. A recurrence was defined as an episode of symptoms or genital lesions compatible with herpes. Source partners were also asked to record recurrences on diary cards during the 8-month study period and come to clinic during such recurrences. Lesions noted during the study had to reach the papular/vesicular stage of development to be considered an HSV-2 recurrence. During recurrences, subjects had the option of receiving episodic therapy with valacyclovir 500 mg twice daily for 5 days. Routine visits for dispensing of medication and diary review were done monthly.

Source partners at 4 study sites were invited to participate in a substudy that examined genital HSV-2 shedding. Participants in this substudy were taught to collect swabs daily for 2 months. Women swabbed the cervicovaginal, vulvar, and perianal areas and men swabbed the penile and perianal areas. Swabs were placed in buffer and brought in to clinic at subsequent visits. Real-time HSV DNA polymerase chain reaction was used for HSV detection.13

Susceptible partners provided serum samples for HSV antibody testing during routine monthly visits. Diaries that recorded sexual activity, condom use, and symptoms suggestive of incident genital herpes were reviewed from the preceding month. The susceptible partners were instructed to visit the clinic when they experienced any symptoms or signs/lesions compatible with genital herpes. Acquisition of HSV-2 infection was defined as detection of HSV in the genital tract and/or seroconversion to HSV-2 in susceptible partners.9

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Statistical Methods

An outcome of the study was overall transmission of HSV-2: the acquisition of laboratory-confirmed, clinically symptomatic first episode of genital herpes, and/or asymptomatic HSV-2 seroconversion in the susceptible partner. We analyzed the association between HSV-2 transmission and clinical severity of genital herpes in the source partner as measured either by reported frequency of recurrences or by the observed recurrence rate during the study period. We also examined whether the risk of sexual HSV-2 transmission varied by the HSV-2 viral shedding frequency in the source partner.

Normally distributed continuous variables were compared by use of t test and categorical variables by the χ2 test or Fisher exact test as appropriate. Variables that were not normally distributed were compared using the 2-sample Mann-Whitney U test. Log rank test was used to compare time to HSV-2 transmission for groups dichotomized to <5 versus ≥5 recurrences in the prior year. Cox proportional hazards model was used to calculate the hazards ratios with covariates as previously described.9 Two-sided P values <0.05 were considered significant. Analysis of the data was performed at GlaxoSmithKline, the sponsor of the original randomized trial. The authors at the University of Washington directed the analyses. All statistical calculations were performed using SAS software, Version 8.2 (Cary, NC).

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Results

Among the 1484 couples enrolled in the Valacyclovir HSV Transmission Study, 1376 (93%) source partners were able to provide a history of genital herpes recurrences in the prior year as they were not taking suppressive antiviral therapy—684 of 741 (92%) in the placebo arm and 692 of 743 (93%) in the valacyclovir arm. Table 1 outlines the demographic and clinical characteristics of the 1376 HSV-2 infected source partners and HSV-2 seronegative susceptible partners based on recurrence history.

Table 1
Table 1
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Frequency of Recurrences Before Study Entry

The median number of genital herpes recurrences in the year before study enrollment was 5 (range, 0–10) for both placebo and valacyclovir recipients. Of 1376 source partners with available baseline history, 748 (54%) had 5 or more recurrences in the prior year.

Forty-one susceptible partners acquired HSV-2 infection during the course of the study. Forty of those infected had source partners on whom there was available recurrence history and 20 had symptoms of HSV-2 infection confirmed by clinical and laboratory evidence. Clinical severity of HSV-2 disease in the source partner, as defined by number of recurrences in the prior year, was not associated with transmission of HSV-2 (odds ratio for HSV-2 transmission was 0.89 for comparison with next higher recurrence category as shown in Figure 1A, 95% confidence interval, CI 0.67–1.19; P = 0.44). Counterintuitively, there was a trend toward fewer symptomatic transmission events among those source partners with a greater number of recurrences in the prior year (odds ratio 0.68; 95% CI 0.44–1.04; P = 0.08; Fig. 1B).

Fig. 1
Fig. 1
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The distribution of reported frequency of recurrences did not differ significantly between source partners who did not transmit (n = 1336) versus those who transmitted (n = 40) HSV-2 infection (Fig. 2). Source partners who had <5 recurrences in the prior year were responsible for 50% of transmission events. The mean number of recurrences before study entry did not differ between source partners who transmitted and those who did not, 4.8 versus 5.1, respectively.

Fig. 2
Fig. 2
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Figure 3 demonstrates the time of acquisition of overall HSV-2 infection according to reported frequency of recurrences, dichotomized to ≥5 versus <5 recurrences in the prior year. Time-to-event analyses revealed no evidence of a significant difference between these groups; the unadjusted hazard ratio for those whose source partner had a recurrence history of ≥5 compared with <5 in the prior year was 0.84 (95% CI 0.45–1.56; P = 0.58). Multivariate analyses were performed to control for treatment group, sex of susceptible partner, HSV-1 status of susceptible partner, duration of infection, duration of relationship, frequency of sexual contact, and condom use (as a time-dependent variable) (Table 2). The adjusted hazard ratio for time to HSV-2 infection for those whose source partners had ≥5 recurrences compared with <5 in the prior year was 1.04 (95% CI 0.55–1.97; P = 0.91).

Fig. 3
Fig. 3
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Table 2
Table 2
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Frequency of Recurrences During the Study

The mean annualized frequency of recurrences observed during the study also did not differ among HSV-2 seropositive partners who transmitted versus those who did not for placebo (4.4 vs. 4.8) or valacyclovir (1.4 vs. 1.3) recipients. Among the 41 source partners who transmitted HSV-2, 8 of 27 (30%) placebo recipients and 7 of 14 (50%) valacyclovir recipients had no recurrences during the study.

The overall transmission rate did not differ between those source partners who had the highest quartile of recurrence rate [16 of 639 (2.7%) among those with ≥0.37 recurrence per month] and those who had the lowest quartile [10 of 370 (2.5%) among those with <0.12 per month]. Moreover, within the placebo arm, there was a trend toward a higher transmission rate in those source partners who did not report any recurrences (8 of 151 or 5.3%) compared with those with ≥0.37 recurrences per month (9 of 306 or 2.9%).

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HSV Shedding and Reported Recurrence Rate

Among the 89 source partners who participated in the shedding substudy and collected daily samples of genital secretions for a median of 58 days, 81 were able to provide a recurrence history. Thirty-four (42%) reported ≥5 recurrences in the prior year; of these, 25 (74%) shed HSV-2 on ≥1 day compared with 30 (64%) of source partners who reported <5 recurrences in the prior year, P = 0.36. Among subjects who shed, the median proportion of days on which HSV-2 detected was 6.9% (range, 1.6%–34%) for the group with ≥5 recurrences compared with 8.7% (1.6%–45%) for those with <5. The observed shedding rate did not correlate with the reported rate of recurrences (Fig. 4; Spearman's rank correlation coefficient rs = 0.03; P = 0.77). None of the source partners who participated in the shedding study transmitted HSV.

Fig. 4
Fig. 4
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Conclusion

We found no association between the frequency of clinical recurrences in source partners and the risk of sexual HSV-2 transmission to susceptible partners in further analyses from the Valacyclovir Transmission Study. Additionally, time to acquisition of HSV-2 infection did not differ significantly by recurrence frequency in the source partner. Concordant with these findings was the poor correlation between HSV-2 shedding and frequency of recurrences in source partners. These results support current knowledge that both symptomatic and asymptomatic persons shed virus intermittently from genital mucosal surfaces, that persons with a history of symptoms are not more likely to have subclinical HSV-2 reactivation, and that most transmissions among persons knowledgeable about the clinical manifestations of genital herpes appear to occur during episodes of subclinical viral reactivation.6,14,15

The Valacyclovir Transmission Study is 1 of 2 large clinical trials to date to examine HSV-2 transmission in serodiscordant heterosexual partners.9,16 The other transmission study was a randomized double-blind placebo-controlled trial of a candidate recombinant HSV-2 subunit vaccine that was found to be ineffective. Secondary analyses of this study also revealed that recurrence history in the source partner was not associated with HSV-2 acquisition in the susceptible partner.10 However, source partners in the vaccine study were seen only once to document history of genital herpes and serologic status. The Valacyclovir Study measured disease severity not only by baseline history but also through prospective follow-up of source partners. Our analyses provide the opportunity to evaluate more precisely whether disease severity in the source partner predicts transmission.9

Our measure of severity of genital herpes was the reported frequency of recurrences the year before the study and the observed recurrence rate during the study period; this may not represent the full spectrum of disease severity. We did not measure duration of symptoms, quantitative levels of viral shedding, or some other mode of assessing disease severity. However, frequency of symptomatic recurrences is a standard, easily ascertainable measure widely used by clinicians and researchers to represent clinical severity of genital herpes and assess the need for suppressive antiviral therapy.

Our observations were limited by the fact that source partners were aware of their clinical disease and counseled to avoid sexual intercourse when they had lesions. Hence, any association between frequency of recurrences and transmission of HSV-2 might have been attenuated by avoidance of sexual activity during recurrences. We did not, however, observe differences in sexual contacts per month between couples defined by recurrence frequency in the source partner. Our study results may also not be generalizable to all HSV-2-discordant couples, particularly those early in a relationship or with recently acquired genital HSV-2.

Clinical assessment of HSV-2 disease severity as defined by number of recurrences appears to be a poor predictor of the risk of transmission to sexual partners. Though persons with frequent recurrences are most likely to benefit clinically from suppressive antiviral therapy, they do not appear to represent any higher risk of transmission than those with less frequent recurrences. Suppressive antiviral therapy has historically been directed to those symptomatic persons with frequent recurrences of genital herpes, i.e., ≥6 episodes per year. Our data suggest that focusing our efforts on this subset of patients would not be an effective strategy for preventing transmission, as source partners with <5 recurrences in the prior year comprised 50% of the transmitting partners in our study and 15 (38%) of the 40 transmitting source partners had no recurrences during the observation period.

Recent mathematical modeling of HSV-2 epidemics suggests that if we can identify a “virological core group” of persons with high rates of HSV-2 shedding who cause a disproportionately large percentage of transmissions, then fewer person-years of suppressive antiviral therapy would be necessary to prevent one HSV-2 infection.17 Because frequent sampling of genital surfaces to identify high-frequency shedders remains available in only research settings, perhaps prevention efforts can be targeted to persons with recent HSV-2 infection (<2 years duration), because viral reactivation and infectiousness are thought to be highest at this time9,18,19 and mathematical modeling has suggested suppressive therapy would have the greatest impact soon after infection.20

Our findings underscore the importance of teaching patients and partners to consider risk reduction as a continuous effort and not one isolated to periods of recurrences. When discussing prevention of transmission with HSV-2-serodiscordant couples, health care providers should consider suppressive antiviral medication in patients with a clinical history of genital HSV-2 infection regardless of disease severity in the infected partner, particularly in younger adults who are most likely to have recent infection, as part of an overall strategy that includes condom use, disclosure to partners, and abstinence during recurrences.

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References

1. Mertz KJ, Trees D, Levine WC, et al. Etiology of genital ulcers and prevalence of human immunodeficiency virus coinfection in 10 US cities. The Genital Ulcer Disease Surveillance Group. J Infect Dis 1998; 178:1795–1798.

2. Sanchez J, Volquez C, Totten PA, et al. The etiology and management of genital ulcers in the Dominican Republic and Peru. Sex Transm Dis 2002; 29:559–567.

3. Beyrer C, Jitwatcharanan K, Natpratan C, et al. Molecular methods for the diagnosis of genital ulcer disease in a sexually transmitted disease clinic population in northern Thailand: Predominance of herpes simplex virus infection. J Infect Dis 1998; 178:243–246.

4. Bruisten SM, Cairo I, Fennema H, et al. Diagnosing genital ulcer disease in a clinic for sexually transmitted diseases in Amsterdam, The Netherlands. J Clin Microbiol 2001; 39:601–605.

5. Ahmed HJ, Mbwana J, Gunnarsson E, et al. Etiology of genital ulcer disease and association with human immunodeficiency virus infection in two Tanzanian cities. Sex Transm Dis 2003; 30:114–119.

6. Gottlieb SL, Douglas JM Jr, Schmid DS, et al. Seroprevalence and correlates of herpes simplex virus type 2 infection in five sexually transmitted-disease clinics. J Infect Dis 2002; 186:1381–1389.

7. Xu F, Sternberg MR, Kottiri BJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA 2006; 296:964–973.

8. Carney O, Ross E, Bunker C, et al. A prospective study of the psychological impact on patients with a first episode of genital herpes. Genitourin Med 1994; 70:40–45.

9. Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 2004; 350:11–20.

10. Wald A, Langenberg AGM, Link K, et al. Effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women. JAMA 2001; 285:3100–3106.

11. Wald A, Langenberg AG, Krantz E, et al. The relationship between condom use and herpes simplex virus acquisition. Ann Intern Med 2005; 143:707–713.

12. Ashley RL, Militoni J, Lee F, et al. Comparison of Western blot (immunoblot) and glycoprotein G-specific immunodot enzyme assay for detecting antibodies to herpes simplex virus types 1 and 2 in human sera. J Clin Microbiol 1988; 26:662–667.

13. Jerome KR, Huang M-L, Wald A, et al. Quantitative stability of DNA after extended storage of clinical specimens as determined by real-time PCR. J Clin Microbiol 2002; 40:2609–2611.

14. Wald A, Zeh J, Selke S, et al. Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N Engl J Med 2000; 342:844–850.

15. Wald A, Zeh J, Selke S, et al. Genital shedding of herpes simplex virus among men. J Infect Dis 2002; 186(suppl 1):S34–S39.

16. Corey L, Langenberg AG, Ashley R, et al. Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection: Two randomized controlled trials. Chiron HSV Vaccine Study Group. JAMA 1999; 282:331–340.

17. Blower S, Wald A, Gershengorn H, et al. Targeting virological core groups: A new paradigm for controlling herpes simplex virus type 2 epidemics. J Infect Dis 2004; 190:1610–1617.

18. Wald A, Zeh J, Selke S, et al. Virologic characteristics of subclinical and symptomatic genital herpes infections. N Engl J Med 1995; 333:770–775.

19. Koelle DM, Benedetti J, Langenberg A, et al. Asymptomatic reactivation of herpes simplex virus in women after the first episode of genital herpes. Ann Intern Med 1992; 116:433–437.

20. Williams JR, Jordan JC, Davis EA, et al. Suppressive valacyclovir therapy: Impact on the population spread of HSV-2 infection. Sex Transm Dis 2007; 34:123–131.

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