Skip Navigation LinksHome > March 2008 - Volume 35 - Issue 3 > The Effect of Daily Valacyclovir Suppression on Herpes Simpl...
Sexually Transmitted Diseases:
doi: 10.1097/OLQ.0b013e31815b0132
Article

The Effect of Daily Valacyclovir Suppression on Herpes Simplex Virus Type 2 Viral Shedding in HSV-2 Seropositive Subjects Without a History of Genital Herpes

Sperling, Rhoda S. MD*; Fife, Kenneth H. MD†; Warren, Terri J. RN, ANP‡; Dix, Lynn P. PhD§; Brennan, Clare A. MSPH§

Free Access
Article Outline
Collapse Box

Author Information

From the *Mount Sinai Medical Center, New York City, New York; †Indiana University, School of Medicine, Indianapolis, Indiana; ‡Westover Heights Clinic, Portland, Oregon; and §GlaxoSmithKline, Research Triangle Park, North Carolina

The VLX103596 study group consisted of Jeanne Ballard (Northern Indiana Women’s Health Research, Inc., South Bend, IN), Sandra Calman (Solano Clinical Research, Davis, CA), Stephen Goldstone (Laser Surgery Care, NY, NY), Helen Henry (Westover Heights Clinic, Portland, OR), John Kriesel (University of Utah, Salt Lake City, UT), Peter Leone (University of North Carolina Clinical Research, Raleigh, NC), Mark Martens (University of Oklahoma, Tulsa, OK), Amit Patel (Integrated Research Group, Inc., Riverside, CA), Stephen Tyring (Center for Clinical Studies, Houston, TX), Anna Wald (University of Washington, Seattle, WA), Douglas Young (Northern California Research Corp., Carmichael, CA).

Correspondence: Clare A. Brennan, MSPH, GlaxoSmithKline, Five Moore Drive, PO Box 13398, Research Triangle Park, NC 27709-3398. E-mail: clare.a.brennan@gsk.com.

Received for publication June 8, 2007, and accepted for publication September 12, 2007.

Collapse Box

Abstract

Background: A substantial number of HSV-2 seropositive individuals lack a history of clinically recognized genital herpes. These individuals can transmit disease during periods of asymptomatic viral shedding. The frequency of asymptomatic shedding and the efficacy of antiviral therapy in reducing shedding has not been assessed in this population.

Objective: To compare the effect of valacyclovir 1 g once daily for 60 days versus placebo on asymptomatic viral shedding in immunocompetent, HSV-2 seropositive subjects without a history of symptomatic genital herpes infection.

Study Design: Seventy-three subjects were randomized to receive valacyclovir 1 g daily or placebo for 60 days each in a 2-way crossover design. A daily swab of the genital area was self-collected for HSV-2 detection by polymerase chain reaction.

Results: Fifty-six subjects with at least 1 polymerase chain reaction measurement in both treatment periods comprised the primary efficacy population. Valacyclovir significantly reduced shedding during subclinical days compared to placebo [mean, 1.5% vs. 5.1% of subclinical days (P <0.001), a 71% reduction]. Eighty-four percent of subjects had no shedding while receiving valacyclovir versus 54% of subjects on placebo (P <0.001). Eighty-eight percent of patients receiving valacyclovir had no recognized signs or symptoms versus 77% for placebo (P = 0.033). Valacyclovir was not associated with any safety risk compared with placebo.

Conclusions: In this study, asymptomatic viral shedding occurred in a substantial number of HSV-2 seropositive subjects without a history of genital herpes. Valacyclovir 1 g daily significantly reduced asymptomatic shedding compared with placebo in this population.

RECURRENT GENITAL HERPES (GH) is most commonly caused by infection with herpes simplex virus type 2 (HSV-2) and is the most prevalent sexually transmitted disease in the United States.1,2 The clinical presentation of HSV-2 can range from multiple, painful genital lesions to much more subtle symptoms including erythema, fissures, or irritated skin patches.3 At least 50 million persons in the United States have genital HSV infection; of these, nearly 90% are unaware of their infection either because they do not have symptoms, they have symptoms that are undiagnosed, their symptoms are mistaken for a different condition, or their symptoms are ignored.4–7 These findings are important since virus frequently is shed when patients do not have symptoms,8 and asymptomatic viral shedding (AVS) is considered to be the primary means of transmitting HSV to sexual partners.4,9 In an earlier study of 53 HSV-2 seropositive, asymptomatic subjects with no reported history of GH, HSV was isolated by viral culture in 72% of subjects who self-collected viral swabs for a median of 98 days.8 As serologic testing for HSV has become more widely used to identify those infected with HSV-2, more individuals with asymptomatic infection are being identified. Questions regarding the frequency of AVS in this population have been raised as clinicians seek out correct counseling messages to provide these patients.

Previous studies have demonstrated the ability of antivirals to reduce HSV-2 viral shedding.10–17 We conducted this study to investigate the effect of suppressive valacyclovir 1 g once daily versus placebo on viral shedding in HSV-2 seropositive subjects with no previous history of symptomatic GH.

Back to Top | Article Outline

Materials and Methods

Design

This randomized, double-blind, placebo-controlled, multicenter, 2-way crossover study was conducted between March 2005 and January 2006 at 13 centers in the United States. Subjects were randomized in a 1:1 allocation to receive either oral valacyclovir 1 g once daily or matching placebo for 60 days each in a 2-way crossover design (Fig. 1). There was a washout period of 7 days between treatment periods. The primary endpoint was the percentage of subclinical days with HSV-2 viral shedding over 60 days defined for each subject as the percent of subclinical (without a genital lesion) days with polymerase chain reaction (PCR) data for which HSV-2 shedding was detected by a positive PCR result. Secondary endpoints included percent of all days with total HSV-2 shedding, proportion of subjects with any shedding, average log HSV-2 DNA copy number on days with subclinical shedding, average log HSV-2 DNA copy number on days with total shedding, and the proportion of subjects who recognized signs or symptoms of GH infection during the study.

Fig. 1
Fig. 1
Image Tools
Back to Top | Article Outline
Study Population

Convenience sampling was used at the site and subject level. The 13 participating centers were selected based on feasibility estimates and geographic location in the United States. Men and women aged ≥ 18 years and in general good health were eligible for the study. Subjects were HSV-2 seropositive, with no active lesions or symptoms consistent with GH, no reported history of ever having symptomatic GH, and no history of recurrent undiagnosed symptoms that could be consistent with GH. Subjects were recruited from various clinical settings (sexually transmitted disease clinics, primary care clinics or gynecology practices) where they had undergone specific HSV serologic testing either as part of their clinical care or in response to local advertisements that offered free HSV serologic testing. Subjects included high-risk individuals, i.e., subjects with a partner with GH, with multiple sex partners, or subjects engaging in unprotected sex.

Back to Top | Article Outline
Procedures

Subjects attended a screening evaluation within 30 days before randomization, a randomization visit, and 8 study visits (4 visits per treatment period, with a 15-day interval between each visit). Informed consent was obtained from patients at screening, prior to any study procedures being completed, in accordance with the human experimentation guidelines of the US Department of Health and Human Services and Institutional Review Boards at each study site. At screen, blood samples were collected for HSV-1 and HSV-2 serological testing and routine hematology and clinical chemistry tests. Urine samples were collected for urinalysis and urine HCG pregnancy testing.

At randomization, a genital examination was conducted. Subjects initiated study medication, received an electronic diary to record study-related information, and were given specific instructions on how to collect daily home swabs of the genitalia. Education on recognizing signs and symptoms of GH also was provided at both the screening and randomization visits. Subjects were instructed to return to the clinic for routine visits and at any time they suspected a GH outbreak. Subjects with a confirmed GH outbreak temporarily discontinued assigned study medication and were treated with valacyclovir 500 mg twice daily for 3 days, after which double-blind therapy resumed.

During each 60-day treatment period and the 7-day washout period, a single swab was self-collected once daily from the genital/anal-rectal area for HSV-2 detection by PCR.11 Subjects were instructed to use the flat side of a dry Dacron tipped swab to aggressively rub the surface of the genitalia once a day, before showering or bathing. The swab was then placed into PCR collection medium, the tip broken off, and the lid replaced. Specimens were refrigerated until they were returned to the clinic at regular 2 week intervals. During an outbreak, lesional swabs also were collected for HSV-2 detection by PCR and culture. HSV-2 isolates from subjects not responding fully to 3 days of episodic treatment with valacyclovir 500 mg twice daily were evaluated for in vitro sensitivity to acyclovir.

Valacyclovir safety was assessed by changes in serum chemistry and hematology, and adverse event reporting. Adverse events were collected at every visit after discussion with the subject and review of the subject’s diary.

Back to Top | Article Outline
Laboratory Methods

Serum samples were tested for HSV-1 and HSV-2 antibodies by HerpeSelect ELISA glycoprotein G-based assay (Focus Diagnostics, Cypress, CA). Samples demonstrating an index value of 1.1 to 3.5 were confirmed with HSV-2 IgG Inhibition assay to eliminate false-positive test results.18–21 Viral isolates from positive cultures were confirmed and typed with monoclonal antibodies at Quest Diagnostics Clinical Trials Laboratories, Van Nuys, CA. HSV-2 isolates from subjects not responding fully to 3 days of episodic treatment with valacyclovir 500 mg twice daily were sent to ViroMed Laboratories, Minnetonka, MN, for the evaluation of in vitro sensitivity to acyclovir by plaque reduction assay.22 HSV-2 DNA was measured by quantitative fluorescent-based real-time PCR assay at the University of Washington Virology Research Laboratory, Seattle, WA.23

Back to Top | Article Outline
Statistical Analyses

In an earlier study, the mean (standard deviation) HSV-2 subclinical shedding rates in GH patients with a known GH recurrence pattern were 7.8% (9.5) in the placebo arm and 2.8% (5.3) in the valacyclovir arm.14 In our study, it was estimated that 44 completed subjects provided at least 90% power to detect a similar reduction. To allow for dropouts, a sample size of 65 subjects was chosen. A higher than expected dropout rate was observed, and the study was overenrolled by approximately 10%. This decision did not warrant a protocol amendment.

Populations considered in the overall analysis included:

1. Intent-to-Treat (ITT) Exposed: all subjects who received at least 1 dose of investigational product and at least 1 clinical evaluation. This was the primary population for assessing safety.

2. Intent-to-Treat Crossover (ITTC): all ITT subjects who had at least 1 PCR result in each treatment period. This was the primary population for assessing efficacy.

The treatment comparison for continuous endpoints, including the primary endpoint, was tested using nonparametric crossover analysis methods in the ITTC population.24 The test of treatment difference was preceded by a test of carryover effect. If this test was significant, then the treatment comparison would be tested using period 1 data only. Hodges-Lehmann 95% confidence interval for the difference between treatments was also provided.25

For the HSV-2 DNA copy number analysis, the daily maximum from swab samples was log transformed to stabilize the variance before averaging over the relevant set of days. No imputations were performed for missing PCR data regardless of lesion status. The binomial secondary endpoints were analyzed using Prescott’s method.26 Confidence intervals for the difference in proportions were prepared using McNemar’s method.27 The reported safety measures were adverse events and laboratory data.

Back to Top | Article Outline

Results

Subject Characteristics

Seventy-three subjects from 13 centers in the United States were randomized into the study, 36 subjects to the valacyclovir-placebo treatment sequence (VAL-PBO), and 37 subjects to the placebo-valacyclovir treatment sequence (PBO-VAL). Of the 36 ITT subjects randomized to the VAL-PBO sequence, 9 subjects withdrew from the study before or while receiving valacyclovir in treatment period 1. Of the remaining 27 subjects, 3 withdrew while receiving placebo in treatment period 2. Of the 37 ITT subjects randomized to the PBO-VAL sequence, 7 withdrew from the study before or while receiving placebo in treatment period 1, and of the remaining 30 subjects, 2 withdrew while receiving valacyclovir in treatment period 2.

The study population was primarily female (75%) and white (65%). The mean age was 37 years (range, 20–62). There was some difference in race distribution between the treatment groups: 77% of subjects in VAL-PBO group were white and 14% were black, compared with 53% and 39%, respectively, in the PBO-VAL group. Equal numbers of subjects, just over half in each group, were seropositive for HSV-1 (Table 1). Overall, baseline demographics were not significantly different between the 2 treatment sequences.

Table 1
Table 1
Image Tools
Back to Top | Article Outline
Viral Shedding

For the ITTC population, the mean percent of subclinical days with shedding was 5.1% while receiving placebo compared with 1.5% while receiving valacyclovir (P <0.001), a significant decrease representing a 71% reduction from placebo in subclinical shedding (Table 2). The Hodges-Lehman estimate of the arithmetic difference between treatments (VAL-PBO) was −1.8% with a 95% confidence interval of −4.4 to 0.

Table 2
Table 2
Image Tools

The mean percent of subclinical days with shedding was higher in the treatment period 1 placebo arm (6.3%) than in the treatment period 2 placebo arm (3.9%), suggesting a possible carryover effect of active treatment; however, the test of treatment residuals was not significant (P = 0.345). The supporting first period ITT analysis confirms the finding from the crossover analysis; subclinical shedding was reported on a mean 7% of subclinical days in subjects while receiving placebo, compared with a mean 1.3% of subclinical days in subjects while receiving valacyclovir, an 81% reduction (P = 0.003).

For the ITTC population, total shedding (both clinical and subclinical) was reported on a mean 5.5% of days in subjects while receiving placebo compared with a mean 1.5% of days in subjects while receiving valacyclovir (P <0.001), a significant decrease representing a 73% reduction in total shedding (Table 3). The Hodges-Lehman estimate of the arithmetic difference between treatments was −2.7% with a 95% confidence interval of −5.2 to −0.8.

Table 3
Table 3
Image Tools

In subjects receiving valacyclovir, a significant difference was seen compared with the placebo group in the proportion of subjects with no shedding; 47 of 56 (84%) of subjects experienced no shedding days while receiving valacyclovir compared to 30 of 56 (54%) of subjects while receiving placebo (P <0.001). The arithmetic difference between treatments was 30% with a 95% confidence interval of 15 to 46. Significantly more subjects while on valacyclovir (49 of 56, 88%) had no recognized signs or symptoms of GH compared with subjects while on placebo (43 of 56, 77%) (P = 0.033). The arithmetic difference between treatments was 11% with a 95% confidence interval of −0.6 to 22. The mean of the average log DNA copy number per day on subclinical days and on all days was similar in subjects while receiving valacyclovir compared with placebo (data not shown).

Back to Top | Article Outline
HSV Resistance Testing

One subject in the study required greater than 3 days of open-label treatment with valacyclovir for management of a GH outbreak. Two separate HSV-2 isolates obtained from this subject had IC50 values of 0.7 and 0.6 μg/mL; IC50 values of <2.0 μg/mL are considered sensitive to acyclovir.

Back to Top | Article Outline
Safety

The nature and incidence of adverse events reported were similar for subjects receiving valacyclovir compared with placebo. Adverse events reported with valacyclovir versus placebo included dizziness (6% vs. 2%), headache (5% vs. 6%), and nausea (5% vs. 2%). Hematology and clinical chemistry values across treatment groups were similar over time.

Back to Top | Article Outline

Discussion

This study investigated the effect of suppressive therapy with valacyclovir 1 g once daily on HSV-2 shedding in a population of HSV-2 seropositive subjects with no previous history of symptomatic GH. As such, our study is the first to demonstrate a clinically significant reduction in viral shedding in this distinct patient population. For the primary endpoint (mean percent days with subclinical shedding), a statistically significant decrease (71%) was demonstrated among subjects receiving valacyclovir compared with subjects receiving placebo (mean, 1.5% vs. 5.1%, P <0.001). A 73% reduction in total days of viral shedding also was observed for the secondary endpoint. The results of the primary endpoint compared with this secondary endpoint are similar and reflect the fact that shedding days were likely to be subclinical rather than clinical in this asymptomatic population. The proportion of subjects with no shedding at all was higher while receiving valacyclovir (84%) compared with placebo (54%). The percent of days with subclinical shedding was similar between the overall population and the subset of subjects who reported no signs or symptoms of GH during the study (data not shown), and reflects success in enrolling truly asymptomatic subjects.

In our study, antiviral therapy reduced total and subclinical viral shedding. The magnitude of the reduction in AVS observed in our study with valacyclovir was similar to that observed by Corey and Fife in earlier studies enrolling patients with a known GH recurrence pattern.14,16 However, the rate of AVS and the proportion of subjects with any shedding in our study was less than that observed in these earlier studies and may reflect a true difference between symptomatic and asymptomatic populations. Every effort was made in this current study to recruit subjects who were truly asymptomatic; those who had a history of any recurrent genital symptoms that could have been caused by GH were not eligible for enrollment.

As with nearly all clinical treatment trials, convenience sampling was used in this study, and thus introduces a possible source of bias in the study results. This study was not population-based but rather included a high-risk group of subjects, many of whom were seeking medical care. As such, the authors acknowledge the difficulty in generalizing these results.

In the Wald study, after education and counseling on GH was provided, 87% of the subjects who reported no prior history of GH reported having either genital lesions or localized genital symptoms during the study.8 This finding is contrary to our study, in which, despite the longer study duration, only 23% of asymptomatic subjects were able to recognize signs or symptoms of GH during the study. As noted above, this disparity may reflect differences in study enrollment criteria since subjects with a history of any undiagnosed, recurrent genital symptoms were not eligible for our study.

Famciclovir also has been shown to suppress viral shedding in HSV-2 seropositive individuals. In one recently published study, 129 subjects with or without a clinical history of GH were randomly assigned to famciclovir 250 mg twice daily or placebo in a crossover design for 42 days. Famciclovir demonstrated a significant reduction in viral shedding compared with placebo in persons with a clinical history of GH yet, contrary to the results reported with valacyclovir in the current study, no significant differences in viral shedding were observed in persons without a clinical history of GH.17 Whether this finding represents a true difference between populations, methodology, or treatment is not known.

Although the 1 week washout was believed to be sufficiently long based on known pharmacokinetics, and the test of residuals was not significant, we cannot definitively rule out a protective effect of valacyclovir from the first period. However, any residual effect would serve only to reduce the observed treatment difference and does not compromise the study conclusion. Further supporting evidence is provided by the analysis of the period 1 data that shows significant reduction in shedding with valacyclovir.

Valacyclovir 1 g once daily was well tolerated as evidenced by the safety and adverse event information collected during this study. There were no significant clinical adverse events or clinically significant abnormal laboratory findings.

The results of this study support the fact that viral shedding is reduced by chemoprophylaxis even in asymptomatic subjects with no history of symptomatic GH infection. This reduced frequency of viral shedding may translate to a reduced risk of transmission to an uninfected partner, although this would require further study to demonstrate. However, as clinicians seek to answer questions about infectivity in patients who are seropositive but without symptoms, this study provides more information about reducing viral shedding with suppressive antiviral therapy.

Back to Top | Article Outline

References

1. Cates W. Estimates of the incidence and prevalence of sexually transmitted diseases in the United States. Sex Transm Dis 1999;26(suppl);S2–S7.

2. Centers for Disease Control (CDC) and Prevention. Tracking the Hidden Epidemics: Trends in STDs in the United States. 2000.

3. Handsfield HH. Genital Herpes. New York, NY. McGraw-Hill; 2001.

4. Centers for Disease Control (CDC) and Prevention. Sex Transm Dis Treatment Guidelines 2006;55 [No. RR-11].

5. Fleming DT, McQuillan GM, Johnson RE, et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 1997;337:1105–1111.

6. 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.

7. Leone PA, Fleming DT, Gilsenan AW, et al. Seroprevalence of herpes simplex virus-2 in suburban primary care offices in the United States. STD 2004;31:311–316.

8. 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.

9. Mertz GJ, Benedetti J, Ashley R, et al. Risk factors for the sexual transmission of genital herpes. Ann Intern Med 1992;116:197–202.

10. Straus SE, Rooney JF, Hallahan C. Acyclovir suppresses subclinical shedding of herpes simplex virus. Ann Intern Med 1996;125:776–777.

11. Wald A, Zeh J, Barnum G, et al. Suppression of subclinical shedding of herpes simplex virus type 2 with acyclovir. Ann Intern Med 1996;124:8–15.

12. Wald A, Corey L, Cone R, et al. Frequent genital herpes simplex virus 2 shedding in immunocompetent women: Effect of acyclovir treatment. J Clin Invest 1997;99:1092–1097.

13. Diaz-Mitoma F, Ruben M, Sacks S, et al. Detection of viral DNA to evaluate outcome of antiviral treatment of patients with recurrent genital herpes. J Clin Microbiol 1996;34:657–663.

14. 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.

15. Gupta R, Wald A, Krantz E, et al. Valacyclovir and acyclovir for suppression of shedding of herpes simplex virus in the genital tract. J Infect Dis 2004;190:1374–1381.

16. Fife K, Warren T, Ferrera D, et al. Effect of valacyclovir on viral shedding in immunocompetent patients with recurrent herpes simplex virus 2 genital herpes: A US-based randomized, double-blind, placebo-controlled trial. May Clin Proc 2006;81:1321–1327.

17. Leone P, Warren T, Hamed K, et al. Famciclovir reduces viral mucosal shedding in herpes simplex virus (HSV)-seropositive persons. Sex Transm Dis. 2007;34:900–907.

18. Hogrefe W, Su X, Song J, et al. Detection of herpes simplex virus type 2-specific immunoglobulin G antibodies in African sera by using recombinant gG2, Western blotting and gG2 inhibition. J Clin Microbiol 2002;40:3635–3640.

19. Brennan CA, Kelley T. Use of the Focus Diagnostics Inhibition Assay as a confirmatory test for HSV-2 infection in a viral shedding study [abstract LBP4]. In Late Breaker Program and abstracts of the 2006 National STD Prevention Conference (Jacksonville). Atlanta, GA: Centers for Disease Control and Prevention, 2006;10.

20. Morrow RA, Friedrich D. Inaccuracy of certain commercial enzyme immunoassays in diagnosing genital infections with herpes simplex virus type 1 (HSV-1) and HSV-2. Am J Clin Pathol 2003;120:839–44.

21. Morrow RA, Nollkamper J, Robinson NJ, et al. Performance of Focus ELISA tests for herpes simplex virus type 1 (HSV-1) and HSV-2 antibodies among women in ten diverse geographic locations. Clin Microbiol Infect 2004;10:530–6.

22. Collins P, Oliver NM. Sensitivity monitoring of herpes simplex virus isolates from patients receiving acyclovir. J Antimicrob Chemother 1986;18(suppl B):103–12.

23. Ryncarz AJ, Goddard J, Wald A, et al. Development of a high-throughput quantitative assay for detecting herpes simplex virus DNA in clinical samples. J Clin Microbiol 1999;37:1941–1947.

24. Koch GG. The use of non-parametric methods in the statistical analysis of the two-period change-over design. Biometrics 1972;328:579–584.

25. Gibbons JD. Non Parametric Methods for Quantitative Analysis. New York: Holt, Rinehart and Winston; 1976.

26. Senn S. Crossover Trials in Clinical Research. 2nd ed. England: Wiley; 2002.

27. Fleiss JL. Statistical methods for rates and proportions. New York: Wiley; 1981.

Cited By:

This article has been cited 7 time(s).

Current Medical Research and Opinion
One-day famciclovir vs. placebo in patient-initiated episodic treatment of recurrent genital herpes in immunocompetent Black patients
Leone, P; Abudalu, M; Mitha, E; Gani, M; Zhou, WC; Hamed, K
Current Medical Research and Opinion, 26(3): 653-661.
10.1185/03007990903554471
CrossRef
Sexually Transmitted Infections
Use of the designation "shedder'' in mucosal detection of herpes simplex virus DNA involving repeated sampling
Magaret, AS; Johnston, C; Wald, A
Sexually Transmitted Infections, 85(4): 270-275.
10.1136/sti.2008.034751
CrossRef
Investigative Ophthalmology & Visual Science
A Double-Blind Placebo-Controlled Study to Evaluate Valacyclovir Alone and with Aspirin for Asymptomatic HSV-1 DNA Shedding in Human Tears and Saliva
Kumar, M; Hill, JM; Clement, C; Varnell, ED; Thompson, HW; Kaufman, HE
Investigative Ophthalmology & Visual Science, 50(): 5601-5608.
10.1167/iovs.09-3729
CrossRef
Clinical & Developmental Immunology
Mucosal Herpes Immunity and Immunopathology to Ocular and Genital Herpes Simplex Virus Infections
Chentoufi, AA; BenMohamed, L
Clinical & Developmental Immunology, (): -.
ARTN 149135
CrossRef
Sexually Transmitted Diseases
Screening for HSV-2 Infection in STD Clinics and Beyond: A Few Answers But More Questions
Douglas, JM; Berman, SM
Sexually Transmitted Diseases, 36(11): 729-731.
10.1097/OLQ.0b013e3181c04dea
PDF (112) | CrossRef
Sexually Transmitted Diseases
Implementation of Routine Access to Herpes Simplex Virus Type 2 Antibody Testing in a Public Health Sexually Transmitted Disease Clinic
Fife, KH; Van Der Pol, B; Roth, AM; Brand, J; Arno, JN; Madlem, J; Juliar, BE; Katz, BP; Williams, JA; Zimet, GD; Fortenberry, JD
Sexually Transmitted Diseases, 36(11): 724-728.
10.1097/OLQ.0b013e3181bc9a2f
PDF (176) | CrossRef
Sexually Transmitted Diseases
Herpes Simplex Virus Type 2 Infection in Young Adult Women: Risk Factors for Infection and Frequency of Viral Shedding
Fife, KH; Williams, JA; Thomas, AL; Ofner, S; Katz, BP; Fortenberry, JD
Sexually Transmitted Diseases, 37(4): 248-252.
10.1097/OLQ.0b013e3181d4f866
PDF (181) | CrossRef
Back to Top | Article Outline

© Copyright 2008 American Sexually Transmitted Diseases Association

Login