Background The frequency, pattern, and anatomical sites of subclinicalshedding of herpes simplex virus (HSV) in the genital tract,along with factors that predict such shedding, have not beenwell characterized.
Methods We studied prospectively the clinical and virologiccourse of genital herpes in 110 women. The women kept symptomdiaries and provided daily samples from the vulva, cervix, andrectum for viral culture.
Results During a median follow-up of 105 days, subclinical sheddingof virus was identified in 36 of 65 women (55 percent) withHSV type 2 (HSV-2), in 16 of 31 women (52 percent) with HSVtype 1 (HSV-1) and HSV-2, and in 4 of 14 women (29 percent)with only HSV-1. Among women with genital HSV-2 infection, subclinicalshedding occurred on a mean of 2 percent of the days. The meanduration of viral shedding during subclinical episodes was 1.5days, as compared with 1.8 days during symptomatic episodes.HSV was isolated from several sites in the genital tract andrectum in 17 percent of subclinical episodes and 22 percentof symptomatic episodes. Half the episodes of subclinical sheddingof HSV occurred within seven days of a symptomatic recurrence.The risk of subclinical shedding increased with the frequencyof symptomatic recurrences. Subclinical shedding was more frequentamong women with more than 12 recurrences per year than amongthose with no symptomatic recurrences (odds ratio, 3.3; 95 percentconfidence interval, 1.4 to 7.9); it was also more frequentamong women who had recently acquired genital herpes (odds ratiofor women with HSV acquired in the past year as compared withthose who had had the infection for a year or more, 1.85; 95percent confidence interval, 1.1 to 3.1).
Conclusions Among women with a history of genital herpes infection,subclinical shedding of HSV is common and accounts for nearlyone third of the total days of reactivation of HSV infectionin the genital tract. Women with frequent symptomatic recurrencesalso have frequent subclinical shedding and may be at high riskfor transmitting HSV.
Subclinical shedding of herpes simplex virus (HSV) occurs inpersons with a history of genital herpes and is instrumentalin transmitting HSV infection to sexual partners and neonates.1,2,3,4,5,6,7The rate of subclinical shedding among persons with recurrentgenital herpes and the factors associated with such sheddingare largely undefined. The most important factor influencingthe detection of subclinical shedding is the frequency of sampling,since episodes of reactivation have been considered infrequentand brief.8 We conducted a prospective study of a large cohortof women with a history of symptomatic genital herpes infectionwho provided daily samples for viral cultures from genital sitesand the rectum.
Methods
Subjects, Setting, and Procedures
Between 1987 and 1992, we recruited otherwise healthy womenwith a history of genital herpes infection specifically fora study of the frequency of subclinical and symptomatic viralshedding. The entry criteria included a clinical history ofgenital herpes and HSV infection confirmed by Western blot analysis.9All the women were counseled about the clinical signs and symptomsof genital herpes and were taught techniques of genital self-examinationto detect lesions10; the women used Dacron swabs to collectvulvar, cervicovaginal, and rectal samples for viral cultures.8The swabs were immersed in viral transport medium, refrigeratedimmediately after collection, and delivered to the laboratoryat least three times each week. The women recorded the datesof onset and the duration of genital lesions in diaries andwere seen in the clinic every four to six weeks and at the timeof recurrences. At these visits, the diaries were collected,and transport medium and new diary cards were dispensed. Thewomen were asked to obtain samples from the genital tract andrectum for at least 60 consecutive days. None of the women tookacyclovir for the suppression of genital herpes during the study.The study was approved by the Human Subjects Review Committeeat the University of Washington.
Laboratory Methods
Antibodies to HSV were detected by Western blot assay.9 Sampleswere inoculated in triplicate into wells of human diploid fibroblastcultures in 48-well microtiter plates. The wells were examinedevery day for three days, then every other day for two weeks.Cultures with evidence of cytopathic effects were confirmedto contain HSV with type-specific immunofluorescence.11
Statistical Analysis
Subclinical shedding was defined by the isolation of HSV fromthe cervix, vulva, or rectum in the absence of genital or perianallesions noted by the subjects or the clinicians. To calculatethe rate of subclinical shedding, we used the number of dayswithout genital lesions on which secretions for culture wereobtained as the denominator.
An episode of subclinical or symptomatic shedding was definedas one or more consecutive days on which HSV was isolated. Thus,if a single day with a negative or missing culture interrupteda sequence of positive cultures, the sequence was treated astwo episodes rather than one. Since this definition tended toshorten the duration of an episode, we also used an alternatedefinition that treated a single negative culture or missingculture as positive if there were positive cultures on the previousand succeeding days; we assumed that if there were missing culturesfor up to seven days between two positive cultures, those cultureswere also positive. This definition tended to lengthen the durationof an episode.
A recurrence was defined as one or more consecutive days onwhich genital lesions were present. A recurrence was calledculture-positive if HSV was isolated on any day during the recurrence,and culture-negative otherwise. Data on 50 women who providedsamples for cultures both within seven days of a recurrenceand more than seven days before or after a recurrence and whohad subclinical shedding at least once were used to describethe temporal association of subclinical and symptomatic episodes.Potential predictors of subclinical viral shedding were assessedby means of logistic-regression analysis, with the culturesfor each woman grouped together. The variability among womenwas greater than expected with the classic logistic-regressionmodel, so a scale factor was used to account for this variationin assessing the significance of predictors.12
Results
Study Population
Altogether, 110 women with a clinical history of genital herpesparticipated in the study. Their median age was 30.5 years (range,16 to 53); 94 percent of the women were white. Fourteen (13percent) had genital HSV type 1 (HSV-1) infection; 96 (87 percent)had genital HSV type 2 (HSV-2) infection, of whom 65 (59 percentof the study population) had antibodies only to HSV-2 and 31(28 percent) had antibodies to both HSV-1 and HSV-2. Twelvewomen had been followed in the clinic since the initial episodeof genital herpes, and the remaining women had a clinical historyof genital herpes. The median length of time from the acquisitionof genital herpes infection to enrollment in the study was 462days (range, 1 to 9803). The demographic characteristics ofthe women and the observed rates of recurrences of genital herpeswere similar to those described by Benedetti et al.13
We followed the women for a median of 105 days (range, 5 to799). specimens were obtained for culture on a median of 82days (range, 5 to 714) and a total of 12,335 days (Table 1).Overall, women provided specimens for culture on 85 percentof the study days. Forty-six women provided specimens for periodsof up to 60 days without having lesions, 39 women for 61 to120 days, 14 women for 121 to 180 days, and 11 women for morethan 180 days. The median number of sites sampled daily wasthree; overall, 31,197 specimens were cultured and analyzedfor this report.
Table 1. Frequency of Reactivation of HSV-1 and HSV-2 on Days with and Days without Genital Lesions, According to Serotype and Site of Specimen for Culture, among 110 Women.
To assess the reliability of viral cultures of specimens obtainedby subjects at home as compared with that of specimens obtainedby the clinical staff at the research clinic, we compared therates of isolation of HSV on 1360 days on which specimens wereobtained by both techniques. The rate of concordance for theresults was 97.4 percent. HSV was isolated from 4.3 percentof the cultures of samples obtained by patients, as comparedwith 3.5 percent of those of samples obtained by clinic staff(P = 0.05 by McNemar's test).
Frequency of Subclinical Shedding of HSV
Of the 110 women, 56 (51 percent) had at least one day of subclinicalreactivation of HSV. Subclinical shedding of HSV was identifiedin 36 of the 65 women with HSV-2 infection (55 percent), 16of the 31 with both HSV-1 and HSV-2 infection (52 percent),and 4 of the 14 with HSV-1 infection alone (29 percent). Overall,subclinical shedding was documented on 2.0 percent of the daysin women with genital HSV-2 and 0.7 percent of the days in thosewith genital HSV-1 (Table 1). Among the women, shedding occurredon 0 to 35 percent of days sampled (Figure 1).
Figure 1. Frequency of Subclinical Shedding of HSV in the Genital Tract or Rectum among 110 Women.
Fourteen women had only HSV-1, and 96 had HSV-2 (31 of whom also had HSV-1).
The rate of detection of subclinical reactivation reflectedthe number of days on which samples were obtained. Sixty-threepercent of the women who provided specimens for up to 60 dayswithout having lesions never had subclinical shedding, as comparedwith 39 percent of the women who provided samples for more than60 days. Table 2 shows the rates of subclinical shedding for64 women who provided samples for at least 60 days. The 60-dayduration of sampling was selected to eliminate both falselylow and falsely high rates of shedding due to short periodsof sampling. Thirty-five of 54 HSV-2–seropositive women(65 percent) had subclinical shedding during a median samplingperiod of 106 days (range, 61 to 425), whereas 19 women (35percent) did not have viral shedding despite a median samplingperiod of 97 days (range, 63 to 307). Eleven percent had sheddingon more than 5 percent of the days on which samples were obtained.The rate of subclinical shedding was similar in the HSV-2–seropositivewomen and those who were seropositive for both HSV-1 and HSV-2.
Table 2. Rates of Subclinical Shedding among 64 Women Who Provided Samples for Culture on More Than 60 Days, According to Serotype.
Virologic Characteristics of Subclinical Shedding
Subclinical shedding occurred on 32 percent of the total dayswhen viral shedding was detected. Of the 128 episodes of subclinicalshedding, 96 (75 percent) lasted for one day, 18 (14 percent)for two days, 7 (5.5 percent) for three days, and 7 (5.5 percent)for four or more days. The durations of clinically recognizedand unrecognized episodes of viral shedding are shown in Table 3.Analysis of the data with use of an alternative definition,according to which days without culture results were treatedas positive, revealed a similar pattern; 70 percent of the episodesof unrecognized shedding of HSV lasted one day, 15 percent twodays, 4 percent three days, and 11 percent four days or longer.
Table 3. Virologic Characteristics of Subclinical and Clinical Episodes of HSV Shedding among 110 Women.
Subclinical shedding occurred at all the anatomical sites sampled.The rates of isolation of HSV from cultures of samples obtainedon days when genital lesions were absent were 0.7 percent forthe vulva, 0.7 percent for the cervix, and 1.1 percent for therectum (Table 1). Nineteen of 56 women who had subclinical shedding(34 percent) shed the virus from more than one site on the sameday. The HSV subtype was the same on all days on which HSV wasisolated from more than one site. Shedding from more than onesite occurred on 32 of 186 culture-positive days (17 percent).The most common sites of dual shedding were the vulva and cervix,which accounted for 19 days. Other episodes of shedding frommultiple sites involved the vulva and rectum (nine days), thecervix and rectum (two days), or all three sites (two days).
Virologic Characteristics of Symptomatic Shedding
Episodes of symptomatic shedding of HSV were documented in 72of the 110 women (65 percent): 5 of the 14 women with only HSV-1infection (36 percent), 43 of the 65 women with HSV-2 infectionalone (66 percent), and 24 of the 31 women with both HSV-1 andHSV-2 infection (77 percent). The median rate of recurrenceper year was 0 among women seropositive only for HSV-1 and 7.5among women who had genital HSV-2 infection. Since 37 percentof the episodes of genital lesions were culture-negative, theaverage number of episodes of symptomatic shedding was 6.5 peryear (Table 3). HSV was isolated from two of the sampled siteson 18 percent of the culture-positive days when symptoms werepresent and from three sites on 4 percent of such days. Themost common sites for such multiple shedding were the vulvaand rectum (39 days) and the vulva and cervix (21 days).
Association between Subclinical and Symptomatic Shedding of HSV
To evaluate the temporal relation between subclinical and symptomaticepisodes, we calculated the rate of subclinical shedding withinseven days of a symptomatic recurrence. The rate of subclinicalshedding was 4.9 percent within seven days of a recurrence (6.5percent in the seven days before and 3.5 percent in the sevendays after a recurrence), as compared with 1.8 percent on thedays more than seven days from a recurrence. Thirty percentof the episodes of subclinical shedding occurred in the sevendays preceding a symptomatic recurrence and 20 percent in theseven days after such a recurrence. Figure 2 illustrates theanatomical distribution and duration of subclinical and symptomaticshedding and the relation between these types of shedding infour representative subjects.
Figure 2. Pattern of Shedding of HSV during 31 Days in Four Women.
Plus signs indicate positive HSV cultures, empty boxes negative cultures, and solid boxes genital lesions. Subject 1 had intermittent, subclinical vulvar and rectal shedding. Subject 2 had subclinical shedding from the rectum closely following the healing of a perineal lesion. Subject 3 had subclinical shedding from multiple sites shortly before a symptomatic recurrence on the vulva. Subject 4 had a prolonged episode of subclinical cervical shedding.
Predictors of Subclinical Viral Shedding
In a univariate analysis, women infected with HSV-2 or withboth HSV-1 and HSV-2 had viral shedding more frequently thanwomen infected only with HSV-1 (odds ratio, 2.8; 95 percentconfidence interval, 1.1 to 7.5; and odds ratio, 3.1; 95 percentconfidence interval, 1.1 to 8.5, respectively) (Table 4). Womenwho had acquired genital herpes within 12 months of enrollmentwere also more likely to have subclinical shedding than womenwho had been infected for a longer time (odds ratio, 2.1; 95percent confidence interval, 1.2 to 3.7). The likelihood ofsubclinical shedding also increased with the annual number ofrecurrences. Women with more than 12 recurrences per year hadsubclinical shedding more often than women with no recurrencesin the past year (odds ratio, 5.1; 95 percent confidence interval,2.2 to 11.8). The rate of subclinical shedding among women with1 to 12 recurrences per year did not differ significantly fromthat of women without recurrences. Age did not influence therate of subclinical shedding.
Table 4. Characteristics Associated with High Rates of Subclinical Shedding among 110 Women with Genital Herpes.
In a multivariate analysis, frequent recurrences and the recentacquisition of genital herpes were independent predictors ofsubclinical reactivation. Women with more than 12 recurrencesper year had significantly more episodes of subclinical sheddingthan women with no recurrences (odds ratio, 3.3; 95 percentconfidence interval, 1.4 to 7.9), suggesting that these womenhad high rates of both symptomatic and subclinical reactivationof HSV. Women who had acquired genital herpes within a yearbefore enrollment also had more frequent shedding (odds ratio,1.85; 95 percent confidence interval, 1.1 to 3.1) than the womenwho had had genital herpes for a year or more.
Discussion
To elucidate the frequency and pattern of subclinical sheddingof HSV, we conducted a prospective study of a large cohort ofwomen with a history of genital herpes. Subclinical sheddingof HSV accounted for nearly one third of the total days of reactivationof genital herpes. Episodes of subclinical shedding occurredin clusters of days, similar to episodes of symptomatic reactivation;many episodes involved more than one anatomical site, and theywere most likely to occur shortly before or after a symptomaticreactivation. Although subclinical shedding of HSV-2 occurredon 2 percent of the days sampled overall, 11 percent of thewomen with HSV-2 infection had subclinical shedding on morethan 5 percent of the days, suggesting that a subgroup of womenwith HSV-2 may have a high likelihood of transmitting HSV.
The proportion of women who had subclinical viral shedding inour study (51 percent) and the rate of subclinical sheddingwere higher than previously reported8,14,15,16,17,18,19 andreflected the relatively long study period. Our results indicatethat there is great variability in the rates of subclinicalshedding among women with genital herpes. Significant correlatesof subclinical shedding included a short time since the acquisitionof genital herpes and a high frequency of symptomatic recurrences.The HSV serotype, which was a significant predictor of the rateof subclinical shedding in the univariate analysis,14 was nolonger significant after adjustment for the recurrence rate.
Daily sampling of the genital tract and rectum for a prolongedperiod allowed us to observe patterns of subclinical reactivationof HSV. Our preliminary studies showed that samples obtainedby the patients were at least as reliable for the detectionof HSV as samples obtained by clinicians. Thus, we feel thatthe patterns of subclinical shedding we observed were not affectedby the sampling technique. The daily sampling and reportingmethods allowed us to characterize all symptomatic recurrences,not just those that were severe enough to prompt a visit toa medical provider or participation in a clinical trial of treatmentfor genital herpes.
The pattern of subclinical shedding that we observed also helpsto explain the wide range of shedding frequencies in previousstudies of asymptomatic shedding.8,14,15,16,17,18,19,20 Theduration of sampling, biologic variation in the expression ofthe infection, and the varying length of episodes all appearto influence the observed rates of subclinical shedding. Therates of shedding were likely to vary most among women withfew days of sampling, with most having no episodes of sheddingand a few with extremely high rates of shedding, depending onwhether a prolonged shedding episode happened to be includedin the days sampled.
Our cohort of women was selected for their willingness to providedaily samples for culture and to adhere to the protocol. Demographiccharacteristics, recurrence rates, and duration of HSV beforeenrollment in this group were similar to those of women withsymptomatic genital herpes whom we have studied over the pastdecade.13,14,21 However, this type of study should be carriedout in other HSV-2–seropositive populations. The patternof subclinical shedding among men also requires characterization.
Our definition of subclinical viral shedding included sheddingon all days on which the subject did not note a lesion. Fromthe standpoint of patient education, perhaps the term "unrecognizedgenital herpes" is the best description of what we have termed"subclinical herpes." It is possible that some episodes of sheddingfrom the cervical or vulvar area were associated with smalllesions that would have been apparent on colposcopic examinationor that were associated with nonspecific symptoms such as itching,without a noticeable lesion or ulcer.10,15,22,23 The high rateof subclinical shedding from the perianal area can also be explainedin part by the difficulty of visualizing lesions. Although itis possible that more frequent visits to a clinician would haveresulted in the identification of a greater number of genitallesions, daily visits to the clinic were not feasible. Furthermore,it is the recognition of genital lesions by the patient thatmay be relevant in preventing transmission to sexual partners.
Clinical and Epidemiologic Implications
Recommendations for preventing the transmission of genital herpesto sexual partners have focused on abstinence from sexual intercourseduring symptomatic recurrences. However, studies of the transmissionof HSV indicate that most new infections are acquired from partnerswith unrecognized or subclinical disease.1,2,3,4,5,6,7 The seroprevalenceof HSV-2 in the adult population has increased from 16 percentto 22 percent in the past decade24 (and Johnson RE: personalcommunication). Emphasis on the importance and high frequencyof unrecognized reactivation of HSV may be necessary to containthe current epidemic of genital herpes.
In summary, our data indicate that most women with symptomaticHSV-2 infection also had subclinical viral shedding and thatwomen with frequent symptomatic recurrences also had frequentsubclinical reactivations. When such women are involved in sexualrelationships with partners without genital herpes, they shouldbe encouraged to be sure that condoms are used for all sexualintercourse. Strategies to reduce subclinical shedding, suchas the use of antiviral therapy, need to be developed.
Supported by a grant (AI-30731) from the National Institutesof Health. Dr. Wald is the recipient of an American Social HealthAssociation Postdoctoral Research Fellowship.
We are indebted to the technologists at the University of WashingtonVirology Herpes Culture Laboratory, without whom this studycould not have been performed, for their skill and dedication.
Source Information
From the Departments of Medicine (A.W., L.C.), Statistics (J.Z.), Laboratory Medicine (S.S., R.L.A., L.C.), and Microbiology (L.C.), University of Washington, Seattle.
Address reprint requests to Dr. Corey at the Virology Division, University of Washington, Rm. 9301, 1200 12th Ave. South, Seattle, WA 98144.
References
Mertz GJ, Benedetti J, Ashley R, Selke SA, Corey L. Risk factors for the sexual transmission of genital herpes. Ann Intern Med 1992;116:197-202.
Mertz GJ, Schmidt O, Jourden JL, et al. Frequency of acquisition of first-episode genital infection with herpes simplex virus from symptomatic and asymptomatic source contacts. Sex Transm Dis 1985;12:33-39. [Medline]
Bryson YJ, Dillon M, Bernstein DI, Radolf J, Zakowski P, Garratty E. Risk of acquisition of genital herpes simplex virus type 2 in sex partners of persons with genital herpes: a prospective couple study. J Infect Dis 1993;167:942-946. [Medline]
Brown ZA, Benedetti J, Ashley R, et al. Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor. N Engl J Med 1991;324:1247-1252. [Abstract]
Barton SE, Davis JM, Moss VM, Tyms AS, Munday PE. Asymptomatic shedding and subsequent transmission of genital herpes simplex virus. Genitourin Med 1987;63:102-105. [Medline]
Brown ZA, Vontver LA, Benedetti J, et al. Genital herpes in pregnancy: risk factors associated with recurrences and asymptomatic viral shedding. Am J Obstet Gynecol 1985;153:24-30. [Medline]
Rooney JF, Felser JM, Ostrove JM, Straus SE. Acquisition of genital herpes from an asymptomatic sexual partner. N Engl J Med 1986;314:1561-1564. [Medline]
Brock BV, Selke S, Benedetti J, Douglas JM Jr, Corey L. Frequency of asymptomatic shedding of herpes simplex virus in women with genital herpes. JAMA 1990;263:418-420. [Free Full Text]
Ashley RL, Militoni J, Lee F, Nahmias A, Corey L. Comparison of Western blot (immunoblot) and glycoprotein G-specific immunodot enzyme assay for detecting antibodies to herpes simplex virus type 1 and 2 in human sera. J Clin Microbiol 1988;26:662-667. [Free Full Text]
Langenberg A, Benedetti J, Jenkins J, Ashley R, Winter C, Corey L. Development of clinically recognizable genital lesions among women previously identified as having "asymptomatic" herpes simplex virus type 2 infection. Ann Intern Med 1989;110:882-887.
Lafferty WE, Krofft S, Remington M, et al. Diagnosis of herpes simplex virus by direct immunofluorescence and viral isolation from samples of external genital lesions in a high-prevalence population. J Clin Microbiol 1987;25:323-326. [Free Full Text]
McCullagh P, Nelder JA. Generalized linear models. London: Chapman and Hall, 1983:73.
Benedetti J, Corey L, Ashley R. Recurrence rates in genital herpes after symptomatic first-episode infection. Ann Intern Med 1994;121:847-854. [Free Full Text]
Koelle DM, Benedetti J, Langenberg A, Corey L. Asymptomatic reactivation of herpes simplex virus in women after the first episode of genital herpes. Ann Intern Med 1992;116:433-437.
Adam E, Dreesman GE, Kaufman RH, Melnick JL. Asymptomatic virus shedding after herpes genitalis. Am J Obstet Gynecol 1980;137:827-830. [Medline]
Adam E, Kaufman RH, Mirkovic RR, Melnick JL. Persistence of virus shedding in asymptomatic women after recovery from herpes genitalis. Obstet Gynecol 1979;54:171-173. [Medline]
Stenzel-Poore MP, Hallick LM, Fendrick JL, Neuburg M, Storrs FJ, Hanifin JM. Herpes simplex virus shedding in genital secretions. Sex Transm Dis 1987;14:17-22. [Medline]
Barton SE, Wright LK, Link CM, Munday PE. Screening to detect asymptomatic shedding of herpes simplex virus (HSV) in women with recurrent genital HSV infection. Genitourin Med 1986;62:181-185. [Medline]
Bowman CA, Woolley PD, Herman S, Clarke J, Kinghorn GR. Asymptomatic herpes simplex virus shedding from the genital tract whilst on suppressive doses of oral acyclovir. Int J STD AIDS 1990;1:174-177. [Medline]
Straus SE, Seidlin M, Takiff HE, et al. Effect of oral acyclovir treatment on symptomatic and asymptomatic virus shedding in recurrent genital herpes. Sex Transm Dis 1989;16:107-113. [Medline]
Corey L, Adams HG, Brown ZA, Holmes KK. Genital herpes simplex virus infections: clinical manifestations, course, and complications. Ann Intern Med 1983;98:958-972.
Rattray MC, Corey L, Reeves WC, Vontver LA, Holmes KK. Recurrent genital herpes among women: symptomatic v. asymptomatic viral shedding. Br J Vener Dis 1978;54:262-265. [Medline]
Koutsky LA, Stevens CE, Holmes KK, et al. Underdiagnosis of genital herpes by current clinical and viral-isolation procedures. N Engl J Med 1992;326:1533-1539. [Abstract]
Johnson RE, Nahmias AJ, Magder LS, Lee FK, Brooks CA, Snowden CB. A seroepidemiologic survey of the prevalence of herpes simplex virus type 2 infection in the United States. N Engl J Med 1990;321:7-12. [Abstract]
Magaret, A S, Johnston, C, Wald, A
(2009). Use of the designation "shedder" in mucosal detection of herpes simplex virus DNA involving repeated sampling. Sex. Transm. Infect.
85: 270-275
[Abstract][Full Text]
Kelly, N C, Zimet, G D, Aalsma, M C, Bernstein, D I, Fortenberry, J D, Rosenthal, S L
(2009). Intent to accept and acceptance of herpes testing in adolescents and young adults. Sex. Transm. Infect.
85: 296-299
[Abstract][Full Text]
Mayaud, P, Nagot, N, Konate, I, Ouedraogo, A, Weiss, H A, Foulongne, V, Defer, M-C, Sawadogo, A, Segondy, M, Van de Perre, P, on behalf of the ANRS 1285 Study Group,
(2008). Effect of HIV-1 and antiretroviral therapy on herpes simplex virus type 2: a prospective study in African women. Sex. Transm. Infect.
84: 332-337
[Abstract][Full Text]
Pinna, D., Oreste, P., Coradin, T., Kajaste-Rudnitski, A., Ghezzi, S., Zoppetti, G., Rotola, A., Argnani, R., Poli, G., Manservigi, R., Vicenzi, E.
(2008). Inhibition of Herpes Simplex Virus Types 1 and 2 In Vitro Infection by Sulfated Derivatives of Escherichia coli K5 Polysaccharide. Antimicrob. Agents Chemother.
52: 3078-3084
[Abstract][Full Text]
Hook, L. M., Huang, J., Jiang, M., Hodinka, R., Friedman, H. M.
(2008). Blocking Antibody Access to Neutralizing Domains on Glycoproteins Involved in Entry as a Novel Mechanism of Immune Evasion by Herpes Simplex Virus Type 1 Glycoproteins C and E. J. Virol.
82: 6935-6941
[Abstract][Full Text]
Terry-Allison, T., Smith, C. A., DeLuca, N. A.
(2007). Relaxed Repression of Herpes Simplex Virus Type 1 Genomes in Murine Trigeminal Neurons. J. Virol.
81: 12394-12405
[Abstract][Full Text]
Bellner, L., Karlsson, J., Fu, H., Boulay, F., Dahlgren, C., Eriksson, K., Karlsson, A.
(2007). A Monocyte-Specific Peptide from Herpes Simplex Virus Type 2 Glycoprotein G Activates the NADPH-Oxidase but Not Chemotaxis through a G-Protein-Coupled Receptor Distinct from the Members of the Formyl Peptide Receptor Family. J. Immunol.
179: 6080-6087
[Abstract][Full Text]
Orroth, K. K, Freeman, E. E, Bakker, R., Buve, A., Glynn, J. R, Boily, M.-C., White, R. G, Habbema, J D. F, Hayes, R. J
(2007). Understanding the differences between contrasting HIV epidemics in east and west Africa: results from a simulation model of the Four Cities Study. Sex. Transm. Infect.
83: i5-i16
[Abstract][Full Text]
Freeman, E. E, Orroth, K. K, White, R. G, Glynn, J. R, Bakker, R., Boily, M.-C., Habbema, D., Buve, A., Hayes, R.
(2007). Proportion of new HIV infections attributable to herpes simplex 2 increases over time: simulations of the changing role of sexually transmitted infections in sub-Saharan African HIV epidemics. Sex. Transm. Infect.
83: i17-i24
[Abstract][Full Text]
Fife, K. H., Warren, T. J., Ferrera, R. D., Young, D. G., Justus, S. E., Heitman, C. K., Burroughs, S. M.
(2006). 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 Clinical Trial. Mayo Clin Proc.
81: 1321-1327
[Abstract][Full Text]
Hosken, N., McGowan, P., Meier, A., Koelle, D. M., Sleath, P., Wagener, F., Elliott, M., Grabstein, K., Posavad, C., Corey, L.
(2006). Diversity of the CD8+ T-Cell Response to Herpes Simplex Virus Type 2 Proteins among Persons with Genital Herpes.. J. Virol.
80: 5509-5515
[Abstract][Full Text]
Rosenthal, S L, Zimet, G D, Leichliter, J S, Stanberry, L R, Fife, K H, Tu, W, Bernstein, D I
(2006). The psychosocial impact of serological diagnosis of asymptomatic herpes simplex virus type 2 infection.. Sex. Transm. Infect.
82: 154-157
[Abstract][Full Text]
Smith, J S, Rosinska, M, Trzcinska, A, Pimenta, J M, Litwinska, B, Siennicka, J
(2006). Type specific seroprevalence of HSV-1 and HSV-2 in four geographical regions of Poland.. Sex. Transm. Infect.
82: 159-163
[Abstract][Full Text]
Rana, R K, Pimenta, J M, Rosenberg, D M, Warren, T, Sekhin, S, Cook, S F, Robinson, N J, on behalf of the Valaciclovir HSV Transmission Stu,
(2006). Sexual behaviour and condom use among individuals with a history of symptomatic genital herpes. Sex. Transm. Infect.
82: 69-74
[Abstract][Full Text]
Eriksson, K., Bellner, L., Gorander, S., Lowhagen, G.-B., Tunback, P., Rydberg, K., Liljeqvist, J.-A.
(2004). CD4+ T-cell responses to herpes simplex virus type 2 (HSV-2) glycoprotein G are type specific and differ in symptomatic and asymptomatic HSV-2-infected individuals. J. Gen. Virol.
85: 2139-2147
[Abstract][Full Text]
Wald, A, Ericsson, M, Krantz, E, Selke, S, Corey, L
(2004). Oral shedding of herpes simplex virus type 2. Sex. Transm. Infect.
80: 272-276
[Abstract][Full Text]
Pebody, R G, Andrews, N, Brown, D, Gopal, R, de Melker, H, Francois, G, Gatcheva, N, Hellenbrand, W, Jokinen, S, Klavs, I, Kojouharova, M, Kortbeek, T, Kriz, B, Prosenc, K, Roubalova, K, Teocharov, P, Thierfelder, W, Valle, M, Van Damme, P, Vranckx, R
(2004). The seroepidemiology of herpes simplex virus type 1 and 2 in Europe. Sex. Transm. Infect.
80: 185-191
[Abstract][Full Text]
Corey, L., Wald, A., Patel, R., Sacks, S. L., Tyring, S. K., Warren, T., Douglas, J. M. Jr., Paavonen, J., Morrow, R. A., Beutner, K. R., Stratchounsky, L. S., Mertz, G., Keene, O. N., Watson, H. A., Tait, D., Vargas-Cortes, M., the Valacyclovir HSV Transmission Study Group,
(2004). Once-Daily Valacyclovir to Reduce the Risk of Transmission of Genital Herpes. NEJM
350: 11-20
[Abstract][Full Text]
Solomon, L, Cannon, M J, Reyes, M, Graber, J M, Wetherall, N T, Reeves, W C
(2003). Epidemiology of recurrent genital herpes simplex virus types 1 and 2. Sex. Transm. Infect.
79: 456-459
[Abstract][Full Text]
Sharp, R. P, Gales, B. J
(2003). Short-Course Oral Antiviral Treatment for Recurrent Genital Herpes. The Annals of Pharmacotherapy
37: 1900-1903
[Abstract][Full Text]
Mbopi-Keou, F.-X., Belec, L., Dalessio, J., Legoff, J., Gresenguet, G., Mayaud, P., Brown, D. W. G., Ashley Morrow, R.
(2003). Cervicovaginal Neutralizing Antibodies to Herpes Simplex Virus (HSV) in Women Seropositive for HSV Types 1 and 2. CVI
10: 388-393
[Abstract][Full Text]
Posavad, C. M., Wald, A., Hosken, N., Huang, M. L., Koelle, D. M., Ashley, R. L., Corey, L.
(2003). T Cell Immunity to Herpes Simplex Viruses in Seronegative Subjects: Silent Infection or Acquired Immunity?. J. Immunol.
170: 4380-4388
[Abstract][Full Text]
Mullan, H M, Munday, P E
(2003). The acceptability of the introduction of a type specific herpes antibody screening test into a genitourinary medicine clinic in the United Kingdom. Sex. Transm. Infect.
79: 129-133
[Abstract][Full Text]
Fisman, D N, Hook, E W III, Goldie, S J
(2003). Estimating the costs and benefits of screening monogamous, heterosexual couples for unrecognised infection with herpes simplex virus type 2. Sex. Transm. Infect.
79: 45-52
[Abstract][Full Text]
Brown, Z. A., Wald, A., Morrow, R. A., Selke, S., Zeh, J., Corey, L.
(2003). Effect of Serologic Status and Cesarean Delivery on Transmission Rates of Herpes Simplex Virus From Mother to Infant. JAMA
289: 203-209
[Abstract][Full Text]
Koelle, D. M., Corey, L.
(2003). Recent Progress in Herpes Simplex Virus Immunobiology and Vaccine Research. Clin. Microbiol. Rev.
16: 96-113
[Abstract][Full Text]
Howard, M., Sellors, J. W., Jang, D., Robinson, N. J., Fearon, M., Kaczorowski, J., Chernesky, M.
(2003). Regional Distribution of Antibodies to Herpes Simplex Virus Type 1 (HSV-1) and HSV-2 in Men and Women in Ontario, Canada. J. Clin. Microbiol.
41: 84-89
[Abstract][Full Text]
Huff, J. L., Eberle, R., Capitanio, J., Zhou, S. S., Barry, P. A.
(2003). Differential detection of B virus and rhesus cytomegalovirus in rhesus macaques. J. Gen. Virol.
84: 83-92
[Abstract][Full Text]
Ikoma, M., Liljeqvist, J.-A., Groen, J., Glazenburg, K. L., The, T. H., Welling-Wester, S.
(2002). Use of a Fragment of Glycoprotein G-2 Produced in the Baculovirus Expression System for Detecting Herpes Simplex Virus Type 2-Specific Antibodies. J. Clin. Microbiol.
40: 2526-2532
[Abstract][Full Text]
Jerome, K. R., Huang, M.-L., Wald, A., Selke, S., Corey, L.
(2002). Quantitative Stability of DNA after Extended Storage of Clinical Specimens as Determined by Real-Time PCR. J. Clin. Microbiol.
40: 2609-2611
[Abstract][Full Text]
Scoular, A
(2002). Using the evidence base on genital herpes: optimising the use of diagnostic tests and information provision. Sex. Transm. Infect.
78: 160-165
[Abstract][Full Text]
Korenromp, E L, Bakker, R, Gray, R, Wawer, M J, Serwadda, D, Habbema, J D F
(2002). The effect of HIV, behavioural change, and STD syndromic management on STD epidemiology in sub-Saharan Africa: simulations of Uganda. Sex. Transm. Infect.
78: i55-63
[Abstract][Full Text]
Buka, S. L., Tsuang, M. T., Torrey, E. F., Klebanoff, M. A., Bernstein, D., Yolken, R. H.
(2001). Maternal Infections and Subsequent Psychosis Among Offspring. Arch Gen Psychiatry
58: 1032-1037
[Abstract][Full Text]
Wald, A., Langenberg, A. G. M., Link, K., Izu, A. E., Ashley, R., Warren, T., Tyring, S., Douglas, J. M. Jr, Corey, L.
(2001). Effect of Condoms on Reducing the Transmission of Herpes Simplex Virus Type 2 From Men to Women. JAMA
285: 3100-3106
[Abstract][Full Text]
Ohana, B., Lipson, M., Vered, N., Srugo, I., Ahdut, M., Morag, A.
(2000). Novel Approach for Specific Detection of Herpes Simplex Virus Type 1 and 2 Antibodies and Immunoglobulin G and M Antibodies. CVI
7: 904-908
[Abstract][Full Text]
Drake, S., Taylor, S., Brown, D., Pillay, D.
(2000). Regular review: Improving the care of patients with genital herpes. BMJ
321: 619-623
[Full Text]
Van Doornum, G. J. J., Slomka, M. J., Buimer, M., Groen, J., Van den Hoek, J. A. R., Cairo, I., Vyse, A., Brown, D. W. G.
(2000). Comparison of a Monoclonal Antibody-Blocking Enzyme-Linked Immunoassay and a Strip Immunoblot Assay for Identifying Type-Specific Herpes Simplex Virus Type 2 Serological Responses. CVI
7: 641-644
[Abstract][Full Text]
Wald, A., Zeh, J., Selke, S., Warren, T., Ryncarz, A. J., Ashley, R., Krieger, J. N., Corey, L.
(2000). Reactivation of Genital Herpes Simplex Virus Type 2 Infection in Asymptomatic Seropositive Persons. NEJM
342: 844-850
[Abstract][Full Text]
Corey, L., Handsfield, H. H.
(2000). Genital Herpes and Public Health: Addressing a Global Problem. JAMA
283: 791-794
[Abstract][Full Text]
Cohen, F., Kemeny, M. E., Kearney, K. A., Zegans, L. S., Neuhaus, J. M., Conant, M. A.
(1999). Persistent Stress as a Predictor of Genital Herpes Recurrence. Arch Intern Med
159: 2430-2436
[Abstract][Full Text]
Langenberg, A. G.M., Corey, L., Ashley, R. L., Leong, W. P., Straus, S. E., The Chiron HSV Vaccine Study Group,
(1999). A Prospective Study of New Infections with Herpes Simplex Virus Type 1 and Type 2. NEJM
341: 1432-1438
[Abstract][Full Text]
Bourne, N., Bernstein, D. I., Stanberry, L. R.
(1999). Civamide (cis-Capsaicin) for Treatment of Primary or Recurrent Experimental Genital Herpes. Antimicrob. Agents Chemother.
43: 2685-2688
[Abstract][Full Text]
Sanna, P. P., Deerinck, T. J., Ellisman, M. H.
(1999). Localization of a Passively Transferred Human Recombinant Monoclonal Antibody to Herpes Simplex Virus Glycoprotein D to Infected Nerve Fibers and Sensory Neurons In Vivo. J. Virol.
73: 8817-8823
[Abstract][Full Text]
Corey, L., Langenberg, A. G. M., Ashley, R., Sekulovich, R. E., Izu, A. E., Douglas, J. M. Jr, Handsfield, H. H., Warren, T., Marr, L., Tyring, S., DiCarlo, R., Adimora, A. A., Leone, P., Dekker, C. L., Burke, R. L., Leong, W. P., Straus, S. E., for the Chiron HSV Vaccine Study Group,
(1999). Recombinant Glycoprotein Vaccine for the Prevention of Genital HSV-2 Infection: Two Randomized Controlled Trials. JAMA
282: 331-340
[Abstract][Full Text]
Benedetti, J. K., Zeh, J., Corey, L.
(1999). Clinical Reactivation of Genital Herpes Simplex Virus Infection Decreases in Frequency over Time. ANN INTERN MED
131: 14-20
[Abstract][Full Text]
Mikloska, Z., Sanna, P. P., Cunningham, A. L.
(1999). Neutralizing Antibodies Inhibit Axonal Spread of Herpes Simplex Virus Type 1 to Epidermal Cells In Vitro. J. Virol.
73: 5934-5944
[Abstract][Full Text]
Ryncarz, A. J., Goddard, J., Wald, A., Huang, M.-L., Roizman, B., Corey, L.
(1999). Development of a High-Throughput Quantitative Assay for Detecting Herpes Simplex Virus DNA in Clinical Samples. J. Clin. Microbiol.
37: 1941-1947
[Abstract][Full Text]
Eis-Hübinger, A. M., Däumer, M., Matz, B., Schneweis, K. E.
(1999). Evaluation of Three Glycoprotein G2-Based Enzyme Immunoassays for Detection of Antibodies to Herpes Simplex Virus Type 2 in Human Sera. J. Clin. Microbiol.
37: 1242-1246
[Abstract][Full Text]
Ashley, R. L., Wald, A.
(1999). Genital Herpes: Review of the Epidemic and Potential Use of Type-Specific Serology. Clin. Microbiol. Rev.
12: 1-8
[Abstract][Full Text]
Schacker, T., Ryncarz, A. J., Goddard, J., Diem, K., Shaughnessy, M., Corey, L.
(1998). Frequent Recovery of HIV-1 From Genital Herpes Simplex Virus Lesions in HIV-1-Infected Men. JAMA
280: 61-66
[Abstract][Full Text]
Lekstrom-Himes, J. A., Pesnicak, L., Straus, S. E.
(1998). The Quantity of Latent Viral DNA Correlates with the Relative Rates at Which Herpes Simplex Virus Types 1 and 2 Cause Recurrent Genital Herpes Outbreaks. J. Virol.
72: 2760-2764
[Abstract][Full Text]
do Nascimento, M. C., Sumita, L. M., de Souza, V. A. U. F., Pannuti, C. S.
(1998). Detection and Direct Typing of Herpes Simplex Virus in Perianal Ulcers of Patients with AIDS by PCR. J. Clin. Microbiol.
36: 848-849
[Abstract][Full Text]
Ashley, R., Wu, L, Pickering, J., Tu, M., Schnorenberg, L
(1998). Premarket evaluation of a commercial glycoprotein G-based enzyme immunoassay for herpes simplex virus type-specific antibodies [In Process Citation]. J. Clin. Microbiol.
36: 294-295
[Abstract][Full Text]
Jerome, K. R., Tait, J. F., Koelle, D. M., Corey, L.
(1998). Herpes Simplex Virus Type 1 Renders Infected Cells Resistant to Cytotoxic T-Lymphocyte-Induced Apoptosis. J. Virol.
72: 436-441
[Abstract][Full Text]
Fleming, D. T., McQuillan, G. M., Johnson, R. E., Nahmias, A. J., Aral, S. O., Lee, F. K., St. Louis, M. E.
(1997). Herpes Simplex Virus Type 2 in the United States, 1976 to 1994. NEJM
337: 1105-1111
[Abstract][Full Text]
Arvin, A. M., Prober, C. G.
(1997). Herpes Simplex Virus Type 2 -- A Persistent Problem. NEJM
337: 1158-1159
[Full Text]
Brown, Z. A., Selke, S., Zeh, J., Kopelman, J., Maslow, A., Ashley, R. L., Watts, D. H., Berry, S., Herd, M., Corey, L.
(1997). The Acquisition of Herpes Simplex Virus during Pregnancy. NEJM
337: 509-516
[Abstract][Full Text]
Mertz, G. J., Loveless, M. O., Levin, M. J., Kraus, S. J., Fowler, S. L., Goade, D., Tyring, S. K.
(1997). Oral Famciclovir for Suppression of Recurrent Genital Herpes Simplex Virus Infection in Women: A Multicenter, Double-Blind, Placebo-Controlled Trial. Arch Intern Med
157: 343-349
[Abstract]
Pannuti, C. S., Finck, M. C. D. S., Grimbaun, R. S., Sumita, L. M., Almeida, A. L. S., Rezende, N. F., Gomes, M. P. S., Pinho, J. R. R., Kirchhoff, L. V.
(1997). Asymptomatic Perianal Shedding of Herpes Simplex Virus in Patients With Acquired Immunodeficiency Syndrome. Arch Dermatol
133: 180-183
[Abstract]
Patel, R., Cowan, F. M, Barton, S. E
(1997). Advising patients with genital herpes. BMJ
314: 85-85
[Full Text]
Previous
