Nancy Glass, Ph.D., M.P.H., R.N.a; Heidi D. Nelson, M.D., M.P.H.b; Laurie Huffman, M.S.c
The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Address correspondence to: Heidi D. Nelson, M.D., M.P.H., Oregon Evidence-based Practice Center, Oregon Health & Science University, Mailcode BICC 504, 3181 SW Sam Jackson Park Rd., Portland, OR, 97239; E-mail: nelsonh@ohsu.edu
Select for copyright, source, and reprint information. The USPSTF recommendation based on this review is available online.
Background
Types of Genital HSV Infections
HSV Detection Methods
HSV Education and Prevention
Previous USPSTF Recommendations
Updates
Methods
Results
Cost Analyses
Conclusions
Acknowledgments
References
Available Products and Reprints
Copyright and Electronic Dissemination
Systematic Evidence Reviews serve as the basis for U.S. Preventive Services Task Force (USPSTF) recommendations on clinical prevention topics. The USPSTF tailors the scope of these reviews to each topic. The USPSTF determined that a brief update was needed to assist in updating its 1996 recommendations on screening for genital herpes.
To assist the USPSTF, the Oregon Evidence-based Practice Center, under contract to the Agency for Healthcare Research and Quality (AHRQ), performed a targeted review of the literature published on this topic from 1994 to 2002.
Herpes simplex virus (HSV) is a DNA virus with 2 subtypes: herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2). Although each is a distinct virus, they share some antigenic components. HSV causes vesicular and ulcerative lesions in healthy individuals and may cause severe systemic disease in neonates and immunosuppressed hosts.1 Infection with HSV-1 commonly causes oropharyngeal infection, and transmission is primarily by non-genital personal contact, whereas infection with HSV-2 most often results in genital lesions, and transmission is usually sexual.1,2 However, either virus may cause oropharyngeal or genital infection and can produce mucosal lesions that are clinically indistinguishable.1,3
HSV is the most prevalent sexually transmitted disease (STD) in the United States.3 The most accurate estimates derived from seroprevalence surveys show that 1 person in 5, aged 12 years and older in the United States, has been infected with HSV-2, and the rate is even higher among adults and women.1 These estimates do not include the contribution of sexually acquired HSV-1 to the epidemic of genital herpes. An estimated 1.6 million new HSV-2 infections occur in the United States annually.4
In a primary infection, the patient has an initial exposure to HSV and no type-specific antibodies to either HSV-1 or HSV-2 exist at the time of the infection. Lesions may appear 2 to 14 days after exposure and, without antiviral therapy, may persist for an average of 20 days. Lesions begin as tender vesicles that may rupture and ulcerate. Additional symptoms associated with primary infections may include intense pain, dysuria, itching, lymphadenopathy, fever, headache, nausea, malaise, and myalgia. Women may have vaginal discharge. Approximately 75 percent of patients with primary genital HSV infection are asymptomatic. Viral shedding lasts an average of 12 days and ceases before complete resolution of lesions, if present. Antibody response occurs 2 to 12 weeks after the infection and is lifelong. Unlike protective antibodies to other viruses, antibodies to HSV do not prevent local recurrences.
A non-primary first-episode infection is the first genital HSV infection in an individual who has heterologous HSV antibodies. For example, if an individual acquires a non-primary first-episode HSV-2 infection, he/she would have antibodies against HSV-1 at the time of the genital infection. Because of the partial protection of the preexisting antibodies, symptoms may be fewer and of shorter duration; however, this varies. The duration of lesions in a non-primary first-episode averages 15 days, and shedding lasts for approximately 7 days. The clinical presentation of a primary infection cannot be reliably distinguished from a non-primary first-episode infection. The diagnosis is based on type-specific culture and type-specific serology.
Recurrent infections may be symptomatic or asymptomatic. Although genital HSV is a chronic infection, the frequency of symptomatic reactivation decreases over time in a majority of individuals.5 Most symptoms are localized and can include lesions, pain, itching, and, in women, vaginal discharge. Lesions from recurrent infections are present for approximately 7 days with viral shedding for 4 days.
Asymptomatic viral shedding occurs with intermittent viral reactivation without associated clinical symptoms. A prospective study of HSV-2 seropositive adults randomly tested in family practice clinics indicated high rates of asymptomatic viral shedding.6 Genital secretions were sampled daily and cultured for HSV-2 over a 3-month period. Sixty-one percent of patients with a previous history of genital herpes and 68 percent of patients without known genital herpes had asymptomatic shedding. HSV-2 is often transmitted during episodes of asymptomatic shedding. Results of this study indicate that HSV-2 seropositive adults are capable of transmitting genital HSV-2 whether or not they had prior symptoms.
HSV can be vertically transmitted to the infant during the antenatal, intranatal, or postnatal periods. A woman experiencing a primary episode of HSV in the third trimester who has not completed seroconversion by the onset of labor has a 33-percent chance of transmitting the virus to her infant.7 In contrast, a woman experiencing a recurrent infection of HSV during the intrapartum period has an approximately 3-percent chance of transmitting to her infant.7 Of known HSV infected infants, only 30 percent had either mothers or sexual partners of mothers with symptomatic HSV infection.1
Neonatal HSV disease is diagnosed in approximately 1 of every 3,000 deliveries in the United States, resulting in an estimated 1,500 cases annually.8 Most infections are caused by HSV-2 and 15 to 30 percent are caused by HSV-1.9 Infants infected with HSV may be born prematurely and have low birth weights. Congenital HSV infection (approximately 4 percent of all neonatal infections) can cause microcephaly, hydrocephalus, chorioretinitis, and vesicular skin lesions.9
Three types of neonatal HSV infection acquired at delivery have been identified:
The clinical presentation is nonspecific and includes lethargy, fever, irritability and failure to feed at 1 week of age. Mortality is high despite treatment with antiviral therapy. Infants with encephalitis have a 15-percent increase in mortality, and those with disseminated disease have a 57-percent increase in mortality compared with infants with SEM disease only. Long-term morbidity is common among infants with both encephalitis and disseminated disease, and may include seizures, psychomotor retardation, spasticity, blindness, or learning disabilities.9
Viral culture is the gold standard for diagnosis of HSV infection, and has a sensitivity of 50 percent and a specificity of nearly 100 percent. A culture may take 3 to 7 days to process. The sensitivity of HSV culture is related to the HSV type and sample site.
Polymerase chain reaction (PCR) is a molecular test for HSV DNA. PCR is considered the gold standard for detection of HSV in CNS infections. PCR is available at many large laboratories and takes approximately 1 day to process. Sensitivity is 80 to 90 percent for specimens obtained from lesions, although sensitivity and specificity vary by laboratory.
Serological tests are used to detect previous infection with HSV-1 and HSV-2 in asymptomatic patients, or to diagnose infection in a symptomatic patient when culture is not feasible or the clinical syndrome is unclear. Currently available tests are described in Table 1. The Western blot assay is the most validated method for identifying type-specific antibodies and is considered the gold standard.10,11 The Western blot assay has been used to define the spectrum of clinical manifestations of genital herpes and to study the natural history of unrecognized HSV.12 The Western blot assay is conducted exclusively at the University of Washington where clinical specimens can be sent and processed. Two type-specific glycoprotein G serological tests are commercially available in the United States. Sensitivity and specificity of these tests are comparable to the Western blot assay.12 These tests cost $10 to $40 (U.S. dollars).
Antiviral medications (acyclovir, famciclovir, and valacyclovir) are approved for treatment of genital HSV. These drugs are selective for cells infected with HSV and stop viral replication. They are considered safe and effective when used by otherwise healthy adults. There is limited evidence of acyclovir use and safety during pregnancy. These drugs relieve discomfort caused by HSV lesions, speed healing in uncomplicated primary and recurrent genital HSV infections, and reduce viral shedding. They are used as a short course during recurrent episodes or for chronic daily suppressive therapy.
The goals of educating infected individuals and their sexual partners are to assist them in coping with recurrent symptoms and to prevent sexual and perinatal transmission. Specific educational messages recommended by the Centers for Disease Control and Prevention (CDC) include:
A prospective study of asymptomatic HSV-2 seropositive adults randomly tested in family practice clinics described the impact of patient education.6 Of the participants who reported no previous history of genital herpes despite seropositive test results, 63 percent reported having typical lesions following education on signs and symptoms of genital HSV infection.6
A prospective study of pregnant women evaluated whether education and counseling about symptoms of HSV genital infection would lead to improved recognition.14 Recognition of active infection could alert clinicians to potential transmission risk during delivery. Women underwent a detailed interview and a HSV serological test using Western blot assay. Women who were HSV-2 seropositive but had no reported or recognized recurrences were followed. After education and counseling regarding genital HSV, 45 percent of women who were HSV-2 positive but did not report recurrences were able to precisely report symptomatic reactivations of genital HSV.
The U.S. Preventive Services Task Force (USPSTF) recommendations for screening for genital herpes were published in 1996 and included15:
A topic update was conducted by investigators at the University of North Carolina/Research Triangle Institute (UNC/RTI) during 2002 using 2 approaches ("review" and "traditional") and included MEDLINE® searches from 1994-2002. In addition, expert reviewers were contacted for comment. This report and its methods were provided to the USPSTF in an earlier briefing book. A brief update was deemed necessary by the UNC/RTI update process and expert reviewers because of new literature in areas of testing (HSV-2 specific assays, PCR), effectiveness of condoms and antivirals in reducing transmission, and use of prophylactic medications.
The current update includes new publications since the last USPSTF recommendations. The rationale for screening would be to identify asymptomatic infected individuals capable of unknowingly transmitting HSV to partners and neonates. Identification could occur by serological testing or by education followed by diagnostic testing of newly recognized lesions.
The target population for this update includes adolescents, adults, and pregnant women/neonates. The analytic framework and key questions guiding the literature searches are described in the Figure (13 KB).
MEDLINE® was searched from 1996-March 2004 (Appendix 1). References cited in the 2002 report and references suggested by expert reviewers were also included. Captured titles and/or abstracts were downloaded and imported into the EndNote® program to create a library. Titles and/or abstracts were dual reviewed for inclusion or exclusion. Full-text papers were retrieved and reviewed using specific inclusion/exclusion criteria. Trials of antiviral therapy were rated for quality by 2 independent reviewers using USPSTF criteria (Appendix 2).
One hundred and twenty-seven abstracts and titles were identified from our MEDLINE® search. We identified an additional 33 titles from the UNC/RTI report and 27 titles from suggestions of experts and reference lists. We found 13 duplicate titles in our EndNote® library. Therefore, we reviewed a total of 174 abstracts and titles (Appendix 3). Seventy-nine full-text articles were obtained and reviewed for the update. Further, a systematic review of antenatal HSV screening in the United Kingdom was reviewed.
No studies were identified that directly evaluated whether screening asymptomatic individuals for genital HSV reduces symptomatic recurrences and transmission of disease.
No studies were identified that directly evaluated whether screening asymptomatic pregnant women for genital HSV reduces neonatal HSV and complications.
A descriptive study of adult pregnant women (n = 1,355) with no previous history of genital HSV determined rates of genital HSV and asymptomatic HSV shedding in late pregnancy.16 Participants were referred from 3 private obstetrics practices and were provided with education on signs and symptoms of genital HSV. HSV-2 antibody was detected in 32 percent of women with no clinical history of HSV. Asymptomatic HSV shedding was detected in late pregnancy and during delivery in 0.43 percent. Sixteen percent of seropositive women reported a first episode of clinical genital HSV during their pregnancy, demonstrating that education can assist asymptomatic, seropositive women in recognizing lesions.
A decision analysis estimated the benefit of serological screening in pregnancy by determining the number of cases of neonatal HSV-1 prevented by screening using models parameterized with data from published sources.17 When screening pregnant women, a 90-percent specific/90-percent sensitive test for HSV-1 could avert 71 to 90 percent of the expected cases of infection, requiring about 14,000 tests per case averted. Screening pregnant women and their partners resulted in more tests for the same benefit than screening only pregnant women (about 24,000 tests per case averted).
No studies were identified that defined a set of risk factors and used them to guide selective serological screening for HSV-1 or HSV-2.
Four studies estimated the incidence and prevalence of HSV-1 and HSV-2 and examined associated factors for HSV infection.
A cross-sectional study examined the epidemiology of HSV-2 antibody and its suitability as a serological marker of sexual behavior in populations with high and low HSV-2 prevalence.18 A sample of 869 adult patients attending a genitourinary medicine clinic and 1,494 consecutive adult blood donors were tested. Prevalence of HSV-2 antibody differed significantly between the groups: 22.7 percent in clinic participants and 7.6 percent in blood donor participants. In both groups, HSV-2 antibody was strongly associated with female gender, years of sexual activity, number of lifetime sexual partners, and past infection with STDs. Forty-five percent of those with HSV-2 antibody reported having symptoms suggestive of HSV infection, and only 27.4 percent had a previous diagnosis of HSV.
A cross-sectional study of a national sample indicated that at least 45 million adolescents and adults aged 12 years and older, 1 out of 5, have had HSV-2 infections.1 The seroprevalence of HSV-2 infection was 25.6 percent in women and 17.8 percent in men. Other independent predictors of HSV-2 infection included less education (defined by last year of education completed), poverty, cocaine use, and a greater lifetime number of sexual partners.
Seroprevalence rates based on HSV-2 results do not include the contribution of sexually acquired HSV-1. In a cross-sectional study, the characteristics of urban STD clinic patients who had HSV-1 were compared with those who had HSV-2.3 Participants included 1,145 patients with positive genital HSV cultures treated from 1993-1997 with a mean age of 28 years. Participants defined themselves as:
Overall, 17.1 percent of cultures were positive for HSV-1 and 82.9 percent were positive for HSV-2. Of the 821 isolates from individuals with first episode HSV infection, 20 percent had HSV-1. This compares with 9.9 percent of the 324 isolates with recurrent HSV infection. HSV-1 was found significantly more often in initial than in recurrent lesions (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.5-3.5). The proportion of isolates from initial lesions that were HSV-1 was greater for MSM (46.9 percent) than for women (21.4 percent), and was lowest for heterosexual men (14.6 percent). White race (OR, 3.7; 95% CI, 2.3-5.9) and receptive oral sex in the preceding 2 months (OR, 2.8; 95% CI, 1.9-4.3) significantly increased the odds that initial infections were HSV-1 rather than HSV-2. Age was not significantly associated with HSV-1 versus HSV-2 infection.
A prospective cohort study described incident cases of both HSV-1 and HSV-2 among HSV-2 seronegative sexually active participants.19 Of the 2,393 HSV-2 seronegative participants, 1,508 were seropositive for HSV-1 at baseline. The rates of new HSV-1 and HSV-2 were 1.6 and 5.1 cases per 100 person-years respectively. Of the 155 new HSV-2 infections, 37 percent were symptomatic. Women participants were more likely than men to acquire HSV-2 (P < 0.01) and to have symptomatic infections. The higher rate of asymptomatic infection in men may be a factor in the higher rate of male to female HSV-2 transmission. Previous HSV-1 infection did not reduce the rate of HSV-2 infection, but it did increase the likelihood of asymptomatic seroconversion by a factor of 2.6 (P < 0.001). Of the 19 new cases of HSV-1 infections, 12 were symptomatic. The rates of symptomatic genital HSV-1 infection and oropharyngeal HSV-1 infection were the same (0.5 case per 100 person-years).
New technologies include polymerase chain reaction (PCR) and glycoprotein G based, type-specific HSV serological tests.
A comparison of viral cell culture, direct antigen detection by HSV enzyme immunoassay (EIA), and PCR for diagnosis and typing of genital HSV was conducted in symptomatic adults. Of 194 patients, HSV was detected in 93 (48 percent) by viral cell culture, 76 (39 percent) by HSV EIA, and 115 (59 percent) by PCR. Comparison of the 3 methods indicated:
The frequency of asymptomatic HSV-2 viral shedding was determined by culture and PCR.21 Thirteen HSV-2 seropositive pregnant women (9 completed the study) in prenatal care at a University clinic had daily genital tract samples collected during their third trimester for culture and PCR screening. Asymptomatic shedding was detected more frequently by PCR than by culture (13.8 percent vs 2.3 percent, P < 0.0001).
A comparison of the rate of isolation of HSV from viral culture with the rate of HSV DNA by PCR was examined in a study including both men and women.22 Mucosal secretions (> 36,000 samples) from 296 HSV infected adults, enrolled in various studies from 1994-2001, were compared. Overall, HSV was isolated in 3 percent of samples and HSV DNA was detected in 12.1 percent of samples. The investigators reported a linear relationship between the ability to isolate viruses in the culture and the log number of copies of HSV DNA in the sample. Importantly, this relationship persisted with men and women in HIV negative and HIV positive participant samples and on days when lesions were present or absent. The ratio of PCR positivity to viral culture positivity rose from 3.8:1.0 in the winter to 8.8:1.0 in the summer.
The FDA approved (1999-2000) the new glycoprotein G based, type-specific HSV serological tests for use in adults. Performance characteristics of commercial tests suggest that they are comparable to each other and to the gold standard Western blot assay for sensitivity and specificity (Table 1).10,12,23,24 The commercial HerpeSelect® ELISA (enzyme-linked immunosorbent assay) and Immunoblot tests (Focus Technologies, Cypress CA) can detect HSV-1 specific antibodies. However, no test can distinguish between HSV-1 antibodies that are generated in response to oral infection and those arising after a genital HSV-1 infection.12 Type-specific tests for HSV-1 tend to be 5 to 10 percent less sensitive than their HSV-2 counterparts and may require more time for seroconversion to occur.
The accuracy of the Gull/Meridan ELISA test compared to the Western blot assay was assessed for 61 children aged 1 to 13 years (median age, 7.4 years).25 The Gull/Meridian ELISA had a sensitivity of 100 percent for HSV-1 and specificities of 74 percent for HSV-1 and 48 percent for HSV-2; no patient in the sample (n = 61) was HSV-2 positive. When the Gull/Meridan test was removed from the market, the investigators extended the study to include 128 similarly aged patients (median age, 5.7 years) using the HerpeSelect ELISA test compared with Western blot assay. The HerpeSelect® showed sensitivities of 80 percent for HSV-1 and 88 percent for HSV-2, and specificities of 97 percent for HSV-1 and 100 percent for HSV-2. The study did not provide age specific information regarding accuracy of HSV serological testing.
We found no studies that evaluated the optimal time to screen during pregnancy.
We found no studies that evaluated screening partners.
A qualitative assessment of the psychosocial impact of receiving a serological diagnosis of HSV-2 in individuals without a previous history of infection was examined.26 Investigators recruited 24 individuals who were seropositive for HSV-2 by Western blot assay and reported no clinical history of infection. Participants were recruited from clinical settings (STD, maternal and infant care, family medicine, and research clinics) over a 10-month period and completed an in-depth interview on their responses to receiving a HSV-2 diagnosis.
The qualitative analysis identified 3 categories of themes:
Participants exhibited strong emotional and psychological responses to their serological diagnoses of HSV-2.
A descriptive study focused on physicians' skills in managing the potential psychological effects on parents when screening neonates for HSV.27 The investigators conducted a series of semi-structured interviews with 15 physicians from 1 pediatric institution, and coded the resulting audiotapes for common themes. Themes included how physicians prepared families for screening and treatment, managed stigma, and perceived parental reactions. Techniques for fostering good communication included being direct and honest and ensuring that the time and place for discussion were appropriate. Strategies for managing stigma associated with screening included placing the diagnosis in epidemiological context and discussing the potential severity of the disease.
Four randomized controlled trails (RCTs) (3 rated good-quality,28-30 1 rated fair-quality31) examined the effectiveness of antiviral agents in the suppression of HSV recurrences, and 1 good-quality RCT32 evaluated the effectiveness of an antiviral agent in reducing subclinical viral shedding (Table 2).
A randomized, multicenter, multinational, double blind, placebo controlled trial assessed the effectiveness of oral famciclovir for suppression of recurrent HSV.28 Eligible men and women (n = 455; 6 or more recurrences per year) were randomly assigned to receive 1 of 3 famciclovir regimens:
In an intention-to-treat analysis, famciclovir significantly delayed the time to the first recurrence at all dose regimens compared with placebo (P < 0.001; hazard ratio [HR], 2.9-3.3; CI, 2.0-4.8). Median time to recurrence was 222 to 336 days for famciclovir groups compared with 47 days for the placebo group. The proportion of patients remaining free of HSV recurrence was significantly higher in the 3 treatment groups (79 percent to 86 percent) than in the placebo group (27 percent) at 6 months (relative risk [RR], 2.9-3.1; P < 0.001), and efficacy was maintained at 12 months. There was no reported difference in efficacy between the treatment regimens or between men and women. Famciclovir was well tolerated in all treatment groups with an adverse experience profile comparable to the placebo group.
A randomized, double blind, placebo controlled trial of famciclovir included women with recurrent genital HSV infections.29 A total of 375 women with 6 or more recurrences per year were randomly assigned to 5 different famciclovir regimens:
An intention-to-treat analysis indicated that the median time to first recurrence was significantly prolonged for those taking 125 mg of famciclovir twice daily (HR, 1.8; 95% CI, 1.0-3.0; P = 0.03) and 250 mg of famciclovir twice daily (HR, 3.6; 95% CI, 1.9-6.9; P < 0.001). The proportion of women who remained free of recurrences during the followup period was greatest with 250 mg of famciclovir twice daily (78 percent) compared with placebo (42 percent; P < 0.001). No significant differences were reported in the frequency and severity of clinical adverse experiences between the famciclovir and placebo groups.
Another randomized, multicenter, double blind, placebo controlled trial compared valacyclovir with placebo for the suppression of recurrent HSV.31 Men and women (n = 382) with 8 or more recurrences per year were randomly assigned to receive either 500 mg oral valacyclovir once daily or a placebo for 16 weeks. Results indicated a significant difference in the time to first recurrence between the valacyclovir and placebo groups (P < 0.0001; HR, 0.16; 95% CI, 0.11-0.21). After the treatment period, 69 percent of the patients who received valacyclovir were recurrence free compared with 9.5 percent of the patients assigned to placebo. The safety of valacyclovir and placebo were comparable, with adverse experiences being infrequent and generally mild (e.g., headache and nausea).
A randomized, double blind, placebo controlled trial compared the effectiveness in suppressing recurrent HSV using different valacyclovir regimens with placebo and acyclovir.30 Men and women patients (n = 1,479) with 6 or more recurrences per year were randomly assigned to 4 different valacyclovir regimens:
The patients were followed in all groups for 1 year. Seventy-one percent of patients completed the study. Results of an intention-to-treat analysis showed that all the antiviral regimens were effective in suppressing HSV recurrences compared with placebo (P < 0.001; HR, 0.21-0.46; CI, 0.16-0.59). The adverse experiences reported were similar for each of the 4 valacyclovir groups, the acyclovir group, and the placebo group. Most adverse experiences reported by all groups were considered mild (e.g., headaches, flu-like symptoms).
A randomized, double blind, placebo controlled, crossover trial assessed the use of acyclovir on the frequency of subclinical viral shedding in the genital tract.32 Thirty-four eligible women (HSV-2 antibody only and genital HSV of less than 2 years' duration) were randomly assigned to receive either acyclovir (400 mg daily) for 70 days, followed by a 2 week wash out period, and then followed by placebo for 70 days, or the study protocol in the reverse order. In an intention-to-treat analysis, 88 percent (15/17) of women who received placebo and 18 percent (3/17) who received acyclovir had at least 1 day of subclinical viral shedding (P < 0.001). The relative risk for subclinical viral shedding was 0.09 (95% CI, 0.03-0.35) for the women who received acyclovir compared with the women who received placebo.
A good-quality, randomized, multicenter, double blind, placebo controlled trial was conducted to determine the effectiveness of once-daily valacyclovir to reduce sexual transmission of genital HSV (Table 2).33 Eligible healthy, monogamous, heterosexual couples (n = 1,484 at 96 centers) were discordant for HSV-2 infection. The source partner was aged 18 or older, had recurrent HSV-2 with fewer than 10 episodes per year, and did not use daily antiviral therapy. The susceptible partner was aged 18 or older and HSV-2 seronegative on Western blot assay.
Couples were randomly assigned to receive either 500 mg of valacyclovir once daily or placebo for 8 months. The susceptible partner was evaluated monthly for clinical signs and symptoms of genital HSV, and the source partner was followed for recurrence of genital HSV. Both partners received counseling on safer sex and were offered condoms at each visit. The study endpoint was the reduction in transmission of symptomatic genital herpes.
Clinical symptoms of HSV-2 infection developed in 4/743 (0.5 percent) susceptible partners who were given valacyclovir compared with 16/741 (2.2 percent) susceptible partners who were given placebo (HR, 0.25; 95% CI, 0.08-0.75; P = 0.008). Acquisition of HSV-2 was observed in 14 (1.9 percent) susceptible partners who received valacyclovir compared with 27 (3.6 percent) who received placebo (HR, 0.52; 95% CI, 0.27-0.99; P = 0.04). HSV DNA using PCR was detected in samples of genital secretions on 2.9 percent of the days among the HSV-2 source partners who received valacyclovir, compared with 10.8 percent of days among those source partners who received placebo (P < 0.001). Viral shedding was detected in 48.7 percent of source partners who received valacyclovir compared with 82 percent of source partners who received placebo (RR, 0.60; 95% CI, 0.43-0.83; P = 0.002).
After counseling, 37 percent of the couples reported at each monthly visit that they never used condoms for vaginal or anal intercourse during the study. Covariate analyses, accounting for reported use of condoms during the study, indicated that once-daily valacyclovir use continued to be associated with reduced rates of transmission. The lowest observed rates of transmission were among couples who reported almost always using condoms during intercourse, and the source partner was taking once-daily valacyclovir. The frequency of harms was similar in the valacyclovir and placebo groups.
A prospective cohort study suggested that male condom use may decrease the risk for sexual transmission of HSV-2 among women who have a sexual partner discordant for HSV-2.34 In the study, 528 monogamous couples discordant for HSV-2 infection (261 susceptible men and 267 susceptible women) were followed for 18 months The findings suggested that male condom use in 25 percent of episodes of sexual intercourse was associated with a lower risk for HSV-2 acquisition among women (adjusted HR, 0.09; 95% CI, 0.01-0.67) but not for men (adjusted HR, 2.02; 95% CI, 0.32-12.50). Condom use was low throughout the study; only 61 percent of the couples reported ever using condoms and only 8 percent reported condom use for each sexual act, despite counseling at each clinic followup visit.
The efficacy of condom use against HSV-2 transmission was evaluated in a prospective cohort study of adult men and women attending STD clinics.35 A cohort of 1,862 HSV-2 susceptible persons with 4 or more sexual partners, or 1 or more STDs in the past year, was followed for 18 months. One hundred and eighteen (6.4 percent) persons acquired HSV-2, for an overall rate of 5.2/100 person-years. The rates for women and men were similar (5.7 vs 5.1/100 person-years). In multivariate models, frequency of sexual activity (HR, 1.11; 95% CI, 1.04-1.2) and an STD in the year prior to the study (HR, 1.31; 95% CI, 1.01-1.71) were associated with increased risk for HSV-2. Use of condoms for more than 65 percent of sex acts offered significant protection against HSV-2 acquisition for men (HR, 0.56; 95% CI, 0.33-0.97), as well as for the total population (HR, 0.58; 95% CI, 0.37-0.92). The degree of protection was comparable in women (HR, 0.66; 95% CI, 0.30-1.46), heterosexual men (HR, 0.59; 95% CI, 0.32-1.08), and MSM (HR, 0.42; 95% CI, 0.12-1.49).
Vaccines to prevent genital HSV have not been approved by the FDA, and vaccine trials are ongoing. Four RCTs conducted by 2 investigative groups examined the efficacy of HSV-2 vaccines for the prevention of genital HSV.36,37 Additionally, 3 RCTs examined the efficacy of vaccine in the treatment of recurrent genital HSV.38-40 All of the RCTs are testing different forms of vaccine.
Two randomized, multinational, double blind, placebo controlled trials of a HSV-2 glycoprotein-D adjuvant vaccine were conducted in patients whose regular sexual partners had a history of genital HSV.36 In study 1, eligible patients (n = 847; 268 women) were seronegative for HSV-1 and HSV-2. In study 2, eligible patients (n = 1,867; 710 women) were of any serological status. Patients received vaccine or control injections at 0, 1, and 6 months, and were then followed for 19 months. The endpoints of the studies were occurrence of genital HSV disease in the patients in study 1 and in seronegative women patients in study 2. Intention-to-treat analysis indicated efficacy of 38 percent (95% CI, 18 percent to 68 percent) in study 1 and 42 percent (95% CI, 31 percent to 74 percent) for women patients in study 2. In the post-hoc subgroup analysis, the vaccine provided higher levels of protection in women but not in men. The vaccine efficacy was 73 percent (95% CI, 9 percent to 91 percent; P = 0.01) in women who were seronegative for both HSV-1 and HSV-2 at baseline in study 1. In study 2, the efficacy for women was 74 percent (95% CI, 9 percent to 93 percent; P = 0.02). The vaccine was not efficacious in women who were seropositive for HSV-1 and seronegative for HSV-2 at baseline or in men regardless of their HSV serological status. The vaccine was generally well tolerated. The majority of doses of vaccine were followed by soreness at site of injection, and most symptoms reported were mild to moderate.
Two additional randomized, multicenter, double blind, placebo controlled trials of a recombinant glycoprotein vaccine for prevention of HSV-2 infection were also reported.37 A total of 2,268 eligible patients (seronegative for HSV, seronegative partners of HSV infected persons and persons attending an STD clinic) were randomized to placebo or vaccine groups. The patients were followed for up to 1 year after 3 vaccine administrations. The study outcomes were time to HSV acquisition during the study period. Overall vaccine efficacy was 9 percent (95% CI, -29 percent to 36 percent). The vaccine induced high levels of HSV-2 specific antibodies in vaccinated persons who did and did not develop genital HSV. The vaccine was safe and well tolerated.
A randomized, double blind, placebo controlled trial evaluated the Skinner vaccine for the treatment of recurrent genital herpes.38 Eligible patients (n = 316 with 6 or more genital HSV recurrences per year) were randomly assigned to receive vaccination or a placebo at 0, 1, and 2 months. Recurrence severity was significantly reduced in the intervention group (P = 0.04). The frequency of recurrences was reduced in the vaccinated women patients at both 3- and 6-months followup. Overall recurrence reduction for both men and women after 6 months did not reach statistical difference. There were no serious systemic or local adverse reactions to the vaccination.
A randomized, double blind, placebo controlled trial was conducted to examine the efficacy of a recombinant HSV-2 glycoprotein D and B vaccine in the treatment of recurrent genital herpes.39 Eligible participants (n = 202; 4-14 recurrences per year) were randomly assigned to HSV vaccine or a placebo injection at 0, 2, 12, and 14 months, and followed-up at 18 months. The duration and severity of the first clinically confirmed outbreak after vaccination was significantly reduced in the vaccination group (P = 0.003 for differences in severity; P = 0.002 for differences in duration). However, the monthly rate of recurrences was not significantly improved in the vaccine group. Adverse experiences were generally mild to moderate but statistically higher after each vaccination compared with the placebo injection (P < 0.01).
A randomized, double blind, placebo controlled trial evaluated a recombinant glycoprotein-D vaccine for recurrent HSV-2.40 Eligible patients (n = 98, 4-14 recurrences per year and free from genital lesions) were randomly assigned to vaccine or placebo injection at baseline, and after 2 months, and followed up at 1 year. The vaccine group experienced a lower median number of clinically and virologically confirmed recurrences than the placebo group (3 vs 4; P = 0.025). Time to first genital HSV recurrence was not significantly different by group. Adverse experiences were reported frequently (100 percent vaccine groups and 90 percent of placebo group) but typically mild (e.g., headaches, chills, nausea).