Transmission Of Herpes Simplex Virus Research Articles

Asymptomatic Shedding of Herpes Simplex Virus 1 and 2: Implications for Prevention of Transmission

It is counterintuitive that sexual transmission of herpes simplex virus (HSV) more commonly results from contact during a short episode of asymptomatic shedding than from contact with lesions. After all, virus titers are much higher and the average duration of shedding is much longer when lesions are present [1, 2], and the risk of transmission following a single contact with lesions is undoubtedly much higher than a single contact with asymptomatic shedding. More than 2 decades ago, the role of asymptomatic shedding in transmission of HSV was suggested by evaluation of recent sex partners implicated in transmission of genital herpes and by evaluation of mothers who transmitted HSV to neonates yet lacked a history of genital herpes [3-6]. In a study published in 1985, recent sex partners of persons with first-episode genital herpes were interviewed and eval-

Guidelines for the Management of Herpes Simplex Virus in Pregnancy

ObjectiveTo provide recommendations for the management of genital herpes infection in women who want to get pregnant or are pregnant and for the management of genital herpes in pregnancy and strategies to prevent transmission to the infant. OutcomesMore effective management of complications of genital herpes in pregnancy and prevention of transmission of genital herpes from mother to infant. EvidenceMedline was searched for articles published in French or English related to genital herpes and pregnancy. Additional articles were identified through the references of these articles. All study types and recommendation reports were reviewed. ValuesRecommendations were made according to the guidelines developed by the Canadian Task Force on Preventive Health Care. Recommendations1.Women’s history of genital herpes should be evaluated early in pregnancy. (III-A)2.Women with known recurrent genital herpes simplex virus (HSV) should be counselled about the risks of transmission of HSV to their neonates at delivery. (III-A)3.At delivery, women with recurrent HSV should be offered a Caesarean section if there are prodromal symptoms or in the presence of a lesion suggestive of HSV. (II-2A)4.Women with known recurrent genital HSV infection should be offered acyclovir or valacyclovir suppression at 36weeks’ gestation to decrease the risk of clinical lesions and viral shedding at the time of delivery and therefore decrease the need for Caesarean section. (I-A)5.Women with primary genital herpes in the third trimester of pregnancy have a high risk of transmitting HSV to their neonates and should be counselled accordingly and should be offered a Caesarean section to decrease this risk. (II-3B)6.A pregnant woman who does not have a history of HSV but who has had a partner with genital HSV should have type-specific serology testing to determine her risk of acquiring genital HSV in pregnancy before pregnancy or as early in pregnancy as possible. Testing should be repeated at 32 to 34weeks’ gestation. (III-B) ValidationThese guidelines have been reviewed and approved by the Infectious Diseases Committee of the SOGC. SponsorThe Society of Obstetricians and Gynaecologists of Canada

Understanding Herpes Simplex Virus: Transmission, Diagnosis, and Considerations in Pregnancy Management

Genital herpes simplex virus (HSV) infections are frequently asymptomatic or undiagnosed, but more than half the US population is seropositive for HSV, and about one-fifth are positive for HSV-2. These two factors contribute to the risk for sexual transmission and therefore to the risk of late-pregnancy acquisition of HSV. Most neonatal herpes infections are the result of undiagnosed, new-onset HSV infection in the mother. This article reviews the epidemiology of HSV, risks of transmission, and testing and management of HSV during pregnancy. Options for evaluation and management are presented.

Epigallocatechin Gallate Inactivates Clinical Isolates of Herpes Simplex Virus

In the absence of a fully effective herpes simplex virus (HSV) vaccine, topical microbicides represent an important strategy for preventing HSV transmission. (-)-Epigallocatechin gallate (EGCG) (molecular weight, 458.4) is the primary catechin in green tea. The present study shows that EGCG has greater anti-HSV activity than other green tea catechins and inactivates multiple clinical isolates of HSV type 1 (HSV-1) and HSV-2. EGCG reduced HSV-2 titers by >or=1,000-fold in 10 to 20 min and reduced HSV-1 titers by the same amount in 30 to 40 min. The anti-HSV activity of EGCG is due to a direct effect on the virion, and incubating Vero and CV1 cells with EGCG for 48 h prior to infection with HSV-1 and HSV-2, respectively, does not reduce HSV production. Electron microscopic (EM) studies showed that purified virions exposed to EGCG were damaged, and EM immunogold labeling of the envelope glycoproteins gB and gD was significantly reduced following EGCG treatment while capsid protein labeling was unchanged. When purified HSV-1 envelope glycoproteins gB and gD were incubated with EGCG and then examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, lower-molecular-weight gB and gD bands decreased and new higher-molecular-weight bands appeared, indicating the EGCG-dependent production of macromolecular complexes. gB and gD are essential for HSV infectivity, and these results suggest that EGCG could inactivate HSV virions by binding to gB, gD, or another envelope glycoprotein. EGCG is stable in the pH range found in the vagina and appears to be a promising candidate for use in a microbicide to reduce HSV transmission.

Unexpected high prevalence of herpes simplex virus (HSV) type 2 seropositivity and HSV genital shedding in pregnant women living in an East Paris suburban area

Both herpes simplex virus type 2 (HSV-2) seroprevalence and the proportion of HSV-1 genital ulcers are increasing in industrialized countries. The consequences of these epidemiological changes, in pregnant women in France, for both the genital shedding of HSV and vertical transmission, have been poorly evaluated. The HSV-1 and HSV-2 seroprevalence and the rate of subclinical genital shedding of herpes close to delivery were evaluated in pregnant women, with no history of genital herpes, living in the East Paris suburban area. HSV-2 antibody prevalence of 26% was significantly associated with country of origin and was higher than that reported in 2002 in French women from the general population (18%). HSV-2 and HSV-1 genital reactivations were observed in 10% of HSV-2 seropositive and in 4% of HSV-1 seropositive and HSV-2 seronegative women, respectively. The high rates of HSV-2 seropositivity and subclinical herpes genital shedding observed in this study should be considered to promote a national survey in pregnant women to propose strategies to prevent the spread of HSV within the population and to the neonate.

Incidence of Neonatal Herpes Simplex Virus Infections in a Managed-Care Population

To determine the incidence of possible neonatal herpes simplex virus (HSV) infections, HSV infection status of women with infected infants, and use of measures to reduce risk of HSV transmission to the neonate in a large US managed-care population. Retrospective analysis of administrative claims from the Integrated Health Care Information Services National Managed Care Benchmark database. Of 233,487 infants born to 252,474 mothers from January 1997 to June 2002, the numbers assigned an ICD-9 code reflecting possible neonatal HSV infection </=30 and </=90 days of birth were 178 (0.08%) and 338 (0.15%), respectively. Of the 338 mothers delivering infants with possible neonatal HSV </=90 days postnatally, 12% had a prior HSV diagnosis, 5% were prescribed an antiviral medication during the study period, and 3% used antiviral medication and had a cesarean delivery. These results support national surveillance of neonatal HSV to better define its incidence, strengthen health policies, and improve prevention and treatment.

Herpes Simplex Virus Type‐Specific Serology: Where Does it Fit in the Diagnostic Armamentarium?

Herpes Simplex Virus Type‐Specific Serology: Where Does it Fit in the Diagnostic Armamentarium?

Maternal herpes simplex virus antibody avidity and risk of neonatal herpes

The objective of the study was to assess whether herpes simplex virus antibody avidity is associated with risk of transmission of herpes simplex virus to the neonate. We developed a novel herpes simplex virus type 1 avidity test based on the commercially available Focus HerpeSelect-1 enzyme-linked immunosorbent assay kit using sera from nonpregnant subjects with genital herpes simplex virus-1 infection. We used this test, and the previously developed herpes simplex virus type 2 avidity test, to compare maternal herpes simplex virus-1 and herpes simplex virus-2 antibody avidity in women who transmitted herpes simplex virus to the neonate and women who had herpes simplex virus isolated from genital secretions at delivery but who did not transmit herpes simplex virus to their infants. Among nonpregnant subjects with genital herpes simplex virus-1 infection whose sera were used to develop the herpes simplex virus-1 avidity test, a significant relationship between herpes simplex virus-1 antibody avidity and time since herpes simplex virus-1 acquisition was observed (P < .001, mixed-effects model), with median avidity values increasing over time after primary infection. Among pregnant, herpes simplex virus-1, or herpes simplex virus-2 seropositive women, 4 of 8 women (50%) with avidity 40 or greater transmitted herpes simplex virus to the neonate, compared with only 12 of 97 (12%) of women with avidity greater than 40 (P = .02). Herpes simplex virus-1 antibody avidity increased over time after genital herpes simplex virus-1 acquisition, as has been previously observed for herpes simplex virus-2. Among women with herpes simplex virus antibody at delivery, low antibody avidity was associated with herpes simplex virus transmission to the neonate and may be a useful marker for recent seroconversion.

Surveillance sérologique pour les Herpesvirus chez les receveurs de cornée

Herpesviruses are ubiquitous viruses, providing circulating antibodies in a wide range of patients. Donor-to-host transmission of Herpes simplex virus via corneal graft has been proven, leading to primary graft failure. However, the serological survey of the corneal recipient for Herpesviruses has not yet been investigated. Circulating antibodies to HSV, VZV, CMV, and EBV were tested in 117 corneal recipients prior to surgery as well as 8 days and 3 months following surgery. Twenty-two patients had a history of corneal herpes. All patients were treated with local steroids, and no patient received systemic immunosuppressive therapy. No seroconversion was encountered, in particular, no CMV--patient was found CMV+ after grafting. The mean concentration of antibodies significantly decreased after grafting in a few patients. A serological profile of EBV reactivation was detected after surgery in four patients at day 8 and three more patients at 3 months. This study shows no significant seroconversion after grafting. However, it shows a postoperative decrease in antibody levels as well as a serological profile of EBV reactivation, possibly related to local steroids or graft immune processes.

Risk factors for herpes simplex virus transmission to pregnant women: A couples study

This study was undertaken to determine risk factors for herpes simplex virus (HSV) acquisition among at risk pregnant women. Women in a prospective study of HSV acquisition in pregnancy invited their sexual partners for HSV type-specific serologic testing. Risk factors for HSV susceptibility, exposure, and acquisition were examined. A total of 3192 couples enrolled; 22% included women at risk for HSV-1 or HSV-2. Among 582 HSV-1 seronegative women with HSV-1 seropositive partners, 14 (3.5% adjusted for gestation length) acquired HSV-1. Having a partner with a history of oral herpes was associated with HSV-1 acquisition (odds ratio [OR] 8.1, 95% CI: 1.8-36.0) and accounted for 75% of incident infections. Among 125 HSV-2 seronegative women with HSV-2 seropositive partners, 17 (20% adjusted for gestation length) acquired HSV-2. Duration of partnership of 1 year or less was associated with HSV-2 acquisition (OR 7.8, 95% CI: 2.3-25.7) and accounted for 63% of incident infections. No combination of clinical characteristics could identify the majority of susceptible women with serologically discordant partners. HSV acquisition rates in pregnancy are high in discordant couples, especially for HSV-2. Interventions that address risk factors for HSV acquisition should be studied in pregnancy. Clinical profiles cannot replace serologic screening to identify susceptible women with serologically discordant partners.

New management of the pregnant patient to reduce the risk of transmitting herpes to the newborn

Growing understanding of the mechanisms and epidemiology of neonatal herpes simplex virus acquisition allows for the development of a new management of the pregnant patient, one that will reduce the risk of transmitting herpes to the newborn. Maternal herpes simplex virus infection, especially acquired during pregnancy, can result in transmission to the newborn. Infection of the CNS of the newborn results in death or significant neurodevelopmental impairment in most of these infected babies. Herpes simplex virus infection acquired prior to or during pregnancy has a physical and psychologic impact on the health of the mother. Newer, more sensitive and specific serology testing for herpes simplex virus in combination with antiviral pharmacotherapy is now recognized as an important option for reducing the risk of herpes simplex virus transmission from mother to newborn. This review discusses new information concerning the prevention, diagnosis and treatment options for the management of herpes simplex virus infection during pregnancy with a focus on the evolving role of prevention.

Genital Herpes Complicating Pregnancy

Approximately 22% of pregnant women are infected with herpes simplex virus (HSV)-2, and 2% of women will acquire HSV during pregnancy. Remarkably, up to 90% of these women are undiagnosed because they are asymptomatic or have subtle symptoms attributed to other vulvovaginal disorders. Diagnosis of genital herpes relies on laboratory confirmation with culture or polymerase chain reaction assay of genital lesions and type-specific glycoprotein G-based serologic testing. Neonatal herpes is the most severe complication of genital HSV infection and is caused by contact with infected genital secretions at the time of labor. Maternal acquisition of HSV in the third trimester of pregnancy carries the highest risk of neonatal transmission. Despite advances in the diagnosis and treatment of neonatal herpes, little change in the incidence or serious sequelae from this infection has occurred. As such, prevention of the initial neonatal infection is critically important. Obstetricians are in a unique position to prevent vertical HSV transmission by identifying women with genital lesions at the time of labor for cesarean delivery, prescribing antiviral suppressive therapy as appropriate, and avoiding unnecessary invasive intrapartum procedures in women with genital herpes. Enhanced prevention strategies include identification of women at risk for HSV acquisition during pregnancy by testing women and possibly their partners for HSV antibodies and providing counseling to prevent transmission to women in late pregnancy.

Antiviral therapy for genital herpes infections in pregnancy

One of the most deleterious consequences of maternal infection with herpes simplex virus is neonatal herpes, which results in death or significant neurodevelopmental impairment in the majority of infected babies. Herpes simplex virus infection during pregnancy can also impact the psychologic health of the mother. The ability to minimize the risk of herpes simplex virus transmission has improved in tandem with advances in understanding of the mechanisms and epidemiology of acquisition of neonatal herpes simplex virus. In particular, antiviral pharmacotherapy is now recognized as an important option both for reducing the risk of transmission of herpes simplex virus from a seropositive to a seronegative partner and, potentially, for modifying several risk factors for transmission of the virus from a herpes simplex virus-infected mother to the neonate. This review discusses the consequences and management of herpes simplex virus infection during pregnancy, with a focus on the evolving role of antiviral therapy.

Topical microbicides for the prevention of genital herpes infection

Genital herpes is one of the most prevalent sexually transmitted infections worldwide and is the most common cause of genital ulcers. Despite increased public awareness and the initiation of efforts to prevent transmission, the prevalence of herpes simplex virus (HSV) type 2 continues to increase. What makes HSV so difficult to control is that most sexual and perinatal transmission occurs during unrecognized or asymptomatic shedding. The impact of genital herpes as a public health threat is amplified because of its epidemiological synergy with HIV/AIDS. Thus, there is an urgent need for novel prophylactic methods, such as topical microbicides designed for genital application, to prevent both HSV and HIV transmission. Several candidate microbicides are being advanced to clinical trials based on in vitro activity and animal studies. These include compounds that inactivate virus directly, those that enhance innate immunity, and drugs that block viral binding and entry. A more vigorous evaluation of the safety of these and other candidate topical microbicides in development should include assessment of the impact of repeated application on innate host defences in the genital tract.

Seroprevalence, incidence of prenatal infections and reliability of maternal history of varicella zoster virus, cytomegalovirus, herpes simplex virus and parvovirus B19 infection in South‐Western Finland

To study seroprevalence and incidence and fetal transmission of varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex virus (HSV) types 1 and 2 and parvovirus B19 infections during pregnancy and to evaluate the reliability of maternal past history of VZV, HSV and parvovirus infections. Prospective study of parturient women. South-Western Finland. Five hundred and fifty-eight parturient women. IgG and IgM antibodies against VZV, CMV, HSV-1 and -2, and parvovirus B19 were measured from maternal serum in the first trimester and at delivery and from cord serum, mother's own information of her past infections was compared with her serological status. Seroprevalence, seroconversions and fetal transmission of VZV, CMV, HSV and parvovirus B19, reliability of maternal history of VZV, HSV and parvovirus B19. Seroprevalences were 96.2% for VZV, 56.3% for CMV, 54.3% for HSV, 46.8% for HSV-1, 9.3% for HSV-2 and 58.6% for parvovirus B19. Parity was associated with CMV seropositivity, maternal age differed only between HSV-2 seropositive and seronegative women, while area of residence (urban or rural) had no effect. Six seroconversions were observed: two VZV, one CMV and three parvovirus infections. No cases of primary HSV infections occurred. Fetal transmission was observed in two cases of parvovirus infection. No infants with anti-CMV IgM antibodies were born to CMV immunised women. False positive history of chickenpox was given only by 1.5% of the women, history of herpes infections was less reliable, and history of parvovirus infection was unreliable. Seroprevalence and the risk of viral infections during pregnancy cannot be extrapolated from one pregnant population to another.

Daily Antiviral Therapy Reduces Transmission of Genital HSV

In patients who are infected with genital herpes simplex virus (HSV), daily antiviral therapy limits the frequency of symptomatic episodes and

Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant.

Neonatal herpes most commonly results from fetal exposure to infected maternal genital secretions at the time of delivery. The risk of transmission from mother to infant as it relates to maternal herpes simplex virus (HSV) serologic status and exposure to HSV in the maternal genital tract at the time of labor has not been quantified. Furthermore, no data exist on whether cesarean delivery, the standard of care for women with genital herpes lesions at the time of delivery, reduces HSV transmission. To determine the effects of viral shedding, maternal HSV serologic status, and delivery route on the risk of transmission of HSV from mother to infant. Prospective cohort of pregnant women enrolled between January 1982 and December 1999. A university medical center, a US Army medical center, and 5 community hospitals in Washington State. A total of 58 362 pregnant women, of whom 40 023 had HSV cultures obtained from the cervix and external genitalia and 31 663 had serum samples tested for HSV. Rates of neonatal HSV infection. Among the 202 women from whom HSV was isolated at the time of labor, 10 (5%) had neonates with HSV infection (odds ratio [OR], 346; 95% confidence interval [CI], 125-956 for neonatal herpes when HSV was isolated vs not isolated). Cesarean delivery significantly reduced the HSV transmission rate among women from whom HSV was isolated (1 [1.2%] of 85 cesarean vs 9 [7.7%] of 117 vaginal; OR, 0.14; 95% CI, 0.02-1.08; P =.047). Other risk factors for neonatal HSV included first-episode infection (OR, 33.1; 95% CI, 6.5-168), HSV isolation from the cervix (OR, 32.6; 95% CI, 4.1-260), HSV-1 vs HSV-2 isolation at the time of labor (OR, 16.5; 95% CI, 4.1-65), invasive monitoring (OR, 6.8; 95% CI, 1.4-32), delivery before 38 weeks (OR, 4.4; 95% CI, 1.2-16), and maternal age less than 21 years (OR, 4.1; 95% CI, 1.1-15). Neonatal HSV infection rates per 100 000 live births were 54 (95% CI, 19.8-118) among HSV-seronegative women, 26 (95% CI, 9.3-56) among women who were HSV-1-seropositive only, and 22 (95% CI, 4.4-64) among all HSV-2-seropositive women. Neonatal HSV infection rates can be reduced by preventing maternal acquisition of genital HSV-1 and HSV-2 infection near term. It can also be reduced by cesarean delivery and limiting the use of invasive monitors among women shedding HSV at the time of labor.

Current treatment options to prevent perinatal transmission of herpes simplex virus

Neonatal herpes is a potentially devastating consequence of perinatal transmission of the herpes simplex virus (HSV), with significant morbidity and mortality. Treatment options are available, but must begin early in disease with manifestations that are often protean. Thus, preventive measures need to be optimised. Antiviral suppression in late pregnancy of women with a history of recurrent genital herpes will decrease symptomatic recurrence at delivery and appears to reduce caesarian section rates. However, primary HSV Type 2 and primary HSV Type 1 episodes have the highest neonatal transmission rates and thus, effective prevention may require the identification and suppression of the discordant partner. Significant experience has been gained with the use of acyclovir in pregnancy and it is recommended for both episodic and suppressive therapy in pregnant women. Its use has been demonstrated to be cost-effective in suppressive therapy, although issues regarding compliance and the potential for neonatal neutropenia need to be addressed. The more conveniently dosed prodrugs valacyclovir and famciclovir are being evaluated for use in pregnancy.

Syncytiotrophoblast is a barrier to maternal-fetal transmission of herpes simplex virus.

Herpes simplex virus (HSV)-1 has been discovered in placental tissue from spontaneous miscarriages, but reports of transplacental transmission and fetal infection are extremely rare. Previously, we demonstrated that the villous syncytiotrophoblast, which forms a continuous layer between the maternal and fetal circulation, is resistant to HSV entry. Here, we tested our hypothesis that the villous syncytiotrophoblast prevents transplacental transmission of HSV secondary to decreased expression of HSV entry mediators (HveA, HveB, and HveC). In addition, we investigated the ability of HSV to infect extravillous trophoblast cells, which mediate placental attachment to the uterine wall, and the expression of HSV receptors in these cells. We performed fluorescence-activated cell sorting (FACS) analyses and immunostaining to demonstrate that HveA, HveB, and HveC were not expressed in third-trimester villous trophoblast cells. Consequently, villous explants obtained from third-trimester placentas were resistant to infection by a recombinant HSV-1 vector, HSV-1 KOS, but approximately 20% of mesenchymal cells within the villous core were infected when villous explants were pretreated with trypsin to disrupt the villous trophoblast layer. Conversely, FACS analysis and immunostaining demonstrated that extravillous trophoblast cells expressed HveA, HveB, and HveC, and these cells were efficiently infected by HSV vectors. Infection of extravillous trophoblast cells by HSV-1 was not reduced when the cells were pretreated with an antibody against HveA but was partially reduced when the cells were pretreated with antibodies directed against HveB and HveC. Thus, the decreased expression of herpesvirus entry mediators in villous syncytiotrophoblast prevents placental villous infection, thereby limiting maternal-fetal transmission of HSV.

Evidence of dual sites of action of dendrimers: SPL-2999 inhibits both virus entry and late stages of herpes simplex virus replication

Dendrimers are macromolecules with broad-spectrum antiviral activity and minimal toxicity effective in animal models in preventing transmission of herpes simplex virus (HSV) infection. In order to further understand the mechanism of action, and toxicity profiles of the dendrimer SPL-2999 against HSV, we investigated in vitro activities as follows: modified plaque reduction assays for SPL-2999 showed that 50% effective concentrations (EC 50) determined by pre-treatment of cells with SPL-2999 were 0.5 μg/ml (30 nM) for HSV-2 and 1 μg/ml (60 nM) for HSV-1, respectively. SPL-2999 was not toxic to Vero cells at concentration up to the highest tested (CC 50 greater than 1000 μg/ml). SPL-2999 appears to completely inhibit both viral adsorption and penetration to Vero cells at concentrations of higher than 3 μg/ml. Additionally, virus yield reduction assay showed that SPL-2999 was effective on cells already infected with HSV with EC 90s (effective concentration giving 90% virus yield reduction) approximately 29.2 μg/ml for HSV-1 and 6.7 μg/ml for HSV-2. When Vero cells were infected with HSV at moi (multiplicity of infection) of 0.01 pfu/cell, the infected cells could be completely protected from viral cytopathic effect (CPE) by SPL-2999 with EC 90s (effective concentration that protects 90% of cells from virus lysis) of 15 μg/ml for HSV-1 and 10 μg/ml for HSV-2. Results from Southern blot hybridization indicated that SPL-2999 inhibited DNA synthesis in HSV infected cells. We conclude that SPL-2999 inhibits both HSV entry into susceptible cells and late stages of HSV replication. Our data indicate that SPL-2999 is a potent inhibitor of both HSV-1 and -2 with the potential for further development as either a topical microbicide or a therapeutic agent.