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Genital herpes
Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1098e1110
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Genital herpes Suzanne M. Garland, MBBS, MD, FRCPA, FRANZCOG Ad Eundem, FAChSHM, FASM, FFSc (RCPA), Director Microbiology and Infectious Diseases, Senior Consultant Microbiology, Honorary Research Fellow, Professor a, b, c, d, *, Marc Steben, MD, Medical Advisor, Medical Director, Associate Professor e, f, g, 1, 2 a
Royal Women's Hospital, Australia Royal Children's Hospital, Australia c Murdoch Childrens Research Institute, Australia d Department of Obstetrics and Gynaecology, University of Melbourne, Australia e STI unit, Direction des risques biologiques et de la sant e au travail, Institut national de sant e publique du Quebec, 190, Boulevard Cremazie Est, Montreal, Quebec, Canada H2P 1E2 f Clinique A rue McGill, Canada g Social and Preventive Medicine, School of Public Health, Universite de Montreal, Canada b
Keywords: genital herpes simplex virus (HSV) HSV infection HSV treatment HSV transmission HSV in pregnancy
Genital herpes is a relatively common infection caused by herpes simplex virus (HSV) type one or two (HSV-1, HSV-2) respectively. It is acquired most commonly via sexual activity. More recently there has been an increase in infections due to HSV-1. Most new cases of genital HSV are not diagnosed due to HSV infections having short-lived signs and symptoms, or in many instances are asymptomatic. Hence many people infected with HSV are unaware that they have it. The risk of transmission to a partner is highest during outbreak periods, when there are visible lesions, although genital HSV can also be transmitted during asymptomatic periods. Use of condoms and antiviral medications assist in preventing transmission. Antiviral agents are effective in controlling clinical episodes, but do not eradicate infection, which remains latent for the life of a patient. Despite the surge in
* Corresponding author. Royal Women's Hospital, Microbiological Research, Clinical Microbiology and Infectious Diseases, Australia. Tel.: þ61 3 8345 3670. E-mail addresses: [email protected] (S.M. Garland), [email protected] (M. Steben). 1 Tel.: þ1 514 864 1600x3234; Fax: þ1 514 864 7646. 2 www.inspq.qc.ca.
http://dx.doi.org/10.1016/j.bpobgyn.2014.07.015 1521-6934/Crown Copyright © 2014 Published by Elsevier Ltd. All rights reserved.
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vaccine research, there is unfortunately no readily available preventative or therapeutic vaccine for HSV to date. Crown Copyright © 2014 Published by Elsevier Ltd. All rights reserved.
Introduction: HSV virus Herpes simplex viruses (HSV) are double stranded, enveloped DNA viruses of the Herpesviridae family. There are two distinct serotypes or “types” for short, HSV-1 and HSV-2. These two types share 40% sequence homology of their genome structure, which reaches 83% for their protein-coding regions, which explains antigenic cross-reactivity between them. Typically, due to tropism for specific anatomical sites, HSV-1 predominantly infects the mucus membranes and skin of the orolabial area. However, HSV-1 is now being seen more often in the genitalia due to the decreasing prevalence of orolabial HSV-1 in the young adult population and increase in frequency of oral sex. HSV-2 typically infects the genitalia. Despite this tropism for sites “above and below the umbilicus”, there is no absolute site for either virus, as there is mixing and matching of both viral subtypes [1,2]. Accordingly, statements that HSV-2 equals genital herpes and HSV-1 equals orolabial herpes should be avoided. HSV infection and clinical presentation HSV typically infects the epithelial cells of the skin and mucosa through minor breaks and then travels by retrograde transport along sensory nerves to the sensory root ganglia. Here there is viral replication. Establishment of latency occurs for the life of the host. Periodically there is reactivation from the latent state, with anterograde transfer from sensory ganglions to the periphery (skin or mucous membranes), where subclinical shredding as well as overt symptomatic and asymptomatic clinical lesions result. Typical clinical lesions following primary infection occur only in the order of 10e25% of infections. The remainder of lesions are either undiagnosed, have a short lived atypical presentation or are asymptomatic. Hence, transmission occurs not only by penetrative sexual intercourse, but also through genital skin to genital skin contact with infected partners. These infected partners are shedding virus either during a clinically evident but not necessarily symptomatic, herpetic episode (clinical reactivation) or more commonly during an episode of asymptomatic infection, otherwise known as either subclinical shedding or asymptomatic shedding. With a clinically overt lesion, even during the prodrome of erythema and papule formation, there is viral replication and infectivity, just as it occurs when a vesicle and ultimately an ulcer forms (see Fig. 1). In fact the peak viral titre occurs within the first 24 hours of lesion development. Once the lesions crust over, the viral titre falls. (See Fig. 2). The host immune response allows healing, which occurs rapidly, as HSV lesions are self-limiting. In the early phase of edema, erythema and fissuring, which may be painful or itchy, the diagnosis may not be readily realised until the development of typical blisters and ulcers are evident. (See Figs. 3 to 5). When a clinically overt lesion is evident, this may represent a primary infection or in fact, be the first episode of an infection acquired years before this manifestation. Differentiating an initial from recurrent disease can be difficult; however, initial disease more often presents bilaterally whereas recurrent outbreaks are often unilateral (men ¼ 15% and female ¼ 4% bilateral) [3]. Subclinical HSV is more frequently detected by nucleic acid amplification techniques such as polymerase chain reaction assays (PCR), which in comparison to culture has a fourfold greater sensitivity at detecting virus. This shedding may occur with minimal or no symptoms and thus explaining how HSV infection is transmitted unintentionally to uninfected partners [4]. Yet it is unknown if this increased detection of HSV by PCR translates to greater infectivity, which was presumed when viral culture was used to detect asymptomatic shedding. The minimal viral infecting dose is also not known.
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Fig. 1. Typical ulcerative HSV lesions noted bilaterally in a classic primary infection.
Infection terminology Initial primary genital infection is defined as the acquisition of either HSV-1 or HSV-2 of the genital skin or mucosa in the absence of both HSV-1 and 2 serum antibodies (ie no previous exposure or infection).
Fig. 2. The time course of primary genital HSV infection from symptoms to lesion development [31].
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Fig. 3. Atypical presentation with labial oedema, pain, swelling and dysuria. Tell-tale lesions are noted on the upper thigh.
Fig. 4. Atypical presentation of recurrent HSV lesions presenting in the sacral dermatome of the buttock.
Fig. 5. Atypical presentation of a primary HSV presenting with labial oedema pain mimicking labial abscess (note patient went to surgery for drainage prior to diagnosis).
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Initial non-primary is defined as having pre-existing antibodies to HSV-1 or HSV-2 (IgG), but not necessarily from a previous clinically overt infection. For example, in the setting of someone who has had pre-existing HSV-2 (defined by IgG HSV-2), a new genital infection with HSV-1 can develop, since this person has had no pre-existing HSV-1 infection (as defined by HSV-1 IgG negative). In these settings, over time, there will be a serological response to the new subtype. One might expect to see an IgM response during a primary infection, but it is not conclusive as an initial primary infection since an IgM response can occur from reactivation. Recurrent infection occurs when there are pre-existing antibodies to an HSV subtype (of the lesion infecting type). Meaning, there is pre-existing IgG to the specific infectious strain. For example, an individual with a clinically apparent HSV-2 infection also has IgG to HSV-2 (from pre-existing infection). A first episode is the first clinical outbreak evident to the patient and is often the reason for seeking clinical consultation. Many first episodes are indeed recurrences with an initial infection that was either subclinical or atypical. Most patients with recurrences will have diagnosed themselves with a more socially acceptable diagnosis before seeking medical attention. This list is expansive and includes the following: vaginitis from candida, contact dermatitis (ie from topical medications, toilet paper, sanitary napkins, soaps, condoms or other menstrual products), trauma from lack of lubrication during sexual intercourse, frequent sexual intercourse, irritation from tight jeans, irritation from G-string, irritation from bicycle seat, urinary tract infection, vaginal dryness, shaving burns, reactions to hair removal products, haemorrhoids or anal fissures [5]. All these conditions mimic the symptoms of HSV infection. Sero-epidemiology There have been changes in the patterns of acquisition of HSV-1 infection in the past few decades in developed populations. Seropositivity for HSV-1 has decreased from near 100% in the past resulting from extended family living. Now, family units are more nuclear and common, especially in higher socio-economic families. This provides less opportunity to acquire HSV-1 in childhood via the oral route [6]. This has resulted in an increase in HSV-1 infections being acquired sexually and presenting as genital infections, which in some populations approaches nearly 50% of clinically evident primary genital infections. This change in epidemiology may also be related to more frequent oro-genital sexual practices in young individuals as a means of preventing unwanted pregnancies or an expansion of pleasurable or desired sexual activities. Hence, HSV-1 seropositivity varies from one community to another; it approaches 100% in childhood in poorer socio-economic groups. Defining the type of an infecting HSV strain can help predict clinical patterns of the virus for the clinician and patient. For instance, HSV-1 is less likely to recur in the genital tract than HSV-2. Clinical recurrences occurring within 1 year of symptomatic genital lesions occur in 20e50% for HSV-1, whereas for HSV-2 it occurs in 70e90% of cases [7]. Seropositivity for HSV-2 increases with the onset of sexual activity. It varies by populations too, with the worldwide range in the order of 10e40%. High risk behaviours populations have higher prevalence rates. It is also higher in HIV positive populations (60e95%) compared to general population, women compared to men, and MSM compared to heterosexual men. The prevalence in Australia is in the order of 13% [6,8], whereas in the US, it is higher in the order of 25% [9].The ageadjusted prevalence for HSV-2 In British Columbia, Canada is 17.3% (95% CI, 15.2-19.4). Prevalence ranges from 7.1% (ages, 15-19 years) to 28.1% (ages, 40e44 years), with the largest increase after the age of 24 years [10]. Viral shedding In recent studies of symptomatic and asymptomatic patients with past infection of HSV-2 (as defined by positive serology for HSV-2 by Western Blot) where data collection included intense daily swabbing (intravaginally, labial, perennial, perianal swabs) and patient diary entries, symptomatic patients were found to shed 20% of the time, whilst asymptomatic patients only shed 10% of the time [4]. Of note the quantity of shedding was not different for either group, despite the
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different rates. When even more intensive screening was performed, (4 times daily), it was noted that shedding is very frequent, although usually short lived, with most shedding being less than 24 hours [11]. In general, shedding is greater for those with more clinical recurrences, than those without symptoms. However, there was no significant differences in gender, sexual preferences, serotype positivity or age [4]. In further sophisticated studies where patients swabbed at different anatomical sites, shedding was found to be widespread throughout the genital tract. Moreover, when biopsies were performed in areas of reactivation and viral shedding, it was apparent that shedding was rapidly cleared by the local immunological responses, as measured by local CD8 resident memory cells [12]. Thus there is a local, chronic immune response, which contributes in part to the increased susceptibility of HIV acquisition (in the order of 2-3 fold) [13]. This may also be the explanation of why suppressive antiviral therapy for HSV-2 does not decrease HIV acquisition. Diagnostic methods Viral identification Viral culture used to be the mainstay of diagnosis, but took over 24 hours to obtain a result [14]. Direct immunofluorescence of infected cells collected from a fresh lesion (by first breaking the vesicle and rubbing the base of the lesion then smearing onto a glass slide) is faster, being performed in a few hours, is inexpensive and has a sensitivity of around 95%. PCR can be used on lesions, CSF, ETA blood, and Guthrie cards (these are filter paper cards for storing infant heel prick collected blood and which are used for the purposes of neonatal screening for various conditions such as cystic fibrosis). PCR has the advantage of providing an answer within hours. Viral serology Non type-specific serology testing is of value if it is negative after a suggested window period of at least 12 weeks. A positive non-type specific serology is not as helpful, as it does not differentiate type 1 from type 2 or dual infections. Serology that is type-specific for HSV-1 or HSV-2 is useful in determining seroconversion to a specific type [15,16]. Type-specific serology can help support a diagnosis of initial infection, when seroconversion is observed for one serotype. It is also useful for situations where lesions have not been positive on viral identification test, particularly those with recurrent symptoms or lesions suggestive of HSV. When a lesion is present, a viral identification test should always be done as the initial test; a type serology test can be used secondarily to assess if the lesion was a primary, non-primary or recurrent infection. Prevention Screening Type-specific serology is not suggested in patients with no history of genital lesions. If done, it should be accompanied with appropriate counseling. The low positive value of serology are not very specific, thus the positive predictive value in a low prevalence group is low. Moreover, confirmatory testing by a more specific test such as a Western blot is not readily available at most laboratories. Type specific serology is useful for high risk scenarios such as knowing that a partner is positive and the other is unsure of his/her status. Results can be very useful in counseling discordant couples; for example, when one of the couple has HSV-2 and the partner with unknown status is found to have detectable HSV-2 antibodies, then a lot of stress around potential transmission of HSV can be taken out of the relationship. If the partner has no detectable antibody then counseling regarding the use of condoms and oral valacyclovir can decrease the risk of transmission to a level that may be more acceptable in the couple.
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Condom Data pooled from 6 studies has shown that there was a 3.6% increase in the odds of HSV-2 acquisition with each unprotected act of intercourse (odds ratio (OR) 1.036; 95% confidence interval [CI]: 1.021-1.052), but no increase in the odds of acquisition associated with protected acts (OR 1.008; 95% CI: 0.987-1.030) [17].
Partner notification Unlike bacterial STIs and HIV, partner notification is not a regulatory requirement for communicable disease notification. However, most partners should be advised of the diagnosis and seek evaluation and counseling when appropriate.
Prevention of stigmatisation When a person is diagnosed with HSV-2 genital herpes, rapid assessment for adverse psychosexual issues should be done and referral for counseling should be made if necessary. Many negative feelings are associated with genital herpes, including depressive mood, isolation, fear of rejection, fear of being discovered, and self-destructive behavior [18].
Rapid disclosure of status Rapid disclosure of HSV status to a partner is important since it has been shown that those with newly acquired genital herpes have a median duration of relationships of 3.5 months. Furthermore the transmission rate is approximately halved when the source partner knew that he or she had genital herpes and informed their respective partner [19]. Hence efforts should be made for proper and timely disclosure of HSV status to ensure barrier methods are used with or without antiviral protection. Most persons resisting disclosure do in fact fear rejection. They should be educated on the need for informed consent for all sexual partners and an appropriate way to do so. Because genital herpes creates many negative emotions and reactions, proper management of these personal concerns helps the infected person develop healthy sexual relations.
Vaccination Despite many attempts to produce prophylactic vaccines, one does not exist for the prevention of HSV [20]. In phase 3 trials, females seronegative to HSV-1 and HSV-2 showed protective responses to administered vaccine, but no effect for seronegative males [20,21]. These unexpected poor outcomes may relate to the complexity of the HVS viral genome, as well as the intricacies of understanding viral pathogenesis and disease. Treatment Standard treatment regimens for initial either primary or non-primary HSV include acyclovir 200 mg five times daily, valacyclovir 1 gm bd, and famciclovir 125 mg bd [22,23]. (See Table1) [24]. Recurrent episodic treatment regimens include shorter course of antivirals commenced at a prodrome or early in lesion development. (See Table 1). Standard treatment regimens of valacyclovir 500 mg bid for suppression of HSV shedding in recurrent infection have been shown to reduce the frequency and quantity of genital HSV shedding by 91e97% when measured by culture and by 76e82% as measured by PCR, when patients are using standard dosing [24,25]. However, even at non-standard, increased doses of antiviral therapy, suppression is still incomplete [26].
Recommended treatment Adult and adolescents aged 14 and over, excluding pregnant and nursing women Episode
Indications
First choice
Second choice
Antiviralb Initial
Clinically important symptoms
Recurrent
Episodic treatment
In the presence of:- Infrequent recurrences (less than 6 per year) OR- Mildly symptomatic lesions
Suppressive treatmenta
In the presence of: eFrequent recurrences (6 or more per year) OR eSerious lesions OR eImpaired quality of life OR eDesire to reduce the risk of transmission
a b c
c
Famciclovir (FamvirTM) OR Valacyclovir (ValtrexTM) Famciclovir (FamvirTM) OR Valacyclovir (ValtrexTM) Valacyclovir (ValtrexTM)
Dosage
Antiviralb
Dosage
250 mg, orally, 3 times a day for 5 days 1g, orally, twice a day for 10 days
Acyclovir (ZoviraxTM)
200mg, orally, 5 times a day for 5-10 days
Acyclovir (ZoviraxTM) OR Famciclovir (FamvirTM)
400mg, orally, twice a day 250mg, orally, twice a day
125 mg, orally twice a day for 5 days 1g, orally, daily for 3 days OR 500mg, orally, twice a day for 3 days 500mg, orally, daily (if 9 or less recurrences per year) OR 1g, orally, daily (if more than 9 recurrences per year)
The order in which antivirals are presented takes into account efficacy and safety data, ease of administering the regimen and cost. Only one brand name is provided, although several manufacturers may offer products under other brand names. A variety of generic versions are also available. This product is recommended in the Canadian Guidelines on Sexually Transmitted Infections, although it has not received approval from Health Canada for this purpose.
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Table 1 Recommended HSV treatment for adults and adolescents aged 14 and over, excluding pregnant and nursing women [24]. Printed with permission from Institut National d'Excellence en Sante et en Services Sociaux (INESSS). Any reproduction of this document in whole or in part for non-commercial use is permitted on condition that the source is mentioned.
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Follow-up cultures Follow-up cultures are not indicated, except when unusual recurrent symptoms appear or when resistance is suspected as a cause for therapeutic failure and in order to determine in vitro susceptibility. Since resistance to antiviral is rare in immunocompetent patients, careful evaluation should include questions regarding compliance of antiviral therapy and HIV status (offer HIV test if not performed lately). Referral to an experienced colleague for further evaluation is warranted.
Genital HSV in pregnancy The greatest risk of transmission to the fetus or neonate is a primary infection in a mother close to labour or within the last trimester. Infection prior to pregnancy or earlier in gestation allows seroconversion and the transmission of neutralizing antibodies to the infant [27]. Without these neutralizing antibodies, the risk of transmission is in the order of 50%. The clinical presentation of neonatal HSV is local skin/mucous membrane disease, central nervous system disease or disseminated infection. Unrecognised and untreated local infection can progress to disseminated disease which has significant morbidity and mortality if not diagnosed and treated quickly. Just as in the genital tract, neonatal skin or mucous membrane presentations can be diverse (see Figs. 6e8). Obstetric risk factors for mother to child transmission include having an HSV serodiscordant partner, invasive obstetric procedures such as fetal scalp electrodes, artificial rupture of the membranes, assisted delivery (ventouse or forceps), low maternal neutralizing antibody levels to HSV, route of delivery (vaginal more than Caesarean section), and infecting strain being HSV-1 rather than HSV-2 (this applies whether looking at maternal primary infections or reactivation [28]. In a cohort of 58,362 pregnant women who were followed through to term, Caesarean delivery was shown to significantly reduce the HSV transmission rate to the neonate among women who were actively shedding HSV; thus whilst the likelihood of HSV infection in the neonate was less (1 (1.2%) of 85 caesarean vs 9 (7.7%) of 117 vaginal; OR, 0.14; 95% CI, 0.02-1.08; P ¼ .047), the 95% CI did however cross one [29]. As such, Caesarean sections are indicated for women with active lesions at delivery, where rupture of membranes is less than 6 hours. (if rupture of membranes is more than 6 hours, then proceed to vaginal delivery). Use of suppressive antiviral treatment for those with recurrent clinically overt lesions in pregnancy should be considered as this can translate into a reduction in the rate of Caesarean delivery. In contrast, with recurrent maternal HSV infections there is partial protection against neonatal disease because of the transfer of maternal neutralizing antibodies and a reduction in duration of shedding. The risk of transmission is in the order of 1e3% if lesions are present at vaginal delivery and
Fig. 6. Neonatal HSV presenting with pustular lesions in the scalp.
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Fig. 7. Neonatal HSV presenting in a premature infant as large bullae (this plantar lesion has broken).
Fig. 8. Neonatal HSV in premature infant with chest lesions.
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only 0.04% if asymptomatic shedding is present at vaginal delivery [30]. Furthermore, the risk is greater for recurrent genital HSV-1 (15%) compared to recurrent genital HSV-2 infection (<0.01%) [29]. Whilst HSV can be transmitted transplacentally (5 to 8% of cases) [31] and postnatally (8-10%), the major route is intrapartum at 85% when infected genital secretions during a vaginal delivery are inoculated into the infant eye, nasopharynx, or skin or mucosal abrasions during the delivery process [32]. Once, it was recommended to collect serial genital swabs antepartum for cases of recurrent HSV to predict shedding intrapartum; however, this practice is not recommended as it is a poor predictor of intrapartum shedding and risk of transmission to the infant [32]. Similarly, type specific HSV serological screening is not recommended routinely in asymptomatic women, as it is has not been shown to be cost effective. For those women with a history of genital HSV and no lesions at labour, vaginal delivery is recommended with care to avoid obstetric interventions that may increase risk of transmission (ie avoid fetal scalp electrodes and vacuum delivery), artificial rupture of membranes, etc). It is recommended then to obtain a maternal genital sweep (cervico- vaginal) sample at delivery to look for asymptomatic shedding and potential infant exposure at delivery. It is also important to counsel parents regarding potential signs of neonatal HSV [33]. Prophylactic acyclovir or valacyclovir should be considered from 36 weeks of gestation until delivery for women with a history of multiple recurrences of genital herpes during pregnancy to reduce shedding and prevent a Caesarean section. It is important to definitively diagnose a first episode of HSV infection in pregnancy as to whether it is a true primary or a first episode [34]. Type specific serology collected at the time of routine antenatal blood collection and then post first lesion should allow differentiation between a true primary and first episode. Request total IgG from a current blood and the first antenatal blood, run in parallel. If the serology shows seroconversion (negative to positive) HSV IgG, then a primary infection has occurred sometime between the two bloods. If both are positive, then the laboratory needs to perform typespecific serology, to see in fact whether there has been a primary to one type in the setting of the other type. Or it may show the same serotype on both occasions and as a reflection of a recurrence. If one orders an IgM, this can be helpful when the serology to one serotype has become positive. However in the setting of pre-existing antibodies to one type, with a reactivation of a lesion, there can be an IgM response, yet not be indicative of the primary infection. Care in the interpretation of serology and involvement with a specialist in infectious diseases in pregnancy may well be required. Decision to recommend vaginal delivery depends on the gestational age at first lesion, and the presences/absence of lesions on clinical exam at the time of labour presentation. If a primary outbreak is confirmed in a woman less than 34 weeks gestation, then labour with a vaginal delivery is recommended if her clinical exam is free of disease. Genital sweep culture or PCR at delivery may be collected to ensure the absence of asymptomatic shedding. However, if there are lesions present at delivery, whether a previous primary or first episode or recurrence, then Caesarean section is recommended. For a primary infection greater than 34 weeks gestation, a Caesarean delivery is recommended along with suppressive acyclovir or valacyclovir treatment should be considered through the remainder of pregnancy (valacyclovir 500 mg tid) (acyclovir 400 mg tid). However, whilst antenatal antiviral prophylaxis reduces viral shedding and recurrences at delivery, it will not eliminate all maternal to child transmission. Clinical trials have been underpowered to evaluate the efficacy of preventing transmission to the newborn [35e37]. Moreover, neonatal disease has been reported after maternal suppression [38]. Suppressive treatment has reduced Caesarean section rates for genital HSV, but it has not eliminated all transmission [29]. Conclusion Genital herpes is a relatively common infection with a prevalence rate of 13e25% in western countries. Many infections go unrecognized as they maybe clinically atypical, short lived and the majority is asymptomatic. This largely explains the constant transmission rate from one partner to another. Latency is a feature of infection, thus an outbreak is not predictable and preventable. There has been a change in the epidemiology of this virus, particularly in the higher socio-economic groups, with more HSV-1 genital infections. Despite great efforts to prevent infection with prophylactic vaccines, these have been largely unsuccessful. An antiviral agent is successful in reducing pain and length of
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time of a clinical episode, but does not permanently eradicate the virus from the host. Despite genital HSV being relatively common, neonatal infection is fortunately uncommon and usually occurs as a consequence of a primary infection in a mother near term.
Practice points First episodes are not all recently acquired infections; many are in fact unrecognized recurrent infections. All HSV infections are life-long; infectivity is unpredictable, but greatest after a primary outbreak. Persons with genital herpes can prevent transmission by rapidly discussing their status with new partners, daily suppressive antiviral treatment and using condoms. In general, herpes serology should be type specific. It can be used to clarify diagnosis where cultures were not performed or negative, yet lesions are consistent with HSV. They can be helpful in discordant couples who are making decisions about prevention of transmission and in the case of pregnancy of neonatal transmission. No effective HSV vaccine is on the horizon. Screening by serology in a low risk patient without a history of genital lesions is not advisable because of the low positive predictive value. Oral antiviral therapy is safe. It can be used not only for acute episodes but also decrease transmission rates markedly if taken to treat initial infection but also used to abort episodes when taken early in a prodrome. Oral suppressive daily therapy can also prevent recurrent episodes and decrease transmission rates. Diagnosis of genital herpes can be made by the use of definitive viral identification testing, such as PCR, DFT, culture of lesions. In cases of negative results, herpes serology can aid in making a diagnosis.
Research agenda To determine how PCR can be translated to contagiousness. To determine the best combination of prevention strategies against HSV for women in their various life stages. To present evidence based serology testing algorithms for the women's health practitioner to use for routine screening. To determine the optimal antiviral regimen to prevent genital herpes in various clinical circumstances. To create a safe vaccine to prevent HSV.
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Immune surveillance by CD8[agr][agr]þ skin-resident T[thinsp]cells in human herpes virus infection. Nature 2013;497(7450):494e7. *[13] Johnson KE, Redd AD, Quinn TC, et al. Effects of HIV-1 and herpes simplex virus type 2 infection on lymphocyte and dendritic cell density in adult foreskins from Rakai, Uganda. JID 2011;203(5):602e9. *[14] Belec L. Laboratory diagnosis of sexually transmitted infections, including human immunodeficiency virus. In: Unemo M, Ballard R, Ison C, et al., editors. Chapter 9 herpes simplex virus (HSV) infections WHO; 2013. *[15] Garland S, Lee T, Ashley R, et al. Automated microneutralization: method and comparison with Western blot for typespecific detection of herpes simplex antibodies in two pregnant populations. J Virological Methods 1995;55(3):285e94. [16] Carmody C, Garland SM, Kent HE. I. D. Prevalence of type-specific herpes simplex virus antibodies in partners of patients with recurrent genital herpes. Venereology 2001;14(4):160e1. *[17] Stanaway JD, Wald A, Martin ET, et al. Case-crossover analysis of condom use and HSV-2 acquisition. Sexual Transm Dis 2012;39(5):388. [18] Clarke P. The impact of a herpes diagnosis and the implications for patient counselling. In: Sacks SL, Straus S, Whitley RJ, et al., editors. Clinical management of herpes viruses. Amsterdam: IOS; 1995. p. 75e86. [19] Wald A, Krantz E, Selke S, et al. Knowledge of partners' genital herpes protects against herpes simplex virus type 2 acquisition. J Infect Dis 2006;194(1):42e52. [20] Stanberry LR, Spruance SL, Cunningham AL, et al. Glycoprotein-Deadjuvant vaccine to prevent genital herpes. NEJM 2002;347(21):1652e61. *[21] Belshe RB, Leone PA, Bernstein DI, et al. Efficacy results of a trial of a herpes simplex vaccine. NEJM 2012;366(1):34e43. [22] Fife KH, Barbarash RA, Rudolph T, et al. Valaciclovir versus acyclovir in the treatment of first-episode genital herpes infection: results of an international, multicenter, double-blind, randomized clinical trial. Sexual Trans Dis 1997;24(8): 481e6. [23] Antibiotic Expert Group. Therapeutic guidelines: antibiotic. Version 14. Melbourne: Therapeutic Guidelines Limited; 2010. [24] INESSS. Pharmacological treatment of STBBI: genital herpes. Institut national d'excellence en sante et en services sociaux; 2013. cited, Available from:, http://www.inesss.qc.ca/fileadmin/doc/INESSS/Outils/Guides_ITSS/herpes_GUIDE_ITSS_ 17jan_EN.pdf. [25] Gupta R, Wald A, Krantz E, et al. Valacyclovir and acyclovir for suppression of shedding of herpes simplex virus in the genital tract. JID 2004 October 15, 2004;190(8):1374e81. *[26] Johnston C, Saracino M, Kuntz S, et al. Standard-dose and high-dose daily antiviral therapy for short episodes of genital HSV-2 reactivation: three randomised, open-label, cross-over trials. The Lancet 2012;379(9816):641e7. [27] Brown ZA, Selke S, Zeh J, et al. The acquisition of herpes simplex virus during pregnancy. NEJM 1997;337(8):509e16. [28] Brown ZA, Gardella C, Wald A, et al. Genital herpes complicating pregnancy. Am J Obstet Gynecol 2005;106(4):845e56. http://dx.doi.org/10.1097/01.AOG.0000180779.35572.3a. [29] Brown ZA, Wald A, Morrow R, et al. Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA 2003;289(2):203e9. [30] Brown ZA, Benedetti J, Ashley R, et al. Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor. NEJM 1991;324(18):1247e52. [31] Garland SM, Doyle L, Kitchen W. Herpes simplex virus type 1 infections presenting at birth. J Paediatr Child Health 1991 Dec;27(6):360e2. *[32] Garland SM, Lee TN, Sacks S. Do antepartum herpes simplex virus cultures predict intrapartum shedding for pregnant women with recurrent disease? Infect Dis Obstet Gynecol 1999;7(5):230e6. [33] Palasanthiran P., Starr M, Jones C. HSV algorithms “Management of Perinatal Infections”. Australasian Society for Infectious Diseases. [34] Garland SM, Jones C. Herpes simplex virus in pregnancy. Aust N Z J Obstet Gynaecol 2001;3(2):108e13. *[35] Hollier LM, Wendel GD. Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection. Cochrane Database Syst Rev 2008;1. [36] Watts DH, Brown ZA, Money D, et al. A double-blind, randomized, placebo-controlled trial of acyclovir in late pregnancy for the reduction of herpes simplex virus shedding and cesarean delivery. Am J Obstet Gynecol 2003;188(3):836e43. [37] Jones CA. Vertical transmission of genital herpes: prevention and treatment options. J Pediatr 2009;69(4):421e34. *[38] Pinninti SG, Angara R, Feja KN, et al. Neonatal herpes disease following maternal antenatal antiviral suppressive therapy: a multicenter case series. The Journal of Pediatrics 2012;161(1):134e8. e3.
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Genital herpes Suzanne M. Garland, MBBS, MD, FRCPA, FRANZCOG Ad Eundem, FAChSHM, FASM, FFSc (RCPA), Director Microbiology and Infectious Diseases, Senior Consultant Microbiology, Honorary Research Fellow, Professor a, b, c, d, *, Marc Steben, MD, Medical Advisor, Medical Director, Associate Professor e, f, g, 1, 2 a
Royal Women's Hospital, Australia Royal Children's Hospital, Australia c Murdoch Childrens Research Institute, Australia d Department of Obstetrics and Gynaecology, University of Melbourne, Australia e STI unit, Direction des risques biologiques et de la sant e au travail, Institut national de sant e publique du Quebec, 190, Boulevard Cremazie Est, Montreal, Quebec, Canada H2P 1E2 f Clinique A rue McGill, Canada g Social and Preventive Medicine, School of Public Health, Universite de Montreal, Canada b
Keywords: genital herpes simplex virus (HSV) HSV infection HSV treatment HSV transmission HSV in pregnancy
Genital herpes is a relatively common infection caused by herpes simplex virus (HSV) type one or two (HSV-1, HSV-2) respectively. It is acquired most commonly via sexual activity. More recently there has been an increase in infections due to HSV-1. Most new cases of genital HSV are not diagnosed due to HSV infections having short-lived signs and symptoms, or in many instances are asymptomatic. Hence many people infected with HSV are unaware that they have it. The risk of transmission to a partner is highest during outbreak periods, when there are visible lesions, although genital HSV can also be transmitted during asymptomatic periods. Use of condoms and antiviral medications assist in preventing transmission. Antiviral agents are effective in controlling clinical episodes, but do not eradicate infection, which remains latent for the life of a patient. Despite the surge in
* Corresponding author. Royal Women's Hospital, Microbiological Research, Clinical Microbiology and Infectious Diseases, Australia. Tel.: þ61 3 8345 3670. E-mail addresses: [email protected] (S.M. Garland), [email protected] (M. Steben). 1 Tel.: þ1 514 864 1600x3234; Fax: þ1 514 864 7646. 2 www.inspq.qc.ca.
http://dx.doi.org/10.1016/j.bpobgyn.2014.07.015 1521-6934/Crown Copyright © 2014 Published by Elsevier Ltd. All rights reserved.
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vaccine research, there is unfortunately no readily available preventative or therapeutic vaccine for HSV to date. Crown Copyright © 2014 Published by Elsevier Ltd. All rights reserved.
Introduction: HSV virus Herpes simplex viruses (HSV) are double stranded, enveloped DNA viruses of the Herpesviridae family. There are two distinct serotypes or “types” for short, HSV-1 and HSV-2. These two types share 40% sequence homology of their genome structure, which reaches 83% for their protein-coding regions, which explains antigenic cross-reactivity between them. Typically, due to tropism for specific anatomical sites, HSV-1 predominantly infects the mucus membranes and skin of the orolabial area. However, HSV-1 is now being seen more often in the genitalia due to the decreasing prevalence of orolabial HSV-1 in the young adult population and increase in frequency of oral sex. HSV-2 typically infects the genitalia. Despite this tropism for sites “above and below the umbilicus”, there is no absolute site for either virus, as there is mixing and matching of both viral subtypes [1,2]. Accordingly, statements that HSV-2 equals genital herpes and HSV-1 equals orolabial herpes should be avoided. HSV infection and clinical presentation HSV typically infects the epithelial cells of the skin and mucosa through minor breaks and then travels by retrograde transport along sensory nerves to the sensory root ganglia. Here there is viral replication. Establishment of latency occurs for the life of the host. Periodically there is reactivation from the latent state, with anterograde transfer from sensory ganglions to the periphery (skin or mucous membranes), where subclinical shredding as well as overt symptomatic and asymptomatic clinical lesions result. Typical clinical lesions following primary infection occur only in the order of 10e25% of infections. The remainder of lesions are either undiagnosed, have a short lived atypical presentation or are asymptomatic. Hence, transmission occurs not only by penetrative sexual intercourse, but also through genital skin to genital skin contact with infected partners. These infected partners are shedding virus either during a clinically evident but not necessarily symptomatic, herpetic episode (clinical reactivation) or more commonly during an episode of asymptomatic infection, otherwise known as either subclinical shedding or asymptomatic shedding. With a clinically overt lesion, even during the prodrome of erythema and papule formation, there is viral replication and infectivity, just as it occurs when a vesicle and ultimately an ulcer forms (see Fig. 1). In fact the peak viral titre occurs within the first 24 hours of lesion development. Once the lesions crust over, the viral titre falls. (See Fig. 2). The host immune response allows healing, which occurs rapidly, as HSV lesions are self-limiting. In the early phase of edema, erythema and fissuring, which may be painful or itchy, the diagnosis may not be readily realised until the development of typical blisters and ulcers are evident. (See Figs. 3 to 5). When a clinically overt lesion is evident, this may represent a primary infection or in fact, be the first episode of an infection acquired years before this manifestation. Differentiating an initial from recurrent disease can be difficult; however, initial disease more often presents bilaterally whereas recurrent outbreaks are often unilateral (men ¼ 15% and female ¼ 4% bilateral) [3]. Subclinical HSV is more frequently detected by nucleic acid amplification techniques such as polymerase chain reaction assays (PCR), which in comparison to culture has a fourfold greater sensitivity at detecting virus. This shedding may occur with minimal or no symptoms and thus explaining how HSV infection is transmitted unintentionally to uninfected partners [4]. Yet it is unknown if this increased detection of HSV by PCR translates to greater infectivity, which was presumed when viral culture was used to detect asymptomatic shedding. The minimal viral infecting dose is also not known.
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Fig. 1. Typical ulcerative HSV lesions noted bilaterally in a classic primary infection.
Infection terminology Initial primary genital infection is defined as the acquisition of either HSV-1 or HSV-2 of the genital skin or mucosa in the absence of both HSV-1 and 2 serum antibodies (ie no previous exposure or infection).
Fig. 2. The time course of primary genital HSV infection from symptoms to lesion development [31].
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Fig. 3. Atypical presentation with labial oedema, pain, swelling and dysuria. Tell-tale lesions are noted on the upper thigh.
Fig. 4. Atypical presentation of recurrent HSV lesions presenting in the sacral dermatome of the buttock.
Fig. 5. Atypical presentation of a primary HSV presenting with labial oedema pain mimicking labial abscess (note patient went to surgery for drainage prior to diagnosis).
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Initial non-primary is defined as having pre-existing antibodies to HSV-1 or HSV-2 (IgG), but not necessarily from a previous clinically overt infection. For example, in the setting of someone who has had pre-existing HSV-2 (defined by IgG HSV-2), a new genital infection with HSV-1 can develop, since this person has had no pre-existing HSV-1 infection (as defined by HSV-1 IgG negative). In these settings, over time, there will be a serological response to the new subtype. One might expect to see an IgM response during a primary infection, but it is not conclusive as an initial primary infection since an IgM response can occur from reactivation. Recurrent infection occurs when there are pre-existing antibodies to an HSV subtype (of the lesion infecting type). Meaning, there is pre-existing IgG to the specific infectious strain. For example, an individual with a clinically apparent HSV-2 infection also has IgG to HSV-2 (from pre-existing infection). A first episode is the first clinical outbreak evident to the patient and is often the reason for seeking clinical consultation. Many first episodes are indeed recurrences with an initial infection that was either subclinical or atypical. Most patients with recurrences will have diagnosed themselves with a more socially acceptable diagnosis before seeking medical attention. This list is expansive and includes the following: vaginitis from candida, contact dermatitis (ie from topical medications, toilet paper, sanitary napkins, soaps, condoms or other menstrual products), trauma from lack of lubrication during sexual intercourse, frequent sexual intercourse, irritation from tight jeans, irritation from G-string, irritation from bicycle seat, urinary tract infection, vaginal dryness, shaving burns, reactions to hair removal products, haemorrhoids or anal fissures [5]. All these conditions mimic the symptoms of HSV infection. Sero-epidemiology There have been changes in the patterns of acquisition of HSV-1 infection in the past few decades in developed populations. Seropositivity for HSV-1 has decreased from near 100% in the past resulting from extended family living. Now, family units are more nuclear and common, especially in higher socio-economic families. This provides less opportunity to acquire HSV-1 in childhood via the oral route [6]. This has resulted in an increase in HSV-1 infections being acquired sexually and presenting as genital infections, which in some populations approaches nearly 50% of clinically evident primary genital infections. This change in epidemiology may also be related to more frequent oro-genital sexual practices in young individuals as a means of preventing unwanted pregnancies or an expansion of pleasurable or desired sexual activities. Hence, HSV-1 seropositivity varies from one community to another; it approaches 100% in childhood in poorer socio-economic groups. Defining the type of an infecting HSV strain can help predict clinical patterns of the virus for the clinician and patient. For instance, HSV-1 is less likely to recur in the genital tract than HSV-2. Clinical recurrences occurring within 1 year of symptomatic genital lesions occur in 20e50% for HSV-1, whereas for HSV-2 it occurs in 70e90% of cases [7]. Seropositivity for HSV-2 increases with the onset of sexual activity. It varies by populations too, with the worldwide range in the order of 10e40%. High risk behaviours populations have higher prevalence rates. It is also higher in HIV positive populations (60e95%) compared to general population, women compared to men, and MSM compared to heterosexual men. The prevalence in Australia is in the order of 13% [6,8], whereas in the US, it is higher in the order of 25% [9].The ageadjusted prevalence for HSV-2 In British Columbia, Canada is 17.3% (95% CI, 15.2-19.4). Prevalence ranges from 7.1% (ages, 15-19 years) to 28.1% (ages, 40e44 years), with the largest increase after the age of 24 years [10]. Viral shedding In recent studies of symptomatic and asymptomatic patients with past infection of HSV-2 (as defined by positive serology for HSV-2 by Western Blot) where data collection included intense daily swabbing (intravaginally, labial, perennial, perianal swabs) and patient diary entries, symptomatic patients were found to shed 20% of the time, whilst asymptomatic patients only shed 10% of the time [4]. Of note the quantity of shedding was not different for either group, despite the
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different rates. When even more intensive screening was performed, (4 times daily), it was noted that shedding is very frequent, although usually short lived, with most shedding being less than 24 hours [11]. In general, shedding is greater for those with more clinical recurrences, than those without symptoms. However, there was no significant differences in gender, sexual preferences, serotype positivity or age [4]. In further sophisticated studies where patients swabbed at different anatomical sites, shedding was found to be widespread throughout the genital tract. Moreover, when biopsies were performed in areas of reactivation and viral shedding, it was apparent that shedding was rapidly cleared by the local immunological responses, as measured by local CD8 resident memory cells [12]. Thus there is a local, chronic immune response, which contributes in part to the increased susceptibility of HIV acquisition (in the order of 2-3 fold) [13]. This may also be the explanation of why suppressive antiviral therapy for HSV-2 does not decrease HIV acquisition. Diagnostic methods Viral identification Viral culture used to be the mainstay of diagnosis, but took over 24 hours to obtain a result [14]. Direct immunofluorescence of infected cells collected from a fresh lesion (by first breaking the vesicle and rubbing the base of the lesion then smearing onto a glass slide) is faster, being performed in a few hours, is inexpensive and has a sensitivity of around 95%. PCR can be used on lesions, CSF, ETA blood, and Guthrie cards (these are filter paper cards for storing infant heel prick collected blood and which are used for the purposes of neonatal screening for various conditions such as cystic fibrosis). PCR has the advantage of providing an answer within hours. Viral serology Non type-specific serology testing is of value if it is negative after a suggested window period of at least 12 weeks. A positive non-type specific serology is not as helpful, as it does not differentiate type 1 from type 2 or dual infections. Serology that is type-specific for HSV-1 or HSV-2 is useful in determining seroconversion to a specific type [15,16]. Type-specific serology can help support a diagnosis of initial infection, when seroconversion is observed for one serotype. It is also useful for situations where lesions have not been positive on viral identification test, particularly those with recurrent symptoms or lesions suggestive of HSV. When a lesion is present, a viral identification test should always be done as the initial test; a type serology test can be used secondarily to assess if the lesion was a primary, non-primary or recurrent infection. Prevention Screening Type-specific serology is not suggested in patients with no history of genital lesions. If done, it should be accompanied with appropriate counseling. The low positive value of serology are not very specific, thus the positive predictive value in a low prevalence group is low. Moreover, confirmatory testing by a more specific test such as a Western blot is not readily available at most laboratories. Type specific serology is useful for high risk scenarios such as knowing that a partner is positive and the other is unsure of his/her status. Results can be very useful in counseling discordant couples; for example, when one of the couple has HSV-2 and the partner with unknown status is found to have detectable HSV-2 antibodies, then a lot of stress around potential transmission of HSV can be taken out of the relationship. If the partner has no detectable antibody then counseling regarding the use of condoms and oral valacyclovir can decrease the risk of transmission to a level that may be more acceptable in the couple.
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Condom Data pooled from 6 studies has shown that there was a 3.6% increase in the odds of HSV-2 acquisition with each unprotected act of intercourse (odds ratio (OR) 1.036; 95% confidence interval [CI]: 1.021-1.052), but no increase in the odds of acquisition associated with protected acts (OR 1.008; 95% CI: 0.987-1.030) [17].
Partner notification Unlike bacterial STIs and HIV, partner notification is not a regulatory requirement for communicable disease notification. However, most partners should be advised of the diagnosis and seek evaluation and counseling when appropriate.
Prevention of stigmatisation When a person is diagnosed with HSV-2 genital herpes, rapid assessment for adverse psychosexual issues should be done and referral for counseling should be made if necessary. Many negative feelings are associated with genital herpes, including depressive mood, isolation, fear of rejection, fear of being discovered, and self-destructive behavior [18].
Rapid disclosure of status Rapid disclosure of HSV status to a partner is important since it has been shown that those with newly acquired genital herpes have a median duration of relationships of 3.5 months. Furthermore the transmission rate is approximately halved when the source partner knew that he or she had genital herpes and informed their respective partner [19]. Hence efforts should be made for proper and timely disclosure of HSV status to ensure barrier methods are used with or without antiviral protection. Most persons resisting disclosure do in fact fear rejection. They should be educated on the need for informed consent for all sexual partners and an appropriate way to do so. Because genital herpes creates many negative emotions and reactions, proper management of these personal concerns helps the infected person develop healthy sexual relations.
Vaccination Despite many attempts to produce prophylactic vaccines, one does not exist for the prevention of HSV [20]. In phase 3 trials, females seronegative to HSV-1 and HSV-2 showed protective responses to administered vaccine, but no effect for seronegative males [20,21]. These unexpected poor outcomes may relate to the complexity of the HVS viral genome, as well as the intricacies of understanding viral pathogenesis and disease. Treatment Standard treatment regimens for initial either primary or non-primary HSV include acyclovir 200 mg five times daily, valacyclovir 1 gm bd, and famciclovir 125 mg bd [22,23]. (See Table1) [24]. Recurrent episodic treatment regimens include shorter course of antivirals commenced at a prodrome or early in lesion development. (See Table 1). Standard treatment regimens of valacyclovir 500 mg bid for suppression of HSV shedding in recurrent infection have been shown to reduce the frequency and quantity of genital HSV shedding by 91e97% when measured by culture and by 76e82% as measured by PCR, when patients are using standard dosing [24,25]. However, even at non-standard, increased doses of antiviral therapy, suppression is still incomplete [26].
Recommended treatment Adult and adolescents aged 14 and over, excluding pregnant and nursing women Episode
Indications
First choice
Second choice
Antiviralb Initial
Clinically important symptoms
Recurrent
Episodic treatment
In the presence of:- Infrequent recurrences (less than 6 per year) OR- Mildly symptomatic lesions
Suppressive treatmenta
In the presence of: eFrequent recurrences (6 or more per year) OR eSerious lesions OR eImpaired quality of life OR eDesire to reduce the risk of transmission
a b c
c
Famciclovir (FamvirTM) OR Valacyclovir (ValtrexTM) Famciclovir (FamvirTM) OR Valacyclovir (ValtrexTM) Valacyclovir (ValtrexTM)
Dosage
Antiviralb
Dosage
250 mg, orally, 3 times a day for 5 days 1g, orally, twice a day for 10 days
Acyclovir (ZoviraxTM)
200mg, orally, 5 times a day for 5-10 days
Acyclovir (ZoviraxTM) OR Famciclovir (FamvirTM)
400mg, orally, twice a day 250mg, orally, twice a day
125 mg, orally twice a day for 5 days 1g, orally, daily for 3 days OR 500mg, orally, twice a day for 3 days 500mg, orally, daily (if 9 or less recurrences per year) OR 1g, orally, daily (if more than 9 recurrences per year)
The order in which antivirals are presented takes into account efficacy and safety data, ease of administering the regimen and cost. Only one brand name is provided, although several manufacturers may offer products under other brand names. A variety of generic versions are also available. This product is recommended in the Canadian Guidelines on Sexually Transmitted Infections, although it has not received approval from Health Canada for this purpose.
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Table 1 Recommended HSV treatment for adults and adolescents aged 14 and over, excluding pregnant and nursing women [24]. Printed with permission from Institut National d'Excellence en Sante et en Services Sociaux (INESSS). Any reproduction of this document in whole or in part for non-commercial use is permitted on condition that the source is mentioned.
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Follow-up cultures Follow-up cultures are not indicated, except when unusual recurrent symptoms appear or when resistance is suspected as a cause for therapeutic failure and in order to determine in vitro susceptibility. Since resistance to antiviral is rare in immunocompetent patients, careful evaluation should include questions regarding compliance of antiviral therapy and HIV status (offer HIV test if not performed lately). Referral to an experienced colleague for further evaluation is warranted.
Genital HSV in pregnancy The greatest risk of transmission to the fetus or neonate is a primary infection in a mother close to labour or within the last trimester. Infection prior to pregnancy or earlier in gestation allows seroconversion and the transmission of neutralizing antibodies to the infant [27]. Without these neutralizing antibodies, the risk of transmission is in the order of 50%. The clinical presentation of neonatal HSV is local skin/mucous membrane disease, central nervous system disease or disseminated infection. Unrecognised and untreated local infection can progress to disseminated disease which has significant morbidity and mortality if not diagnosed and treated quickly. Just as in the genital tract, neonatal skin or mucous membrane presentations can be diverse (see Figs. 6e8). Obstetric risk factors for mother to child transmission include having an HSV serodiscordant partner, invasive obstetric procedures such as fetal scalp electrodes, artificial rupture of the membranes, assisted delivery (ventouse or forceps), low maternal neutralizing antibody levels to HSV, route of delivery (vaginal more than Caesarean section), and infecting strain being HSV-1 rather than HSV-2 (this applies whether looking at maternal primary infections or reactivation [28]. In a cohort of 58,362 pregnant women who were followed through to term, Caesarean delivery was shown to significantly reduce the HSV transmission rate to the neonate among women who were actively shedding HSV; thus whilst the likelihood of HSV infection in the neonate was less (1 (1.2%) of 85 caesarean vs 9 (7.7%) of 117 vaginal; OR, 0.14; 95% CI, 0.02-1.08; P ¼ .047), the 95% CI did however cross one [29]. As such, Caesarean sections are indicated for women with active lesions at delivery, where rupture of membranes is less than 6 hours. (if rupture of membranes is more than 6 hours, then proceed to vaginal delivery). Use of suppressive antiviral treatment for those with recurrent clinically overt lesions in pregnancy should be considered as this can translate into a reduction in the rate of Caesarean delivery. In contrast, with recurrent maternal HSV infections there is partial protection against neonatal disease because of the transfer of maternal neutralizing antibodies and a reduction in duration of shedding. The risk of transmission is in the order of 1e3% if lesions are present at vaginal delivery and
Fig. 6. Neonatal HSV presenting with pustular lesions in the scalp.
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Fig. 7. Neonatal HSV presenting in a premature infant as large bullae (this plantar lesion has broken).
Fig. 8. Neonatal HSV in premature infant with chest lesions.
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only 0.04% if asymptomatic shedding is present at vaginal delivery [30]. Furthermore, the risk is greater for recurrent genital HSV-1 (15%) compared to recurrent genital HSV-2 infection (<0.01%) [29]. Whilst HSV can be transmitted transplacentally (5 to 8% of cases) [31] and postnatally (8-10%), the major route is intrapartum at 85% when infected genital secretions during a vaginal delivery are inoculated into the infant eye, nasopharynx, or skin or mucosal abrasions during the delivery process [32]. Once, it was recommended to collect serial genital swabs antepartum for cases of recurrent HSV to predict shedding intrapartum; however, this practice is not recommended as it is a poor predictor of intrapartum shedding and risk of transmission to the infant [32]. Similarly, type specific HSV serological screening is not recommended routinely in asymptomatic women, as it is has not been shown to be cost effective. For those women with a history of genital HSV and no lesions at labour, vaginal delivery is recommended with care to avoid obstetric interventions that may increase risk of transmission (ie avoid fetal scalp electrodes and vacuum delivery), artificial rupture of membranes, etc). It is recommended then to obtain a maternal genital sweep (cervico- vaginal) sample at delivery to look for asymptomatic shedding and potential infant exposure at delivery. It is also important to counsel parents regarding potential signs of neonatal HSV [33]. Prophylactic acyclovir or valacyclovir should be considered from 36 weeks of gestation until delivery for women with a history of multiple recurrences of genital herpes during pregnancy to reduce shedding and prevent a Caesarean section. It is important to definitively diagnose a first episode of HSV infection in pregnancy as to whether it is a true primary or a first episode [34]. Type specific serology collected at the time of routine antenatal blood collection and then post first lesion should allow differentiation between a true primary and first episode. Request total IgG from a current blood and the first antenatal blood, run in parallel. If the serology shows seroconversion (negative to positive) HSV IgG, then a primary infection has occurred sometime between the two bloods. If both are positive, then the laboratory needs to perform typespecific serology, to see in fact whether there has been a primary to one type in the setting of the other type. Or it may show the same serotype on both occasions and as a reflection of a recurrence. If one orders an IgM, this can be helpful when the serology to one serotype has become positive. However in the setting of pre-existing antibodies to one type, with a reactivation of a lesion, there can be an IgM response, yet not be indicative of the primary infection. Care in the interpretation of serology and involvement with a specialist in infectious diseases in pregnancy may well be required. Decision to recommend vaginal delivery depends on the gestational age at first lesion, and the presences/absence of lesions on clinical exam at the time of labour presentation. If a primary outbreak is confirmed in a woman less than 34 weeks gestation, then labour with a vaginal delivery is recommended if her clinical exam is free of disease. Genital sweep culture or PCR at delivery may be collected to ensure the absence of asymptomatic shedding. However, if there are lesions present at delivery, whether a previous primary or first episode or recurrence, then Caesarean section is recommended. For a primary infection greater than 34 weeks gestation, a Caesarean delivery is recommended along with suppressive acyclovir or valacyclovir treatment should be considered through the remainder of pregnancy (valacyclovir 500 mg tid) (acyclovir 400 mg tid). However, whilst antenatal antiviral prophylaxis reduces viral shedding and recurrences at delivery, it will not eliminate all maternal to child transmission. Clinical trials have been underpowered to evaluate the efficacy of preventing transmission to the newborn [35e37]. Moreover, neonatal disease has been reported after maternal suppression [38]. Suppressive treatment has reduced Caesarean section rates for genital HSV, but it has not eliminated all transmission [29]. Conclusion Genital herpes is a relatively common infection with a prevalence rate of 13e25% in western countries. Many infections go unrecognized as they maybe clinically atypical, short lived and the majority is asymptomatic. This largely explains the constant transmission rate from one partner to another. Latency is a feature of infection, thus an outbreak is not predictable and preventable. There has been a change in the epidemiology of this virus, particularly in the higher socio-economic groups, with more HSV-1 genital infections. Despite great efforts to prevent infection with prophylactic vaccines, these have been largely unsuccessful. An antiviral agent is successful in reducing pain and length of
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time of a clinical episode, but does not permanently eradicate the virus from the host. Despite genital HSV being relatively common, neonatal infection is fortunately uncommon and usually occurs as a consequence of a primary infection in a mother near term.
Practice points First episodes are not all recently acquired infections; many are in fact unrecognized recurrent infections. All HSV infections are life-long; infectivity is unpredictable, but greatest after a primary outbreak. Persons with genital herpes can prevent transmission by rapidly discussing their status with new partners, daily suppressive antiviral treatment and using condoms. In general, herpes serology should be type specific. It can be used to clarify diagnosis where cultures were not performed or negative, yet lesions are consistent with HSV. They can be helpful in discordant couples who are making decisions about prevention of transmission and in the case of pregnancy of neonatal transmission. No effective HSV vaccine is on the horizon. Screening by serology in a low risk patient without a history of genital lesions is not advisable because of the low positive predictive value. Oral antiviral therapy is safe. It can be used not only for acute episodes but also decrease transmission rates markedly if taken to treat initial infection but also used to abort episodes when taken early in a prodrome. Oral suppressive daily therapy can also prevent recurrent episodes and decrease transmission rates. Diagnosis of genital herpes can be made by the use of definitive viral identification testing, such as PCR, DFT, culture of lesions. In cases of negative results, herpes serology can aid in making a diagnosis.
Research agenda To determine how PCR can be translated to contagiousness. To determine the best combination of prevention strategies against HSV for women in their various life stages. To present evidence based serology testing algorithms for the women's health practitioner to use for routine screening. To determine the optimal antiviral regimen to prevent genital herpes in various clinical circumstances. To create a safe vaccine to prevent HSV.
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