Herpes Simplex Virus

VIROLOGY 

Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are two of the eight known viruses which comprise the human herpesvirus family. As with all herpesviruses, they are large, enveloped virions with an icosahedral nucleocapsid consisting of 162 capsomeres, arranged around a linear, double-stranded DNA core. The genome consists of two covalently linked components, designated as L (long) and S (short). Each component consists of a unique sequence flanked by inverted repeats. Additionally, the unique L and S components can invert relative to one another, yielding four linear isomers. Each intact HSV virion contains only one of these four isomers, and each of the four are equally virulent (functionally equivalent) in the host cell.

The DNAs of HSV-1 and HSV-2 are largely colinear, and a great degree of homology exists between the HSV-1 and HSV-2 genomes. These homologous sequences are distributed over the entire genomic map, and most of the polypeptides specified by one viral type are antigenically related to polypeptides of the other viral type. This results in considerable cross-reactivity between the HSV-1 and HSV-2 glycoproteins, although unique antigenic determinants exist for each virus. Viral surface glycoproteins mediate attachment and penetration of HSV into cells, and provoke host immune responses. Eleven glycoproteins of HSV have been identified (gB, gC, gD, gE, gG, gH, gI, gJ, gK, gL, and gM), with a twelfth being predicted (gN). Glycoprotein D is the most potent inducer of neutralizing antibodies and appears related to viral entry into a cell, and gB also is required for infectivity. Antigenic specificity is provided by gG, with the resulting antibody response allowing for the distinction between HSV-1 (gG-1) and HSV-2 (gG-2).

EPIDEMIOLOGY 

HSV-1

HSV-1 infections in humans are very common and usually are of a benign nature. As discussed below, gingivostomatitis and recurrent herpes labialis represent the most common clinical manifestations of HSV infections. Using type-specific serologic assays, the seroprevalence of HSV-1 infections has been redefined utilizing sera obtained from the United States National Health and Nutrition Examination Survey (NHANES). By 5 years of age, 20-40% of children are seropositive for HSV-1, and by 60 years of age up to 90% of persons have HSV-1 antibodies (83, 100, 160, 263). A similarly high prevalence of antibodies to HSV-1 exists among persons worldwide, although variability from country to country is seen. HSV-1 infection occurs in both developed and underdeveloped countries. Animal vectors for human HSV infections have not been described, and humans remain the sole reservoir for transmission to other humans. Virus is transmitted from infected to susceptible individuals during close personal contact. There is no seasonal variation in the incidence of infection. Because infection is rarely fatal and HSV establishes latency, over one third of the world's population has recurrent HSV infections and, therefore, the capability of transmitting HSV during episodes of productive infection.

HSV-2

 HSV-2 most commonly causes genital herpes infections. HSV-2 antibodies do not routinely appear prior to adolescence (100,132), and antibody prevalence rates correlate with prior sexual activity. The primary route of acquisition of HSV-2 infections is via genital-genital sexual contact with an infected partner (56, 101, 102, 167). Since the late 1970s, seroprevalence rates for HSV-2 in the United States have increased by 30% (75), although recent data suggest that this trend may be diminishing (262). Approximately one in five adult Americans have acquired HSV-2 (75, 262), although most do not realize that they have been infected. Among Americans> 30 years of age, one in four has had HSV-2. These infection rates and their rise over the past two decades suggest that genital herpes is nearing epidemic proportions.

Predictors of HSV-2 serologic status include female sex, black race or Mexican-American ethnic background, a greater lifetime number of sexual partners, older age, less formal education, and an income below the poverty line (75, 100, 160). For sexually active Americans with a single lifetime sexual partner, the probability of acquisition of HSV-2 is 10.2%. This figure increases to 20.7%, 25.9%, 30.9%, and 46.1% as the number of lifetime sexual partners increases to 2-4, 5-9, 10-49, and > 50, respectively (75). Despite these high seroprevalence rates, most HSV-2-infected American adults do not report ever having had genital herpes, and it is this lack of recognition of one’s own infection which contributes to the surreptitious spread of this virus.

CLINICAL MANIFESTATIONS

Orolabial Herpes 

Gingivostomatitis and recurrent herpes labialis represent the most common clinical manifestations of HSV infections, and are caused by HSV-1. As common as these clinical entities are, however, most HSV-1 infections are asymptomatic. Primary oropharyngeal infection with HSV-1 occurs most commonly in young children between one and three years of age. The incubation period ranges from two to 12 days, with an average of four days. Symptomatic disease is characterized by fever to 104oF, oral lesions, sore throat, fetor oris, anorexia, cervical adenopathy, and mucosal edema. Oral lesions initially are vesicular but rapidly rupture, leaving 1- to 3-mm shallow gray-white ulcers on erythematous bases. These lesions are distributed on the hard palate, the anterior portion of the tongue, along the gingiva, and around the lips (Figure 1). In addition, the lesions may extend down the chin and neck due to drooling. Total duration of illness is 10 to 21 days. Primary gingivostomatitis results in viral shedding in oral secretions for an average of seven to 10 days. Virus can be isolated from the saliva of asymptomatic children as well.

Recurrences of herpes labialis may be associated with physical or emotional stress, fever, exposure to ultraviolet light, tissue damage, and immune suppression. Recurrent orolabial HSV lesions are frequently preceded by a prodrome of pain, burning, tingling, or itching. These symptoms generally last for less than six hours, followed within 24 to 48 hours by the appearance of painful vesicles, typically at the vermillion border of the lip (Figure 2). Lesions usually crust within three to four days, and healing is complete within eight to 10 days. Recurrences occur only rarely in the mouth or on the skin of the face of immunocompetent patients. As with primary HSV-1 infection, recurrent infection may occur in the absence of clinical symptoms.

Genital Herpes

Genital herpes is usually caused by HSV-2, although an increasing number of cases of HSV-1 genital disease are occurring in the United States (126) and around the world (18, 41, 139, 162, 191, 227). When a person with no prior HSV-1 or -2 antibody acquires either virus in the genital tract, a first-episode primary infection results. If a person with preexisting HSV-1 antibody acquires HSV-2 genital infection, a first-episode nonprimary infection ensues. Viral reactivation from latency and subsequent antegrade translocation of virus back to skin and mucosal surfaces produces a recurrent infection. The incubation period following genital acquisition of HSV-1 or -2 is approximately four days (range, 2-12 days). A “typical” clinical presentation following acquisition of genital HSV is that of macules and papules which subsequently form vesicles, pustules, and ulcers  (46). The ulcers then crust and then heal altogether. It is increasingly recognized that acquisition of genital HSV goes unrecognized as such in the majority of patients, emphasizing the need to consider genital HSV disease even when the “typical” presentation is not recognized (Figure 3) (123).

As compared with recurrent episodes of genital herpes, first episodes of genital herpes infection may have associated systemic symptoms, involve multiple sites including nongenital sites, and have longer lesion duration and viral shedding (49). First episode primary infections are more likely to have systemic symptoms than are first episode nonprimary infections, and have higher rates of complications and a longer duration of disease (Table 1) (103, 233). *They also have a greater number of lesions and a longer duration of viral shedding. Constitutional symptoms such as fever, headache, malaise, and myalgias are seen in two-thirds of women with clinically apparent first-episode genital herpes caused by HSV-2, as compared with ~ 40% of men (Table 2). Women are also more likely to have meningeal symptoms and dysuria. The overwhelming majority of both men and women with clinically apparent first-episode genital HSV-2 disease have localized symptoms such as pain at the site of the lesions and tender regional adenopathy, with pruritis, dysuria, and vaginal or urethral discharge also occurring commonly. Local symptoms peak at about one week following onset, and generally resolve by the end of the second week. Viral shedding as detected by culture lasts 10-12 days, and lesions resolve over 16-20 days. Primary genital herpes caused by HSV-1 are more likely to be symptomatic than are those caused by HSV-2 (130).

Not all people with first clinical episodes of symptomatic genital herpes actually have first episode primary or nonprimary infections: approximately 20% of such persons will have serologic evidence of HSV-2 at presentation, indicative of past asymptomatic acquisition of HSV-2 (62, 139). Thus, first clinical episode of genital herpes does not necessarily equate with acquisition of HSV in the genital tract, a fact that should be remembered in counseling couples in long-term monogamous relationships in whom one partner has a first clinically recognized case of genital herpes.

Recurrent genital HSV-2 infection is clinically very different from first episode infections. Genital HSV-2 recurrences can be either symptomatic (recognized by the patient) or asymptomatic (unrecognized throughout the time of recurrence) (181). When clinically apparent, symptoms remain localized to the genital region (46, 88, 167). Approximately half of patients experience prodromal symptoms ranging from mild tingling sensations to sacral neuralgia prior to the development of at least some of their clinically apparent recurrences (Table 3). The duration of viral shedding is shorter during recurrent infection, and there are fewer lesions present. However, there is considerable interpatient and intrapatient variability in the severity and duration of disease from recurrence to recurrence.

As the incidence of genital HSV-2 infections have increased over the past two decades (discussed above), so too has there been a dramatic rise in the incidence of genital HSV-1 acquisition. In the early 1980s, approximately 10% of cases of genital herpes in the United States were caused by HSV-1 (27, 46, 118, 160, 183). By the mid-1990s, the percentage of primary cases of genital herpes caused by HSV-1 had doubled to 20% (126). In other parts of the world, HSV-1 accounts for an even larger percentage of genital herpes cases, with rates in excess of 40% reported from Singapore, Sweden, England, Norway, and Japan (18, 41, 139, 162, 191, 227). HSV-1 genital infections can result from either genital-genital contact or oral-genital contact with an infected person who is actively shedding virus. Given the decreased propensity of HSV-1 to reactivate at the genital site, however, it is likely that oral-genital contact accounts for most genital HSV-1 infections (126). Whites with genital herpes are more likely than blacks with genital HSV to have infection caused by HSV-1 (126). This possibly relates to the younger ages at which orolabial HSV-1 infection acquired among minorities, thereby providing a degree of protection against genital HSV-1 infection in adulthood.

The vast majority of patients with documented first episode genital HSV-2 infection develop recurrences within 12 months: 90% have at least one recurrence, 38% have at least six recurrences, and 20% have at least 10 recurrences during the first year following diagnosis (20). Patients whose primary HSV-2 infection lasts 35 days or more are more likely to have frequent recurrences than are persons whose primary HSV-2 infection lasts fewer than 35 days. Genital HSV-1 infections recur less frequently than do genital HSV-2 infections (46, 125, 183), a finding which could explain why recurrent genital herpes infections are caused by HSV-2 in more than 90% of cases (126). During the first year following acquisition of genital HSV-1 infection, 60% of persons will develop one or more clinical recurrences. Regardless of the viral type causing genital infection, recurrence rates decrease over time (21).

The importance of asymptomatic (subclinical) viral shedding on the epidemiology and transmission of HSV cannot be overstated (243). Utilizing polymerase chain reaction (PCR) technology, HSV DNA can be detected from genital swab specimens from HSV-2 seropositive women on 28% of days (239). Thus, within the course of a year, women who are completely asymptomatic will shed virus on average in excess of 100 days. Transmission to a sexual partner may occur during such periods of subclinical shedding (188). Given that 20-25% of the United States population is infected with HSV-2, as discussed above, subclinical viral shedding likely accounts for the majority of spread of genital herpes. Over the course of several years, the frequency of subclinical HSV shedding generally diminishes. With education regarding the clinical signs and symptoms of genital disease and including photographs, HSV-2 seropositive women without previously recognized genital HSV infection can begin to recognize atypical signs and symptoms as being associated with HSV recurrences (78, 129). This finding is of importance in educational programs on genital herpes which have a focus on reduction of HSV transmission.

Herpetic Whitlow

Herpetic whitlow of a distal phalanx can arise from either HSV-1 or HSV-2. It is characterized by pain, swelling, erythema, and nonpurulent vesicle formation. Herpetic whitlow follows direct inoculation (exogenous or autogenous) or reactivation of latent virus. In children, it most frequently occurs following a primary oral herpes labialis.  In adults, is most often associated with genital herpesinfections. It frequently occurs in healthcare personnel especially dentists who have contact with patients' oral secretions.  Recurrences are common. Extensive necrosis of the nail and digit has been seen in HIV patients.

Neonatal Herpes 

Herpes simplex virus disease of the newborn is acquired in one of three distinct times: intrauterine (in utero), peripartum (perinatal), and postpartum (postnatal). Among infected infants, the time of transmission for the overwhelming majority (~ 85%) of neonates is in the peripartum period. An additional 10% of infected neonates acquire the virus postnatally, and the final 5% are infected with HSV in utero.

Herpes simplex virus infections acquired either peripartum or postpartum can be classified as: 1) disseminated disease involving multiple visceral organs, including lung, liver, adrenal glands, skin, eye, and the brain (disseminated disease); 2) central nervous system disease, with or without skin lesions (CNS disease); and 3) disease limited to the skin, eyes, and/or mouth (SEM disease). This classification system is predictive of both morbidity and mortality (112, 113, 246, 247, 257). Patients with disseminated or SEM disease generally present to medical attention at 10-12 days of life, while patients with CNS disease on average present somewhat later at 16-19 days of life (113).

One-third of all neonates with HSV infection are categorized as having CNS disease (with or without skin, eye, and/or mouth involvement) (253). Clinical manifestations of encephalitis, either alone or in association with disseminated disease, include seizures (both focal and generalized), lethargy, irritability, tremors, poor feeding, temperature instability, and bulging fontanelle. Of those infants with CNS disease without visceral dissemination, between 60% and 70% have associated skin vesicles at any point in the disease course (113, 224). With the current utilization of high-dose intravenous acyclovir (60 mg/kg/day), mortality from neonatal CNS HSV disease is 4%, but 69% of survivors are left with neurologic sequelae (112).

Historically, disseminated HSV infections have accounted for approximately one-half to two-thirds of all children with neonatal HSV disease. However, this figure has been reduced to about 23% since the development and utilization of antiviral therapy, likely the consequence of recognizing and treating SEM infection before its progression to more severe disease (253). Encephalitis is a common component of this category of infection, occurring in about 60% to 75% of infants with disseminated disease (249). While the presence of a vesicular rash can greatly facilitate the diagnosis of HSV infection, over 20% of neonates with disseminated HSV disease will not develop cutaneous vesicles during the course of their illness (7, 113, 224, 253). With high-dose acyclovir therapy, the mortality rate for disseminated neonatal HSV disease is 29% (112). Survivors, however, are likely to do very well, with only 17% experiencing neurologic sequelae (112).

Infection localized to the skin, eye, and/or mouth (SEM disease) has historically accounted for approximately 18% of all cases of neonatal HSV disease. With the introduction of early antiviral therapy, this frequency has increased to 43% (253). By definition, no babies with SEM disease die from their infection. At most, only 2-6% of patients recovering from neonatal SEM disease will experience any neurologic sequelae if they receive optimal diagnostic and therapeutic support during the acute period.

Herpes Simplex Encephalitis 

Herpes simplex virus can invade and replicate in both neurons and glia, resulting in necrotizing encephalitis and widespread hemorrhagic necrosis throughout infected brain parenchyma but particularly the temporal lobe. The manifestations of herpes simplex encephalitis (HSE) in the older child and adult are indicative of the areas of the brain affected. These include primarily focal encephalitis associated with fever, altered consciousness, bizarre behavior, disordered mentation, and localized neurologic findings. Clinical signs and symptoms reflect the area(s) of the brain affected, with disease typically localized to the temporal lobe (259). While no signs are pathognomonic for HSE, a progressively deteriorating level of consciousness, fever, abnormal cerebrospinal fluid (CSF) indices, and focal neurologic findings in the absence of other causes should make this disease highly suspect. Diagnostic evaluations should be initiated immediately, since other treatable diseases mimic HSV encephalitis (40, 252).

Characteristic abnormalities of the CSF of patients with HSE include elevated levels of white blood cells (usually mononuclear cells), red blood cells, and protein. The electroencephalogram (EEG) generally localizes spike and slow wave activity to the temporal lobe. A burst suppression pattern is characteristic of, but not pathognomonic for, HSE (periodic lateralizing epileptiform discharges, or PLEDS). Imaging will allow for localization of disease to the temporal lobe. Early after onset, only evidence of edema is detectable, if at all (92). This finding is followed by evidence of hemorrhage and midline shift in the cortical structures.

In untreated patients, mortality exceeds 70% and only 2.5% of survivors return to normal neurologic function. Even with the utilization of antiviral therapy, substantial mortality and morbidity remain (205), with 19% of patients dying and 62% of survivors having residual neurologic sequelae (251). Patients with a Glasgow coma score of less than 6, those older than 30 years, and those with encephalitis for longer than 4 days have a poorer outcome (251).

Among HSE patients with concurrent herpetic lesions on the lip or in the mouth, restriction endonuclease analysis has confirmed that identical isolates are found in approximately 65% of subjects (248). When the virus was proven to be identical, invariably the patient was experiencing a primary infection, as determined serologically. Thus, virus excreted from the mouth of patients with HSE may be identical to that of the brain or may be entirely different. Of all patients with HSE, approximately one-third have primary infections and two-thirds have recurrent infections (161, 260).

Other CNS Manifestations of HSV Infections

HSV has been associated with radiculomyelitis (73, 204) and Mollaret’s meningitis (22, 43, 99, 229), as well as Bell’s palsy (44, 208), cluster headaches (86, 89), migraines (225). The most common CNS manifestation of HSV, however, is aseptic meningitis (46). As noted above, women are more likely than men to have meningeal symptoms, with approximately one-third of women with primary HSV-2 genital infection having meningeal symptoms as compared with approximately one in ten men with such symptoms (Table 2). Nuchal rigidity and detection of HSV in CSF occurs much more frequently with HSV-2 genital herpes than with HSV-1 genital herpes (165, 206). Aseptic meningitis associated with genital HSV lesions appears to be a benign disease in immunocompetent persons, with full recovery expected. The role of antiviral therapy in the management of aseptic meningitis associated with genital herpes has not been systematically evaluated, although use of systemic antiviral therapy in the treatment of primary genital herpes decreases the subsequent development of aseptic meningitis (47).

HSV Disease in the Immunocompromised Host 

Not unexpectedly, immunocompromised persons can experience frequent mucocutaneous HSV infections, including genital HSV infections, which have a prolonged course (235, 256). In a majority of HSV seropositive renal transplant and bone marrow transplant recipients, reactivation of latent virus occurs within the first month post-transplantation. Administration of prophylactic acyclovir prior to bone marrow transplantation can prevent such reactivation (195,234).

Genital ulcer disease, including that caused by HSV-2, has been recognized as a risk factor for HIV transmission since the early years of the HIV epidemic (93, 105). High titers of HIV are found in genital herpes ulcerations (197), and plasma HIV viral load increases when HSV-2 infection reactivates in HIV-infected persons (154). It is likely that a substantial proportion of new HIV infections are attributable to underlying genital HSV infection (48).

LABORATORY DIAGNOSIS

 A summary of diagnostic tests for HSV infection and disease can be found in Table 4. More specific information on the newer, type-specific serologic tests is provided in Table 5.

Serology

Until recently, the commercially available serologic assays were unable to distinguish between HSV-1 and HSV-2 antibodies, severely limiting their utility. In the past few years, several type-specific antibody assays have received FDA approval and are now commercially available (Table 5). Two of these, the HerpeSelect® HSV-1 and HSV-2 ELISA and the HSV-1 and HSV-2 Immunoblot tests, are manufactured by Focus Technologies, Inc. (172). Another type-specific serologic assay originally manufactured by Diagnology and known as POCkit HSV-2 (9, 11, 118) received FDA approval for the rapid type-specific detection of HSV-2 IgG. This assay is now available in the United States under the new names of “biokitHSV-2,” marketed by biokit USA (Lexington, MA), and “Sure-Vue HSV-2,” from Fisher Healthcare. Several additional tests which claim to distinguish between HSV-1 and HSV-2 antibody are commercially available, but high cross-reactivity rates due to their use of crude antigen preparations limit their utility to documentation of primary seroconversion, rather than distinguishing between viral types (8).

At the current time, the optimal application of these type-specific assays has not been determined. As these standards are being established, though, recommendations from leaders in the field can be found (Table 6). Serologic tests may be useful when lesions are inaccessible or invisible (e.g., cervical or urethral), or in individuals with persistently culture-negative genital ulcerative lesions. In the latter group, a negative HSV serology result means that genital herpes can be ruled out as the cause of ulceration (10, 54, 130). Type-specific serology could also prove helpful for couples in long-term monogamous relationships where one partner has developed genital herpes. In such circumstances, it is imperative to test for both HSV-1 and HSV-2, since a negative HSV-2 serologic test does not exclude the diagnosis of genital herpes.

Detection of intrathecal antibodies directed against HSV has been studied extensively in the diagnosis of HSE. However, it is of little diagnostic value today due to the delay in the development of intrathecal antibody for a disease that requires rapid diagnosis in order to facilitate therapeutic decisions. Normally, intrathecally synthesized IgG antibodies are measured in the postacute stage of HSE from day 10 to day 12 of the disease, reaching maximum values over a one month period of time and then persisting for several years (135, 161, 196, 231, 232). Furthermore, intrathecal immune responses may be delayed or absent when antiviral therapy is started early (138). Two methods for diagnosis of HSE by detection of intrathecal antibodies have been validated. The first is a calculation of an HSV-specific antibody index, and the second is HSV-specific immunoblotting of oligoclonal IgG (155). Both require comparison of HSV-specific antibody reactivity in CSF and serum samples taken on the same day. Overall, the sensitivity and specificity values of the assay are about 80% (255).

In contrast to other congenital and neonatal infections, serologic diagnosis of neonatal HSV infection is not of great clinical value. With the availability of reliable type-specific assays, one barrier to interpreting serologic results in babies with suspected HSV disease has been removed. However, the presence of transplacentally acquired maternal IgG still confounds the assessment of the neonatal antibody status during acute infection, especially given the large proportions of the adult American population who are HSV-1- and HSV-2-seropositive. As a result, serologic studies generally play no role in the diagnosis of neonatal HSV disease.

Culture

Isolation of HSV by culture remains the definitive diagnostic method of documenting an HSV infection, including establishing neonatal HSV disease. Skin or mucous membrane lesions are scraped and transferred in appropriate viral transport media on ice to a diagnostic virology laboratory (3). Such specimens are inoculated into cell culture systems, which are then monitored for cytopathic effects characteristic of HSV replication. Culture results are usually available within ~ 5 days. Viral culture is widely available, and results in the attainment of a viral isolate, which can then be typed. Typing of the viral isolate can provide useful prognostic information regarding reactivation and transmission, which can be used in counseling the patient.

The reliability of viral culture, however, is dependent on the stage of the genital herpes episode, with the quantity of virus being higher during the prodromal and vesicular stages than in the crusting stage (157). As such, confirmatory diagnosis of genital herpes in a patient presenting with crusting or healed lesions should not include viral culture, since the likelihood of a false-negative result is high.

While isolation of HSV by culture remains the definitive diagnostic method of establishing HSV disease outside of the CNS, low viral culture yields from CSF cultures in patients with CNS HSV disease significantly limit the value of viral culture in the diagnosis of CNS HSV infections. For example, HSV can be cultured from only 4% of CSF specimens from older children and adults with HSE (161). While HSV can be cultured from the CSF of 40% of infants with neonatal HSV CNS disease (113), it still has been replaced as the gold standard for virologic confirmation of CNS involvement by PCR due to markedly greater sensitivity of the PCR assay, as discussed below. Thus, sending CSF for viral culture in cases of suspected HSV CNS disease (HSE or neonatal HSV disease with CNS involvement), which requires significant volumes of CSF to be plated on cell lines for subsequent attempts at HSV isolation, has been replaced in recent years with performing HSV PCR on these limited and precious CSF specimens. As with any test, though, false-negatives can occur, and in the case of neonatal HSV disease involving the CNS a positive cutaneous or mucosal culture and evidence for CNS involvement such as seizures, abnormal CSF indices, abnormal neuroimaging studies, etc., will suffice to confirm the CNS disease. In such a situation, virologic confirmation of infection is provided by the non-CNS culture, and documentation of CNS involvement is provided by the additional clinical, laboratory, and/or radiographic findings.

Nucleic Acid Detection Methods

Genital Herpes 

PCR has had a considerable impact on the understanding of HSV-2 shedding in the genital tract. Subclinical shedding of HSV-2 occurs commonly when PCR is utilized, detecting HSV DNA on 20-25% of all days (239). Overall, PCR is three to four times more sensitive for detecting HSV on mucosal surfaces than culture, independent of the presence of lesions or the immune status of the patient (240). Notably, patients who are PCR-positive but culture-negative for HSV-2 remain infectious. The 50% culture-positivity rate corresponds to 106 copies of DNA in the CPR assay (240).

PCR has primarily been utilized in research settings to better define the natural history of HSV reactivation from latency. PCR oftentimes is more expensive than viral culture, although price disparities are diminishing. As such, it will increasingly be utilized for diagnosis of individual patients in the future. PCR may be particularly useful in detecting viable or nonviable viral genomes in genital lesions which have already crusted but which do not yield positive cultures.

HSE 

Prior to the development of PCR technology, diagnosis of HSE required viral culture of material obtained by brain biopsy. Many reports have now demonstrated that PCR of CSF is both highly sensitive and specific for the rapid diagnosis of HSE (4, 12, 13, 60, 87,96, 128, 153, 175, 192, 228). While these investigations have utilized a variety of methodologies, making direct comparisons of results difficult, the overall utility of PCR to provide a relatively noninvasive means of rapidly establishing the diagnosis of HSE has lead to its replacing brain biopsy as the “gold standard” for diagnosis.

A pivotal report of the utility of PCR for the diagnosis of HSE involved assessment of PCR of CSF specimens from a large number of patients with brain biopsy-proven HSE (128). In this report, HSV DNA was detected in the CSF of 53 of 54 biopsy-positive patients. The overall sensitivity and specificity of PCR in this patient cohort was 98% and 94%, respectively, with a positive predictive value of 95% and a negative predictive value of 98% (128). In other large studies of PCR, diagnosis of HSE had been made by a variety of methods. The sensitivity of PCR for the diagnosis of HSE in children and adults from these studies range from 95-100% (12,58, 87, 128).

Recognizing the differences among these reports both in the original case-definition of HSE and in the methodology of PCR employed, it is nevertheless useful to calculate a cumulate sensitivity and specificity of PCR in the diagnosis of HSE, with a relatively recent review of the literature suggesting that overall sensitivity is 96% and overall specificity is 99% (226). Furthermore, PCR has allowed the detection of perhaps 15-20% of patients identified as having mild or atypical forms of HSE who likely would have been unrecognized in the pre-PCR era (65, 76, 119).

Neonatal HSV

The diagnosis of neonatal HSV infections also has been revolutionized by the application of PCR technology to clinical specimens, including CSF (4, 111, 116, 141, 192, 198, 228) and blood (16, 61, 116, 141). In the largest series, CSF specimens from 77 neonates in the United States with culture-proven HSV disease were evaluated retrospectively by PCR (111). Results of this analysis both enhanced the understanding of the spectrum of natural history of neonatal HSV disease and validated the utilization of PCR in the management of such infants. These 77 infants had been previously enrolled during the 1980s in a comparative study of vidarabine and acyclovir for the treatment of neonatal HSV disease. As such, categorization of infants by extent of disease (e.g., SEM disease, CNS disease, and disseminated disease) reflected the laboratory technologies available at the time. HSV DNA was detected by PCR in the CSF of almost one-quarter of infants who had previously been categorized as having SEM disease (111). Among infants with disseminated neonatal HSV disease, HSV DNA was detected in the CSF of 13 (93%) of 14 infants classified as having disseminated disease, while 26 (76%) of the 34 infants categorized as having CNS disease were PCR-positive in their CSF. This is remarkably similar to the Swedish experience of applying PCR to stored specimens from patients with neonatal HSV diagnosed between 1973 and 1996, where 78% of neonates with CNS HSV disease were found to be PCR-positive from CSF (141). Of the 8 neonates with CNS disease and negative CSF PCR results in the U.S. study, 7 had a single CSF specimen available for retrospective PCR analysis (111). Furthermore, the specimens for 6 of the 8 infants were obtained  5 days after initiation of antiviral therapy, and one could speculate that this time interval could explain why the samples were PCR-negative. Thus, the PCR assay in the U.S. investigation had an overall sensitivity of 80% (due to the failure to detect HSV DNA from CSF specimens of 8 infants with CNS disease) and an overall specificity of 71% (due to the finding of HSV DNA in the CSF of 7 infants with presumed SEM disease) (111). In comparison, the sensitivities of PCR assays used in two other investigations of neonatal HSV disease were 100% (116) and 75% (228), and the specificities were 100% in both studies (116, 228).

PCR of blood components from babies with neonatal HSV has been evaluated to a much lesser extent, with only six relatively small studies reported to date in the literature. (16, 61, 116, 117, 136, 141) Further study of blood PCR in neonatal HSV infection is needed, as illustrated by one recent report questioning the sensitivity of serum PCR analysis from neonates with disseminated HSV disease (107).

PATHOGENESIS

Two biologic properties of HSV which directly influence human disease are neurovirulence and latency. Neurovirulence refers to the affinity with which HSV is drawn to and propagated in neuronal tissue. This can result in profound disease with severe neurologic sequelae, as is the case with HSE in children and adults, and with neonatal HSV CNS disease. Sites on the herpes simplex genome which mediate this propensity for neurovirulence have been mapped to the thymidine kinase (TK) gene as well as the termini of the L component. Of note, the gene identified as γ134.5 is required for replication in central nervous system tissue and prevents apoptosis of infected neuronal cells. Genetically engineered HSV virions lacking the γ134.5 gene are currently being investigated as therapies for brain tumors (143, 144).

Latency perpetuates the virus within the host in an “inactive” state. During primary HSV infection, virions are transported by retrograde flow along axons that connect the point of entry into the body to the nuclei of sensory neurons (Figure 4) (219). Viral multiplication occurs in a small number of sensory neurons, and the viral genome then remains in a latent state for the life of the host. With periodic reactivation brought on by events such as physical or emotional stress, fever, ultraviolet light, and tissue damage, the virus is transported back down the axon to replicate again at or near the original point of entry into the body (Figure 4). Such reactivation can result in clinically apparent disease (lesions) or clinically inapparent (asymptomatic, or subclinical) infection. The mechanisms by which HSV establishes latency are being intensely investigated, but remain incompletely understood at this time.

Cutaneous HSV infection causes ballooning of infected epithelial cells, with nuclear degeneration and loss of intact cellular membranes. Infected epithelial cells either lyse or fuse to form multinucleated giant cells. With cell lysis, clear fluid containing large quantities of virus, cellular debris, and inflammatory cells accumulates between the epidermal and dermal layers. Multinucleated giant cells usually are present at the base of the vesicle. An intense inflammatory response extends from the base of the vesicle into the dermis. As the lesions heal, vesicular fluid becomes purulent as more inflammatory cells are recruited to the site of infection. Scab formation then follows. Scarring is uncommon. When infection involves mucous membranes, shallow ulcers are more common than vesicles because of rapid rupture of the very thin cornified epithelium present at mucosal sites. The histopathologic findings of mucosal lesions are similar to those of skin lesions.

Host immune responses to HSV infections in children and adults include nonspecific mechanisms such as interferons, neutrophils, complement, macrophages, and natural killer cells, as well as specific mechanisms including humoral (antibody) immunity, T cell-mediated immunity (such as cytotoxic T cells and T helper activity), and cytokine release. The relative importance of these various mechanisms is different for initial versus recurrent HSV disease. Animal studies suggest that activated macrophages, interferons, and, to a lesser extent, natural killer cells are important in limiting initial HSV infection, whereas humoral immunity and cell-mediated immunity are important in controlling both initial and recurrent infections. Adoptive transfer studies suggest that either virus-specific antibody or lymphocytes can protect animals against initial HSV infection (as discussed below), but several lines of evidence suggest that cell mediated immunity responses play the central role in controlling recurrent HSV infections (120, 169, 170,171, 217). Mucocutaneous herpes is more severe in patients with impaired or defective cell mediated immunity (171, 254), but not in patients with agammaglobulinemia.

Following acquisition of HSV-1 or HSV-2, IgM antibodies appear transiently and are followed by production of IgG and IgA antibodies which persist over time. Both neutralizing antibodies and antibody-dependent cellular cytotoxic (ADCC) antibodies generally appear between two weeks and six weeks following infection and persist for the lifetime of the host. The host response to virus-specific infected cell polypeptides and the development of neutralizing antibodies have been defined through immunoblot and immunoprecipitation assays (24, 68). Following infection, antibodies directed against gB, gC, gD, gE, gG1, gG2, and ICP-4 appear sequentially. Depending upon the time following infection, commercially available laboratory testing can detect both HSV-specific IgM and IgG. Of note, the intensity of host immune response to virus-specific polypeptides and the quantitative levels of neutralizing antibodies are not protective against recurrences.

Lymphocyte blastogenesis responses develop between two weeks and six weeks following infection (51, 223). With viral reactivation from latency and subsequent recurrence of infection, boosts in blastogenic responses can be noted promptly, and subsequently decrease over time. However, nonspecific blastogenic responses do not correlate with a history of recurrences.

The host responses of neonates with HSV disease differ from those of older children and adults. Infected neonates will produce HSV-specific IgM antibodies (as detected by immunofluorescence) within three weeks of acquisition of the viral infection. HSV-specific IgM concentrations increase rapidly during the first two to three months, and in some infants may be detectable for as long as one year following neonatal infection. The viral surface glycoproteins gB and gD are the most reactive immunodeterminants (223) and, indeed, account for the majority of neutralizing antibodies.

T-lymphocyte proliferative responses are delayed in babies with neonatal HSV disease as compared with older children and adults (223). At two to four weeks following onset of clinical symptoms, most neonates lack detectable T-lymphocyte responses to HSV (180, 223). These delayed responses may be associated with disease progression (223).

HSV-infected neonates also have decreased alpha-interferon production in response to HSV antigens as compared with adults suffering from primary HSV infection (223). Lymphocytes from infected babies also have diminished HSV antigen-stimulated lymphocyte proliferation and gamma-interferon production in the first three to six weeks after onset of infection (37).

 

SUSCEPTIBILITY IN VITRO AND IN VIVO

Acyclovir is most active in vitro against HSV, with activity against varicella-zoster virus (VZV) being about 10 fold less. Although Epstein-Barr virus (EBV) has only minimal TK activity, EBV DNA polymerase is susceptible to inhibition by acyclovir triphosphate and thus EBV is moderately susceptible to acyclovir in vitro. Activity against cytomegalovirus (CMV) is limited by CMV’s lack of a gene for TK; furthermore, CMV DNA polymerase is poorly inhibited by acyclovir triphosphate. As a prodrug of acyclovir, valaciclovir has the same in vitro and in vivo spectrum of susceptibilities as its parent drug, acyclovir.

Penciclovir’s (and thus famciclovir’s) spectrum of activity against herpesviruses is similar to that of acyclovir. In addition to HSV, penciclovir has demonstrable in vitro activity against VZV, EBV, and hepatitis B virus (HBV).

 

ANTIVIRAL THERAPY

Drug of Choice

Acyclovir

 Acyclovir remains the drug of choice for the management of HSV infections. It has been available for clinical use for over 2 decades and has demonstrated remarkable safety and efficacy against mild to severe infections caused by HSV and VZV in both normal and immunocompromised patients. Acyclovir is a deoxyguanosine analogue with an acyclic side chain that lacks the 3'- hydoxyl group of natural nucleosides (236). Following preferential uptake by infected cells, acyclovir is monophosphorylated by virus encoded TK; host cell TK is approximately 1 millionfold less capable of converting acyclovir to its monophosphate derivative. Subsequent diphosphorylation and triphosphorylation are catalyzed by host cell enzymes, resulting in acyclovir triphosphate concentrations that are 40 to 100 times higher in HSV-infected cells than in uninfected cells (69). Acyclovir triphosphate prevents viral DNA synthesis by inhibiting the viral DNA polymerase. In vitro, acyclovir triphosphate competes with deoxyguanosine triphosphate as a substrate for viral DNA polymerase. Because acyclovir triphosphate lacks the 3'-hydroxyl group required to elongate the DNA chain, the growing chain of DNA is terminated. In the presence of the deoxynucleoside triphosphate complementary to the next template position, the viral DNA polymerase is functionally inactivated (182). In addition, acyclovir triphosphate is a much better substrate for the viral polymerase than for cellular DNA polymerase α, resulting in little incorporation of acyclovir into cellular DNA.

The oral bioavailability of acyclovir is poor, with only 15-30% of the oral formulations being absorbed (173). Following a 200 mg dose, a peak concentration of about 0.5 µg/ml is attained at approximately 1.5 to 2.5 hours (236). Higher doses of acyclovir result in higher serum concentrations. Food does not substantially alter extent of absorption. After intravenous doses of 2.5 to 15 mg/kg, steady state concentrations of acyclovir range from 6.7 to 20.6 µg/ml. Acyclovir is widely distributed; high concentrations are attained in kidneys, lung, liver, heart, and skin vesicles; concentrations in the CSF are about 50% of those in the plasma (236). Acyclovir crosses the placenta and accumulates in breast milk. Protein binding ranges from 9% to 33% and less than 20% of drug is metabolized to biologically inactive metabolites.

In the absence of compromised renal function, the half life of acyclovir is 2 to 3 hours in older children and adults and 2.5 to 5 hours in neonates with normal creatinine clearance. More than 60% of administered drug is excreted in the urine (236). Elimination is prolonged in patients with renal dysfunction; the half life is approximately 20 hours in persons with end stage renal disease, necessitating dose modifications for those with creatinine clearance less than 50 ml/min/1.73 m2 (131). Acyclovir is effectively removed by hemodialysis but not by continuous ambulatory peritoneal dialysis (124).

Acyclovir is a safe drug which is generally very well tolerated. Oral acyclovir sometimes causes mild gastrointestinal upset, rash, and headache. If it extravasates, intravenous acyclovir can cause severe inflammation, phlebitis, and sometimes a vesicular eruption leading to cutaneous necrosis at the injection site. If given by rapid intravenous infusion or to poorly hydrated patients or those with pre existing renal compromise, intravenous acyclovir can cause reversible nephrotoxicity due to the formation of acyclovir crystals precipitating in renal tubules and causing an obstructive nephropathy. Administration of acyclovir by the intravenous route occasionally is associated with rash, sweating, nausea, headache, hematuria, and hypotension. High doses of intravenous acyclovir (60 mg/kg/day) in neonates and prolonged use of oral acyclovir following neonatal disease have been associated with neutropenia (108,113).

The most serious side effect of acyclovir is neurotoxicity, which usually occurs in subjects with compromised renal function who attain high serum concentrations of drug (186). Neurotoxicity is manifest as lethargy, confusion, hallucinations, tremors, myoclonus, seizures, extrapyramidal signs, and changes in state of consciousness, developing within the first few days of initiating therapy. These signs and symptoms usually resolve spontaneously within several days of discontinuing acyclovir.

Although acyclovir is mutagenic at high concentrations in some in vitro assays, it is not teratogenic in animals. Limited human data suggest that acyclovir use in pregnant women is not associated with congenital defects or other adverse pregnancy outcomes (220).

A limited number of adverse drug interactions with acyclovir have been reported. Subjects being treated with both zidovudine and acyclovir can develop severe somnolence and lethargy. The likelihood of renal toxicity is increased when acyclovir is administered with nephrotoxic drugs such as cyclosporine and amphotericin B. Concomitant administration of probenicid decreases renal clearance of acyclovir and prolongs its half life; conversely, acyclovir can decrease the clearance of drugs such as methotrexate that are eliminated by active renal secretion.

Alternative Therapy

Valaciclovir

 Valaciclovir is the L valyl ester of acyclovir that is rapidly converted to acyclovir after oral administration by first-pass metabolism in the liver (98). Licensed in 1995, it has a safety and efficacy profile similar to which of acyclovir but offers potential pharmacokinetic advantages.

As a prodrug of acyclovir, valaciclovir has the same mechanism of action, antiviral spectrum, and resistance profiles as those of its parent drug, acyclovir. Following oral administration of valaciclovir, rapid and complete conversion to acyclovir occurs with first pass intestinal and hepatic metabolism. The bioavailability of valaciclovir exceeds 50%, which is three to five times greater than that of acyclovir (207). Peak serum concentrations, attained about 1.5 hours after a dose, are proportional to the amount of drug administered; they range from 0.8 to 8.5 µg/ml for doses of 100 to 2,000 mg (245). The area under the drug concentration time curve approximates that seen after intravenous acyclovir. All other pharmacokinetic characteristics are similar to those of acyclovir (158).

The profiles of adverse effects and potential drug interactions observed with valaciclovir therapy are the same as those observed with acyclovir treatment. Neurotoxicity has not been reported in humans to date, although it has been observed in animal models (98). Manifestations resembling thrombotic microangiopathy have been described in patients with advanced HIV disease receiving very high doses of valaciclovir (8 grams per day), but the multitude of other medications being administered to such patients makes the establishment of a causal relationship to valaciclovir difficult (19). Although causation has not been established, use of valaciclovir at such high doses should involve evaluation of potential risks and benefits.

With decreasing creatinine clearance, the dosing interval should be spread. With significant renal impairment, the dose should also be reduced in half. Acyclovir is removed during hemodialysis, and therefore an extra dose of valaciclovir should be administered following completion of hemodialysis. Supplemental doses of valaciclovir are not required following chronic ambulatory peritoneal dialysis (CAPD) and continuous arteriovenous hemofiltration/dialysis (CAVHD).

Famciclovir

 Famciclovir is the inactive diacetyl ester prodrug of penciclovir, an acyclic nucleoside analogue. Following oral ingestion and systemic absorption, famciclovir is rapidly deacetylated and oxidized to form the active parent drug penciclovir.

In cells which are infected with HSV, the viral TK phosphorylates penciclovir to its monophosphate derivative, which in turn is converted to the active penciclovir triphosphate by cellular kinases. Penciclovir triphosphate inhibits viral DNA polymerase by competing with deoxyguanosine triphosphate for incorporation into the growing DNA strand. While penciclovir triphosphate is neither an obligate DNA chain terminator nor an inactivator of the DNA polymerase, once incorporated penciclovir triphosphate does retard the rate of subsequent nucleotide incorporation. Penciclovir is approximately 100 fold less potent than acyclovir in inhibiting herpesvirus DNA polymerase activity. By virtue of its high intracellular concentrations and long intracellular half-life (7 to 20 hours), though, it remains an effective antiviral agent.

The bioavailability of penciclovir following oral administration of famciclovir is about 70%. Peak concentrations of drug after intravenous administration of 10 mg/kg are approximately six-fold higher than those attained after oral doses of 250 mg. Food delays absorption but does not affect the final plasma drug concentration. Following oral administration, little or no famciclovir is detected in plasma or urine. The plasma half life of penciclovir is about 2.5 hours, and almost three quarters is recovered unchanged in the urine. Measurable penciclovir concentrations are not detectable in plasma or urine following topical administration of penciclovir cream. A 12 hour dosing interval is recommended for those with creatinine clearances between 30 and 50 ml/min/1.73m2, and a 24 hour interval for those with creatinine clearances less than 30 ml/min/1.73m2 (25).

Famciclovir is as well tolerated as acyclovir. Complaints of nausea, diarrhea, and headache occurred in clinical trials, but at frequencies similar to those reported by placebo recipients. No clinically significant drug interactions have been reported to date, although concentrations of famciclovir among volunteers increase by about 20% in patients receiving concomitant cimetidine or theophylline administration. Dose reduction of famciclovir is recommended for patients with compromised renal function. A 12 hour dosing interval is recommended for persons with creatinine clearances between 30 and 50 ml/min/1.73m2, and a 24 hour interval for those with creatinine clearances less than 30 ml/min/1.73m2 (25). 
Abudalu M, et al. Single-day, Patient-Initiated Famciclovir Therapy Versus 3-Day Valacyclovir Regimen for Recurrent Genital Herpes: A Randomized, Double-Blind, Comparative Trial. Clin Infect Dis. 2008 Sep 1;47:651-8.

Resistance to Antiviral Agents Used for Treatment and Prevention of HSV

Resistance of HSV to acyclovir has become an important clinical problem, especially among immunocompromised patients exposed to long-term therapy (71). Viral resistance to acyclovir usually results from mutations in the viral TK gene although mutations in the viral DNA polymerase gene also occur rarely. Although these acyclovir resistant isolates exhibit diminished virulence in animal models, among HIV infected patients they can cause severe, progressive, debilitating mucosal disease and (rarely) visceral dissemination (80). Acyclovir resistant strains of HSV also have been recovered from cancer chemotherapy patients, bone marrow and solid organ transplant recipients, children with congenital immunodeficiency syndromes, and neonates (108, 134, 164, 166, 176). Although it is uncommon, genital herpes caused by acyclovir resistant isolates has also been reported in immunocompetent hosts who usually have received chronic acyclovir therapy (122, 156).

Because penciclovir, like acyclovir, must be activated by the viral encoded TK enzyme, TK deficient viral strains are resistant to both acyclovir and penciclovir. Strains of HSV whose resistance to acyclovir is conferred by alteration of the TK enzyme or by DNA polymerase mutations may remain sensitive to penciclovir (110).

Special/Specific Infections

Orolabial Herpes 

Treatment of primary gingivostomatitis in pediatric patients using oral acyclovir decreases time to cessation of symptoms by 30-50%, and time to lesion healing by 20-25% (6). Compared with patients receiving placebo, subjects treated with oral acyclovir at 600 mg/m2/dose administered four times per day for 10 days (Table 7) experienced cessation of drooling in 4 days (vs. 8 days in placebo recipients) and resolution of gum swelling in 5 days (vs. 7 days in placebo recipients). Intraoral lesions in acyclovir recipients healed at 6 days (vs. 8 days in placebo recipients), and extraoral lesions healed in 7 days (vs. 9 days in placebo recipients) (6).

Oral acyclovir has a more modest effect in the treatment of recurrent herpes labialis (178, 179), and treatment of these patients should be individualized (Table 7) (114). In general, therapeutic benefit is enhanced if treatment is initiated as soon as possible after onset of symptoms, preferably within 24 to 48 hours of onset of the recurrence. Among patients who start treatment in the prodrome or erythema lesion stage, acyclovir therapy (400 mg five times a day for five days) reduces the duration of pain by approximately one-third, and the healing time to loss of crust by approximately one-fourth (215). Topical acyclovir cream may also modestly decrease the duration of a clinical recurrence of herpes labialis by approximately half a day (approximately four and a half days for topical acyclovir recipients, compared with approximately five days for placebo recipients) (213), although benefit of topical acyclovir is not conferred by acyclovir ointment, which has a polyethylene glycol base (201, 209).

Prophylactic acyclovir also has been used to prevent reactivation of herpes labialis following exposure to ultraviolet radiation, facial surgery, or exposure to sun and wind while skiing (84, 210, 211). Topical acyclovir cream also is effective in preventing recurrent herpes labialis in skiers (177) and in persons with a history of frequent recurrences of herpes labialis (82). Long-term suppressive therapy reduces the number of recurrences of oral infection in those with histories of frequent recurrences (189). In one study of 400 mg of oral acyclovir administered twice daily for four months, clinical recurrences were reduced by more than half, and culture-confirmed recurrences were reduced by more than two-thirds (189).

Topical penciclovir (Denavir) for the treatment of recurrent herpes labialis reduces time to healing and duration of pain by about half a day (26). Topical penciclovir cream decreases the time to lesion healing by approximately one to two days when compared with placebo (26, 214), and is equally effective as topical acyclovir cream (137). Additional benefit is noted in a reduction in lesion area; faster loss of lesion-associated symptoms; and reductions in daily assessments of pain, itching, burning, and tenderness (26). Faster healing and pain resolution occurs both among patients who first apply penciclovir cream in the prodrome and erythema stages and among those who start treatment in the papule and vesicle lesion stages (214). Application of medicine should begin as early as possible, preferably during the prodromal phase, and should be continued every two hours during waking hours for four days (Table 7).

Valaciclovir administered at high doses for short periods of time (2 grams orally twice a day for 1 day) reduces the time to lesion healing and time to cessation of pain and/or discomfort compared to placebo, with the overall duration of the episode being decreased by approximately one day (Table 7) (212). However, early valaciclovir treatment does not appear to increase the likelihood that a clinical recurrence will be aborted prior to cold sore lesion development (42, 212). Valaciclovir administered as a 500 mg dose once daily is effective in suppressing recurrences of herpes labialis, with almost two-thirds of treated patients remaining recurrence-free during four months of suppressive therapy compared with approximately one-third of placebo recipients (14, 15).

Genital Herpes

For the treatment of first episode genital herpes, the dose of oral acyclovir is 200 mg orally five times per day, or 400 mg orally three times per day (Table 8). Neither higher doses of oral acyclovir nor the addition of topical acyclovir provide added benefit (237). Duration of therapy in first episode disease is 7-10 days (5). Acyclovir therapy for the treatment of first episode genital herpes reduces the duration of viral shedding by about a week, time to healing of lesions by approximately four days, and time to complete resolution of signs and symptoms by approximately two days (36, 146).

For the episodic treatment of recurrent genital herpes, dosing options for acyclovir include 200 mg orally five times per day, or 800 mg orally two times per day, administered for five days (5) (Table 8). Topical acyclovir provides no clinical benefit in the episodic management of recurrences and is not recommended (50, 140). A recent study indicates that two days of oral acyclovir therapy (800 mg three times per day) is also efficacious in the episodic treatment of genital HSV recurrences (238). When started within 24 hours of the onset of a genital herpes recurrence, oral acyclovir reduces the duration of viral shedding by approximately two days, time to healing by just over a day, and time to complete resolution of signs and symptoms by approximately a day (230). Episodic treatment does not reduce the length of time to subsequent recurrence (163, 184, 193).

In addition to the treatment of an active genital herpes infection, acyclovir has been effectively used to prevent recurrences of genital herpes. The most frequent indication for suppressive acyclovir therapy is in patients with frequently recurrent genital infections, in whom chronic suppressive acyclovir therapy reduces the frequency of recurrences by approximately 75% (66, 147, 148, 151, 221). One quarter to one third of patients on suppressive therapy experience no further recurrences while taking acyclovir. Daily administration of acyclovir maintains a high degree of efficacy and little toxicity, even after more than 5 years of continuous suppressive therapy (85). Suppressive therapy reduces the frequency of asymptomatic shedding of HSV in the genital tract by more than 80% (239, 242). The acyclovir dose when used as suppressive therapy is 400 mg administered twice daily (Table 8).

In the episodic treatment of genital herpes, famciclovir reduces time to healing, time to cessation of viral shedding, and durations of lesion edema, vesicles, ulcers, and crusts when compared with placebo (194). Times to cessation of all symptoms and of moderate to severe lesion tenderness, pain, and burning are also reduced (194). For suppression of genital HSV recurrences, famciclovir delays the time to the first recurrence of genital herpes when compared with placebo (63, 149). For the episodic treatment of recurrent genital HSV disease, the dosage of famciclovir is 125 mg twice daily, administered for 5 days (Table 8). The recommended dose for suppression of genital HSV is 250 mg twice daily for up to one year (Table 8). Note that the lack of harmonization of treatment regimens resulted from different doses of famciclovir being studied in the clinical trials; this produced the unusual dosage recommendation of decreasing the suppression dose to treat a genital HSV recurrence. The safety and efficacy of famciclovir therapy beyond one year of treatment have not been established.

 Valaciclovir treatment of first-episode genital HSV is as effective as acyclovir therapy, while at the same time providing a more favorable dosing schedule compared with acyclovir (74). In the treatment of recurrent genital HSV, valaciclovir decreases the duration of lesions, the duration of pain, and the duration of viral shedding when compared to placebo (216). Valaciclovir also is as effective as acyclovir for the episodic treatment of recurrent genital HSV, again providing a more favorable dosing schedule compared with acyclovir (230). It should be administered for three to five days when administered as episodic treatment (5, 133). Valaciclovir is also effective in suppressing recurrences of genital HSV when administered as once-daily suppressive therapy (185). Adult treatment doses for HSV-1 and HSV-2 infections (Table 8) are: 1) 1 gram orally twice daily for 7-10 days for first episode genital herpes; 2) 500 mg orally twice daily for 3-5 days for episodic treatment of recurrent genital HSV disease; and 3) 1 gram orally once daily for suppression of recurrent genital HSV. Suppression of recurrent oral herpes infections also has been accomplished with single daily doses of 500 mg.

Herpetic Whitlow

Herpetic whitlow is a self-limited infection.  Oral acyclovir has been useful in selected patients including HIV patients with extensive involvement.  Surgery is not indicated.

Neonatal Herpes

For neonatal HSV disease, intravenous acyclovir at 60 mg/kg/day delivered in three divided daily doses is currently recommended (Table 7) (3, 112). The dosing interval of intravenous acyclovir may need to be increased in premature infants, based upon their creatinine clearance (70). Duration of therapy is 21 days for patients with disseminated or CNS neonatal HSV disease, and 14 days for patients with HSV infection limited to the SEM (3). The primary apparent toxicity associated with the use of this dose of intravenous acyclovir is neutropenia, with approximately one-fifth of patients with localized HSV disease (CNS or SEM) developing an absolute neutrophil count (ANC) of <1,000/µL (112). Although the neutropenia resolves either during continuation of intravenous acyclovir or following its cessation, it is prudent to monitor neutrophil counts at least twice weekly throughout the course of intravenous acyclovir therapy, with consideration being given to decreasing the dose of acyclovir or administering granulocyte colony stimulating factor (GCSF) if the absolute neutrophil count (ANC) remains below 500/µL for a prolonged period of time (112). All patients with CNS HSV involvement should have a repeat lumbar puncture at the end of intravenous acyclovir therapy to determine that the specimen is PCR-negative in a reliable laboratory, and to document the end-of-therapy CSF indices (113). Those persons who remain PCR-positive should continue to receive intravenous antiviral therapy until PCR-negativity is achieved (111, 113).

Herpes Simplex Encephalitis

For herpes simplex encephalitis, intravenous acyclovir should be administered at 30 mg/kg/day for 14-21 days for the treatment of HSE (Table 7) (251). Some experts recommend higher dosages of intravenous acyclovir be considered (45 mg/kg/day), although neurotoxicity can be a limiting factor in increasing the dose in larger children and adults. A randomized, controlled trial of long-term suppressive oral valaciclovir therapy following the treatment of the acute HSE disease is currently being conducted by the National Institute of Allergy and Infectious Diseases (NIAID) Collaborative Antiviral Study Group. This study will determine whether subclinical reactivation of HSV within the brain contributes to the neurologic impairment experienced by many HSE survivors. At the current time, however, no evidence exists to suggest that suppressive oral valaciclovir therapy is beneficial in preventing neurologic complications.

HSV keratitis or keratoconjunctivitis

Topical therapy with acyclovir for HSV ocular infections is effective, but probably not superior to trifluridine (Table 7) (94). Long-term suppressive therapy reduces the number of recurrences of ocular infection in those with histories of frequent recurrences (90, 91).

Underlying Diseases

HSV Disease in the Immunocompromised Host

 Acyclovir also is indicated for the treatment of disseminated HSV infections in otherwise normal hosts, including pregnant women, and mucocutaneous HSV infections in immunocompromised hosts (114). Similarly, HSV infections of the lip, mouth, skin, perianal area, or genitals may be much more severe in immunocompromised patients than in normal hosts, with HSV lesions tending to be more invasive, slower to heal, and associated with prolonged viral shedding. Intravenous acyclovir therapy is very beneficial in such patients (Table 7) (235). Immunocompromised patients receiving acyclovir have a shorter duration of viral shedding and more rapid healing of lesions than patients receiving placebo (150). Oral acyclovir therapy is also very effective in immunocompromised patients (203).

Acyclovir prophylaxis of HSV infections is of clinical value in severely immunocompromised patients, especially those undergoing induction chemotherapy or transplantation. Intravenous or oral administration of acyclovir reduces the incidence of symptomatic HSV infection from about 70% to 5-20% (195). A sequential regimen of intravenous acyclovir followed by oral acyclovir for 3 to 6 months can virtually eliminate symptomatic HSV infections in organ transplant recipients. A variety of oral dosing regimens, ranging from 200 mg 3 times daily to 800 mg twice daily, have been used successfully.

Alternative Therapy

Combinations of Antiviral Agents

Unlike antiviral management of HIV infections, combination antiviral therapy is not employed in the antiviral treatment of HSV infections. Empiric changes in classes of antiviral agents are sometimes made based upon the clinician’s judgment that a resistant virus could be present.

Passive Immunotherapy with Polyclonal Antibodies

As noted above, cell mediated immune responses likely play the central role in controlling recurrent HSV infections (120, 169, 170, 171, 217). While there is some degree of cross-protection conferred by pre-existing HSV-1 antibody on the acquisition of HSV-2 infection (32, 55, 67, 75, 81, 100, 145, 160, 190), the protection is incomplete. Similarly, vaccines have been developed which generate robust humoral responses yet fail to protect against HSV-2 infection (217). As such, it is difficult to envision a circumstance whereby passive antibody immunotherapy will play a role in the management of genital HSV infection and disease.

In contrast to genital disease, the protection against infection and amelioration of disease severity afforded by neutralizing and ADCC antibodies in neonatal HSV may portend a future role for passive immunotherapy in conjunction with antiviral treatment. Both human and humanized antibodies directed against gB and gD have been shown to be beneficial as prophylactic and therapeutic agents in animal models of HSV infection (17, 31, 106, 127). In humans, both maternal antibody status (35, 174, 264, 265) and type of maternal infection (primary vs. recurrent) (33, 34, 35, 52, 159) influence transmission of HSV from mother to baby. Neonates with higher neutralizing antibody titers are less likely to become infected with HSV following perinatal exposure of passage through an infected birth canal (174), illustrating the protective effects of preexisting antibody in preventing neonatal HSV disease. Among HSV-infected neonates, anti-HSV neutralizing antibody titers have been shown to correlate with the extent of the disease (223), with babies with higher neutralizing antibody titers being more likely to have localized disease (and less likely to have disseminated disease) once they are infected. Similarly, high maternal or neonatal anti-HSV ADCC antibody levels or high neonatal antiviral neutralizing levels are each independently associated with an absence of disseminated HSV infection (121).

While antibody therapy offers promise for improving neonatal HSV disease prevention and outcome, studies in humans have yet to be performed. In addition, an HSV hyperimmune globulin preparation does not exist, and the amount of anti-HSV antibodies present in conventional intravenous gammaglobulin (IVIG) preparations is low and variable, such that unacceptable large volumes would need to be injected to potentially confer protective immunity. For these reasons, use of IVIG in the management of neonates with HSV disease cannot be recommended at this time. Any development of a monoclonal antibody against HSV would of course require extensive testing in humans before therapeutic recommendations could be made.

ADJUNCTIVE THERAPY AND OTHER ISSUES

Despite the advances in our understanding of genital herpes, considerable shame, embarrassment, and stigma remain among infected persons (2). For many patients, the psychological impact is far more severe than the physical consequences of the disease (39). Shock, anger, guilt, low self-esteem, fear of transmission of the infection to others, and impaired sexual function are common and can interfere substantially with relationships (2). Anecdotal experience suggests that the diagnosis of neonatal herpes has a similar negative impact on the parents' relationship, with guilt and anger over the baby's illness and its association with genital herpes often leading to separation and divorce. A listing of helpful resources which provide reliable herpes information can be found in Table 9.

ENDPOINTS FOR MONITORING THERAPY

HSE

Persistence of viral DNA in the CSF as detected by PCR occurs in virtually all cases of HSE through the first week following initiation of antiviral therapy (128, 175, 187). During the second week of therapy, HSV DNA is detected in the CSF of approximately half of the patients, and 20% or fewer of patients have a positive PCR result beyond day 15 of antiviral therapy (128, 187). An end-of-therapy lumbar puncture should be performed to document that the CSF has become PCR-negative prior to stopping parenteral antiviral therapy. PCR analysis of sequential CSF specimens will also improve monitoring of viral reactivation during relapses following completion of antiviral therapy (59, 77, 87, 97, 108, 142).

Quantitative PCR may also have a role in monitoring response to therapy (261), although evaluation for this purpose has been limited to date (57). While at least one investigation failed to correlate amount of virus present with severity of outcome (187), other studies have found a relation between HSV viral load in the CSF and likelihood of future neurologic impairment (64). Specifically, HSV DNA concentrations of greater than 100 copies/µL CSF correlate both with reduced level of consciousness at presentation and with likelihood of future neurologic impairment (64).

Neonatal HSV

The available data for neonatal HSV suggest that having HSV DNA detected in CSF at or after completion of intravenous therapy is associated with poor outcomes (111, 141). As such, all patients with CNS HSV involvement should have a repeat lumbar puncture at the end of intravenous acyclovir therapy to determine that the specimen is PCR-negative in a reliable laboratory, and to document the end-of-therapy CSF indices (113). Those persons who remain PCR-positive should continue to receive intravenous antiviral therapy until PCR-negativity is achieved.

VACCINES 

Numerous attempts to develop a vaccine to prevent HSV disease or infection have failed over the past several decades. However, a candidate HSV-2 glycoprotein D subunit vaccine adjuvanted with alum combined with 3-deacylated monophosphoryl lipid A (MPL) has recently demonstrated promising results. In two large Phase III studies, the vaccine has been demonstrated to be safe and, in a subset of volunteers, effective in preventing HSV-1 or -2 genital herpes disease (vaccine efficacy ~ 75%) and HSV-2 infection (vaccine efficacy ~ 40%) (218). In both studies, efficacy was limited to women who were HSV-1 and -2 seronegative prior to vaccination, with no evidence of vaccine efficacy in men or in women who were HSV 1+/2- prior to vaccination. Because these earlier trials were neither designed nor powered to assess efficacy in HSV 1-/2- women, another Phase III trial by GlaxoSmithKline (GSK) and NIAID is currently enrolling subjects.

PREVENTION 

Cesarean Delivery

Cesarean delivery in a woman with active genital lesions can reduce the infant's risk of acquiring HSV (35, 159). To prevent neonatal HSV disease, cesarean section should be performed if genital HSV lesions or prodromal symptoms are present at the time of delivery. As a method to reduce the incidence of neonatal HSV disease, however, cesarean delivery has a number of drawbacks, including the fact that 60-80% of babies who develop neonatal HSV disease are born to women without a history of genital herpes (253, 258, 264), and thus will not be prevented with this approach. Furthermore, neonatal infections have occurred in spite of cesarean delivery performed prior to the rupture of membranes (168, 253).

Antiviral Suppression of Seropositive Partner in Discordant Relationship

In a recent report, suppressive therapy with valaciclovir 500 mg once daily for 8 months decreased the rate of symptomatic HSV infection in the seronegative partner by 75 percent, and reduced the likelihood of acquisition of genital HSV-2 infection (symptomatic or asymptomatic) by 48 percent (53). However, risk of transmission was not completely eliminated.

Condoms

A recent study of 528 monogamous couples discordant for HSV-2 infection found that when condoms were used during more than 70 percent of sexual encounters between an HSV-2-positive man and an HSV-2-negative woman, transmission was reduced by more than 60 percent (241). The means by which to achieve more consistent condom use by discordant couples, however, remains to be determined.

Antiviral Prophylaxis During Pregnancy

Because of acyclovir’s safety record in pregnancy (220), along with a desire to decrease neonatal HSV disease and reduce cesarean deliveries performed for the indication of herpes, utilization of oral acyclovir near the end of pregnancy to suppress genital HSV recurrences has become increasingly common in clinical practice. Several small studies suggest that suppressive acyclovir therapy during the last weeks of pregnancy decreases the occurrence of clinically apparent genital HSV disease at the time of delivery (29, 199, 200), with an associated decrease in cesarean section rates for the indication of genital HSV (29, 200). However, because viral shedding still occurs (albeit with reduced frequency) (199, 244), the potential for neonatal infection likely is not completely avoided. Additional studies are needed to more definitively establish the safety and effectiveness of late pregnancy maternal HSV suppressive therapy, including the potential for neutropenia in neonates born to women receiving antiviral suppressive therapy (108, 109, 202). Data currently do not support the routine utilization of suppressive oral acyclovir or valaciclovir in gravid women with a history of recurrent genital herpes (115).

 

INFECTION CONTROL

Persons with active mucocutaneous herpetic lesions should be managed with contact precautions. If lesions are localized to one area, standard precautions may suffice. Persons with HSV infection of the central nervous system who do not have lesions should be managed with standard precautions.

COMMENTS AND CAVEATS

Perhaps the most prominent challenge impacting clinical benefit of acyclovir therapy relates to the timing of drug initiation following onset of disease symptoms. In the case of life-threatening HSV disease such as HSE or neonatal HSV, consideration of HSV as a possible cause of the illness is needed in order to then initiate acyclovir therapy. In the case of less severe but still consequential infections, such as primary genital herpes, the patient must present to medical attention, be correctly diagnosed, and then started on antiviral therapy as quickly as possible to achieve maximal benefit. Despite the tremendous advances in diagnostics and therapeutics employed in the management of HSV disease, nothing as yet usurps the judgment of the clinician as he or she cares for their patient. For example, false negative (and false positive) CSF PCR results are well documented in the literature. If the physician’s clinical suspicion is that HSV disease of the CNS is likely, the management course should not be diverted solely upon the basis of one negative HSV CSF PCR result. While the technologic achievement represented by PCR is phenomenal, the art of medicine must always prevail over simply the science of medicine.

Over the next decade, continued advances in the development of molecular techniques for the detection of HSV DNA in CSF and perhaps the genital tract will occur. The predominant areas where advances will occur are in decreasing the time required to run the test, increasing the numbers of viruses detected in a single test, developing and applying quantitative assays to detect viral load, and standardizing systems to ensure their reproducibility from clinical laboratory to clinical laboratory. Examples of multiple viruses detected in a single test include herpesvirus consensus PCR (28, 152) and multiplex nested-PCR (79). Quantitative PCR from CSF (1) will allow for monitoring of the therapeutic response to antiviral treatment as experience with interpreting test results increases. Real-time PCR provides advantages of speed and quantitativeness compared with conventional PCR (104), while at the same time reducing the likelihood of contamination because no post-amplification analysis using amplified products is required (104). Examples of new systems capable of yielding reproducible results from lab to lab include LightCycler, with real-time detection of PCR products by fluorescence resonance energy transfer assay (72) and the capability of simultaneous detection and typing of HSV (38), as well as time-resolved fluorometry (95).

An area in which development of new technology could significantly impact neonatal HSV is that of identifying mothers at the time of delivery who are actively shedding HSV from the genital tract. Development of a bedside nucleic acid detection kit for real-time detection of HSV DNA in the maternal genital tract at the time of delivery, as has been explored for the detection of group B Streptococcus colonization (23), could lead to management algorithms designed to minimize neonatal exposure to the virus, thereby preventing neonatal infection in the first place. Such technological advances should be encouraged.

REFERENCES

1. Aberle SW, Puchhammer-Stockl E. Diagnosis of herpesvirus infections of the central nervous system. J Clin Virol. 2002;25:S79-S85.[PubMed]

2. Alexander L, Naisbett B. Patient and physician partnerships in managing genital herpes. J Infect Dis. 2002;186:S57-65. [PubMed]

3. American Academy of Pediatrics. Herpes simplex. In: Pickering LK, ed. 2003 Red Book: Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2003:344-353. [PubMed]

4. Anderson NE, Powell KF, Croxson MC. A polymerase chain reaction assay of cerebrospinal fluid in patients with suspected herpes simplex encephalitis. J Neurol Neurosurg Psychiatry. 1993;56:520-5. [PubMed]

5. Anonymous. Sexually Transmitted Diseases Treatment Guidelines 2002. MMWR Morb Mortal Wkly Rep. 2002;51, RR-6:12-17.[PubMed]

6. Aoki FY, Law BJ, Hammond GW, Cheang M, Boucher FD, Fast M, Sitar DS, Embree J, Williams T, The Acyclovir-Gingivostomatitis Research Group. Acyclovir (ACV) suspension for treatment of acute herpes simplex virus (HSV) gingivostomatitis in children: a placebo(PL) controlled, double blind trial., 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, LA, October 17-20, 1993, 1993.[PubMed]

7. Arvin AM, Yeager AS, Bruhn FW, Grossman M. Neonatal herpes simplex infection in the absence of mucocutaneous lesions. J Pediatr. 1982;100:715-21.[PubMed]

8. Ashley RL. Sorting out the new HSV type specific antibody tests. Sex Transm Infect. 2001;77:232-7.[PubMed]

9. Ashley RL, Eagleton M. Evaluation of a novel point of care test for antibodies to herpes simplex virus type 2. Sex Transm Infect. 1998;74:228-9. [PubMed]

10. Ashley RL, Wald A. Genital herpes: review of the epidemic and potential use of type-specific serology. Clin Microbiol Rev. 1999;12:1-8.[PubMed]

11. Ashley RL, Wald A, Eagleton M. Premarket evaluation of the POCkit HSV-2 type-specific serologic test in culture-documented cases of genital herpes simplex virus type 2. Sex Transm Dis. 2000;27:266-9.[PubMed]

12. Aurelius E, Johansson B, Skoldenberg B, Forsgren M. Encephalitis in immunocompetent patients due to herpes simplex virus type 1 or 2 as determined by type-specific polymerase chain reaction and antibody assays of cerebrospinal fluid. J Med Virol. 1993;39:179-86.[PubMed]

13. Aurelius E, Johansson B, Skoldenberg B, Staland A, Forsgren M. Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid. Lancet. 1991;337:189-92. [PubMed]

14. Baker D, Eisen D. Valacyclovir for prevention of recurrent herpes labialis: 2 double-blind, placebo-controlled studies. Cutis. 2003;71:239-42.[PubMed]

15. Baker DA, Deeter RG, Redder K, Phillips JA. Valacyclovir effective for suppression of recurrent HSV-1 herpes labialis, 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, September 17-20, 2000, 2000.[PubMed]

16. Barbi M, Binda S, Primache V, Tettamanti A, Negri C, Brambilla C. Use of Guthrie cards for the early diagnosis of neonatal herpes simplex virus disease. Pediatr Infect Dis J. 1998;17:251-2. [PubMed]

17. Baron S, Worthington MG, Williams J, Gaines JW. Postexposure serum prophylaxis of neonatal herpes simplex virus infection of mice. Nature. 1976;261:505-6. [PubMed]

18. Barton IG, Kinghorn GR, Najem S, Al-Omar LS, Potter CW. Incidence of herpes simplex virus types 1 and 2 isolated in patients with herpes genitalis in Sheffield. Br J Vener Dis. 1982;58:44-7.[PubMed]

19. Bell WR, Chulay JD, Feinberg JE. Manifestations resembling thrombotic microangiopathy in patients with advanced human immunodeficiency virus (HIV) disease in a cytomegalovirus prophylaxis trial (ACTG 204). Medicine. 1997;76:369-80.[PubMed]

20. Benedetti J, Corey L, Ashley R. Recurrence rates in genital herpes after symptomatic first-episode infection. Ann Intern Med. 1994;121:847-54.[PubMed]

21. Benedetti JK, Zeh J, Corey L. Clinical reactivation of genital herpes simplex virus infection decreases in frequency over time. Ann Intern Med. 1999;131:14-20. [PubMed]

22. Berger JR. Benign aseptic (Mollaret's) meningitis after genital herpes. Lancet. 1991;337:1360-1. [PubMed]

23. Bergeron MG, Ke D, Menard C, Picard FJ, Gagnon M, Bernier M, Ouellette M, Roy PH, Marcoux S, Fraser WD. Rapid detection of group B streptococci in pregnant women at delivery. N Engl J Med. 2000;343:175-9.[PubMed]

24. Bernstein DI, Garratty E, Lovett MA, Bryson YJ. Comparison of Western Blot Analysis to microneutralization for the detection of type-specific herpes simplex virus antibodies. J Med Virol. 1985;15:223-30.[PubMed]

25. Boike SC, Pue MA, Freed MI, Audet PR, Fairless A, Ilson BE, Zariffa N, Jorkasky DK. Pharmacokinetics of famciclovir in subjects with varying degrees of renal impairment. Clin Pharmacol Ther. 1994;55:418-26.[PubMed]

26. Boon R, Goodman JJ, Martinez J, Marks GL, Gamble M, Welch C. Penciclovir cream for the treatment of sunlight-induced herpes simplex labialis: a randomized, double-blind, placebo-controlled trial. Penciclovir Cream Herpes Labialis Study Group. Clin Ther. 2000;22:76-90.[PubMed]

27. Boucher FD, Yasukawa LL, Bronzan RN, Hensleigh PA, Arvin AM, Prober CG. A prospective evaluation of primary genital herpes simplex virus type 2 infections acquired during pregnancy. Pediatr Infect Dis J. 1990;9:499-504.[PubMed]

28. Bouquillon C, Dewilde A, Andreoletti L, Lambert V, Chieux V, Gerard Y, Lion G, Bocket L, Wattre P. Simultaneous detection of 6 human herpesviruses in cerebrospinal fluid and aqueous fluid by a single PCR using stair primers. J Med Virol. 2000;62:349-53.[PubMed]

29. Braig S, Luton D, Sibony O, Edlinger C, Boissinot C, Blot P, Oury JF. Acyclovir prophylaxis in late pregnancy prevents recurrent genital herpes and viral shedding. Eur J Obstet Gynecol Reprod Biol. 2001;96:55-8.[PubMed]

30. Brass A. The CIBA Collection of Medical Illustrations. Illustrated by FH Netter. West Caldwell, NJ: Ciba Pharmaceutical Co., 2001.[PubMed]

31. Bravo FJ, Bourne N, Harrison CJ, Mani C, Stanberry LR, Myers MG, Bernstein DI. Effect of antibody alone and combined with acyclovir on neonatal herpes simplex virus infection in guinea pigs. J Infect Dis. 1996;173:1-6. [PubMed]

32. Breinig MK, Kingsley LA, Armstrong JA, Freeman DJ, Ho M. Epidemiology of genital herpes in Pittsburgh: serologic, sexual, and racial correlates of apparent and inapparent herpes simplex infections. J Infect Dis. 1990;162:299-305.[PubMed]

33. Brown ZA, Benedetti J, Ashley R, Burchett S, Selke S, Berry S, Vontver LA, Corey L. Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor. N Engl J Med. 1991;324:1247-52. [PubMed]

34. Brown ZA, Vontver LA, Benedetti J, Critchlow CW, Sells CJ, Berry S, Corey L. Effects on infants of a first episode of genital herpes during pregnancy. N Engl J Med. 1987;317:1246-51. [PubMed]

35. Brown ZA, Wald A, Morrow RA, Selke S, Zeh J, Corey L. Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA. 2003;289:203-9.[PubMed]

36. Bryson YJ, Dillon M, Lovett M, Acuna G, Taylor S, Cherry JD, Johnson BL, Wiesmeier E, Growdon W, Creagh-Kirk T, Keeney R. Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir. A randomized double-blind controlled trial in normal subjects. N Engl J Med. 1983;308:916-21. [PubMed]

37. Burchett SK, Corey L, Mohan KM, Westall J, Ashley R, Wilson CB. Diminished interferon-gamma and lymphocyte proliferation in neonatal and postpartum primary herpes simplex virus infection. J Infect Dis. 1992;165:813-8.[PubMed]

38. Burrows J, Nitsche A, Bayly B, Walker E, Higgins G, Kok T. Detection and subtyping of Herpes simplex virus in clinical samples by LightCycler PCR, enzyme immunoassay and cell culture. BMC Microbiology. 2002;2:12. [PubMed]

39. Carney O, Ross E, Bunker C, Ikkos G, Mindel A. A prospective study of the psychological impact on patients with a first episode of genital herpes. Genitourin Med. 1994;70:40-5.[PubMed]

40. Chataway J, Davies NW, Farmer S, Howard RS, Thompson EJ, Ward KN. Herpes simplex encephalitis: an audit of the use of laboratory diagnostic tests. QJM. 2004;97:325-30.[PubMed]

41. Cheong WK, Thirumoorthy T, Doraisingham S, Ling AE. Clinical and laboratory study of first episode genital herpes in Singapore. Int J STD AIDS. 1990;1:195-8. [PubMed]

42. Chosidow O, Drouault Y, Garraffo R, Veyssier P; Valaciclovir Herpes Facialis Study Group. Valaciclovir as a single dose during prodrome of herpes facialis: a pilot randomized double-blind clinical trial. British Journal of Dermatology. 2003;148:142-6. [PubMed]

43. Cohen BA, Rowley AH, Long CM. Herpes simplex type 2 in a patient with Mollaret's meningitis: demonstration by polymerase chain reaction. Ann Neurol. 1994;35:112-6.[PubMed]

44. Coker NJ. Bell palsy: a herpes simplex mononeuritis? Arch Otolaryngol Head Neck Surg. 1998;124:823-4. [PubMed]

45. Corey L. Genital herpes. In: Holmes KK, Mardh PA, Sparling JD, Wiesner PJ, Cates WJ, Jr., Lemon SM, Stamm WE, eds. Sex Transm Dis. 2nd ed. New York: McGraw-Hill, 1990:391-413.[PubMed]

46. Corey L, Adams HG, Brown ZA, Holmes KK. Genital herpes simplex virus infections: clinical manifestations, course, and complications. Ann Intern Med. 1983;98:958-72. [PubMed]

47. Corey L, Fife KH, Benedetti JK, Winter CA, Fahnlander A, Connor JD, Hintz MA, Holmes KK. Intravenous acyclovir for the treatment of primary genital herpes. Ann Intern Med. 1983;98:914-21.[PubMed]

48. Corey L, Handsfield HH. Genital herpes and public health: addressing a global problem. JAMA. 2000;283:791-4. [PubMed]

49. Corey L, Holmes KK. Genital herpes simplex virus infections: current concepts in diagnosis, therapy, and prevention. Ann Intern Med. 1983;98:973-83. [PubMed]

50. Corey L, Nahmias AJ, Guinan ME, Benedetti JK, Critchlow CW, Holmes KK. A trial of topical acyclovir in genital herpes simplex virus infections. N Engl J Med. 1982;306:1313-9. [PubMed]

51. Corey L, Reeves WC, Holmes KK. Cellular immune response in genital herpes simplex virus infection. N Engl J Med. 1978;299:986-91. [PubMed]

52. Corey L, Wald A. Genital herpes. In: Holmes KK, Sparling PF, Mardh PA, Lemon SM, Stamm WE, Piot P, Wasserheit JN, eds. Sex Transm Dis. 3rd ed. New York: McGraw-Hill, 1999:285-312. [PubMed]

53. Corey L, Wald A, Patel R, Sacks SL, Tyring SK, Warren T, Douglas JM, Jr., Paavonen J, Ashley Morrow R, Beutner KR, Stratchounsky LS, Mertz G, Keene ON, Watson HA, Tait D, Vargas M, the Valacyclovir HSV Transmission Study Group. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004;350:11-20. [PubMed]

54. Cowan FM. Testing for type-specific antibody to herpes simplex virus--implications for clinical practice. J Antimicrob Chemother. 2000;45:9-13. [PubMed]

55. Cowan FM, Johnson AM, Ashley R, Corey L, Mindel A. Antibody to herpes simplex virus type 2 as serological marker of sexual lifestyle in populations. BMJ 1994;309:1325-9. [PubMed]

56. Deardourff SL, Deture FA, Drylie DM, Centifano Y, Kaufman H. Association between herpes hominis type 2 and the male genitourinary tract. J Urol. 1974;112:126-7.[PubMed]  

57. DeBiasi RL, Kleinschmidt-DeMasters BK, Weinberg A, Tyler KL. Use of PCR for the diagnosis of herpesvirus infections of the central nervous system. J Clin Virol. 2002;25:S5-S11. [PubMed]

58. Dennett C, Cleator GM, Klapper PE. HSV-1 and HSV-2 in herpes simplex encephalitis: a study of sixty-four cases in the United Kingdom. J Med Virol. 1997;53:1-3. [PubMed]

59. Dennett C, Klapper PE, Cleator GM. Polymerase chain reaction in the investigation of "relapse" following herpes simplex encephalitis. J Med Virol. 1996;48:129-32. [PubMed]

60. Dennett C, Klapper PE, Cleator GM, Lewis AG. CSF pretreatment and the diagnosis of herpes encephalitis using the polymerase chain reaction. J Virol Methods. 1991;34:101-4.[PubMed]

61. Diamond C, Mohan K, Hobson A, Frenkel L, Corey L. Viremia in neonatal herpes simplex virus infections. Pediatr Infect Dis J. 1999;18:487-9.[PubMed]

62. Diamond C, Selke S, Ashley R, Benedetti J, Corey L. Clinical course of patients with serologic evidence of recurrent genital herpes presenting with signs and symptoms of first episode disease. Sex Transm Dis. 1999;26:221-5. [PubMed]

63. Diaz-Mitoma F, Sibbald RG, Shafran SD, Boon R, Saltzman RL, the Collaborative Famciclovir Genital Herpes Research Group. Oral famciclovir for the suppression of recurrent genital herpes: a randomized controlled trial. JAMA. 1998;280:887-92. [PubMed]

64. Domingues RB, Lakeman FD, Mayo MS, Whitley RJ. Application of competitive PCR to cerebrospinal fluid samples from patients with herpes simplex encephalitis. J Clin Microbiol. 1998;36:2229-34. [PubMed]

65. Domingues RB, Tsanaclis AM, Pannuti CS, Mayo MS, Lakeman FD. Evaluation of the range of clinical presentations of herpes simplex encephalitis by using polymerase chain reaction assay of cerebrospinal fluid samples. Clin Infect Dis. 1997;25:86-91.[PubMed]

66. Douglas JM, Critchlow C, Benedetti J, Mertz GJ, Connor JD, Hintz MA, Fahnlander A, Remington M, Winter C, Corey L. A double-blind study of oral acyclovir for suppression of recurrences of genital herpes simplex virus infection. N Engl J Med. 1984;310:1551-6. [PubMed]

67. Eberhart-Phillips J, Dickson NP, Paul C, Fawcett JP, Holland D, Taylor J, Cunningham AL. Herpes simplex type 2 infection in a cohort aged 21 years. Sex Transm Infect. 1998;74:216-8.[PubMed]

68. Eberle R, Russell RG, Rouse BT. Cell-mediated immunity to herpes simplex virus: recognition of type-specific and type-common surface antigens by cytotoxic T cell populations. Infect Immun. 1981;34:795-803.[PubMed]

69. Elion GB. Mechanism of action and selectivity of acyclovir. Am J Med. 1982;73:7-13. [PubMed]

70. Englund JA, Fletcher CV, Balfour HH, Jr. Acyclovir therapy in neonates. J Pediatr. 1991;119:129-35. [PubMed]

71. Englund JA, Zimmerman ME, Swierkosz EM, Goodman JL, Scholl DR, Balfour HH, Jr. Herpes simplex virus resistant to acyclovir. A study in a tertiary care center. Ann Intern Med. 1990;112:416-22. [PubMed]

72. Espy MJ, Uhl JR, Mitchell PS, Thorvilson JN, Svien KA, Wold AD, Smith TF. Diagnosis of herpes simplex virus infections in the clinical laboratory by LightCycler PCR. J Clin Microbiol. 2000;38:795-9. [PubMed]

73. Farkkila M, Koskiniemi M, Vaheri A. Clinical spectrum of neurological herpes simplex infection. Acta Neurol Scand. 1993;87:325-8. [PubMed]

74. Fife KH, Barbarash RA, Rudolph T, Degregorio B, Roth R.  Valaciclovir versus acyclovir in the treatment of first-episode genital herpes infection. Results of an international, multicenter, double-blind, randomized clinical trial. The Valaciclovir International Herpes Simplex Virus Study Group. Sex Transm Dis. 1997;24:481-6.[PubMed]

75. Fleming DT, McQuillan GM, Johnson RE, Nahmias AJ, Aral SO, Lee FK, St Louis ME. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med. 1997;337:1105-11. [PubMed]

76. Fodor PA, Levin MJ, Weinberg A, Sandberg E, Sylman J, Tyler KL. Atypical herpes simplex virus encephalitis diagnosed by PCR amplification of viral DNA from CSF. Neurology. 1998;51:554-9. [PubMed]

77. Fonseca-Aten M, Messina AF, Jafri HS, Sanchez PJ. Herpes simplex virus encephalitis during suppressive therapy with acyclovir in a premature infant. Pediatrics. 2005;115:804-809. [PubMed]

78. Frenkel LM, Garratty EM, Shen JP, Wheeler N, Clark O, Bryson YJ. Clinical reactivation of herpes simplex virus type 2 infection in seropositive pregnant women with no history of genital herpes. Ann Intern Med. 1993;118:414-8.[PubMed]

79. Frias C, Matas L, Ferre X, Millan M, Marti S, Hernandez A, Ausina V. Usefulness of adding multiplex nested-polymerase chain reaction assay of cerebrospinal fluid samples to routine diagnostic testing for herpesvirus encephalitis. Eur J Clin Microbiol Infect Dis. 2001;20:670-2.[PubMed]

80. Gateley A, Gander RM, Johnson PC, Kit S, Otsuka H, Kohl S. Herpes simplex virus type 2 meningoencephalitis resistant to acyclovir in a patient with AIDS. J Infect Dis. 1990;161:711-5.[PubMed]

81. Gibson JJ, Hornung CA, Alexander GR, Lee FK, Potts WA, Nahmias AJ. A cross-sectional study of herpes simplex virus types 1 and 2 in college students: occurrence and determinants of infection. J Infect Dis. 1990;162:306-12. [PubMed]

82. Gibson JR, Klaber MR, Harvey SG, Tosti A, Jones D, Yeo JM. Prophylaxis against herpes labialis with acyclovir cream--a placebo-controlled study. Dermatologica. 1986;172:104-7. [PubMed]

83. Glezen WP, Fernald GW, Lohr JA. Acute respiratory disease of university students with special reference to the etiologic role of Herpesvirus hominis. Am J Epidemiol. 1975;101:111-21. [PubMed]

84. Gold D, Corey L. Acyclovir prophylaxis for herpes simplex virus infection. Antimicrob Agents Chemother. 1987;31:361-7.[PubMed]

85. Goldberg LH, Kaufman R, Kurtz TO, Conant MA, Eron LJ, Batenhorst RL, Boone GS. Long-term suppression of recurrent genital herpes with acyclovir. A 5-year benchmark. Acyclovir Study Group. Arch Dermatol. 1993;129:582-7. [PubMed]

86. Graham JR. The migraine connection. Headache. 1981;21:243-50. [PubMed]

87. Guffond T, Dewilde A, Lobert PE, Caparros-Lefebvre D, Hober D, Wattre P. Significance and clinical relevance of the detection of herpes simplex virus DNA by the polymerase chain reaction in cerebrospinal fluid from patients with presumed encephalitis. Clin Infect Dis. 1994;18:744-9.[PubMed]

88. Guinan ME, MacCalman J, Kern ER, Overall JC, Jr., Spruance SL. The course of untreated recurrent genital herpes simplex infection in 27 women. N Engl J Med. 1981;304:759-63.[PubMed]

89. Hardebo JE. An association between cluster headache and herpes simplex. N Engl J Med. 1986;314:30.[PubMed]

90. Herpetic Eye Disease Study Group. Acyclovir for the prevention of recurrent herpes simplex virus eye disease. N Engl J Med. 1998;339:300-6.[PubMed]

91. Herpetic Eye Disease Study Group. Oral acyclovir for herpes simplex virus eye disease: effect on prevention of epithelial keratitis and stromal keratitis. Arch Ophthalmol. 2000;118:1030-6.[PubMed]

92. Hindmarsh T, Lindqvist M, Olding-Stenkvist E, Skoldenberg B, Forsgren M. Accuracy of computed tomography in the diagnosis of herpes simplex encephalitis. Acta Radiologica - Supplementum. 1986;369:192-6. [PubMed]  

93. Hook EW, 3rd, Cannon RO, Nahmias AJ, Lee FF, Campbell CH, Jr., Glasser D, Quinn TC. Herpes simplex virus infection as a risk factor for human immunodeficiency virus infection in heterosexuals. J Infect Dis. 1992;165:251-5. [PubMed]

94. Hovding G. A comparison between acyclovir and trifluorothymidine ophthalmic ointment in the treatment of epithelial dendritic keratitis. A double blind, randomized parallel group trial. Acta Ophthalmologica. 1989;67:51-4. [PubMed]

95. Hukkanen V, Rehn T, Kajander R, Sjoroos M, Waris M. Time-resolved fluorometry PCR assay for rapid detection of herpes simplex virus in cerebrospinal fluid. J Clin Microbiol. 2000;38:3214-8. [PubMed]

96. Ito Y, Ando Y, Kimura H, Kuzushima K, Morishima T. Polymerase chain reaction-proved herpes simplex encephalitis in children. Pediatr Infect Dis J. 1998;17:29-32. [PubMed]

97. Ito Y, Kimura H, Yabuta Y, Ando Y, Murakami T, Shiomi M, Morishima T. Exacerbation of herpes simplex encephalitis after successful treatment with acyclovir. Clin Infect Dis. 2000;30:185-7. [PubMed]

98. Jacobson MA. Valaciclovir (BW256U87): the L-valyl ester of acyclovir. J Med Virol. 1993;Suppl:150-3. [PubMed]

99. Jensenius M, Myrvang B, Storvold G, Bucher A, Hellum KB, Bruu AL. Herpes simplex virus type 2 DNA detected in cerebrospinal fluid of 9 patients with Mollaret's meningitis. Acta Neurol Scand. 1998;98:209-12. [PubMed]

100. Johnson RE, Nahmias AJ, Magder LS, Lee FK, Brooks CA, Snowden CB. A seroepidemiologic survey of the prevalence of herpes simplex virus type 2 infection in the United States. N Engl J Med. 1989;321:7-12. [PubMed]

101. Josey WE, Nahmias AJ, Naib ZM. The epidemiology of Type 2 (genital) herpes simplex virus infection. Obstet Gynecol Surv. 1972;27:suppl:295-302. [PubMed]

102. Josey WE, Nahmias AJ, Naib ZM, Utley PM, McKenzie WJ, Coleman MT. Genital herpes simplex infection in the female. Am J Obstet Gynecol. 1966;96:493-501.[PubMed]

103. Kaufman RH, Gardner HL, Rawls WE, Dixon RE, Young RL. Clinical features of herpes genitalis. Cancer Res. 1973;33:1446-51.[PubMed]

104. Kawada J, Kimura H, Ito Y, Hoshino Y, Tanaka-Kitajima N, Ando Y, Futamura M, Morishima T. Comparison of real-time and nested PCR assays for detection of herpes simplex virus DNA. Microbiol Immunol. 2004;48:411-5. [PubMed]

105. Keet IP, Lee FK, van Griensven GJ, Lange JM, Nahmias A, Coutinho RA. Herpes simplex virus type 2 and other genital ulcerative infections as a risk factor for HIV-1 acquisition. Genitourin Med. 1990;66:330-3.[PubMed]

106. Kern ER, Vogt PE, Co MS, Kohl S, Whitley RJ. Treatment of herpes simplex virus type 2 infections in mice with murine and humanized monoclonal antibodies (MABS), International Society for Antiviral Research, Vancouver, B. C., Canada, March 8-13, 1992, 1992. [PubMed]

107. Kimberlin D, Cloud G, Lakeman F, Jacobs R, Gutierrez K, Powell D, Corey L, Whitley R, for the NIAID Collaborative Antiviral Study Group (CASG). Serum polymerase chain reaction (PCR) may not diagnose neonatal herpes simplex virus (HSV) disease, 42nd Annual Meeting of the Infectious Diseases Society of America, Boston, Massachusetts; Abstract 992, September 30-October 3, 2004.[PubMed]

108. Kimberlin D, Powell D, Gruber W, Diaz P, Arvin A, Kumar M, Jacobs R, Van Dyke R, Burchett S, Soong SJ, Lakeman A, Whitley R, The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Administration of oral acyclovir suppressive therapy after neonatal herpes simplex virus disease limited to the skin, eyes and mouth: results of a phase I/II trial. Pediatr Infect Dis J. 1996;15:247-54. [PubMed]

109. Kimberlin DW. Vertical transmission of HSV, 18th International Union Against Sexually Transmitted Diseases (IUSTI) Europe Congress on Sexually Transmitted Diseases, Vienna, Austria; #SAT12, 2002. Vol. 13 (Suppl 1), p. 60. Int J STD AIDS.[PubMed]

110. Kimberlin DW, Coen DM, Biron KK, Cohen JI, Lamb RA, McKinlay M, Emini EA, Whitley RJ. Molecular mechanisms of antiviral resistance. Antiviral Res. 1995;26:369-401. [PubMed]

111. Kimberlin DW, Lakeman FD, Arvin AM, Prober CG, Corey L, Powell DA, Burchett SK, Jacobs RF, Starr SE, Whitley RJ, The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Application of the polymerase chain reaction to the diagnosis and management of neonatal herpes simplex virus disease. J Infect Dis. 1996;174:1162-7. [PubMed]

112. Kimberlin DW, Lin CY, Jacobs RF, Powell DA, Corey L, Gruber WC, Rathore M, Bradley JS, Diaz PS, Kumar M, Arvin AM, Gutierrez K, Shelton M, Weiner LB, Sleasman JW, de Sierra TM, Weller S, Soong SJ, Kiell J, Lakeman FD, Whitley RJ, The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics. 2001;108:230-8.[PubMed]

113. Kimberlin DW, Lin CY, Jacobs RF, Powell DA, Frenkel LM, Gruber WC, Rathore M, Bradley JS, Diaz PS, Kumar M, Arvin AM, Gutierrez K, Shelton M, Weiner LB, Sleasman JW, de Sierra TM, Soong SJ, Kiell J, Lakeman FD, Whitley RJ, The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics. 2001;108:223-9.[PubMed]

114. Kimberlin DW, Prober CG. Antiviral agents. In: Long SS, Pickering LK, Prober CG, eds. Principles and Practice of Pediatric Infectious Diseases. 2nd ed. Philadelphia: Churchill Livingstone, 2003:1527-1547.[PubMed]

115. Kimberlin DW, Rouse DJ. Clinical practice.  Genital herpes. N Engl J Med. 2004;350:1970-7.[PubMed]

116. Kimura H, Futamura M, Kito H, Ando T, Goto M, Kuzushima K, Shibata M, Morishima T. Detection of viral DNA in neonatal herpes simplex virus infections: frequent and prolonged presence in serum and cerebrospinal fluid. J Infect Dis. 1991;164:289-93.[PubMed]

117. Kimura H, Ito Y, Futamura M, Ando Y, Yabuta Y, Hoshino Y, Nishiyama Y, Morishima T. Quantitation of viral load in neonatal herpes simplex virus infection and comparison between type 1 and type 2. J Med Virol. 2002;67:349-53.[PubMed]

118. Kinghorn GR. Type-specific serological testing for herpes simplex infection. Int J STD AIDS. 1998;9:497-500. [PubMed]

119. Klapper PE, Cleator GM, Longson M. Mild forms of herpes encephalitis. J Neurol Neurosurg Psychiatry. 1984;47:1247-50.[PubMed]

120. Koelle DM, Schomogyi M, Corey L. Antigen-specific T cells localize to the uterine cervix in women with genital herpes simplex virus type 2 infection. J Infect Dis. 2000;182:662-70.[PubMed]

121. Kohl S, West MS, Prober CG, Sullender WM, Loo LS, Arvin AM. Neonatal antibody-dependent cellular cytotoxic antibody levels are associated with the clinical presentation of neonatal herpes simplex virus infection. J Infect Dis. 1989;160:770-6.[PubMed]

122. Kost RG, Hill EL, Tigges M, Straus SE. Brief report: recurrent acyclovir-resistant genital herpes in an immunocompetent patient. N Engl J Med. 1993;329:1777-82.[PubMed]

123. Koutsky LA, Stevens CE, Holmes KK, Ashley RL, Kiviat NB, Critchlow CW, Corey L. Underdiagnosis of genital herpes by current clinical and viral-isolation procedures. N Engl J Med. 1992;326:1533-9.[PubMed]

124. Krasny HC, Liao SH, de Miranda P, Laskin OL, Whelton A, Lietman PS. Influence of hemodialysis on acyclovir pharmacokinetics in patients with chronic renal failure. Am J Med. 1982;73:202-4. [PubMed]

125. Lafferty WE, Coombs RW, Benedetti J, Critchlow C, Corey L. Recurrences after oral and genital herpes simplex virus infection. Influence of site of infection and viral type. N Engl J Med. 1987;316:1444-9.[PubMed]

126. Lafferty WE, Downey L, Celum C, Wald A. Herpes simplex virus type 1 as a cause of genital herpes: impact on surveillance and prevention. J Infect Dis. 2000;181:1454-7. [PubMed]

127. Lake P, Alonso P, Subramanyam J, Nottage B. SDZ HSV 863: A human monoclonal antibody to HSV 1 and HSV 2 (gD Ib) which attenuates acute infection, neurogenic cutaneous lesion formation and the establishment of viral latency, International Society for Antiviral Research, Vancouver, B. C., Canada, March 8 13, 1992.[PubMed]

128. Lakeman FD, Whitley RJ. Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis. 1995;171:857-63.[PubMed]

129. Langenberg A, Benedetti J, Jenkins J, Ashley R, Winter C, Corey L. Development of clinically recognizable genital lesions among women previously identified as having "asymptomatic" herpes simplex virus type 2 infection. Ann Intern Med. 1989;110:882-7.[PubMed]

130. Langenberg AG, Corey L, Ashley RL, Leong WP, Straus SE. A prospective study of new infections with herpes simplex virus type 1 and type 2. Chiron HSV Vaccine Study Group. N Engl J Med. 1999;341:1432-8. [PubMed]

131. Laskin OL, Longstreth JA, Whelton A, Krasny HC, Keeney RE, Rocco L, Lietman PS. Effect of renal failure on the pharmacokinetics of acyclovir. Am J Med. 1982;73:197-201. [PubMed]

132. Lee FK, Coleman RM, Pereira L, Bailey PD, Tatsuno M, Nahmias AJ. Detection of herpes simplex virus type 2-specific antibody with glycoprotein G. J Clin Microbiol. 1985;22:641-4.[PubMed]

133. Leone PA, Trottier S, Miller JM. Valacyclovir for episodic treatment of genital herpes: a shorter 3-day treatment course compared with 5-day treatment. Clin Infect Dis. 2002;34:958-62.[PubMed]

134. Levin MJ, Weinberg A, Leary JJ, Sarisky RT. Development of acyclovir-resistant herpes simplex virus early during the treatment of herpes neonatorum. Pediatr Infect Dis J. 2001;20:1094-7.[PubMed]

135. Levine DP, Lauter CB, Lerner AM. Simultaneous serum and CSF antibodies in herpes simplex virus encephalitis. JAMA. 1978;240:356-60.[PubMed]

136. Lewensohn-Fuchs I, Osterwall P, Forsgren M, Malm G. Detection of herpes simplex virus DNA in dried blood spots making a retrospective diagnosis possible. J Clin Virol. 2003;26:39-48. [PubMed]

137. Lin L, Chen XS, Cui PG, Wang JB, Guo ZP, Lu NZ, Bi ZG, Jia H, Yang XY, Topical Penciclovir Clinical Study G. Topical application of penciclovir cream for the treatment of herpes simplex facialis/labialis: a randomized, double-blind, multicentre, aciclovir-controlled trial. J Dermatol Treat. 2002;13:67-72.[PubMed]

138. Linde A, Klapper PE, Monteyne P, Echevarria JM, Cinque P, Rozenberg F, Vestergaard BF, Ciardi M, Lebon P, Cleator GM. Specific diagnostic methods for herpesvirus infections of the central nervous system: a consensus review by the European Union Concerted Action on Virus Meningitis and Encephalitis. Clin Diagn Virol. 1997;8:83-104. [PubMed]

139. Lowhagen GB, Tunback P, Andersson K, Bergstrom T, Johannisson G. First episodes of genital herpes in a Swedish STD population: a study of epidemiology and transmission by the use of herpes simplex virus (HSV) typing and specific serology. Sex Transm Infect. 2000;76:179-82. [PubMed]

140. Luby JP, Gnann JW, Jr., Alexander WJ, Hatcher VA, Friedman-Kien AE, Klein RJ, Keyserling H, Nahmias A, Mills J, Schachter J. A collaborative study of patient-initiated treatment of recurrent genital herpes with topical acyclovir or placebo. J Infect Dis. 1984;150:1-6.[PubMed]

141. Malm G, Forsgren M. Neonatal herpes simplex virus infections: HSV DNA in cerebrospinal fluid and serum. Arch Dis Child Fetal Neonatal Ed. 1999;81:F24-9.[PubMed]

142. Mandyla H, Anagnostakis D, Koutsovitis P, Siahanidou T, Youroukos S. Late recurrence of herpes simplex virus meningoencephalitis in two infants. Eur J Pediatr. 2001;160:732-5.[PubMed]

143. Markert JM, Gillespie GY, Weichselbaum RR, Roizman B, Whitley RJ. Genetically engineered HSV in the treatment of glioma: a review. Rev Med Virol. 2000;10:17-30. [PubMed]

144. Markert JM, Medlock MD, Rabkin SD, Gillespie GY, Todo T, Hunter WD, Palmer CA, Feigenbaum F, Tornatore C, Tufaro F, Martuza RL. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther. 2000;7:867-874.[PubMed]

145. Mertz GJ, Benedetti J, Ashley R, Selke SA, Corey L. Risk factors for the sexual transmission of genital herpes. Ann Intern Med. 1992;116:197-202. [PubMed]

146. Mertz GJ, Critchlow CW, Benedetti J, Reichman RC, Dolin R, Connor J, Redfield DC, Savoia MC, Richman DD, Tyrrell DL. Double-blind placebo-controlled trial of oral acyclovir in first-episode genital herpes simplex virus infection. JAMA. 1984;252:1147-51.[PubMed]

147. Mertz GJ, Eron L, Kaufman R, Goldberg L, Raab B, Conant M, Mills J, Kurtz T, Davis LG. Prolonged continuous versus intermittent oral acyclovir treatment in normal adults with frequently recurring genital herpes simplex virus infection. Am J Med. 1988;85:14-9. [PubMed]

148. Mertz GJ, Jones CC, Mills J, Fife KH, Lemon SM, Stapleton JT, Hill EL, Davis LG. Long-term acyclovir suppression of frequently recurring genital herpes simplex virus infection. A multicenter double-blind trial. JAMA. 1988;260:201-6.[PubMed]

149. Mertz GJ, Loveless MO, Levin MJ, Kraus SJ, Fowler SL, Goade D, Tyring SK, the Collaborative Famciclovir Genital Herpes Research Group. Oral famciclovir for suppression of recurrent genital herpes simplex virus infection in women. A multicenter, double-blind, placebo-controlled trial. Arch Intern Med. 1997;157:343-9.[PubMed]

150. Meyers JD, Wade JC, Mitchell CD, Saral R, Lietman PS, Durack DT, Levin MJ, Segreti AC, Balfour HH, Jr. Multicenter collaborative trial of intravenous acyclovir for treatment of mucocutaneous herpes simplex virus infection in the immunocompromised host. Am J Med. 1982;73:229-35.[PubMed]

151. Mindel A, Faherty A, Carney O, Patou G, Freris M, Williams P. Dosage and safety of long-term suppressive acyclovir therapy for recurrent genital herpes. Lancet. 1988;1:926-8.[PubMed]

152. Minjolle S, Arvieux C, Gautier AL, Jusselin I, Thomas R, Michelet C, Colimon R. Detection of herpesvirus genomes by polymerase chain reaction in cerebrospinal fluid and clinical findings. J Clin Virol. 2002;25:S59-S70.[PubMed]

153. Mitchell PS, Espy MJ, Smith TF, Toal DR, Rys PN, Berbari EF, Osmon DR, Persing DH. Laboratory diagnosis of central nervous system infections with herpes simplex virus by PCR performed with cerebrospinal fluid specimens. J Clin Microbiol. 1997;35:2873-7.[PubMed]

154. Mole L, Ripich S, Margolis D, Holodniy M. The impact of active herpes simplex virus infection on human immunodeficiency virus load. J Infect Dis. 1997;176:766-70.[PubMed]

155. Monteyne P, Albert F, Weissbrich B, Zardini E, Ciardi M, Cleator GM, Sindic CJ. The detection of intrathecal synthesis of anti-herpes simplex IgG antibodies: comparison between an antigen-mediated immunoblotting technique and antibody index calculations. European Union Concerted Action on Virus Meningitis and Encephalitis. J Med Virol. 1997;53:324-31. [PubMed]

156. Morfin F, Thouvenot D. Herpes simplex virus resistance to antiviral drugs. Journal of Clinical Virology. 2003;26:29-37.[PubMed]

157. Moseley RC, Corey L, Benjamin D, Winter C, Remington ML. Comparison of viral isolation, direct immunofluorescence, and indirect immunoperoxidase techniques for detection of genital herpes simplex virus infection. J Clin Microbiol. 1981;13:913-8.[PubMed]

158. Nadal D, Leverger G, Sokal EM, Floret D, Perel Y, Leibundgut K, Weller S. An investigation of the steady-state pharmacokinetics of oral valacyclovir in immunocompromised children. J Infect Dis. 2002;186:S123-30. [PubMed]

159. Nahmias AJ, Josey WE, Naib ZM, Freeman MG, Fernandez RJ, Wheeler JH. Perinatal risk associated with maternal genital herpes simplex virus infection. Am J Obstet Gynecol. 1971;110:825-37.[PubMed]

160. Nahmias AJ, Lee FK, Beckman-Nahmias S. Sero-epidemiological and -sociological patterns of herpes simplex virus infection in the world. Scand J Infect Dis Suppl. 1990;69:19-36. [PubMed]

161. Nahmias AJ, Whitley RJ, Visintine AN, Takei Y, Alford CA, Jr. Herpes simplex virus encephalitis: laboratory evaluations and their diagnostic significance. J Infect Dis. 1982;145:829-36.[PubMed]

162. Nilsen A, Myrmel H. Changing trends in genital herpes simplex virus infection in Bergen, Norway. Acta Obstet Gynecol Scand. 2000;79:693-6.[PubMed]

163. Nilsen AE, Aasen T, Halsos AM, Kinge BR, Tjotta EA, Wikstrom K, Fiddian AP. Efficacy of oral acyclovir in the treatment of initial and recurrent genital herpes. Lancet. 1982;2:571-3. [PubMed]

164. Nyquist AC, Rotbart HA, Cotton M, Robinson C, Weinberg A, Hayward AR, Berens RL, Levin MJ. Acyclovir-resistant neonatal herpes simplex virus infection of the larynx. J Pediatr. 1994;124:967-71.[PubMed]

165. Olson LC, Buescher EL, Artenstein MS, Parkman PD. Herpesvirus infections of the human central nervous system. N Engl J Med. 1967;277:1271-7.[PubMed] 4294512 

166. Oram RJ, Marcellino D, Strauss D, Gustafson E, Talarico CL, Root AK, Sharma PL, Thompson K, Fingeroth JD, Crumpacker C, Herold BC. Characterization of an acyclovir-resistant herpes simplex virus type 2 strain isolated from a premature neonate. J Infect Dis. 2000;181:1458-61.[PubMed]

167. Parker JD, Banatvala JE. Herpes genitalis; clinical and virological studies. Br J Vener Dis. 1967;43:212-6.[PubMed]

168. Peng J, Krause PJ, Kresch M. Neonatal herpes simplex virus infection after cesarean section with intact amniotic membranes. J Perinatol. 1996;16:397-9. [PubMed]

169. Posavad CM, Huang ML, Barcy S, Koelle DM, Corey L. Long term persistence of herpes simplex virus-specific CD8+ CTL in persons with frequently recurring genital herpes. J Immunol. 2000;165:1146-52. [PubMed]

170. Posavad CM, Koelle DM, Corey L. High frequency of CD8+ cytotoxic T-lymphocyte precursors specific for herpes simplex viruses in persons with genital herpes. J Virol. 1996;70:8165-8. [PubMed]

171. Posavad CM, Koelle DM, Shaughnessy MF, Corey L. Severe genital herpes infections in HIV-infected individuals with impaired herpes simplex virus-specific CD8+ cytotoxic T lymphocyte responses. Proc Natl Acad Sci U S A. 1997;94:10289-94.[PubMed] 

172. Prince HE, Ernst CE, Hogrefe WR. Evaluation of an enzyme immunoassay system for measuring herpes simplex virus (HSV) type 1-specific and HSV type 2-specific IgG antibodies. J Clin Lab Anal. 2000;14:13-6. [PubMed]

173. Prober CG, Kimberlin DW. Antiviral drugs. In: Yaffe SJ, Aranda JV, eds. Neonatal and Pediatric Pharmacology: Therapeutic Principles in Practice. 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2005:475-503. [PubMed]

174. Prober CG, Sullender WM, Yasukawa LL, Au DS, Yeager AS, Arvin AM. Low risk of herpes simplex virus infections in neonates exposed to the virus at the time of vaginal delivery to mothers with recurrent genital herpes simplex virus infections. N Engl J Med. 1987;316:240-4. [PubMed]

175. Puchhammer-Stockl E, Popow-Kraupp T, Heinz FX, Mandl CW, Kunz C. Establishment of PCR for the early diagnosis of herpes simplex encephalitis. J Med Virol. 1990;32:77-82.[PubMed] 

176. Rabalais GP, Nusinoff-Lehrman S, Arvin AM, Levin MJ. Antiviral susceptibilities of herpes simplex virus isolates from infants with recurrent mucocutaneous lesions after neonatal infection. Pediatr Infect Dis J. 1989;8:221-[PubMed] 

177. Raborn GW, Martel AY, Grace MG, McGaw WT. Herpes labialis in skiers: randomized clinical trial of acyclovir cream versus placebo. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;84:641-5.[PubMed] 

178. Raborn GW, McGaw WT, Grace M, Percy J. Treatment of herpes labialis with acyclovir. Review of three clinical trials. Am J Med. 1988;85:39-42. [PubMed]

179. Raborn GW, McGaw WT, Grace M, Tyrrell LD, Samuels SM. Oral acyclovir and herpes labialis: a randomized, double-blind, placebo-controlled study. J Am Dent Assoc. 1987;115:38-42. [PubMed]

180. Rasmussen L, Merigan TC. Role of T lymphocytes in cellular immune responses during herpes simplex virus infection in humans. Proc Natl Acad Sci U S A. 1978;75:3957-61. [PubMed]

181. Rattray MC, Corey L, Reeves WC, Vontver LA, Holmes KK. Recurrent genital herpes among women: symptomatic v. asymptomatic viral shedding. Br J Vener Dis. 1978;54:262-5.[PubMed] 

182. Reardon JE, Spector T. Herpes simplex virus type 1 DNA polymerase. Mechanism of inhibition by acyclovir triphosphate. J Biol Chem. 1989;264:7405-11. [PubMed]

183. Reeves WC, Corey L, Adams HG, Vontver LA, Holmes KK. Risk of recurrence after first episodes of genital herpes. Relation to HSV type and antibody response. N Engl J Med. 1981;305:315-9. [PubMed]

184. Reichman RC, Badger GJ, Mertz GJ, Corey L, Richman DD, Connor JD, Redfield D, Savoia MC, Oxman MN, Bryson Y. Treatment of recurrent genital herpes simplex infections with oral acyclovir. A controlled trial. JAMA. 1984;251:2103-7. [PubMed]

185. Reitano M, Tyring S, Lang W, Thoming C, Worm AM, Borelli S, Chambers LO, Robinson JM, Corey L, the International Valaciclovir HSV Study Group. Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dose range-finding study. J Infect Dis. 1998;178:603-10. [PubMed]

186. Revankar SG, Applegate AL, Markovitz DM. Delirium associated with acyclovir treatment in a patient with renal failure. Clin Infect Dis. 1995;21:435-6. [PubMed]

187. Revello MG, Baldanti F, Sarasini A, Zella D, Zavattoni M, Gerna G. Quantitation of herpes simplex virus DNA in cerebrospinal fluid of patients with herpes simplex encephalitis by the polymerase chain reaction. Clin Diagn Virol. 1997;7:183-91. [PubMed]

188. Rooney JF, Felser JM, Ostrove JM, Straus SE. Acquisition of genital herpes from an asymptomatic sexual partner. N Engl J Med. 1986;314:1561-4. [PubMed]

189. Rooney JF, Straus SE, Mannix ML, Wohlenberg CR, Alling DW, Dumois JA, Notkins AL. Oral acyclovir to suppress frequently recurrent herpes labialis. A double-blind, placebo-controlled trial. Ann Intern Med. 1993;118:268-72. [PubMed]

190. Rosenthal SL, Stanberry LR, Biro FM, Slaoui M, Francotte M, Koutsoukos M, Hayes M, Bernstein DI. Seroprevalence of herpes simplex virus types 1 and 2 and cytomegalovirus in adolescents. Clin Infect Dis. 1997;24:135-9. [PubMed]

191. Ross JD, Smith IW, Elton RA. The epidemiology of herpes simplex types 1 and 2 infection of the genital tract in Edinburgh 1978-1991. Genitourin Med. 1993;69:381-3.[PubMed] 

192. Rowley AH, Whitley RJ, Lakeman FD, Wolinsky SM. Rapid detection of herpes-simplex-virus DNA in cerebrospinal fluid of patients with herpes simplex encephalitis. Lancet. 1990;335:440-1.[PubMed] 

193. Ruhnek-Forsbeck M, Sandstrom E, Andersson B, Eriksson G, Hersle K, Lovhagen GB, Mobacken H, Hillstrom L, Svensson L. Treatment of recurrent genital herpes simplex infections with oral acyclovir. J Antimicrob Chemother. 1985;16:621-8. [PubMed]

194. Sacks SL, Aoki FY, Diaz-Mitoma F, Sellors J, Shafran SD, the Canadian Famciclovir Study Group. Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes. A randomized, double-blind multicenter trial. JAMA. 1996;276:44-9.[PubMed] 

195. Saral R, Burns WH, Laskin OL, Santos GW, Lietman PS. Acyclovir prophylaxis of herpes-simplex-virus infections. N Engl J Med. 1981;305:63-7. [PubMed]

196. Sauerbrei A, Wutzler P. Laboratory diagnosis of central nervous system infections caused by herpesviruses. J Clin Virol. 2002;25:S45-51[PubMed] 

197. Schacker T, Ryncarz AJ, Goddard J, Diem K, Shaughnessy M, Corey L. Frequent recovery of HIV-1 from genital herpes simplex virus lesions in HIV-1-infected men. JAMA. 1998;280:61-6.[PubMed]

198. Schlesinger Y, Storch GA. Herpes simplex meningitis in infancy. Pediatr Infect Dis J. 1994;13:141-4. [PubMed]

199. Scott LL, Hollier LM, McIntire D, Sanchez PJ, Jackson GL, Wendel GD, Jr. Acyclovir suppression to prevent recurrent genital herpes at delivery. Infect Dis Obstet Gynecol. 2002;10:71-7. [PubMed]

200. Scott LL, Sanchez PJ, Jackson GL, Zeray F, Wendel GD, Jr. Acyclovir suppression to prevent cesarean delivery after first-episode genital herpes. Obstet Gynecol. 1996;87:69-73. [PubMed]

201. Shaw M, King M, Best JM, Banatvala JE, Gibson JR, Klaber MR. Failure of acyclovir cream in treatment of recurrent herpes labialis. Br Med J Clin Res Ed. 1985;291:7-9. [PubMed]

202. Sheffield JS, Hollier LM, Hill JB, Stuart GS, Wendel GD, Jr. Acyclovir prophylaxis to prevent herpes simplex virus recurrence at delivery: a systematic review. Obstet Gynecol. 2003;102:1396-1403. [PubMed]

203. Shepp DH, Newton BA, Dandliker PS, Flournoy N, Meyers JD. Oral acyclovir therapy for mucocutaneous herpes simplex virus infections in immunocompromised marrow transplant recipients. Ann Intern Med. 1985;102:783-5. [PubMed]

204. Shyu WC, Lin JC, Chang BC, Harn HJ, Lee CC, Tsao WL. Recurrent ascending myelitis: an unusual presentation of herpes simplex virus type 1 infection. Ann Neurol. 1993;34:625-7. [PubMed]

205. Skoldenberg B, Forsgren M, Alestig K, Bergstrom T, Burman L, Dahlqvist E, Forkman A, Fryden A, Lovgren K, Norlin K. Acyclovir versus vidarabine in herpes simplex encephalitis. Randomised multicentre study in consecutive Swedish patients. Lancet. 1984;2:707-11.[PubMed] 

206. Skoldenberg B, Jeansson S, Wolontis S. Herpes simplex virus type 2 and acute aseptic meningitis. Clinical features of cases with isolation of herpes simplex virus from cerebrospinal fluids. Scand J Infect Dis. 1975;7:227-32.[PubMed] 

207. Soul-Lawton J, Seaber E, On N, Wootton R, Rolan P, Posner J. Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans. Antimicrob Agents Chemother. 1995;39:2759-64.[PubMed] 

208. Spruance SL. Bell palsy and herpes simplex virus. Ann Intern Med. 1994;120:1045-6. [PubMed]

209. Spruance SL, Crumpacker CS, Schnipper LE, Kern ER, Marlowe S, Arndt KA, Overall JC, Jr. Early, patient-initiated treatment of herpes labialis with topical 10% acyclovir. Antimicrob Agents Chemother. 1984;25:553-5. [PubMed]

210. Spruance SL, Freeman DJ, Stewart JC, McKeough MB, Wenerstrom LG, Krueger GG, Piepkorn MW, Stroop WG, Rowe NH. The natural history of ultraviolet radiation-induced herpes simplex labialis and response to therapy with peroral and topical formulations of acyclovir. J Infect Dis. 1991;163:728-34. [PubMed]

211. Spruance SL, Hamill ML, Hoge WS, Davis LG, Mills J. Acyclovir prevents reactivation of herpes simplex labialis in skiers. JAMA. 1988;260:1597-9. [PubMed]

212. Spruance SL, Jones TM, Blatter MM, Vargas-Cortes M, Barber J, Hill J, Goldstein D, Schultz M. High-dose, short-duration, early valacyclovir therapy for episodic treatment of cold sores: results of two randomized, placebo-controlled, multicenter studies. Antimicrob Agents Chemother. 2003;47:1072-80. [PubMed]

213. Spruance SL, Nett R, Marbury T, Wolff R, Johnson J, Spaulding T. Acyclovir cream for treatment of herpes simplex labialis: results of two randomized, double-blind, vehicle-controlled, multicenter clinical trials. Antimicrob Agents Chemother. 2002;46:2238-43. [PubMed]

214. Spruance SL, Rea TL, Thoming C, Tucker R, Saltzman R, Boon R. Penciclovir cream for the treatment of herpes simplex labialis. A randomized, multicenter, double-blind, placebo-controlled trial. Topical Penciclovir Collaborative Study Group. JAMA. 1997;277:1374-9. [PubMed]

215. Spruance SL, Stewart JC, Rowe NH, McKeough MB, Wenerstrom G, Freeman DJ. Treatment of recurrent herpes simplex labialis with oral acyclovir. J Infect Dis. 1990;161:185-90.[PubMed] 

216. Spruance SL, Tyring SK, DeGregorio B, Miller C, Beutner K, the Valaciclovir HSV Study Group. A large-scale, placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis. Arch Intern Med. 1996;156:1729-35. [PubMed]

217. Stanberry LR, Cunningham AL, Mindel A, Scott LL, Spruance SL, Aoki FY, Lacey CJ. Prospects for control of herpes simplex virus disease through immunization. Clin Infect Dis. 2000;30:549-66. [PubMed]

218. Stanberry LR, Spruance SL, Cunningham AL, Bernstein DI, Mindel A, Sacks S, Tyring S, Aoki FY, Slaoui M, Denis M, Vandepapeliere P, Dubin G, The GlaxoSmithKline Herpes Vaccine Efficacy Study Group. Glycoprotein-D-adjuvant vaccine to prevent genital herpes. N Engl J Med. 2002;347:1652-61. [PubMed]

219. Stevens JG, Cook ML. Latent herpes simplex virus in spinal ganglia of mice. Science. 1971;173:843-5. [PubMed]

220. Stone KM, Reiff-Eldridge R, White AD, Cordero JF, Brown Z, Alexander ER, Andrews EB. Pregnancy outcomes following systemic prenatal acyclovir exposure: conclusions from the International Acyclovir Pregnancy Registry, 1984-1999. Birth Defects Research (Part A). 2004;70:201-207. [PubMed]

221. Straus SE, Takiff HE, Seidlin M, Bachrach S, Lininger L, DiGiovanna JJ, Western KA, Smith HA, Lehrman SN, Creagh-Kirk T. Suppression of frequently recurring genital herpes. A placebo-controlled double-blind trial of oral acyclovir. N Engl J Med. 1984;310:1545-50. [PubMed]

222. Strick L, Wald A. Type-specific testing for herpes simplex virus. Expert Rev Mol Diagn. 2004;4:443-53.[PubMed] 

223. Sullender WM, Miller JL, Yasukawa LL, Bradley JS, Black SB, Yeager AS, Arvin AM. Humoral and cell-mediated immunity in neonates with herpes simplex virus infection. J Infect Dis. 1987;155:28-37.[PubMed] 

224. Sullivan-Bolyai JZ, Hull HF, Wilson C, Smith AL, Corey L. Presentation of neonatal herpes simplex virus infections: implications for a change in therapeutic strategy. Pediatr Infect Dis. 1986;5:309-14.[PubMed] 

225. Sureda B, Villalobos F, Gil-Neciga E, Martinez ML, Bautista J. Migraine and cerebrospinal fluid alterations: are they an expression of viral meningoencephalitis? Neurologia. 1987;2:54-6. [PubMed]

226. Tebas P, Nease RF, Storch GA. Use of the polymerase chain reaction in the diagnosis of herpes simplex encephalitis: a decision analysis model. Am J Med. 1998;105:287-95. [PubMed]

227. Thompson C. Genital herpes simplex typing in genitourinary medicine: 1995-1999. Int J STD AIDS. 2000;11:501-2. [PubMed]

228. Troendle-Atkins J, Demmler GJ, Buffone GJ. Rapid diagnosis of herpes simplex virus encephalitis by using the polymerase chain reaction. J Pediatr. 1993;123:376-80. [PubMed]

229. Tyler KL. Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's. HERPES. 2004;11:57A-64A. [PubMed]

230. Tyring SK, Douglas JM, Jr., Corey L, Spruance SL, Esmann J, the Valaciclovir International Study Group. A randomized, placebo-controlled comparison of oral valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections. Arch Dermatol. 1998;134:185-91. [PubMed]

231. Vandvik B, Skoldenberg B, Forsgren M, Stiernstedt G, Jeansson S, Norrby E. Long-term persistence of intrathecal virus-specific antibody responses after herpes simplex virus encephalitis. J Neurol. 1985;231:307-12. [PubMed]

232. Vandvik B, Vartdal F, Norrby E. Herpes simplex virus encephalitis: intrathecal synthesis of oligoclonal virus-specific IgG, IgA and IgM antibodies. J Neurol. 1982;228:25-38.[PubMed] 

233. Vontver LA, Reeves WC, Rattray M, Corey L, Remington MA, Tolentino E, Schweid A, Holmes KK. Clinical course and diagnosis of genital herpes simplex virus infection and evaluation of topical surfactant therapy. Am J Obstet Gynecol. 1979;133:548-54. [PubMed]

234. Wade JC, Newton B, Flournoy N, Meyers JD. Oral acyclovir for prevention of herpes simplex virus reactivation after marrow transplantation. Ann Intern Med. 1984;100:823-8. [PubMed]

235. Wade JC, Newton B, McLaren C, Flournoy N, Keeney RE, Meyers JD. Intravenous acyclovir to treat mucocutaneous herpes simplex virus infection after marrow transplantation: a double-blind trial. Ann Intern Med. 1982;96:265-9. [PubMed]

236. Wagstaff AJ, Faulds D, Goa KL. Aciclovir. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1994;47:153-205. [PubMed]

237. Wald A, Benedetti J, Davis G, Remington M, Winter C, Corey L. A randomized, double-blind, comparative trial comparing high- and standard-dose oral acyclovir for first-episode genital herpes infections. Antimicrob Agents Chemother. 1994;38:174-6. [PubMed]

238. Wald A, Carrell D, Remington M, Kexel E, Zeh J, Corey L. Two-day regimen of acyclovir for treatment of recurrent genital herpes simplex virus type 2 infection. Clin Infect Dis. 2002;34:944-8. [PubMed]

239. Wald A, Corey L, Cone R, Hobson A, Davis G, Zeh J. Frequent genital herpes simplex virus 2 shedding in immunocompetent women. Effect of acyclovir treatment. J Clin Invest. 1997;99:1092-7. [PubMed]

240. Wald A, Huang ML, Carrell D, Selke S, Corey L. Polymerase chain reaction for detection of herpes simplex virus (HSV) DNA on mucosal surfaces: comparison with HSV isolation in cell culture. J Infect Dis. 2003;188:1345-51[PubMed] 

241. Wald A, Langenberg AG, Link K, Izu AE, Ashley R, Warren T, Tyring S, Douglas JM, Jr., Corey L. Effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women. JAMA. 2001;285:3100-6. [PubMed]

242. Wald A, Zeh J, Barnum G, Davis LG, Corey L. Suppression of subclinical shedding of herpes simplex virus type 2 with acyclovir. Ann Intern Med. 1996;124:8-15. [PubMed]

243. Wald A, Zeh J, Selke S, Warren T, Ryncarz AJ, Ashley R, Krieger JN, Corey L. Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N Engl J Med. 2000;342:844-50. [PubMed]

244. Watts DH, Brown ZA, Money D, Selke S, Huang ML, Sacks SL, Corey L. 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;188:836-43. [PubMed]

245. Weller S, Blum MR, Doucette M, Burnette T, Cederberg DM, de Miranda P, Smiley ML. Pharmacokinetics of the acyclovir pro-drug valaciclovir after escalating single- and multiple-dose administration to normal volunteers. Clin Pharmacol Ther. 1993;54:595-605. [PubMed]

246. Whitley R, Arvin A, Prober C, Burchett S, Corey L, Powell D, Plotkin S, Starr S, Alford C, Connor J, The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. N Engl J Med. 1991;324:444-9.[PubMed]

247. Whitley R, Arvin A, Prober C, Corey L, Burchett S, Plotkin S, Starr S, Jacobs R, Powell D, Nahmias A, The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Predictors of morbidity and mortality in neonates with herpes simplex virus infections. N Engl J Med. 1991;324:450-4. [PubMed]

248. Whitley R, Lakeman AD, Nahmias A, Roizman B. DNA restriction-enzyme analysis of herpes simplex virus isolates obtained from patients with encephalitis. N Engl J Med. 1982;307:1060-2. [PubMed]

249. Whitley RJ. Herpes simplex virus infections. In: Remington JS, Klein JO, eds. Infectious Diseases of the Fetus and Newborn Infants. 3rd ed. Philadelphia: W.B. Saunders Company, 1990:282-305. [PubMed]

250. Whitley RJ. Herpes simplex viruses. In: Fields BN, Knipe DM, Chanock RM, Hirsch MS, Melnick JL, Monath TP, Roizman B, eds. Fields Virology. 2nd ed. New York: Raven Press, 1990:1843-1887. [PubMed]

251. Whitley RJ, Alford CA, Hirsch MS, Schooley RT, Luby JP, Aoki FY, Hanley D, Nahmias AJ, Soong SJ. Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N Engl J Med. 1986;314:144-9.[PubMed] 

252. Whitley RJ, Cobbs CG, Alford CA, Jr., Soong SJ, Hirsch MS, Connor JD, Corey L, Hanley DF, Levin M, Powell DA. Diseases that mimic herpes simplex encephalitis. Diagnosis, presentation, and outcome. NIAID Collaborative Antiviral Study Group. JAMA. 1989;262:234-9. [PubMed]

253. Whitley RJ, Corey L, Arvin A, Lakeman FD, Sumaya CV, Wright PF, Dunkle LM, Steele RW, Soong SJ, Nahmias AJ. Changing presentation of herpes simplex virus infection in neonates. J Infect Dis. 1988;158:109-16. [PubMed]

254. Whitley RJ, Kimberlin DW, Roizman B. Herpes simplex viruses. Clin Infect Dis. 1998;26:541-53.[PubMed] 

255. Whitley RJ, Lakeman F. Herpes simplex virus infections of the central nervous system: therapeutic and diagnostic considerations. Clin Infect Dis. 1995;20:414-20. [PubMed]

256. Whitley RJ, Levin M, Barton N, Hershey BJ, Davis G, Keeney RE, Whelchel J, Diethelm AG, Kartus P, Soong SJ. Infections caused by herpes simplex virus in the immunocompromised host: natural history and topical acyclovir therapy. J Infect Dis. 1984;150:323-9. [PubMed]

257. Whitley RJ, Nahmias AJ, Soong SJ, Galasso GG, Fleming CL, Alford CA. Vidarabine therapy of neonatal herpes simplex virus infection. Pediatrics. 1980;66:495-501. [PubMed]

258. Whitley RJ, Nahmias AJ, Visintine AM, Fleming CL, Alford CA. The natural history of herpes simplex virus infection of mother and newborn. Pediatrics. 1980;66:489-94. [PubMed]

259. Whitley RJ, Soong SJ, Hirsch MS, Karchmer AW, Dolin R, Galasso G, Dunnick JK, Alford CA. Herpes simplex encephalitis: vidarabine therapy and diagnostic problems. N Engl J Med. 1981;304:313-8. [PubMed]

260. Whitley RJ, Soong SJ, Linneman C, Jr., Liu C, Pazin G, Alford CA. Herpes simplex encephalitis. Clinical Assessment. JAMA. 1982;247:317-20. [PubMed]

261. Wildemann B, Ehrhart K, Storch-Hagenlocher B, Meyding-Lamade U, Steinvorth S, Hacke W, Haas J. Quantitation of herpes simplex virus type 1 DNA in cells of cerebrospinal fluid of patients with herpes simplex virus encephalitis. Neurology. 1997;48:1341-6. [PubMed]

262. Xu F, McQuillan GM, Kottiri BJ, Sternberg M, Lee F, Nahmias A, Markowitz LE. Trends in Herpes Simplex Virus Type 2 Infection in the United States, 42nd Annual Meeting of the Infectious Diseases Society of America, Boston, MA; Abstract 739, September 30-October 3, 2004. [PubMed]

263. Xu F, Schillinger JA, Sternberg MR, Johnson RE, Lee FK, Nahmias AJ, Markowitz LE. Seroprevalence and coinfection with herpes simplex virus type 1 and type 2 in the United States, 1988-1994. J Infect Dis. 2002;185:1019-24. [PubMed]

264. Yeager AS, Arvin AM. Reasons for the absence of a history of recurrent genital infections in mothers of neonates infected with herpes simplex virus. Pediatrics. 1984;73:188-93. [PubMed]

265. Yeager AS, Arvin AM, Urbani LJ, Kemp JA, 3rd. Relationship of antibody to outcome in neonatal herpes simplex virus infections. Infect Immun. 1980;29:532-8. [PubMed]

 

Table 1.  Clinical Manifestations and Type of Infection*

	Type of First Episode Genital Infection
	Primary HSV-1 N = 20	Primary HSV-2 N=189	NonPrimary HSV-2† n=76
Percent with systemic symptoms	58	62	16
Mean duration local pain, days	12.5	11.8	8.7
Mean number of lesions	24.3	15.5	9.5
Percent with bilateral lesions	100	82	55
Percent forming new lesions during course of disease	68	75	45
Mean duration viral shedding    from genital lesions, days	11.1	11.4	6.8
Mean duration lesions, days	22.7	18.6	15.5

  * Adapted from Reference (45).

   † P<0.05 for each comparison between nonprimary and primary HSV-2 infection.

Table 2.  Clinical Manifestations of Primary HSV-2 Genital Herpes*

	Men	Women
Percent with constitutional symptoms	39	68	P<0.05
Percent with meningitis symptoms	11	36	P<0.05
Percent with local pain	95	99
Mean duration of local pain, days (range)	10.9 (1-40)	11.9 (1-37
Percent with dysuria	44	83	P<0.05
Mean duration of dysuria, days (range)	7.2 (2-20)	11.9 (1-26)	P<0.05
Percent with urethral/vaginal discharge	27	85	P<0.05
Mean duration of discharge, days	5.6	12.9	P<0.05
Percent with tender adenopathy	80	81
Mean duration adenopathy, days	8.6	14.2	P<0.05
Mean area of lesions, mm2 (range)	427 (6-1671)	550 (8-3908)
Mean duration of viral shedding from lesions, days	10.5	11.8
Percent with HSV isolated from urethra	28	76	P<0.05
Percent with HSV isolated from cervix	--	88
Mean duration viral shedding from cervix, days	--	11.4
Mean duration of lesions, days	16.5	19.7

  Adapted from Reference (45).

Table 3.  Clinical Manifestations of Recurrent Genital Herpes*

	Men N = 218	Women N = 144
Percent experiencing prodromal symptoms	53	43
Percent with pain    Mean duration pain, days (range)    Mean duration itching, days (range)	67 3.9 (1-14) 4.6 (1-16)	88 5.9 5.2 (1-15)	P<0.01 P<0.01
Percent with dysuria	9	27
Percent with tender lymph nodes    Mean duration tender nodes, days (range)	23 9.2 (1-25)	31 5.9 (1-15)	P<0.01
Percent with bilateral lesions	15	4	P<0.05
Percent forming new lesions during episode	43	28	P<0.05
Mean number of lesions at onset of episode,   days (range)	7.5 (1-25)	4.8 (1-15)
Mean time to crusting, days (range)	4.1 (1-15)	4.7 (2-13)
Mean time to healing, days (range)	10.6 (5-25)	9.3 (4-29)
Mean duration of viral shedding from lesions, days (range)	4.4 (1-20)	4.1 (2-14)

*  Adapted from Reference (52).

 Table 4.  Diagnostic Tests for HSV Infection and Disease    Download PDF

Diagnostic modality	Description	Sensitivity and/or specificity	Utility in clinical practice	Source(s) of specimen
Cytology	Cytologic examination of cells from skin or mucous membrane	Sensitivity of 60-70%	May be useful for presumptive diagnosis	Maternal cervix   Genital lesion(s)   Infant skin, mouth, conjunctivae, or corneal lesion
Serology	Detection of antibody   Two type-specific antibody assays manufactured by Focus Technologies, Inc., have received FDA approval:  the HerpeSelectÒ HSV-1 and HSV-2 ELISA and the HSV-1 and HSV-2 Immunoblottests.   Several additional tests which claim to distinguish between HSV-1 and HSV-2 antibody are commercially available, but high cross-reactivity rates due to their use of crude antigen preparations significantly limit their utility	HerpeSelectÒ HSV-2 ELISA:  Sensitivity of 96-100%, specificity of 97-98%   HerpeSelectÒ HSV-2 Immunoblot:  Sensitivity of97–100%, specificity of 98%   Type-specific tests for HSV-1 tend to be 5–10% less sensitive than their HSV-2 counterparts	Beyond the infantile period, establishes prior infection with HSV-1 and/or HSV-2.  Does not distinguish site of infection.   Could be considered in patients with symptomatic genital disease with lesions in an advanced stage of healing, and patients with risk factors for HSV but no history of genital herpetic lesions   Not useful for diagnosis of neonatal HSV disease.	Blood
Viral culture	Specimen collected, transferred in appropriate viral transport media on ice to a diagnostic virology laboratory, and inoculated into cell culture systems, which are then monitored for cytopathic effects characteristic of HSV replication.	~ 95% of vesicular genital lesions will grow HSV, compared with 70% of ulcerative lesions and 30% of crusted lesions	The definitive diagnostic method of establishing HSV disease outside of the CNS	Skin vesicles, oropharynx, CSF, urine, blood, stool or rectum, oropharynx, and conjunctivae.
Polymerase chain reaction	Detection of viral DNA by molecular amplification	Neonatal HSV CNS disease: Sensitivity 75-100%; specificity 71-100%   HSE beyond the neonatal period: Sensitivity 95-100%; specificity 94%	The gold standard for documenting CNS HSV disease	CSF   Cutaneous or mucous membrane lesions

 

Table 5. Herpes Blood Tests Quick Reference Guide (from http://www.ashastd.org/pdfs/blood_test.pdf, accessed February 3, 2005)    Download PDF

	biokit HSV-2 Rapid Test†	HerpeSelectÒ		CAPTIAÔ HSV IgG Type Specific ELISA
		ELISA	Immunoblot
Supplier	biokit USA (formerly Diagnology with POCkitÒ test)	Focus Diagnostics, Inc. (formerly Focus Technologies)		Trinity Biotech USA
FDA Approved	Yes (August 1999)	Yes (February 2000)	Yes (April 2000)	Yes (July 2004)
Antibodies Detected	HSV-2 only	HSV-1 or HSV-2	HSV-1 and HSV-2	HSV-1 or HSV-2
Sensitivity (no false negatives)	93-96% accurate*	96-100% accurate*	97-100% accurate*	90-100% accurate**
Specificity (no false positives)	95-98% accurate*	97-100% accurate*	98% accurate*	90-99% accurate**
HRC Recommended Window Period	12 to 16 weeks after exposure	12 to 16 weeks after exposure	12 to 16 weeks after exposure	12 to 16 weeks after exposure
Collection Method	Finger prick/blood	Blood draw (sent to local lab)	Blood draw (sent to local lab)	Blood draw (sent to local lab)
Test Location	In provider office	Various labs	Various labs	Various labs
Result Time	Less than 10 minutes	~ 1 to 2 weeks	~ 1 to 2 weeks	~ 1 to 2 weeks
Can Be Used During Pregnancy	Not FDA approved	Yes	Yes	Yes
Manufacturer’s List Price Per Test (does notinclude provider or lab fees)	~ $20	~ $4	~ $19	~ $4
Phone Number	Toll-free (800) 926-3353	Toll-free (800) 505-0536 (to find a specific lab)		Toll-free (800) 325-3424 (to find a specific lab)
Web site	http://www.biokit.com/	http://www.herpeselect.com/		http://www.trinitybiotech.com

 *  Adapted from Reference (8).

**  Adapted from Reference (8), and from FDA Summary of Safety and Effectiveness Information CAPTIA™ HSV-2 IgG Type Specific Test Kit, July 2004.

†  Also available from Fisher HealthCare as Sure-Vue™ HSV-2 Rapid Test. For more information, call toll-free (800) 766-7000 or log on to www.fisherhealthcare.com.

Table 6.  Recommended uses of HSV type-specific serologic testing*

Indication	HSV type-specific testing
Confirm diagnosis of genital herpes	Clinical diagnosis is not sensitive or specific; therefore, laboratory confirmation of HSV-1 or -2 is recommended
Establish diagnosis of genital herpes	Atypical genital lesions often represent genital herpes; therefore, HSV type-specific serology for HSV-1 and -2 is recommended
Testing of high-risk populations	Serologic testing for HSV-2 should be offered as part of standard sexually transmitted disease screening
Testing partners of HSV-infected people	Discordance in HSV infection can only be established by laboratory testing; therefore, to counsel patients about the risk of transmission, HSV-1 and -2 serology should be offered
Testing of HIV-infected individuals	Given the epidemiologic synergy between HIV and HSV, testing for HSV-2 should be offered routinely to HIV seropositive people
Testing in pregnancy	Serologic testing for HSV-1 and -2 should be offered to pregnant women to identify those susceptible to HSV acquisition in late pregnancy
General screening	Currently not recommended

 *  From Reference (222).

Table 7.  Therapeutic management of nongenital HSV infections   Download PDF

	Primary Oropharyngeal HSV Infections (Gingivostomatitis; HSV-1)	Recurrent Oropharyngeal HSV Infections (Herpes labialis; HSV-1)	Other Primary HSV Skin Infections (HSV-1)	HSV keratitis or keratoconjunctivitis (HSV-1)
Acyclovir	600 mg/m2/dose po QID x 10 d (adult maximum 200 mg/dose po 5X/d)	15 mg/kg/day ¸ q 8h until able to switch to po 200 mg/dose po 5X/day x 7-10 d	Eczema herpeticum: 10 mg/kg/dose po 3-5X/d x 5-7 d (adult maximum 200 mg/dose po 5X/d) Whitlow: 200 mg/dose po 5X/day x 10 d
Valaciclovir		2 grams orally twice a day for 1 day
Famciclovir			Whitlow: 125 mg/dose po BID
Penciclovir (DenavirÒ)		Apply topically q 2 h during waking hours x 4 d
Trifluridine				1 drop q 2h (maximum 9 drops/d) until cornea is re-epithelialized, then q 4h for an additional 7d (maximum 21 d)
Vidarabine				Thick strip of ointment (1.25 cm) q 3h until cornea is completely re-epithelialized, then BID for an additional 7 d

 

Table 8.  Therapeutic management of genital HSV infections (HSV-2 or HSV-1)*     Download PDF

	First Clinical Episode (treat orally for 7-10 days†)	Episodic Recurrent Infection¶ (treat orally for 5 days)	Oral Suppressive therapy	Episodic recurrent infection in HIV-infected persons (treat orally for 5-10 days)	Oral Suppressive therapy in HIV-infected persons	Advantages	Disadvantages
Acyclovir	200 mg 5X/day OR 400 mg 3X/day	200 mg 5X/day OR 800 mg 2X/day	400 mg 2X/day	200 mg 5X/day OR 400 mg 3X/day	400-800 mg 2X/day or 3X/day	Less expensive   Smaller tablets   Liquid formulation available	Less convenient dosing regimens
Valaciclovir	1000 mg/ 2X/day	500 mg 2X/day‡ OR 1000 mg 1X/day	500 mg 1X/day§ OR 1000 mg 1X/day	1000 mg 2X/day	500 mg 2X/day	More convenient dosing regimens	More expensive   Larger caplet
Famciclovir	250 mg 3X/day	125 mg 2X/day	250 mg 2X/day	500 mg 2X/day	500 mg 2X/day	More convenient dosing regimens   Smaller tablet	More expensive

 * Modified from Reference (5).

†  The range of duration of therapy relates to differences in treatment durations in the original clinical studies.  If the shorter course of therapy is initially prescribed, the patient should be reevaluated toward the end of treatment and therapy should be continued if new lesions continue to form, if complications develop, or if systemic signs and symptoms have not abated.

‡  Three-day course of therapy also acceptable

§  For patients with ≤ 9 recurrences/year

¶  When started within 24 hours of the recurrence

Table 9.  Telephone and Online Resources for Herpes Information

Organization	Telephone Information	Website
American Social Health Association (ASHA)	800-230-6039 (Resource Center) 919-361-8488 (Patient Herpes Hotline)	www.ashastd.org (ASHA website) www.ashastd.org/hrc (Herpes Resource Center website) www.ashasdt.org/hrc/helpgrp1.html (HELP support groups for people in the U.S., Canada, and Australia with genital herpes)
The Centers for Disease Control and Prevention (CDC)	800-227-8922 National STD Hotline	www.cdc.gov (CDC website) www.cdc.gov/nchstp/dstd/dstdp.html (CDC fact sheet on STDs)
Planned Parenthood	800-230-7526	www.plannedparenthood.org
GlaxoSmithKline		www.herpeshelp.com www.herpesweb.net www.harduherpes.nu (in Swedish)
Novartis		www.cafeherpe.com www.genitalherpes.com www.herpes.com.au (Australia)
National Institutes of Health		www.nih.gov (NIH website) www.niaid.nih.gov/dmid/stds (NIAID fact sheet on STDs)
American Herpes Foundation		www.herpes-foundation.org
International Herpes Management Forum		www.ihmf.org
DAC Consultants		www.herpesdiagnosis.com
International Herpes Alliance		www.herpesalliance.org
Association Herpès		www.herpes.asso.fr (in French)

Figure 1.

Figure 2.  Recurrent herpes simplex labialis [From Reference (250)]

Figure 3.  Primary genital HSV lesions [From Reference (115)]

 Figure 4.  Illustration of viral latency and reactivation [From Reference (30)]

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Fuchs J, et al. Clinical and Virologic Efficacy of Herpes Simplex Virus Type 2 Suppression by Acyclovir in a Multicontinent Clinical Trial. J Infect Dis 2010;201:1164-1168.

Berrington WR, Jerome KR, et al. Clinical correlates of herpes simplex virus viremia among hospitalized adults. Clin Infect Dis. 2009 Nov 1;49(9):1295-301.

Abudalu M, et al. Single-day, Patient-Initiated Famciclovir Therapy Versus 3-Day Valacyclovir Regimen for Recurrent Genital Herpes: A Randomized, Double-Blind, Comparative Trial. Clin Infect Dis. 2008 Sep 1;47:651-8.

Ihekwaba UK et al. Clinical Features of Viral Meningitis in Adults: Significant Differences in Cerebrospinal Fluid Findings Among Herpes Simplex Virus, Varicella Zoster Virus, and Enterovirus Infections. Clin Infect Dis. 2008 Sep 15;47(6):783-9.

Philip et al. Evaluation of a New Point-of-care Serologic Assay for Herpes Simplex Virus Type 2 Infection. Clin Infect Dis. 2008 Nov 15;47(10):e79-82.

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