Epidemiology of HSV-1 and HSV-2

Herpes simplex viruses are among the most ubiquitous of human infections. The frequency of HSV infection has been measured by testing various populations for the presence of antibody, as both virus and the immune response are thought to persist after infection for the life of the host. Worldwide, ∼90% of people have one or both viruses. HSV-1 is the more prevalent virus, with 65% of persons in the United States having antibodies to HSV-1 (Xu et al., 2002). The epidemiology in Europe is similar, with at least half of the population seropositive for HSV-1. In the developing world, HSV-1 is almost universal, and usually acquired from intimate contact with family in early childhood (Whitley et al., 1998). After childhood, the HSV-1 prevalence rates increase minimally with age. Rates of HSV-1 infection are similar for men and women. In the United States, African-Americans and Asians have higher rates of HSV-1 infection than whites. The majority of infections are oral, although most are asymptomatic. Some data suggest that in developed countries, acquisition of HSV-1 is delayed from early childhood to adolescence or young adulthood (Hashido et al., 1999; Mertz et al., 2003).

HSV-2 infections are markedly less frequent than HSV-1 infections, with 15%–80% of people in various populations infected (Corey and Wald, 1999). The rates of infection vary with country as well as levels of sexual activity. In some countries, such as Spain and the Philippines, the HSV-2 prevalence hovers around 10%, increasing to 20%–30% range for most European countries and the United States (Varela et al., 2001; Smith et al., 2001; Enders et al., 1998; Malkin et al., 2002). Developing countries bear a much higher burden of HSV-2 infection, with many populations in Africa having >50% prevalence in the general population (Weiss et al., 2001). Because HSV-2 infections are transmitted almost exclusively during sexual activity, the risk of HSV-2 reflects a person’s level of sexual activity and the number of partners, and background prevalence of infection in the community. In communities with relatively low rates of infection, the risk of HSV-2 infection reflects more closely sexual activity of the person. However, in communities with high prevalence of infection, demographic rather than behavioral factors reflect HSV-2 risk more accurately (Sucato et al., 2001; Rosenthal et al., 1997; Austin et al., 1999). Women have a greater risk of HSV-2 acquisition, reflecting both increased biologic susceptibility and pattern of relationships with older men, who are more likely to be HSV-2 seropositive. HSV-2 prevalence in the United States is higher among African-Americans than among whites and Asians (Fleming et al., 1997). As a result, there is great disparity in infection rates according to both gender and race. For example, for white women, the risk of HSV-2 increases from about 18% among those with 2–4 lifetime partners to 35% for those with 10 to 49 lifetime partners (Fleming et al., 1997). In contrast, for African-American women the risk increases steeply even with fewer partners, and exceeds 60% for women with more than 4 lifetime partners. For white men, the risk is ∼10% among those who report 2 to 9 lifetime partners, and reaches 40% in those with >50 lifetime partners. Among African-American men, the risk rises from 35% in those with 2–4 lifetime partners to ∼ 50% in those reporting >50 lifetime partners. The increase in the frequency of HSV-2 antibodies starts in adolescence, reflecting the initiation of sexual activity, and levels off in the 40s, probably reflecting cessation of new partner acquisition (Blower and Boe, 1993). In the United States, most people acquire HSV-2 in their 20s with a mean age at presentation of 24 years. In contrast, in South Africa, girls acquire HSV-2 infection in adolescence and >60% are infected by the age of 21 (Chen et al., 2000).

The advent of the HIV epidemic initially eclipsed HSV-2 as a viral sexually transmitted disease of importance, but recent data have increasingly showed multiple interactions between the two viral infections (Corey et al., 2004a). The development of molecular diagnostics has revealed that HSV-2 is the most common etiologic agent of genital ulcers in the developed and developing world (Chen et al., 2000; Serwadda et al., 2003). Even in regions in which syphilis and chancroid have been historically considered responsible for most genital ulcerations, the use of PCR-based techniques has clearly shown a predominance of HSV (Beyrer et al., 1998; Morse et al., 1997). In almost all studies, and in all populations, having HSV-2 infection increases the risk of HIV acquisition (Wald and Link 2002; Freeman et al., 2006). The mechanism probably involves both HSV-2 induced skin or mucosal ulcerations, as well as influx of CD4+ cells into the herpetic lesions, cells that provide receptor for entry of HIV (Koelle et al.,1994). As transmission is more difficult to study than acquisition, the role of HSV-2 in the transmission of HIV is less well defined (Cameron et al., 1989). However, the biology also suggests that HSV-2 infection may amplify HIV transmission, as HIV virions have been demonstrated in herpes ulcers (Schacker et al., 1998c; Ballard, 2001). This topic of HSV and HIV interactions has been recently reviewed (Corey et al., 2004a).

Spectrum of clinical disease

HSV can cause both mucocutaneous and systemic disease, and both HSV-1 and HSV-2 can cause the same syndromes, although the viruses are preferentially more likely to be associated with some syndromes than others. The variability in clinical expression is poorly understood, but the host immune system appears to be the main determinant of the clinical manifestations of HSV infections. The most severely affected are neonates, who usually acquire the disease during birth through exposure to infected genital secretions (Whitley et al.,1980). Rarely, adults can develop severe or fatal HSV infection during acquisition, and pregnant women appear to have a higher risk for this syndrome (Kobberman et al., 1980; Sutton et al., 1974). In most persons, HSV infections are confined to skin and mucosa. However, these can be severe, especially in persons immunocompromised either by other diseases (HIV, lupus), or iatrogenic immunosuppression or transplant, or extensive skin disease, such as eczema (Luchi et al., 1995; Wheeler, Jr and Abele, 1966). Certain HSV-associated syndromes, such as HSV uveitis, have a strong immunopathogenic component and respond to immunosuppressive therapy (Balfour, 1994; Lairson et al., 2003).

Immunocompetent host

Neonatal herpes

The frequency of neonatal herpes varies by region and is estimated to occur from 1 in 3200 to 1 in 15 000 pregnancies (Sullivan-Bolyai et al., 1983a; Tookey and Peckham, 1996; Mindel et al., 2000; Brown et al., 2003; Gutierrez et al., 1999). Reasons for the variant frequency are poorly understood but are likely to result from interplay between sexual behavior in the population and the baseline prevalence and incidence of HSV-1 and HSV-2. Over 85% of neonatal herpes is acquired from intrapartum exposure of the newborn to infected maternal secretions. In 5% of cases, congenital infection of the fetus in the setting of new acquisition of HSV during pregnancy has been reported (Florman, 1973; Sullivan-Bolyai et al., 1983a). These infants are born with clinical evidence of disseminated disease, often including skin lesions, may be premature and have a poor prognosis. Post-natal acquisition of HSV, often from non-maternal sources, has also been reported in about 10% of cases, and is associated with HSV-1 infection.

Recent prospective studies have clarified risk factors for HSV transmission during delivery (Brown et al., 1997; Arvin et al., 1986; Prober et al., 1992). The greatest risk of neonatal herpes is conferred by viral shedding, defined as HSV isolation in maternal genital secretions at the time of parturition, with a relative risk of neonatal HSV of >300 compared with women who do not have HSV isolated during labor (Brown et al., 2003). However, some infants acquire neonatal herpes despite lack of culturable virus at the time of delivery. In some of these cases, HSV DNA can be detected by PCR despite negative viral culture, suggesting that culture can be falsely negative. Of greater concern is the observation that only 5% of women who have HSV isolated from the genital tract at the time of delivery transmit HSV to the infant. As such, these women are at potential risk of unnecessary interventions.

Among women who are shedding HSV in genital secretions at labor, risk factors for neonatal herpes include newly acquired HSV infection (RR = 59), cervical vs. vulvar viral isolation (RR = 15), young mother (RR = 2.7 for women aged <21), and HSV-1 vs. HSV-2 isolation (RR = 5). Cesarean deliveries appear protective as women who are delivered abdominally had a significantly lower risk of HSV transmission compared with women who had vaginal delivery (RR = 0.14). Because even the largest series of neonatal herpes contain only a handful of cases, the exact contribution of each risk factor is difficult to measure. However, overall, most cases of neonatal herpes appear to occur among women who acquire subclinically new genital HSV-1 or HSV-2 and who deliver vaginally (Arvin et al., 1982, Whitley et al., 1991b). In one study, 4 of 9 women who acquired HSV so late in pregnancy that they did not seroconvert by the time of delivery transmitted the virus to their infant (Brown et al., 1997). Management of recognized newly acquired genital herpes at the end of pregnancy needs to be individualized and should include consideration of administration of acyclovir to women toward the end of pregnancy, scheduled abdominal delivery prior to rupture of membranes, and prophylactic antiviral therapy of the newborn (Prober et al., 1992; Sheffield et al., 2003).

Infants with neonatal herpes often present with non-specific complaints such as fever, fussiness, sepsis, or seizures (Whitley et al., 1998). Typical skin lesions are not noted universally, and depending on the disease classification, may develop only in up to 80% of patients. Clinically, neonatal herpes has been divided into 3 syndromes. In recent studies, skin, eye and mouth disease accounted for 42% of cases, and is defined by disease that is present only on skin or mucosa(Whitley et al., 1998, Kimberlin et al., 2001a). This form of infection has the best prognosis with negligible mortality and up to 70% of treated infants having normal development. Of interest, even those infants who did not have any evidence of CNS involvement may subsequently present with neurologic deficits, suggesting that subclinical and/or delayed involvement of the brain is not uncommon. Disseminated disease accounts for 23% of cases and has the highest mortality (60% with therapy). Among the survivors, normal development is noted in about 60%. CNS disease comprises the remaining 35% of newborns with neonatal herpes. Mortality is low, but this form of disease is associated with highest morbidity as less than 50% will have normal development. Comparison of secular trends suggests that a greater proportion of cases are diagnosed with SEM disease in recent years compared with an earlier cohort (Whitley et al., 1988, 1991a, b). A potential explanation is that the diagnosis is made earlier, prior to dissemination or CNS invasion. Many cases are still diagnosed late, or post-mortem, and administration of acyclovir to infants with sepsis-like syndrome is not universally done. Prompt antiviral therapy is associated with decreased morbidity and mortality, but the prognosis remains grave for most children. HSV-2 appears more neuroinvasive in newborns than HSV-1, and as such, has a worse prognosis (Corey et al., 1988).

The observations about risk factors for neonatal herpes suggest that prevention of neonatal herpes relies on prevention of HSV acquisition in late pregnancy. This strategy, in turn, relies on identification of women at risk for HSV infection with the use of type-specific serology, and, potentially, the serologic testing of their sex partners. This approach has not been widely accepted (Wilkinson et al., 2000; Brown, 2000). Reasons for resistance are numerous, including lack of confidence in the performance of commercial type-specific serologies, perception that counseling about results of HSV serologies is burdensome to both providers and patients, lack of simple interventions, and the relative rarity of neonatal HSV. Of note, after institution of universal testing for Group B streptococcus (GBS) during the last trimester, the frequency of neonatal GBS sepsis now approaches that of neonatal HSV (Gibbs et al., 1994; Chuang et al., 2002; Schrag and Schuchat, 2004).

Immunocompromised persons

Immunosuppression, regardless of etiology, is associated with greater risk of HSV reactivation, prolonged viral shedding and more severe clinical recurrences (Meyers et al., 1980; Siegal et al., 1981). While even in severely immunocompromised patients most disease is mucocutaneous, extension to internal organs, such as esophagus, or dissemination, can also occur. Other syndromes include hepatitis and pneumonia (Ramsey et al., 1982). Patients receiving cancer chemotherapy are at risk for HSV recurrences during periods of neutropenia; the risk in organ or marrow transplant patients is prolonged and parallels the duration of immunosuppression (Wade et al., 1984a). However, the greatest risk of HSV reactivation after bone marrow transplant occurs early during the initial neutropenia associated with myeloablation. This is in contrast to other herpesvirus infections, such as VZV and CMV, which tend to occur later during the post-transplant period during maximal suppression of cell-mediated immunity. Because HSV has a significant impact on post-chemotherapy and post-transplant morbidity, acyclovir prophylaxis is administered routinely in this population (Wade et al., 1984b).

In the last two decades, HIV has emerged as the most common cause of immunosuppression worldwide. Not surprisingly, early clinical reports of patients with HIV document extensive clinical HSV recurrences (Siegel et al., 1988). The disease burden is especially great, as persons at risk for sexually transmitted HIV are more likely to have HSV-2 infection than the general population. Prior to the introduction of effective antiretroviral therapy, chronic HSV ulcers accounted for a small proportion of newly diagnosed persons with AIDS, and developed in many other persons as immunosuppression progressed. Despite the frequent presence of HSV-1 and HSV-2 infection (90% overall) in patients with HIV, extensive clinical disease develops only in a minority of patients (Bagdades et al., 1992). The immunologic and virologic risk factors for developing severe disease are not understood. Systematic study of clinical and virologic aspects of genital HSV-2 shows that even in the absence of overt clinical disease, HIV infected persons have high rates of viral shedding. Among a group of 68 men who have sex with men with HIV infection and a mean CD4 count of 351, the rate of genital HSV isolation was 9.7% of days, and the perianal area accounted for 79% of isolates (Schacker et al., 1998b). The relative risk of total viral shedding was elevated at 3.3 compared with men who are HIV negative, but an even greater relative risk of 6.9 was shown for subclinical shedding. These observations show that HIV has a greater effect on the virologic than clinical aspects of the natural history of HIV and may provide an explanation for a burgeoning epidemic of HSV-2 in parallel with HIV in sub-Saharan Africa.

Immune reconstitution with antiretroviral therapy (ART) has resulted in a decrease in risk of several opportunistic infections, and has allowed for stopping of prophylaxis in those patients with vigorous CD4 response. Unfortunately, the data suggest that the increase in CD4 cells associated with ART prevents lesions, with significantly lower risk of mucocutaneous lesions among patients treated with ART compared with patients who are untreated, but has a negligible effect on viral shedding (Posavad et al., 2001). As such, HSV-2 & HIV seropositive patients are likely to continue to be infectious for HIV and HSV-2 and suppressive HSV therapy should be considered in that setting.

Viral shedding

HSV is present intermittently on skin or mucosa in between symptomatic recurrences. This phenomenon, defined as asymptomatic or subclinical shedding, has been described since the early clinical descriptions of genital herpes. However, the frequency, pattern, and the importance of subclinical shedding for transmission of HSV have only recently been elucidated.

The frequency of viral shedding has been measured both by culture and by PCR. Studies using amplification techniques show that HSV DNA PCR is up to 400% more sensitive for detection of HSV on mucosal surfaces than viral isolation (Wald et al., 2003) (Fig. 36.1). The frequency of viral shedding varies with type of HSV, duration of infection, gender, and immune status. Most variability observed in the frequency of viral reactivation is not explained by these risk factors, suggesting that there is a strong host immunogenetic (or viral strain) factor in determining the severity of disease.

Fig. 36.1

The relationship between the probability of HSV isolation in viral culture and the number of copies of HSV DNA as detected by PCR (adapted from Wald (Wald et al., 2003)).

The initial study examining prospectively viral shedding among women with recent genital HSV-2 infection showed that HSV was detected by PCR on 28% of days sampled (Wald et al., 1997). However, as shown in Fig. 36.2, the variability in the frequency of reactivation is great, even among this homogeneous group of women. Subsequent studies have also examined viral shedding among men. In a group of men with either recent acquisition of genital HSV-2 or a history of frequent recurrences, the overall rate of HSV detection from the genital area by PCR was 32% (median 30%; range 0 to 92%) (Wald et al., 2002b). Despite the rough parallel between the frequency of viral shedding and the frequency of recurrent lesions, these two processes are somewhat independent, with some persons having frequent days with lesions, or prolonged lesions, and others having frequent viral shedding but without many recurrences. These observations suggest that the immunologic mechanisms that control viral shedding may differ from those that control lesion formation and resolution. Animal experiments, and findings in persons with immune compromise, indicate that the CD4 response predominates in control of lesions, while CD8 response is more important for control of viral reactivation (see Chapter 34).

Fig. 36.2

Variability in symptomatic and subclinical shedding among 26 women with genital HSV-2 infection for less than 2 years.

Transmission dynamics

Figure 36.3 illustrates the pattern of viral shedding during inadvertent sexual transmission of HSV-2 infection. The woman participating in a daily home sampling study had symptomatic genital HSV-2 infection for 3.5 years, and had initiated a new relationship with a partner who was HSV seronegative. Despite having occasional non-specific symptoms, she did not notice a recurrence during the episode of subclinical viral shedding that resulted in transmission of HSV-2. Studies consistently indicate that transmission to sex partners, or to neonates, usually occurs during such episodes of subclinical shedding (Barton et al., 1987; Mertz et al., 1992).

Fig. 36.3

Sexual transmission of HSV-2 during subclinical shedding.

Prospective studies of HSV-2 discordant couples have been used to estimate rate of transmission and ascertain risk factors for transmission. Unfortunately, only a few such studies have been done that included a sufficiently large number of persons to obtain reliable estimates of rates of transmission and risk factors (Mertz et al., 1988, 1992; Stanberry et al., 2002; Bryson et al., 1993; Wald et al., 2001; Corey et al., 2004b). The rate of HSV-2 acquisition among persons at risk varies from a high of 8.6 per 100 person-years for women, to a low of 2.7 per 100 person-years among men. These studies have also shown that (1) women are at 2-to-6 fold higher risk for HSV-2 acquisition than men; (2) prior infection with HSV-1 does not protect against HSV-2 acquisition; (3) symptoms of first episode HSV-2 infection are less prominent among those with previous HSV-1 infection; (4) frequent sexual activity is a risk factor for HSV-2 transmission, and (5) HSV-2 is transmitted more easily than HSV-1 infection. Other characteristics that have been associated with increased risk of HSV-2 transmission, but inconsistently, or without reaching statistical significance, include short duration of relationship and short duration of genital herpes in the source partner prior to study participation, and sex during recurrences (Corey et al., 2004b). Condoms appear to be protective, but the degree of protection afforded by consistent use, and effect of condom use on female-to-male vs. male-to-female transmission varies among the studies (Wald et al., 2001). In addition, the use of condoms in monogamous, long-term relationships is rare, even in the settings of known HSV-2 discordance and extensive counseling in the context of a clinical trial. Available data indicate that consistent condom use offers partial protection (∼ 50%) against HSV-2 acquisition at best. A recent study of daily suppressive valacyclovir has shown that transmission is decreased by 48% among those couples who were randomized to receive antiviral therapy (Corey et al., 2004b). These results offer couples another option to use to decrease the risk of HSV-2 transmission, and are an added benefit to the use of daily antiviral therapy (see below).

Management and prevention

Treatment

The advent of antiviral drugs for HSV-1 and HSV-2 infections has made clinical management of these infections a part of standard clinical practice (Table 36.1). For mucocutaneous and visceral HSV infections, acyclovir and its related compounds famciclovir and valacyclovir have been the mainstay of therapy (Whitley and Gnann Jr, 1992). Several antiviral agents are available for topical use in HSV eye infections: idoxuridine, trifluorothymidine and topical vidarabine. For HSV encephalitis and neonatal herpes, intravenous acyclovir is the treatment of choice. Acyclovir resistant virus can be encountered in immunocompromised hosts (Erlich et al., 1989; Reyes et al., 2003).

Table 36.1

Treatment of HSV infections.

Acyclovir was the first antiviral clearly demonstrated to be effective against HSV infections (Elion et al., 1977). It is an acyclic nucleoside analogue that is a substrate for HSV-specific thymidine kinase. Acyclovir is selectively phosphorylated by HSV-infected cells to acyclovir-monophosphate. Cellular enzymes then phosphorylate acyclovir-monophosphate to acyclovir-triphosphate, a competitive inhibitor of viral DNA polymerase. Acyclovir-triphosphate is incorporated into the growing DNA chain of the virus and causes chain termination. Acyclovir has potent in vitro activity against both HSV-1 and HSV-2.

Valacyclovir is the valyl ester of acyclovir and is metabolized in the gut, liver and epithelium to acyclovir and produces much higher levels of drug leading to more convenient therapy (Soul-Lawton et al., 1995). Famciclovir, the oral formulation of penciclovir, is also clinically effective in the treatment of a variety of HSV-1 and HSV-2 infections (Pue and Benet, 1993). Ganciclovir has activity against both HSV-1 and HSV-2, but because it is more toxic than acyclovir, valacyclovir, and famciclovir, it is generally not recommended for treatment of HSV infections. Numerous trials of acyclovir in mucocutaneous HSV infections of immunocompetent and immunosuppressed host have been conducted. General recommendations are outlined below (Centers for Disease Control and Prevention 2002). Increasingly, shorter courses of therapy are being utilized for treatment of recurrent mucocutaneous HSV-1 or HSV-2 in immunocompetent patients.

Treatment of recurrent mucocutaneous herpes

Among immunocompetent patients, recent studies have shown the effectiveness of short course therapy to reduce the signs and symptoms of oral and genital HSV infection. These include 2 g twice daily for one day of valacyclovir for oral-labial HSV and 2 and 3 day courses of acyclovir or valacyclovir for recurrent episode genital herpes (Spruance et al., 2003; Leone et al., 2002; Wald et al., 2002a). One-day therapy with famciclovir for genital herpes also appears to increase the probability of an aborted recurrence and to shorten the duration of lesions and symptoms, compared with placebo (Aoki et al., 2006).

Suppression of mucocutaneous herpes

Recognition of the high frequency of subclinical reactivation has provided increasing rationale for the use of daily antiviral therapy to suppress reactivations of HSV. This is especially useful for persons with frequent clinical reactivations such as those with recently acquired genital HSV infection. Immunosuppressed persons, including those with HIV infection, may also benefit from daily antiviral therapy. A variety of dosages have been utilized.

Reduction in transmission to sexual partners

Once daily valacyclovir (500mg) has been shown to reduce transmission of HSV in partnerships in which one partner has symptomatic genital HSV-2 and the other partner is susceptible (Corey et al., 2004b). Serologic screening can be used to identify at risk couples, as many couples identified as discordant by history are concordant on serologic evaluation.

Severe HSV infection

Intravenous acyclovir (30 mg/kg/day, given as a 10 mg/kg infusion over 1 hour at 8-hour intervals) is effective in reducing the morbidity and mortality from HSV encephalitis (Whitley, 1988; Whitley and Lakeman, 1995). Early initiation of therapy is a critical factor in outcome. The major side effect associated with intravenous acyclovir is transient renal insufficiency, usually caused by crystallization of the compound in the renal parenchyma. This adverse reaction can be avoided if the medication is given slowly over 1 hour and the patient is well hydrated. Because CSF levels of acyclovir average only 30% to 50% of plasma levels, the dosage of acyclovir used for treatments of CNS infection (30 mg/kg per day) is double that used for the treatment of mucocutaneous or visceral disease (15 mg/kg per day). For neonatal HSV, high-dose intravenous therapy is recommended (60 mg/kg per day in three divided doses) (Kimberlin et al., 2001b). Intravenous therapy for neonatal herpes should be given for 21 days. Increasingly, serial testing of CSF HSV DNA has been utilized to guide the duration of therapy, and most experts advocate treating until HSV DNA is no longer detected. In immunosuppressed patients, IV acyclovir or oral valacyclovir are utilized to prevent HSV reactivations during transplantation or chemotherapy, and high doses of oral valacyclovir also prevent CMV reactivation (Dignani et al., 2002; Lowance et al., 1999).

Acyclovir-resistant strains of HSV have been identified, especially in HIV-infected persons. Almost all clinically significant acyclovir resistance has been seen in immunocompromised patients. Most acyclovir-resistant strains of HSV have a deficiency in thymidine kinase, the enzyme that phosphorylates acyclovir (Darby et al., 1981). Thus, cross-resistance to famciclovir is usually found. Occasionally, an isolate with altered thymidine kinase specificity will arise and will be sensitive to famciclovir but not to acyclovir. In some patients infected with thymidine kinase–deficient virus, higher doses of acyclovir are associated with clearing of lesions. In others, clinical disease progresses despite high-dose therapy. Isolation of HSV from persisting lesions despite adequate dosages and blood levels of acyclovir should raise the suspicion of acyclovir resistance (Safrin et al., 1992, 1994). In such cases therapy with the antiviral drug foscarnet is useful (Safrin et al., 1991). Because of its toxicity and cost, this drug is usually reserved for patients with extensive mucocutaneous infections. Cidofovir is a nucleotide analogue (Snoeck et al., 1994). Most thymidine kinase–deficient strains of HSV are sensitive to cidofovir. Cidofovir ointment has been shown to speed healing of acyclovir-resistant lesions (Lalezari et al., 1997). Similarly, trifluorothymidine ointment has also been reported to be of utility (Birch et al., 1992).

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