Genital Herpes and Public Health: Title and subTitle BreakAddressing a Global Problem

Genital herpes is a sexually transmitted disease (STD) caused by the herpes simplex viruses (HSVs). It is one of the 3 most prevalent STDs in the United States (with chlamydial and human papillomavirus infections) and probably the one, apart from the acquired immunodeficiency syndrome (AIDS), of greatest concern to sexually active people.^{1 - 3} While most genital herpes is caused by HSV-2, genital infections with HSV-1 are increasingly recognized.^{4 - 5}

Genital herpes is widely perceived to be an uncommon infection that affects only persons at high risk for other STDs, and many clinicians consider genital herpes to be a trivial condition. In reality, genital herpes is one of the most common STDs worldwide,⁶ and although most infections are mild or even subclinical,^{5 ,7} serious complications are frequent and evolving evidence implicates genital HSV infection as a potent facilitator of sexual transmission of the human immunodeficiency virus (HIV).^{8 - 10}

With rare exceptions, genital herpes is not a routinely reported disease and the laboratory tests necessary for an accurate diagnosis have been expensive and are rarely used in clinical or public health settings.¹¹ The recent approval of new laboratory-based and point-of-care diagnostic tests for detection of HSV-2 antibodies provides new opportunities for clinicians and public health providers to more effectively address genital herpes and its prevention.^{12 - 13}

The seroprevalence of HSV-2 infection has been studied in the National Health and Nutrition Examination Survey (NHANES), a large ongoing population-based study, in which it was found that the seroprevalence of HSV-2 in the United States rose from 16.7% in NHANES-II (midpoint 1978) to 21.7% in NHANES-III (midpoint 1991).^{1 ,14} Seroprevalence of HSV-2 is virtually nonexistent in persons younger than 12 years, peaks by the age of 40 years, and remains stable thereafter, indicating that almost all HSV-2 infections are acquired between 15 and 40 years of age, as expected for an STD.^{1 ,14} By contrast, the seroprevalence of HSV-1 approximates 20% in children younger than 5 years and rises in a nearly linear fashion through the age of 70 years.¹⁴ Not surprisingly, among persons attending STD clinics in the United States, the seroprevalence of HSV-2 is higher than in the broad population, varying from 30% to 70% in most clinics.¹¹ While orolabial HSV-2 infection is rare, and when it occurs is almost always seen in conjunction with genital herpes,¹⁵ HSV-2 seroprevalence is a direct measure of genital herpes, albeit an incomplete one that does not account for genital HSV-1 infection. The 22% prevalence in the general population means that about 45 million persons were infected with HSV-2 in 1991; considering that HSV infections persist indefinitely, that many more persons undoubtedly became infected in the next 9 years, and that several million more persons have genital HSV-1 infections, it is likely that more than 50 million persons in the United States have genital herpes.

Similar findings have been reported elsewhere. In Scandinavia, the seroprevalence of HSV-2 infection among pregnant women nearly doubled over the past 2 decades, from 19% to 33%.¹⁶ Data presented at the recent annual meeting of the International Herpes Management Forum indicated that 25% of men and women attending STD clinics in the United Kingdom, 14% to 90% of STD clinic attendees in Sweden, and 5% to 40% in various other populations in Europe are infected with HSV-2.¹⁷ Seroprevalence rates in the developing world are even higher. For example, among gold miners in South Africa and commercial sex workers in Africa, HSV-2 seroprevalence rates are 60% to 90%.^{8 ,18}

Such prevalences are startling for any STD. Further, the National STD Hotline, funded by the Centers for Disease Control and Prevention (CDC), receives about 60,000 herpes-related calls annually, more than for any other STD and almost as many as for all other STDs combined (written communication, Marshall Glover, American Social Health Association, Research Triangle Park, NC, September 1999). This and the substantial media attention to genital herpes over the past 2 decades are measures of the high level of concern about herpes among sexually active persons.

Why then is there so little apparent attention to genital herpes or its prevention by health care providers and the public health establishment? The answers are many, but a central problem is the high proportion of genital HSV infections that are unrecognized by patients and clinicians alike. In NHANES-III, only 9% of HSV-2 seropositive persons reported that they had genital herpes.¹ Even when persons with HSV-2 antibody are asked more probing questions, only a quarter to a third acknowledge symptoms consistent with genital herpes, and a recent cohort study showed that only 38% of pregnant women with well-documented initial acquisitions of HSV-2 were symptomatic.¹⁹ Nevertheless, when persons with previously unrecognized HSV-2 infection are educated about the clinical manifestations of genital herpes, about two thirds come to recognize typical symptoms, and within 3 months most develop typical lesions on examination.²⁰

Thus, many persons infected with HSV-2 have symptomatic, albeit unrecognized, genital herpes. Clinically mild infections often do not bring people to medical attention, and for many infected persons the diagnosis is missed by clinicians. The clinical manifestations of genital herpes include the following: subtle, often painless ulcers; dysuria; urethral and vaginal discharge; vulvar irritation; and perianal, scrotal, and vulvar fissures, in addition to classical vesiculopustular lesions.^{2 ,5 ,7 ,11} As such, there is substantial overlap in the clinical manifestations of genital herpes with those of other common conditions such as cervicovaginal infections, urinary tract infections, and dermatoses that can affect the genitals. The diagnosis of genital herpes increases greatly when sensitive diagnostic tests, such as viral culture and type-specific serologic tests, are made available to clinicians.^{11 ,20}

A critical issue in understanding the epidemiology of HSV-2 infection is the recent recognition that (1) more than 85% of persons who have HSV-2 antibodies but do not report lesions nonetheless shed virus from the genital tract and (2) many who acquire infection subclinically subsequently develop clinical recurrences.^{5 ,21} In immunocompetent young adults typically studied within the first few years after infection, HSV-2 can be isolated by culture from genital or perianal swabs 1% to 5% of days, and HSV-2 DNA can be detected by polymerase chain reaction testing 15% to 20% of days.^{22 - 23} Thus, the large majority of HSV-2–seropositive persons intermittently shed virus from mucosal surfaces and are reservoirs for the potential spread of HSV to their uninfected sex partners. While exacting data on subclinical shedding rates over time are still lacking, emerging data suggest that reactivation and viral shedding persist for at least 8 to 10 years.²⁴

An important and often misunderstood aspect of genital herpes is that transmission can occur in long-standing monogamous relationships.²⁵ For any communicable disease, the longer the period of infectivity, the lower the rate of exposure required to sustain prevalence in the population. Because genital HSV-2 infection persists indefinitely and is communicable for many years, perhaps for life, low rates of sex partner change—rates that are the norm for the population as a whole—are sufficient to sustain prevalence, whereas STDs of brief duration, such as gonorrhea, are largely limited to subsets of the population with especially high rates of partner change. In addition, most STDs are transmitted primarily by the subset of infected persons with mild or absent clinical manifestations, for the simple reason that most persons are less likely to have intercourse in the presence of genital symptoms. Herpes simplex virus may be transmitted to the susceptible partner after longtime sexual contact because infection due to subclinical or unrecognized reactivation in the infected partner is intermittent. Thus, genital herpes can first appear in persons seemingly at low risk for an STD, such as persons in mutually monogamous relationships. In addition, the initial symptoms of genital herpes may first occur months or years after infection, explaining still more apparent acquisitions in monogamous or sexually inactive persons.²¹

The most serious direct consequence of genital HSV infection is neonatal herpes, which results from perinatal transmission from mother to infant.^{26 - 28} Transmission is greatly influenced by the mother's serologic status. If HSV-1 or HSV-2 was recently acquired (eg, during the third trimester) and the mother is seronegative, from 15% to 50% of vaginally delivered infants acquire infection. However, the risk of perinatal transmission is less than 1% among women with long-standing infection.²⁸ Untreated neonatal herpes has among the highest mortality rates of any infection in the neonatal period, upward of 60%, and most survivors suffer crippling developmental deficits. With acyclovir therapy, the mortality of neonatal herpes has been reduced to 10%, but neurological sequelae remain common.^{29 - 30} A related problem is the high rate of abdominal delivery in women with recurrent genital herpes. Although the risk of perinatal transmission is low in such women, even when overt genital lesions are present, current standards of care in the United States dictate cesarean delivery for women with genital herpetic lesions at term. Substantial maternal and neonatal morbidity result from these largely unnecessary cesarean deliveries.³¹

In the late 1980s, soon after the viral etiology of AIDS was defined, it began to be appreciated that genital ulcer disease is a risk factor for sexual acquisition and transmission of HIV infection.^{8 - 10 ,32} If either person in an HIV-discordant sexual partnership has an inflammatory STD, the risk of HIV transmission or acquisition rises substantially, typically by 2-fold to 8-fold or even as much as 32-fold, according to 1 study.³³ However, when public health authorities have addressed genital ulcer disease as a risk for HIV infection, they tended to emphasize syphilis and chancroid. Studies now directly implicate HSV infection in HIV transmission. Herpes is by far the most common cause of genital ulcer disease in the United States, and polymerase chain reaction testing for HSV has shown that herpes is also a major cause of genital ulcer disease in many developing countries.^{34 - 35} In addition to the high titers of HIV found in genital herpes ulcerations and the likely effect on transmission,³⁶ plasma HIV viral load rises when HSV-2 infection reactivates in persons with HIV infection,³⁷ suggesting that herpes may adversely affect the course of HIV disease.

While the population-attributable risk of genital herpes in facilitating HIV transmission or acquisition has not been defined, the association is strong, the prevalence of HSV-2 infection in populations at risk for HIV is extremely high, and subclinical shedding of HSV almost certainly is associated with cutaneous or mucosal ulceration, however inapparent.^{2 ,11 ,23} In addition to these biological factors, there are mutually reinforcing behavioral and epidemiologic links between genital herpes and HIV infection.³⁸ Thus, it is reasonable to suspect that the fraction of HIV infections attributable to underlying genital HSV infection is substantial.³⁹ Why then is there so little apparent understanding of the HSV-HIV transmission link? Perhaps it relates to the mistaken assumption that ulcers must be clinically overt to facilitate transmission. The difficulty in identifying subclinically infected persons, due to the relative unavailability of type-specific serologic assays, also may have fostered a sense of futility about the prospects for HSV control and its potential contribution to HIV prevention. Although antiviral therapy prevents symptomatic recurrences of herpes, the observation that acyclovir and related drugs suppress subclinical viral shedding is recent,^{40 - 41} and it is not yet known whether treatment can reduce transmission of HIV or even HSV itself. Despite these caveats, the accumulating data clearly have shifted the burden of proof to those who would argue against integrating HSV recognition and prevention into HIV prevention efforts.

Recently, one of us (L.C.) proposed prompt institution of comprehensive genital herpes prevention efforts nationwide, modeled on those currently in place or in development for syphilis, gonorrhea, and sexually transmitted chlamydial infections.³⁹ The CDC recently convened an advisory panel to address genital herpes prevention.⁴² The panel's recommendation included determination of the real-world performance of newer type-specific serologic tests and their practical utility for diagnosis and screening, studies of the behavioral impact and responses to serologic diagnosis of subclinical infection, and studies of partner management strategies and related behavioral interventions. In addition, the panel felt that there is sufficient basis to recommend immediate implementation of several prevention actions. These include programs to educate health care providers and persons at risk about the epidemiology and clinical manifestations of genital herpes, with emphasis on subclinical transmission. They also recommended that only type-specific tests, rather than the heretofore more widely available nonspecific assays, be used for HSV serologic diagnosis or case finding. Finally, the panel advised the CDC to recommend that clinicians routinely use viral culture or other tests to detect HSV in the diagnosis of genital ulcer disease, offer HSV serologic testing when patients request comprehensive STD screening, and specifically advise patients whenever STD evaluation does not include serologic testing for HSV.⁴²

While research is needed to evaluate the cost-effectiveness of each of these recommendations for genital herpes (and all other viral STDs), the immediate implementation of some of these general guidelines to HSV infections would benefit patients, health care providers, and the public at large. The use of type-specific HSV serologic tests, which have recently been approved by the Food and Drug Administration, should markedly enhance the accurate diagnosis of persons with recurrent genital ulcers and other manifestations of genital herpes.¹³ They will aid in the assessment of the sex partners of persons with genital herpes, many of whom will then recognize previously subclinical recurrences and take steps to avoid transmission. The specificities of these assays are high (>95%). Their sensitivities vary from 70% to 95% depending on the population studied and assay conditions.^{12 - 13} When using such a test in a population with a true prevalence of HSV-2 infection of 50% or more, as might be expected in patients with symptoms suggestive of herpes or in the partners of infected persons, the positive predictive value will be high. Confirmatory testing may be required when using these tests in persons with lower prior probabilities of infection. How far to extend screening for HSV-2 is as yet unclear, but we believe that type-specific serology probably has an important role in preventing neonatal herpes through screening of pregnant women and their partners. Identifying HSV-discordant couples and counseling them about the risk of specific genital and orogenital sexual practices is one potential strategy. Similarly, serologic screening of selected populations at risk for STD, combined with appropriate counseling to recognize symptoms and to help avoid transmission through condom use (and perhaps, in the future with antiviral therapy) may be useful in preventing genital herpes and perhaps the sexual transmission of HIV.

Physicians, other health care professionals, managed care and health maintenance organizations, insurers, local and state health departments, federal health agencies, and health professions schools have too long ignored the genital herpes epidemic in the United States and worldwide. Professional organizations such as the American Medical Association, academic institutions, and public health departments should provide leadership in promoting basic prevention strategies and prevention-oriented research.