Genital herpes is one of the most common

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1 EMERGING ISSUES IN THE MANAGEMENT OF HERPES SIMPLEX VIRUS INFECTIONS Richard J. Whitley, MD,* Stephen K. Tyring, MD, PhD, Lisa M. Hollier, MD, MPH, and Stephen A. Brunton, MD ABSTRACT Genital herpes, which is caused by herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), has reached epidemic proportions in the United States and other countries. Almost 1 in 5 individuals aged 12 years or older in the United States are seropositive for HSV-2, and the proportion of individuals with genital herpes caused by HSV-1 has been rising dramatically in certain groups, particularly young adults. Without intervention, some healthcare providers estimate that HSV-2 seroprevalence will increase to 39% among men and 49% among women by 2025, with overall annual costs of $2.7 billion. Despite the effectiveness of acyclovir, valacyclovir, and famciclovir in improving lesion healing and preventing outbreaks, many patients remain dissatisfied with their current care. Patient satisfaction may be enhanced by improving communications between physicians and patients and by empowering patients to be more involved in treatment decisions, including the use of patient-initiated therapy. Regimens of shorter duration provide a management alternative that may improve *Professor, Department of Pediatrics, Microbiology, Medicine, and Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama. Professor, Departments of Microbiology & Immunology, Dermatology, and Internal Medicine, University of Texas Health Science Center, Houston, Texas. Associate Professor and Residency Program Director, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Texas Houston Medical School, Houston, Texas. Director of Faculty Development, Stamford Hospital, Columbia University, Charlotte, North Carolina; Cabarrus Family Medicine Residency Program, Concord, North Carolina. Address correspondence to: Richard J. Whitley, MD, 1600 Seventh Avenue, CHB 303, Birmingham, AL rwhitley@peds.uab.edu. patient satisfaction and compliance, in addition to reducing drug costs. A recent study of patientinitiated, 1-day famciclovir (1000 mg twice daily) treatment of recurrent genital herpes demonstrated efficacy and tolerability, and this regimen was approved by the US Food and Drug Administration in July 2006 for the treatment of recurrent genital herpes in immunocompetent patients. Neonatal herpes continues to be problematic in that it remains a significant cause of morbidity and mortality. Furthermore, the synergy between HSV and human immunodeficiency virus infection can result in progressive disease. (Adv Stud Med. 2006;6(10F):S1092-S1103) Genital herpes is one of the most common sexually transmitted diseases in the United States and worldwide. 1 It is associated with both economic and personal costs that impair quality of life and, in rare circumstances, can lead to life-threatening disease. Because it is a recurrent, lifelong condition without a cure, proper patient management is critically important. 2 Genital herpes is caused by herpes simplex virus type 1 (HSV-1) or 2 (HSV-2). The relative proportion of disease caused by each virus type has changed in recent times, along with changes in human sexual practices. 3,4 Three antiviral agents acyclovir, valacyclovir, and famciclovir remain the mainstay of treatment of genital herpes and are used to treat primary and recurrent clinical episodes or as suppressive therapy. 2,3 However, patient compliance and satisfaction with treatment options for genital herpes remain relatively poor. Other drugs are currently in development as potential therapies. S1092 Vol. 6 (10F) December 2006

2 Among the patient subpopulations at highest risk for complications of genital herpes are pregnant women, who can transmit the virus to their infants during birth, often with lethal consequences, 5 highlighting the need for proper education and management in this patient population. Another issue of acute importance is the relationship between genital herpes infection and human immunodeficiency virus (HIV) acquisition, transmission, and progression. 6,7 This review summarizes the current state of knowledge about genital herpes and its management. Particular attention is devoted to patient-initiated antiviral therapy and, more specifically, to a single-day treatment regimen of famciclovir that has recently been approved for patient-initiated treatment of recurrent disease. 8 Regimens such as these may help improve both patient compliance and satisfaction, in addition to reducing the drug costs associated with genital herpes treatment. A single-day regimen of famciclovir has also been approved for the treatment of herpes labialis (cold sores). EPIDEMIOLOGY AND MEDICAL COSTS OF GENITAL HERPES EPIDEMIOLOGY OF GENITAL HERPES Genital herpes is caused by HSV-1 or HSV-2 infection, two closely related α-herpesviruses. The specific rates of infection differ by country and region within countries, sometimes markedly. 2,3,9,10 HSV-2, which is usually acquired through genital-genital contact, has historically been the more common cause of genital herpes and remains the most frequent cause of recurrent genital herpes. HSV-1 more frequently causes orolabial lesions, and transmission may occur during oral-genital as well as genital-genital contact. At initial presentation, genital herpes caused by either virus is clinically indistinguishable. Because HSV-2 is transmitted sexually, genital herpes begins to occur in sexually active adolescents. The strongest predictor of genital herpetic infection is the number of lifetime sexual partners. 2,11 A 2002 study examining the worldwide seroprevalence of infection with HSV-2 and HSV-1 reported that rates of HSV-2 infection were generally highest in areas of Africa and parts of the Americas, with lower rates in northern Europe and North America; the lowest rates were observed in Asia, followed by southern and western Europe. 10 The prevalence of HSV-1 infection was generally higher than that of HSV-2 infection. However, it is impossible to distinguish serologically between HSV-1 of the oropharynx and genital tract. Although HSV-1 can be transmitted via oralgenital contact, it is more commonly transmitted via nonsexual contact and, if symptomatic, usually manifests as oral or facial, rather than genital, lesions. Other studies have reported similar results for worldwide seroprevalence of HSV-2. 12,13 In the United States, HSV-2 seroprevalence increased dramatically during the later half of the 20th century. 14 Using serum samples and questionnaire data collected during the National Health and Nutrition Examination Surveys (NHANES) II ( ) and III ( ), the prevalence of HSV-2 in the United States increased 30% from the late 1970s to the late 1980s/early 1990s. Based on NHANES III data, more than 1 in 5 adults (21.9%) aged 12 years and older were HSV-2 seropositive. Rates were higher in females (25.6%) than in males (17.8%) and higher in African Americans (45.9%) than Caucasians (17.6%), with Mexican Americans exhibiting intermediate rates (22.3%). The greatest increase in HSV-2 seroprevalence rate from NHANES II to III occurred in Caucasians 12 to 19 years of age, with rates more than quadrupling (0.96% 4.5%). A multivariate model identified lifetime number of sexual partners, female sex, African American race or Mexican American ethnic background, and older age as independent predictors of HSV-2 seropositivity (odds ratio >3.0 for each). Based on the 21.9% prevalence rate, it is estimated that approximately 45 million individuals in the United States were infected with HSV-2 in 1991, and that more than 50 million persons in the United States were likely to have genital herpes in It was also estimated that 1.6 million new HSV-2 infections occurred in the United States in 2000, including individuals aged 15 to 24 years. 16 Using a mathematical model of HSV-2 infection, it was estimated that 1.6 million individuals in the United States are newly infected every year. 17 It has also been estimated that, without intervention, an estimated 60 million individuals will be infected by the year However, the most recent data from NHANES IV suggest that the trajectory of increasing HSV-2 seroprevalence in the United States has been reversed. 19 The overall age-adjusted HSV-2 seroprevalence was 17% in the United States in 1999 to 2004 (NHANES IV), representing a relative decrease of 19% compared Johns Hopkins Advanced Studies in Medicine S1093

3 to data from NHANES III. Seroprevalence of HSV-I also showed a relative decrease of 7% from NHANES III to NHANES IV, although the incidence of genital herpes caused by HSV-I may be increasing. MEDICAL COSTS OF GENITAL HERPES It is important to realize that all of the above estimates were only for individuals infected with HSV-2 and do not consider HSV-1 as a cause of genital herpes because no serologic test distinguishes HSV-1 genital and oral infection. Historically, HSV-1 has been estimated to account for approximately 30% of cases of genital herpes. 4 However, recent studies indicate that an increasing proportion of new cases of genital herpes in young adults are caused by HSV-1. In 2001, one study of college students in Wisconsin showed that 78% of new cases of genital herpes were caused by HSV-1, compared to 31% in This increase represents a reversal of the historical HSV-1/HSV-2 ratio and is thought to be largely due to increasing condom use for intercourse, more frequent oral-genital contact without protection, and declining incidence of orolabial HSV-1 infection acquired during childhood. 4 Studies in other industrialized countries have also reported similar findings. 21,22 The economic burden associated with genital herpes in the United States is difficult to determine precisely, but it appears to be significant. For example, it was estimated that genital herpes accounted for nearly clinical visits and more than 2 million pharmacy claims annually in the early 1990s. 23 Based on these numbers, the direct medical costs of genital herpes was estimated at $166 million per year for the years 1992 to 1994, or $207 million in 1999 dollars, with drug costs accounting for 64% of total direct costs. Focusing only on individuals aged 15 to 24 years, the total direct medical costs of genital herpes were estimated at $293 million for the year A third study used 2 different costing approaches to estimate medical costs related to genital herpes management in the United States; depending on the approach used, the annual direct medical costs ranged from $283 million to $984 million. 24 In the approach yielding the maximum estimate, drug expenditures accounted for approximately 50%, or almost $500 million per year. More ominously, using a mathematical model to project the future increase in HSV-2 seroprevalence in adults aged 15 to 39 years in the United States, it was estimated that, without intervention, seroprevalence would increase to 39% among men and 49% among women by Moreover, the direct and indirect costs for incident infections were estimated at $1.8 billion in 2000 and were projected to rise to $2.7 billion by Because all of these studies have estimated that drug costs account for 50% to 64% of total direct costs related to care of individuals with genital herpes, the patientinitiated, single-day famciclovir-treatment regimen and other shorter duration antiviral regimens, discussed later in this article, are expected to help reduce these costs while providing additional patient benefits. CLINICAL MANIFESTATIONS AND DIAGNOSIS: THE IMPORTANCE OF DISTINGUISHING HSV-1 AND HSV-2 CLINICAL MANIFESTATIONS OF GENITAL HERPES Clinical manifestations and the disease course of genital herpes have been reviewed elsewhere. 4,25,26 Classical signs of active disease include red macules that progress to a vesicular eruption; mucosal lesions eventually ulcerate while cutaneous lesions crust and scab. Lesion formation is often preceded by prodromal symptoms, including local paresthesias and burning and/or itching around the area in which a lesion will arise. However, many patients do not experience these classical signs; rather, they present with less severe lesions characterized by minor perigenital chaffing or fissuring, if signs or symptoms are present at all. Lesions in men are often found on the glans or shaft of the penis, the urethra, the coronal sulcus, or in the perineal area, whereas lesions in women frequently occur on the labia or in the introitus, urethral meatus, or perineal area. Cervical infection is also common in women with genital herpes. In both sexes, nongenital lesions may occur on the buttocks or thighs, and active infection is often accompanied by constitutional symptoms, such as headache, fatigue, fever, lymph node swelling, and/or myalgia. Following initial infection with HSV-1 or HSV-2, the virus enters the peripheral nerve axons and travels in retrograde fashion to the dorsal root ganglia. After an initial round of replication(s), viral DNA remains episomal throughout the life span of the infected individual until reactivation occurs. Virus is intermittently reactivated throughout the individual s life, occurring far more commonly with HSV-2 than HSV- 1 infection. Episodes of genital herpes are typically described as primary (initial) infections as defined by S1094 Vol. 6 (10F) December 2006

4 an absence of antibodies to the infecting strain. Nonprimary first episodes represent genital infection caused by the strain of virus heterologous to existing serum antibodies. Recurrent or reactivated disease simply represents the recurrence of the infecting strain of HSV. Any of these episodes may be asymptomatic or unrecognized. This is significant because viral shedding occurs during periods of asymptomatic infection with unrecognized lesions and is the most common cause of transmission to uninfected partners. The primary episode is generally more severe than recurrent episodes, and is traditionally more severe with HSV-2 than with HSV-1. In addition, the frequency, duration, and severity of subsequent episodes may lessen over time, but this cannot be predicted with certainty. Although either type of virus can cause characteristic genital herpes, there are a number of notable differences in the diseases caused by HSV-1 and HSV-2, particularly in natural history and prognosis. For example, genital HSV-1 infections are associated with far fewer symptomatic recurrences and lower rates of viral shedding as compared to that of genital HSV-2 infections. 4 One recent study reported that, in a cohort of patients presenting with primary genital HSV-1 infection, the overall recurrence rate was 1.3 per year during the first year of infection and 0.7 per year in the second year. 27 Moreover, 43% of patients did not have a recurrence in the first year and 67% had no recurrence in the second year. By comparison, a study of patients with genital HSV-2 infection reported an overall recurrence rate of 4.1 per year, with 38% exhibiting at least 6 recurrences during the first year and 20% with more than 10 recurrences. 28 Similarly, another study reported median recurrence rates in the first year of follow-up of 1 per year for patients with newly acquired genital HSV- 1 infection and 5 per year for patients with newly acquired genital HSV-2 infection. 28,29 These differences suggest a better general prognosis for patients with genital HSV-1 infection, a difference that may call for different counseling messages. DIAGNOSIS OF GENITAL HERPES Proper counseling and management of patients with genital herpes requires accurate diagnosis. This is important not only for typical patients, but also for special populations such as pregnant women, partners of individuals with genital herpes, patients with HIV infection, and partners of patients with HIV. The high proportion of genital HSV infections that are unrecognized by both patients and clinicians has been identified as a major public health concern. 30 Patients with unrecognized infections serve as reservoirs for transmission to unsuspecting partners or, in the case of neonates, unwitting participants. Various approaches are now available to aid in the diagnosis of genital herpes, and some of the newer approaches have made it possible to confidently identify previously undiagnosed patients with mild, atypical, or subclinical infection. Although clinical presentation can be useful in diagnosing genital herpes infection, it is often difficult to diagnose infection on the basis of clinical criteria alone because clinical signs and symptoms may be mild, atypical, or unrecognized. Laboratory tests of genital secretions are often used in conjunction with history and physical examination to provide a more accurate diagnosis that may enable typing of the causative HSV. These laboratory tests are most sensitive when typical genital herpes vesicles or moist lesions are present, allowing a healthcare provider to rub the lesion with a swab and obtain an HSV-rich sample. Three major lesion- or tissue-related laboratory tests used for diagnosis of genital herpes are viral culture, antigen detection tests (enzyme immunoassay or immunofluorescence on smears), and nucleic acid detection with polymerase chain reaction (PCR). 30,31 Viral culture has been considered the gold standard of laboratory diagnosis and can be used for typing HSV; however, culture sensitivity is dependent on lesion quality and sampling time, and sensitivity rapidly declines as lesions begin to heal. Sensitivity may also be greater for primary infections than for recurrent infections, and transport of samples is important, as temperature and light can affect outcomes. Isolation of virus from cell cultures must be done by specialized laboratories and thus can be time-consuming and relatively expensive, and the results are usually not available for 2 to 7 days. In contrast, antigen detection tests are simple, rapid to perform, and may be used instead of, or in addition to, viral culture. However, these tests usually cannot distinguish HSV-1 from HSV-2 and may exhibit both lower sensitivity and specificity. PCR, the most sensitive laboratory technique for detecting HSV, can be used for typing HSV, produces rapid results (within 24 hours), and requires no special measures for transport, but its role in diagnosing genital herpes is being defined at this time. The Centers for Disease Control and Prevention (CDC) 2006 treatment guidelines for sexually transmitted diseases Johns Hopkins Advanced Studies in Medicine S1095

5 recommend PCR as the test of choice for detecting HSV in spinal fluid for diagnosis of HSV infection of the central nervous system (CNS); however, PCR tests are not cleared by the US Food and Drug Administration (FDA) for testing of genital specimens. 32 Currently, there is no commercial assay and PCR is more expensive than other techniques on a per-specimen basis, although some have argued that the capital costs of tissue culture may be greater in the long run. 33 Notwithstanding the increased per-specimen costs of PCR, some laboratories have completely switched to PCR for determination of HSV detection and typing. Type-specific serologic tests have helped to advance diagnostic testing, enabling identification of patients with asymptomatic or unrecognized genital herpes who frequently serve as reservoirs for HSV transmission. In the past, serologic tests were unable to distinguish between HSV-2 and HSV-1, which was a problem because many individuals in the general population have serum antibodies to HSV-1 unrelated to genital herpes. However, since 1999, a number of type-specific serologic tests have been developed and approved by the US FDA for the diagnosis of genital herpes (Table 1). 34 These tests make use of specific glycoproteins present on the protein coat of the virus, glycoprotein G1 for HSV- 1 and glycoprotein G2 for HSV-2. Detection of antibodies to glycoprotein G2 is diagnostic of genital herpes because HSV-2 is more rarely associated with other types of herpes infection. Detection of glycoprotein G1 may be used in conjunction with other tests or clinical presentation to diagnose genital herpes. Timing is important the median interval from the onset of symptoms to the detection of antibodies in the bloodstream (ie, seroconversion) has been reported to be 25 days for HSV-1 and 23 days for HSV There was also considerable intrasubject variation, in that only 62% and 77% of patients with HSV-1 and HSV-2 primary infections, respectively, exhibited seroconversion by 6 weeks, and only 59% of patients with HSV-2 nonprimary first episode seroconverted by this time point. These findings indicate that false-negative results may be frequent during early stages of infection, and repeat sampling after passage of time may be required for detection of antibodies. Table 1. US FDA-Approved Glycoprotein G-Based Type-Specific Serologic Tests for HSV Antibody HerpeSelect HerpeSelect Captia HSV-1 HSV-1 ELISA and HerpeSelect HSV-1 and HSV-2 biokithsv-2 ELISA and Captia HSV-2 HSV-2 ELISA Immunoblot Rapid Test* ELISA Manufacturer Focus Diagnostics Focus Diagnostics Biokit USA Trinity Biotech (Cyprus, CA) (Cyprus, CA) (Lexington, MA) (Wicklow, Ireland) Antibodies detected HSV-1 and HSV-2, HSV-1 and HSV-2 HSV-1 and respectively HSV-2, respectively HSV-2, respectively Sensitivity, % HSV-1: 96 HSV-1: HSV-1: HSV-2: 100 HSV-2: 100 not available HSV-2: 96 Specificity, % HSV-1: 95.2 HSV-1: HSV-1: HSV-2: 96.1 HSV-2: 93.7 not available HSV-2: 98 Collection method Blood draw Blood draw Finger stick Blood draw Test location Labs best for Labs best for Provider office Labs high volume labs low volume labs Median time to Unknown seroconversion, d *Formerly POCkit HSV-2 Rapid Test; also known as SureVue HSV-2 from Fisher Healthcare. The sensitivity and specificity of the HerpeSelect ELISA, Immunoblot, biokithsv-2, and Captia ELISA were demonstrated by comparison with Western blot, the research gold standard. The sensitivity and specificity of the Western blot was determined by testing in men and women with symptomatic established infections. ELISA = enzyme-linked immunosorbent assay; HSV = herpes simplex virus; US FDA = US Food and Drug Administration. Adapted with permission from Brown et al. Obstet Gynecol. 2005;106: S1096 Vol. 6 (10F) December 2006

6 The clinical importance of serologic and other diagnostic tests is an area of active debate. The cost effectiveness of using serologic tests to screen the overall population is one issue. Another is the psychological stress that may occur when asymptomatic or unrecognized genital herpes is identified, with some studies suggesting that concerns are warranted, at least during the short term, and others indicating that they may be unwarranted Additionally, screening of groups with low prevalence rates may result in a relatively high rate of false positives, with unnecessary psychological distress. 36 A committee of clinicians and researchers, convened by the California Sexually Transmitted Diseases Controllers Association, recently provided recommendations on the use of serological tests for diagnosis and screening of patients for genital herpes. 39 After a systematic review of the literature, the committee identified 3 situations in which serological tests for HSV-2 may assist in the diagnosis of genital herpes: patients presenting with culture-negative recurrent lesions, patients with a history suggestive of herpes without visible lesions, and patients first presenting with genital lesions when results of culture or antigen detection are negative or unavailable. Testing for HSV-1 infection may be useful in situations in which HSV-2 testing yields negative results and there is high suspicion of a herpes infection. The committee concluded that universal screening of the general population or screening of all pregnant women is unlikely to be beneficial, but they did identify targeted populations in which screening of asymptomatic individuals may be appropriate. In particular, they identified the following groups as suitable for screening: those at high risk of sexually transmitted diseases and HIV infection who are motivated to reduce their sexually risky behavior, HIV-infected patients, and sexual partners of patients with genital herpes. The CDC 2006 guidelines recommend that both virologic and type-specific serologic tests for HSV should be available in clinical settings that provide care for patients with sexually transmitted diseases or those at risk for sexually transmitted diseases. 32 PSYCHOLOGICAL AND PSYCHOSOCIAL ASPECTS OF GENITAL HERPES In addition to the physical pain and other symptoms associated with active infection, genital herpes can have profound effects on infected individuals that extend beyond specific periods of active outbreak. Several studies suggest that psychological and psychosexual or psychosocial morbidity may be frequent and significant problems for many individuals with genital herpes, particularly in those with recurrent episodes In turn, this morbidity may have a negative impact on personal and work relationships, thereby expanding the sphere of impact beyond the infected individual. Genital herpes and other sexually transmitted diseases are generally considered to carry a certain stigma, which may affect an infected individual s sense of selfworth and attitudes about relationships and sexual behavior. 43 The negative stigma may also affect an individual s decisions to seek help or to disclose the infection to others. In large part, the stigma may be linked to the notion that sex is a choice, and hence, that the individual is personally responsible for the condition. The recurrent nature of genital herpes is also troubling because it may serve as a continual reminder to the individual and/or his/her partner of a relationship or incident that would better be forgotten. A wide range of emotional responses has been described in individuals with genital herpes, including anxiety, depression, distress, anger, diminution of selfesteem, and hostility toward the person thought to be the source of the infection. 40,41 Unfortunately, in many cases it is difficult to determine whether these emotions existed prior to contraction of genital herpes or are a response to the disease, and there have been few well-controlled studies in this area. Many individuals with initially negative emotional or psychological responses to a diagnosis of genital herpes seem to adapt or cope over time, but a significant minority does not, and the characteristics differentiating these 2 groups are not well understood. The recurrent nature of genital herpes appears to have a negative impact on psychological well-being. For example, a prospective study examining psychological functioning in patients with a first episode of genital herpes reported that the rate of nonpsychotic psychiatric illness was significantly lower after 3 months in individuals who experienced no recurrences during this 3-month period compared to the rate at initial visit. 44 However, in patients who did experience recurrences during this 3-month period, the rate of nonpsychotic psychiatric illness was no lower at 3 months than at initial visit. Similarly, another study comparing 57 patients with a first episode of genital Johns Hopkins Advanced Studies in Medicine S1097

7 herpes and 50 patients with recurrent episodes reported a significantly higher proportion of nonpsychotic psychiatric illness in the recurrent group. 45 Although it was once widely thought that shortterm stress played a major role in triggering recurrences in patients with genital herpes, the evidence for this is not very compelling, and it seems just as likely that stress follows recurrences, rather than predates them, for many patients Earlier studies that examined the impact of genital herpes on psychological functioning used various scales or measurement tools that were not specific for this condition. Since then, several genital herpes-specific quality of life (QOL) scales have been developed to evaluate the impact of the genital herpes and its treatment on psychological distress and QOL. 49 The most widely used is the Recurrent Genital Herpes Quality of Life Questionnaire (RGHQoL). Using this scale together with the Medical Outcomes Study Short Form 36-item health survey QOL questionnaire, a group in France reported that 23% of respondents indicated emotional trauma due to genital herpes; of these respondents, 57% reported that genital herpes interfered with their sexual relationships, 50% reported that it was difficult to live with this condition, and 37% stated that they thought genital herpes had ruined their lives. 50 Compared to noninfected subjects, patients with genital herpes experienced a lower QOL. Similarly, a multicountry European study reported significantly lower RGHQoL scores in patients with genital herpes experiencing more frequent or more severe recurrences compared to patients with infrequent recurrences or recurrences of milder severity. 51 TREATMENTS AND TREATMENT GOALS reduction in the frequency of recurrences and a decrease in episodes of asymptomatic viral shedding. Suppressive therapy with valacyclovir has been found to reduce the risk of transmission among heterosexual, HSV-2 discordant couples. 53 Suppressive therapy has also been associated with improvements in health-related QOL of patients with recurrent genital herpes. 54 Mathematical models have shown that increased usage of episodic antiviral therapy will help reduce the genital herpes epidemic and that use of suppressive therapy could cause a substantial reduction in the incidence of HSV-2 infections. 55 However, to achieve these societal goals and those of patients, it is necessary to maximize patient compliance. This may include a focus on convenient dosing regimens for currently available agents, in addition to working with patients to individualize therapy and set realistic goals. Using patient-initiated approaches to episodic treatment may also help improve compliance and achieve therapeutic and societal goals for management of this disease but likely will not impact transmission because most shedding is asymptomatic. The remainder of this section describes antiviral management of genital herpes in greater detail, in addition to some of the issues relating to patient convenience and empowerment. PHARMACOLOGICAL MANAGEMENT OF GENITAL HERPES: ANTIVIRAL THERAPIES Although vaccines, immunostimulatory oligodeoxynucleotides, and new antiviral agents are being investigated as potential strategies for the management of genital herpes, at the present time only acyclovir, valacyclovir, and famciclovir have demonstrated sufficient efficacy and safety to warrant approval by the US FDA. All 3 agents are nucleosides that inhibit HSV-1 Three antiviral agents are currently approved for the treatment of initial and recurrent episodes of genital herpes or as suppressive therapy: acyclovir, valacyclovir, and famciclovir (Figure 1). 52 Efficacy is similar for these 3 agents, but they exhibit some differences in pharmacokinetics, approved dosing regimens, and cost. The goals of episodic therapy include a reduction in the severity and duration of pain or other symptoms and shortened duration of viral shedding, which may reduce the risk of transmission. The primary goals for suppressive therapy include a Figure 1. Structures of Acyclovir, Valacyclovir, and Famciclovir Reprinted with permission from Balfour. N Engl J Med. 1999;340: S1098 Vol. 6 (10F) December 2006

8 and HSV-2 replication by interfering with the synthesis of viral but not host DNA. 52,56-61 Acyclovir was the first member of the group to demonstrate effectiveness in patients with genital herpes, but it exhibited low oral bioavailability and a short plasma half-life. This meant that treatment with oral acyclovir required the use of relatively large doses and frequent daily administration. Because of these shortcomings, a search was made for compounds with similar activity but better bioavailability and longer half-lives, enabling lower dosing and less frequent daily administration. This search eventually led to the identification of the 2 other currently approved antiviral treatments for genital herpes, valacyclovir and famciclovir. Valacyclovir is the L-valyl ester of acyclovir. Following oral administration, valacyclovir is rapidly converted in the gastrointestinal tract and liver to acyclovir. 52,61 Famciclovir is a prodrug of penciclovir, a compound with similar activity as acyclovir and even poorer oral bioavailability. 52,61 Following oral administration, famciclovir is rapidly metabolized to penciclovir in the gastrointestinal tract and liver. The very long intracellular half-life of the active drug enables famciclovir to be administered twice daily for a single day when used to treat recurrent genital herpes or as single dose for the treatment of recurrent herpes labialis. 8 Famciclovir is the only antiviral approved as single-day treatment for recurrent genital herpes (or recurrent herpes labialis). Dosage recommendations for oral acyclovir, valacyclovir, and famciclovir are listed in Table 2. 8,62,63 All 3 drugs have demonstrated effectiveness when used to treat first and recurrent episodes and as suppressive therapy. PATIENT SATISFACTION WITH GENITAL HERPES CARE In a recent global survey of patients with genital herpes, 67% of whom were receiving episodic therapy and 30% of whom were receiving suppressive therapy, 51% of the respondents reported being somewhat or very disappointed with their care for physical symptoms, and 63% reported being somewhat or very disappointed with their care for social or emotional issues. 64 In another multicountry study, in which 55% of individuals were receiving episodic therapy and 22% were receiving suppressive therapy, only 41% of the respondents reported a high degree of satisfaction with their current care. 65 For all aspects of therapy, patients receiving suppressive therapy were more satisfied than those receiving episodic therapy. Taken together, these studies suggest that a high percentage of patients with genital herpes are not very satisfied with their current care, and those receiving episodic therapy seem to be more dissatisfied than those receiving suppressive therapy. Patient-initiated, short-course antiviral treatment for recurrent genital herpes Better communication between patients and their physicians may lead to greater patient satisfaction and improved care, in addition to empowering patients to take more responsibility for managing their disease. 65 Patient-initiated treatment of recurrent episodes of herpes infection is one approach that has met with success In these studies, patients were given a supply of antiviral drug and instructed to initiate therapy at the first sign of an impending episode. Not only did this provide patients with a sense of control over a disease Table 2. Dosage Recommendations for Oral Acyclovir, Valacyclovir, and Famciclovir in Patients with Genital Herpes Drug First Clinical Episode Recurrent Episodes Suppressive Therapy Acyclovir* 200 mg 5 times daily for 10 days 200 mg 5 times daily for 5 days 400 mg twice daily for up to 1 year (followed by re-evaluation) Valacyclovir 1 g twice daily for 10 days 500 mg twice daily for 3 days 1 g once daily for up to 1 year 500 mg once daily for up to 1 year (patients w/ 9 recurrences/yr) Famciclovir 250 mg 3 times daily for 10 days 1 g twice daily for 1 day 250 mg twice daily for up to 1 year *Acyclovir is also available for intravenous administration, primarily in patients with severe symptoms or disseminated disease; only the oral formulation is listed here. Alternative regimens have included doses ranging from 200 mg 3 times daily to 200 mg 5 times daily. Data from Famvir (famciclovir) 8 ; Zovirax (acyclovir) [prescribing information] 62 ; Valtrex (valcyclovir hydrochloride) [prescribing information]. 63 Johns Hopkins Advanced Studies in Medicine S1099

9 against which they may otherwise feel helpless, but it led to initiation of therapy early in the course of infection, which has been shown to have increased benefits relative to later initiation of therapy. 66,69,70 Patients with recurrent episodes frequently experience prodromes that enable early initiation of therapy. In one study, 73% of men and 84% of women with recurrent herpes experienced a recognizable prodrome, 71 and 57% of men and 68% of women experienced prodromes prior to at least 1 of every 4 recurrences. Patients with frequent recurrent episodes who do not experience a prodrome may be better served by suppressive therapy. Improved patient satisfaction may also result from the use of shorter treatment regimens. Other potential benefits of shorter course therapy include improved compliance and reduced drug costs. Currently, famciclovir is the only antiviral agent with an approved 1- day treatment regimen for recurrent episodes. 8,72 Valacyclovir is approved for a 3-day treatment course and acyclovir for a 5-day course. A very recent study established the benefits of single-day, patient-initiated famciclovir therapy for recurrent genital herpes. 72,73 In this multicenter, multinational, double-blind, placebo-controlled trial, 329 patients with recurrent genital herpes were randomized 1:1 to receive famciclovir (1000 mg twice daily) or placebo for 1 day and instructed to initiate treatment within 6 hours of onset of prodromal symptoms or herpes lesion appearance. Compared to placebo, 1-day famciclovir therapy was associated with reductions in median healing time of nonaborted lesions (ie, lesions that progressed beyond the papule stage) from 6.1 to 4.3 days (Figure 2), and of all aborted and nonaborted lesions from 5.0 to 3.5 days. In addition, the percentage of patients with aborted lesions was significantly higher in the famciclovir group than in the placebo group (23.3% vs 12.7%; P =.003). Moreover, the median time to resolution of all symptoms was significantly shorter in the famciclovir group than in the placebo group (3.3 vs 5.4 days; P <.001, respectively), as were the resolution times for each of the individual symptoms examined (burning, tingling, itching, tenderness, and pain). There were no notable differences in tolerability or safety between the 2 groups. Adverse events were infrequent in both groups and were generally mild to moderate in severity. The results from this study led to the current approval of famciclovir as single-day treatment for recurrent genital herpes. SPECIAL ISSUES IN MANAGEMENT OF GENITAL HERPES For the vast majority of immunocompetent individuals, genital herpes is associated with significant morbidity, but not with serious, life-threatening consequences. However, in at least 2 situations, the potential consequences of genital herpes can be serious, leading either to death or serious morbidity. In particular, serious consequences may occur when infected women transmit HSV to neonates during birth. Additionally, genital HSV infection has now been linked with HIV and the acquired immunodeficiency syndrome (AIDS) epidemic. This section looks at each of these special situations in turn. MANAGEMENT OF PREGNANT WOMEN WITH GENITAL HERPES Several reviews have examined the problem of neonatal herpes and its prevention. 5,34 Neonatal herpes is defined as a diagnosis of HSV infection in a neonate within the first 28 days of life. 34 It manifests as skin, eye, and mouth (SEM) infection, CNS infection, or disseminated infection. 34 Mortality and morbidity is highest with disseminated infection, which accounts Figure 2. Kaplan-Meier Plot of Time to Healing of All Nonaborted Genital Herpes Lesions (Modified Intent-To-Treat Population) Proportion of patients with healed lesions Famciclovir, 1000 mg twice daily Placebo Time, d No. at risk Famciclovir, 1000 mg twice daily Placebo Reprinted with permission from Aoki et al. Clin Infect Dis. 2006;42: S1100 Vol. 6 (10F) December 2006

10 for 25% of cases. The death rate in untreated neonates with disseminated infection is greater than 80%, with nearly all survivors experiencing neurological impairment. CNS infection accounts for approximately 35% of cases of neonatal herpes and is associated with a death rate of 50%. SEM infection accounts for the remaining 25% of cases; although seldom fatal, it leads to neurological impairment in approximately 33% of infected subjects. Early treatment with high-dose acyclovir can improve outcomes, but treatment is often delayed because the initial signs and symptoms are nonspecific or not apparent. 5 Moreover, even with early intervention, approximately 30% of neonates with disseminated disease die, and 40% of survivors of CNS infection suffer severe neurologic damage. 34 Therefore, the focus is on prevention of neonatal herpes. The incidence of neonatal herpes varies by country and within different regions of a country. In the United States, the average rate is 3200 live births in some parts of the country. 5,34 Transmission of HSV is vertical, from the mother to fetus or neonate, most commonly during vaginal delivery (approximately 85% of cases), and more rarely perinatally or postnatally. 5 Prevention strategies include using caesarean delivery for women with genital lesions at the time of labor, avoiding unnecessary invasive obstetrical procedures in women with genital herpes, and identifying and counseling women at risk for HSV acquisition during pregnancy, particularly late in pregnancy, because HSV infection during the third trimester carries the highest risk of transmission to the neonate. 34 Guidelines from the American College of Obstetrics and Gynecologists also recommend giving antiviral therapy to women with primary HSV during pregnancy. 74 Such treatment is intended to reduce viral shedding and enhance lesion healing, which may help prevent neonatal herpes, although data are currently limited in this area. The guidelines also state that antiviral therapy should be considered for women at or beyond 36 weeks of gestation with a first episode of HSV occurring during pregnancy. 74 TREATING THE IMMUNOCOMPROMISED: HSV/HIV INTERACTIONS Genital herpes exhibits a number of interactions with HIV infection and may be considered a contributing factor to the HIV/AIDS epidemic. A metaanalysis of 31 studies examining the association between HSV-2 infection and the risk of acquiring HIV found that HSV-2 seropositivity was a significant risk factor for HIV acquisition. 73 In the methologically strongest studies, the estimated risk of HIV acquisition in patients with HSV-2 positivity was doubled, but increased risk was observed in essentially all subgroups, geographic regions, and study designs analyzed. Studies have also shown that the risk of HIV-1 transmission to the unaffected partner in a monogamous relationship during sexual intercourse is increased 4-fold when genital ulceration is present, as compared to the absence of genital ulcer disease. 75 This is significant because genital herpes is the most common cause of genital ulcer disease in developed and developing countries. Chronic HSV-2 infection may also facilitate the progression of HIV infection. For example, in vitro studies indicate that HSV infection has a positive effect on HIV replication via various mechanisms. 76 Clinical studies reporting elevations in plasma HIV concentration during active HSV infection are consistent with these preclinical reports. 77 Episodic or suppressive antiviral therapy has been shown to be effective in controlling HSV infection in individuals coinfected with HIV To the extent that HSV infection facilitates progression of HIV disease, antiviral management of HSV may have beneficial effects on HIV disease, in addition to those for genital herpes. This remains to be studied. CONCLUSIONS The incidence of genital herpes has continued to expand, with 20% of individuals aged 12 years and older seropositive for HSV-2, and the proportion of individuals with genital herpes caused by HSV-1 is growing rapidly. Herpesvirus infection may exacerbate the potentially lethal consequences of HIV/AIDS. Among other problems requiring special attention are genital herpes in pregnant women and neonatal herpes. Although currently available antiviral therapies cannot cure genital herpes, they can provide substantial symptom relief, reduce the frequency of recurrent episodes, and reduce the risk of transmission. Patientinitiated therapy and treatment regimens of shorter duration may improve patient satisfaction and compliance, in addition to reducing drug costs. A new highdose, 1-day regimen of famciclovir was recently approved by the US FDA for the treatment of recurrent genital herpes. Johns Hopkins Advanced Studies in Medicine S1101

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