Genital Herpes Simplex Virus Infections

Sexually Transmitted Diseases

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Genital Herpes Simplex Vi rus Infections Gregory J. Mertz, MD*

Major developments in the last decade have enhanced our ability to diagnose and treat genital herpes simplex virus (HSV) infections as well as our understanding of their pathogenesis and transmission. Acyclovir, the first effective treatment, was tested and licensed in the first part of the decade. Our understanding of the risk of sexual and perinatal transmission of genital herpes has been enhanced through several large prospective studies and by the development of serologic tests that reliably differentiate between antibody responses to HSV-1 and HSV-2 infections. This article presents information of interest to the clinician regarding diagnosis, treatment, and counseling of persons with genital herpes infections.

THE VIRUS Herpes simplex virus-1 and HSV-2 are memhers of the human herpes virus family of DNA viruses. The approximately 50% base sequence homology between HSV-1 and HSV-2 and the presence of both typecommon and type-specific antigens have made it technically difficult to differentiate HSV -1 from HSV _2,2. 3, 15 although typing of isolates can now be quickly and easily done in most clinical laboratories with monoclonal antibodies. 25 Herpes simplex virus can infect a wide range of cells and hosts, but infections in the normal human host are limited to mucocutaneous sites and to the neuronal nucleus within the sensory ganglion. After local inoculation and replication in the dermis and epidermis, viral particles are transported to the neuronal nucleus. Infection results in viral replication and cell death in susceptihle cells in the dermis and epidermis, whereas the state of virus infection in neurons, known as latency, is less well understood. 15, 62

*Associate

Professor. Department of Medicine. University of New Mexico School of Medicine, Albuquerque, New Mexico

Medical Clinics of North America-Vo!' 74, No. 6, November 1990

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Neither active viral replication nor cell death occurs during latency, but recent work suggests that a previously unrecognized gene is expressed in about 1% of infected neurons. 62 The role of this gene is unclear, but the limitation of gene expression at any time to a small proportion of infected neurons may explain why HSV recurrences are generally highly localized. Current hypotheses suggest that an isolated neuron assembles and centrifugally transports HSV to a mucocutaneous site where a localized recurrence occurs. In contrast, the closely related varicella-zoster virus (VZV) reactivates in satellite cells, which surround individual neurons in the nerve ganglia, and spreads to other satellite cells and neurons within the ganglia. The resulting mucocutaneous infection (zoster) involves much or all of the dermatome served by the involved ganglion. 62 Both HSV-l and HSV-2 can infect mucous membranes and abraded skin at any site, and the severity and duration of the initial infection are not influenced by virus type. 10.15 Thus, the severity and duration of primary, first-episode genital herpes are similar in persons infected with HSV-l or HSV-2. However, both the site of infection and virus type influence the frequency of recurrences and the likelihood that recurrences will occur. Several investigators have shown that the risk of a recurrence after an episode of primary, first-episode genital herpes is more than 80% with HSV-2 infection versus about 50% with HSV-l, and the median number of genital recurrences in the first year is about four times higher with HSV-2 infection (four versus one recurrences per year, respectively). 10, .56 Lafferty et aPI recently reported that the frequency of oral-labial or genital herpes recurrences in the first year after a primary infection was greatest with genital HSV-2, less frequent with oral-labial HSV-l, still less frequent with genital HSV-l, and least frequent with oral-labial HSV-2 infection. This information can be useful in counseling patients with first-episode disease regarding the likelihood of recurrences and their frequency if a virus culture with typing is obtained. In addition to marked differences in the natural history of genital HSV1 and HSV -2 infections, there is great variation in the frequency of recurrent genital HSV -2 infections in the normal host. The vast majority of persons with genital HSV -2 infection are unaware of their infection and apparently recur infrequently if at all,42, 50 whereas others regularly have one or more recurrences per month. 1,10,11,18,41 To date, no immune mechanisms or virus strains have been identified to explain these differences, although there are data suggesting a tendency for persons with untreated, severe primary first episodes to have the highest rates of long-term recurrences. 7, 11

THE IMMUNE RESPONSE Both humoral and cellular immune responses develop during the first weeks following acquisition of HSV infection and persist for life, In the normal host, immune responses to type-common antigens present in one type appear to influence the risk of acquisition of virus of the other type as well as the severity of the initial episode if infection with the other type occurs. Mertz et aP5 recently reported that the annual risk of transmission

GENITAL HERPES SI~1PLEX VIRUS INFECTIONS

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in couples with one partner with genital HSV-2 infection was 16% in couples with exposed partners without past HSV-l infection and 6% in couples with exposed partners with past HSV-l infection. Also, first-episode genital HSV -2 infection is less severe in persons with past HSV -1 infection. 10 Cell-mediated immune responses appear more important than humoral immune responses in controlling the severity of mucocutaneous HSV infections. In the normal host, frequent recurrences of genital herpes may occur despite high antibody titers, and severe or disseminated infections are common in immunocompromised patients with defects in cell-mediated immunity rather than those with defects in humoral immunity. [,3.44,54.58 At present, the general internist is most likely to encounter severe, prolonged mucocutaneous HSV infections in immunocompromised patients receiving corticosteroid therapy or cancer chemotherapy and in those with acquired immunodeficiency syndrome (AIDS).

EPIDEMIOLOGY Genital herpes is the most common ulcerative sexually transmitted disease diagnosed in persons in North America,14 and the incidence of disease appears to be increasing. In the last 20 years, the number of visits for genital herpes to clinicians in the United States has increased 16-fold. 24 The increase in incidence probably results from increased numbers of sexual partners and earlier sexual activity and from an increased risk of infection with HSV-2 in young adults without past HSV-I infection. The introduction of oral contraceptive pills and other forms of contraception may have contributed to both increases in sexual activity and increased risk of transmission. Furthermore, persons without prior HSV-I infection are more likely to develop severe, symptomatic first-episode genital herpes and are probably more likely to seek medical care. 10 In recent decades, there has been a significant decline in the acquisition of HSV -I infection in childhood, particularly in middle and upper socioeconomic groups in western, developed countries. At present, less than 50% of middle-class teens and young adults in the United States have serologic evidence of HSV-I infection as compared to more than 90% one or two generations ago. 34. 67 In a recent seroepidemiologic study employing a type-specific assay for HSV-2 antibody in sera obtained from over 4000 children and adults in the United States, Johnson et aF8 reported that the prevalence of HSV-2 antibody among persons over 30 years old was almost 20% in white men, 25% in white women, 40% in black men, and over 60% in black women (Fig. I). These rates are higher than previously recognized and are consistent with other studies suggesting that the majority of HSV-2 infections are subclinical. Role of Asymptomatic Infection In addition to seroepidemiologic studies documenting that the majority of persons with HSV-2 antibody lack a history of genital herpes, studies of persons who have transmitted HSV-2 to sex partners and to neonates

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O~--~~~'~--~'~~'--~--~----~------~------~~------~~ 1-14 15-19 20-24 25-29 30-39 40-49 50-59 60-74 Age Group Figure 1. Prevalence of HSV-2 antibody in the United States in 1978, according to age, race, and sex. (From Johnson RE, Nahmias AJ, Magder LS, et al: A seroepidemiologic survey of the prevalence of herpes simplex virus type 2 infection in the United States. N Engl J Med 321:7, 1989; with permission.)

confirm that transmission occurs most commonly from persons without a history of genital herpes. 42 , 50, 68 These studies suggest that asymptomatic shedding of HSV, often from persons without any history of genital herpes, may be the most common source of transmission of genital and neonatal herpes infections, The risk of asymptomatic shedding of HSV from the cervix or vulva has been shown to range from 0.4% to 1.3% per day in pregnant and nonpregnant women with a history of genital herpes, 1, 4 Studies in men have been less conclusive, but it is likely that persons with genital HSV-2 infection shed virus in the absence of symptoms on at least 2 to 5 days each year, Although the risk of transmission from asymptomatic shedding with a single sexual exposure or at delivery is low, 51 the relative frequency of asymptomatic shedding and the inability to determine its occurrence appear to explain the important role of asymptomatic shedding in the transmission of genital HSV infection. Risk of Transmission from Persons with Recognized Genital Herpes Several recent studies have estimated the annual risk of sexual transmission of genital herpes to be about 10% in couples in which one partner is known to have genital herpes. 8,35,37 In a recent placebo-controlled vaccine efficacy study, Mertz et aP5 found that the annual risk of acquisition was about 16% when the partner at risk was a woman or lacked HSV-l antibody versus about 6% when the partner at risk was a man or had HSV-l antibody. The couples were counseled to abstain from skin-to-skin contact with active

1437

GENITAL HERPES SIMPLEX VIRUS INFECTIONS

lesions. None of the partners with genital herpes used suppressive acyclovir therapy, and few couples used condoms with all sexual contact. Association Between Genital Ulcer Disease and Acquisition of HIV Several studies have documented a strong association with the presence of genital ulcers and acquisition of human immunodeficiency virus (HIV) infection. Stamm et al61 reported that acquisition of HIV infection in homosexual men was independently associated with a history of syphilis or genital herpes or with serologic evidence of syphilis or HSV _2.61 Holmberg27 reported an association with HIV seroconversion and antibody to HSV-2, particularly if seroconversion to HSV-2 had occurred. Thus, it may be that programs designed to prevent sexual transmission of HIV should include strategies for prevention and control of genital ulcer diseases, including genital herpes.

CLINICAL MANIFESTATIONS First-Episode Genital Herpes Although acquisition of genital HSV infections is apparently asymptomatic or unrecognized in most cases, symptomatic first-episode infection is often a severe disease characterized by a course of several weeks. 10 Multiple, bilateral lesions, moderate to severe local pain and dysuria, sacral paresthesia, tender inguinal lymphadenopathy, and systemic symptoms such as fever and malaise are typically present (Fig. 2). Lesions begin as vesicles or pustules and progress through stages of ulcer formation, crusting, and healing. The initial crop of lesions is often extensive, and adjacent pustules DURATION VIRAL SHEDDING VESICLE PUSTULE

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often coalesce to form large areas of ulceration (see Color Plate 2B). Deep, necrotic ulcers may also form. Without treatment, most patients form crops of new lesions in the second week and heal all lesions by the end of the third week of illness (Table 1). Complications of first-episode genital herpes may include HSV pharyngitis, extragenital cutaneous lesions acquired by autoinoculation, aseptic meningitis, and urine retention, which may result from local pain or from autonomic nervous system dysfunction. lO Primary first episodes, those occurring in persons without HSV-1 or HSV-2 antibody, tend to be more severe than nonprimary first episodes. The latter occur in persons with antibody to virus of the homologous or heterologous type (see Table 1). Herpes simplex virus-2 is isolated from 75% to 90% of primary first episodes and 99% of nonprimary first episodes. Conversely, HSV-1 is isolated from 10% to 25% of primary and 1% of nonprimary first episodes. Primary first-episode genital herpes also tends to be more severe in women than in men; women are twice as likely as men to have systemic symptoms, aseptic meningitis, and dysuria. 10 Without treatment, the mean duration of viral shedding from lesions in primary genital HSV-1 or HSV-2 infection is 11 days as compared to 7 Table 1. Relation Between Viral Type, Presence of HSV Antibody in Acute-Phase Sera, and Set;erity of Disease of First-Episode Genital Herpes* PRIMARY

HsV-l

HsV-2

NON PRIMARY

Hsv-2

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INFECTION

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26

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11.8

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75

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Patients with systemic symptoms (%) Patients with meningitis symptoms (%) Mean duration of local pain (days) Mean number of lesions Mean lesion area (mm 2 ) Patients with bilateral lesions (%) Patients forming new lesions during course of disease (%) Mean duration of viral shedding from genital lesions (days) Mean duration of lesions (days) Patients developing extragenital lesions (%) Patients shedding herpes simplex virus from cervix (%)

PRIMARY

INFECTION

(n = 189)

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*Only one patient with complement fixation and neutralizing antibody in acute-phase sera had HSV-l isolated from genital lesions. P <0.0.5 for each comparison (except percent shedding from cervix) between nonprimary and primary HSV-2 infection (chi-squared or Student's t test). From Corey L, Adams HG, Brown ZA, et al: Genital herpes simplex virus infection: Clinical manifestations, course, and complications. Ann Intern Med 98:9.58, 1983; with permission.

GENITAL HERPES SI~IPLEX VIRUS INFECTIONS

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days with untreated nonprimary genital herpes. Virus cultures obtained from the cervix are positive in 90% of women with primary HSV-2, 80% with primary HSV-1, and 70% with nonprimary HSV-2 first-episode genital herpes, and the duration of viral shedding from the cervix is similar to that from lesions in primary and nonprimary infections. 10 Complications of Primary First-Episode Genital Herpes Complications such as aseptic meningitis, urine retention, and development of extragenital lesions are seen almost exclusively in primary first episodes. Aseptic meningitis occurs in about a third of women and 10% of men with primary genital herpes. About 15% of those with symptoms of meningitis may be ill enough to require brief hospitalization for supportive care. IQ Although patients, particularly women, often have difficulty urinating because of dysuria, significant urine retention is uncommon in this setting. Difficulty urinating because of dysuria can generally be managed without catheterization by having patients urinate while immersing lesions in warm water to decrease the pain of contact between undiluted urine and lesions. In contrast, when urine retention occurs in the absence of lesion pain or dysuria late in the course of a primary episode, the cause may be autonomic nervous system dysfunction or, less commonly, transverse myelitis. Intermittent catheterization of the bladder may be required for periods of several days to up to 4 to 8 weeks. Fortunately, severe autonomic nervous system dysfunction occurs in less than 1% of primary episodes, and transverse myelitis is exceedingly rare. 10, 38 Extragenital lesions occur more commonly in women than in men with primary genital herpes (26% versus 8%) and typically appear in the second week of illness when acquired by autoinoculation from genital lesions. 10 In contrast, HSV pharyngitis, which complicates about 10% of cases of genital herpes, is usually acquired by oral sexual contact. Pharyngitis is typically present during the first week of illness and may precede the onset of genital lesions. Cutaneous or visceral dissemination is rare, particularly in the normal host; however, both may occur in patients with atopic eczema, in immunocompromised patients, and, rarely, in pregnancy. 23, 32, 34 Visceral dissemination may involve almost any organ but most commonly involves the meninges, lung, and liver. Visceral dissemination is usually but not invariably associated with cutaneous dissemination. Herpes Simplex Proctitis Herpes simplex virus was isolated from 23% of homosexual men with proctitis in Seattle. 26 , 52, .53 Herpes proctitis was characterized by fever, malaise, severe rectal pain, tenesmus, constipation, and discharge. Neurologic symptoms such as sacral paresthesias, impotence, urine retention, and perianal vesicles were present in about 50% of patients with herpes proctitis and were absent in persons with proctitis caused by Neisseria gonorrhoeae or Chlamydia trachomatis,

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Recurrent Genital Herpes Recurrent genital herpes episodes, which occur in the presence of established cellular and humoral immune responses, tend to be much less severe and to heal more quickly than first episodes. 1O Approximately 50% of recurrent episodes are preceded by a prodrome. The prodrome may precede lesions by less than an hour to 1 or 2 days, and is variously described as a tingling sensation, pain in the buttocks, or mild itching or pain. Lesions of recurrent genital herpes tend to be unilateral and well localized (see Color Plate 2C). Lesion development in recurrent genital herpes is similar to first-episode genital herpes, although in the former, vesicles are far more common than pustules, and deep, necrotic ulcers rarely occur. The mean number of lesions is five to seven and new lesions occur in 30% to 40% of episodes. The mean duration of viral shedding is 4 days, and healing occurs a mean of 10 days.1O Pain is more commonly reported, tends to last longer, and is more likely to be considered severe in women than in men. In contrast to first-episode genital herpes, viral shedding from the cervix occurs in only about 12% of recurrences, and shedding from the urethra is uncommon in men and women. Complications of recurrent genital herpes are very uncommon. However, recurrent mucocutaneous herpes infections appear to be the most common cause of erythema multiforme, even in cases in which herpes infections are not clinically evident. 33 Recurrent aseptic meningitis has been described but is thought to be exceedingly uncommon. 34

Genital Herpes Infections in Immunocompromised Patients Genital herpes infections in immunocompromised patients are more severe and prolonged than in the normal host. In the absence of antiviral therapy, lesions, which are typically deep, necrotic, and painful, and viral shedding may persist for a month or more after bone marrow transplantation and may persist indefinitely in persons with AIDS.44. 54. 58 In persons with AIDS, perianal lesions are most common, but the buttocks, scrotum, penis, and oral-labial areas are also common sites of infection. Although the risk of dissemination is clearly increased in the immunocompromised host, most untreated infections do not disseminate.

DIAGNOSIS Differential Diagnosis Genital herpes should be considered in the differential diagnosis of any person with genital vesicles, pustules, or ulcers, particularly if they are recurrent. 14 Zoster is more likely to occur in a dermatomal distribution and is rarely recurrent, but either zoster or genital herpes simplex infections may present with buttock lesions. Herpes simplex virus is the most common single cause of genital ulcers in patients seen in gynecology and sexually transmitted disease clinics in the United States, but syphilis, chancroid, and noninfectious causes such

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as trauma or Beh<;et's syndrome should be considered. 14 Genital herpes is more likely when there are multiple rather than single ulcers, when ulcers are painful, when they are recurrent or preceded by a prodrome, when they are accompanied by sacral paresthesias, and when lymphadenopathy is tender but not fluctuant. Genital ulcers and inguinal nodes tend not to be tender in syphilis, and inguinal nodes tend to be tender and may be fluctuant in chancroid and lymphogranuloma venereum. However, there is considerable overlap in clinical presentations, and many genital herpes infections, particularly first episodes, are atypical. Viral Culture and Antigen Detection Virus culture remains the most sensitive and specific test for mucocutaneous HSV infection. Viral isolation rates are approximately 90% from vesicles and pustules as compared to less than 30% from crusted lesions. 22 Isolation rates are typically more than 80% from ulcers in immunocompromised patients and in first-episode genital herpes versus about 40% from ulcers in normal patients with recurrent genital herpes. After breaking a vesicle or pustule, the lesion should be swabbed with a dacron- or cottontipped swab. The swab should be placed in viral transport media, and it should be refrigerated until received in the laboratory, where the specimen can be inoculated into an appropriate tissue culture cell line. Once the culture is set up, HSV will usually grow within I to 4 days. If indicated, typing can then be performed with commercially available monoclonal antibodies. 25 Although it is appropriate to initiate therapy based on a clinical diagnosis of first-episode genital herpes, laboratory confirmation should be sought whenever possible. In first-episode disease, a positive culture with typing confirms the diagnosis and provides important prognostic information. In general, a culture should be obtained when lesions are present in any person who has not had a previous positive herpes culture and in persons who have atypical symptoms or who are suspected of having acyclovir-resistant HSV. It is often difficult to counsel patients about the risk of transmission or to make recommendations regarding suppressive acyclovir therapy when the diagnosis of genital herpes is uncertain. Unfortunately, a negative lesion culture does not rule out infection, and several attempts may be necessary. Ideally, the culture should be obtained within 7 days oflesion onset in a first episode or within 2 days in recurrent disease. Alternatives to standard viral culture include cytologic diagnosis by Papanicolaou or Tzanck stains, modifications of viral culture, and viral antigen or DNA detection. 22 Cytologic diagnosis is much less sensitive than viral culture and cannot differentiate between HSV-l, HSV-2, and VZV. Several antigen detection techniques such as a direct immunofluorescence test, immunoperoxidase staining, and ELISA are available. These techniques are generally less expensive and more rapid than viral culture, but most studies suggest a sensitivity of 70% to 90% compared to viral culture from lesions. None appear to be acceptably sensitive for detection of asymptomatic shedding.

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Serologic Testing Serologic assays that are widely available include complement fixation, neutralization, immunofluorescence, immunoperoxidase, radioimmunoassay, and ELISA.22 None of these assays reliably differentiate between antibodies to type-specific and type-common antigens, and patients should not be told that they have had HSV -2 infection in the past based on results of currently available serologic tests. However, these tests are easily available and are useful for screening for past HSV infection and for documenting seroconversion in primary genital herpes infection. Recently, several research laboratories have developed assays that can reliably differentiate between antibody responses to HSV -1 and HSV -2. These type-specific assays include an immunodot enzyme assay employing purified, type-specific glycoprotein antigens, gG-l and gG-2, and a Western blot assay that compares binding to HSV-l and HSV-2 antigens. 2 3.22.28 Serologic Evaluation of First-Episode Genital Herpes In a recent report by Bernstein et aP 50% of persons presenting with first-episode genital herpes had true primary infections that could have been documented by comparing acute and convalescent sera with almost any available serologic test. However, more than half of those with nonprimary first episodes had HSV-2 antibody specificity by Western blot assay of acute sera. This indicates that 25% or more of persons presenting with a first clinical episode of genital herpes have had asymptomatic or unrecognized acquisition of HSV-2 infection in the past. Therefore, clinicians should be cautious when implicating a current sexual partner as the source of a first episode, particularly if serologic testing is not done or if serologic testing indicates that it is a nonprimary first episode. PSYCHOSOCIAL ISSUES Questions frequently asked by persons with genital herpes include the risk of transmission to a sexual partner, the risk of transmission to the neonate, the risk of sexual or perinatal transmission during asymptomatic periods, whether to inform and how to inform a sexual partner, and the cost, benefit, and risk of antiviral therapy. Many patients will also exhibit marked anger, depression, guilt, tension, and preoccupation with their disease. These responses are particularly common in persons who have been recently diagnosed, in women, and in persons with frequently recurrent genital herpes. 43 A variety of approaches may be employed when addressing these questions and psychosocial responses. In addition to carefully answering questions, the clinician may find it helpful to see the patient with his or her sexual partner. Anecdotal evidence suggests that patients with frequent recurrences who exhibit preoccupation with disease may benefit from suppressive acyclovir therapy. Support groups, often affiliated with the national Herpes Resource Center (HRC), are available in many cities. The HRC also publishes a quarterly publication, The Helper, for persons with

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genital herpes. Information about local support groups or The Helper can be obtained by sending a self-addressed, stamped envelope to HRC, P. O. Box 13827, Research Triangle Park, NC 27709, or by calling the herpes hotline at (919) 361-2120. ANTIVIRAL THERAPY Although there is no effective vaccine or treatment capable of eradicating established infection, treatment is now available to shorten the course, decrease severity, and suppress HSV episodes in both normal and immunocompromised patients safely and effectively. The currently licensed antiviral drug, acyclovir (ACV), is available in topical, intravenous, and oral formulations, and the latter two now enjoy wide clinical acceptance. 17 Mechanism of Action and Pharmacokinetics of Acyclovir As is the case with most currently available antiviral drugs, ACV, which is an acyclic analogue of guanosine, must be phosphorylated to the triphosphate form (ACV-TP) to exert its antiviral action (Fig. 3). The triphosphate form of ACV is a competitive inhibitor of the nucleotide

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deoxyguanosine triphosphate and inhibits HSV DNA polymerase to a far greater degree than it inhibits human DNA polymerase. In addition, once incorporated into HSV DNA, chain termination results because ACV has no 3' -hydroxyl group available for linkages with additional nucleotides. 20 The safety and specificity of acyclovir result from the relative inability of human cellular enzymes to phosphorylate ACV. Most isolates of HSV-l and HSV-2 are inhibited by concentrations of ACV well below 3.0 flg/mL (13 flM/L), whereas levels of 70 to 700 flg/mL are necessary to produce toxicity in uninfected human cells. 16, 17 It is only in HSV -infected cells that HSV-specified thymidine kinase (TK) phosphorylates ACV to ACV-MP, Human cellular enzymes then form ACV-DP and ACV-TP, The most common mechanism of ACV resistance is the development of thymidine kinase-deficient (TK-) strains of HSV, 21 Peak serum concentrations for ACV are about 9 flg/mL after an intravenous dose of5 mg/kg versus 0,2 to 0,7,0,7 to 1.4, and 1.2 to 2.1 flg/mL after oral doses of 200, 400, and 800 mg, respectively, Plasma halflife is about 3 hours in normal adults versus 20 hours in anephric patients, 17 After oral absorption or intravenous administration, 85% to 90% of the drug is excreted unchanged in the urine, and dose adjustment is necessary in renal failure. 17.23,34

Treatment of First-Episode Genital Herpes Oral ACV (200 mg five times daily for 10 days) is now the treatment of choice for first-episode genital herpes,23, 39 although all three ACV formulations are approved by the US Food and Drug Administration (FDA) for this indication. The preparations have not been directly compared in blinded studies, but comparison of blinded, placebo-controlled studies performed at the same center suggest that systemic therapy is superior to topical therapy. 12 Oral and intravenous ACV appeared to have greater antiviral efficacy and, unlike topical therapy, oral and intravenous therapy shortened the duration of dysuria, systemic symptoms, and the formation of new lesions (Table 2).12 Oral therapy has emerged as the treatment of choice because it is less expensive, safer, and easier to administer than intravenous therapy. Because of the clear clinical efficacy of oral ACV, treatment of first episodes is encouraged whenever active lesions are present. Treatment with oral ACV reduces the mean duration of viral shedding by 8 days, the duration of pain by 4 days, and the time to healing by a week (see Table 2).12 The severity of symptoms or lesions in the first week of illness is a poor predictor of the need for treatment because new lesion formation and worsening of local and systemic symptoms typically occur for a week or more if treatment is not initiated. 10 If hospitalization is needed for supportive care, intravenous ACV (5 mg/kg over 1 hour every 8 hours) can be initiated until the patient can be discharged to complete a lO-day course with oral ACV.13, 23 Patients on intravenous ACV should be kept well hydrated, and renal function should be monitored. Combination treatment with oral ACV plus either topical ACV or isoprinosine has been compared to oral ACV in controlled trials, and neither combination was more effective than oral ACV.29. 46 One study

GENITAL HERPES S['.IPLEX

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INFECTIONS

Table 2. Signs and Symptoms of First-Episode Primary Genital Herpes in Acyclovir Compared with Placebo-Treated Patients* TREATED PATIENTS

Median no. of days Local itching Local pain Dysuria Vaginal discharge Complete crusting of lesions Complete healing of lesions Percent of patients With systemic symptoms at 7 days of treatment Forming new lesions

Topical ACV (n=28)

Placebo Ointment (n =23)

IV ACV (n = 14)

IV Placebo (n = 13)

Oral ACV (n=33)

Oral Placeho (n=27)

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*All comparisons are between patients who had described symptoms at time of enrollment into the study. tP <0.05, Mantel-Cox Test for ACV versus placebo. :l=P <0.01, Mantel-Cox Test for ACV versus placebo. Adapted from Corey L, Benedetti J. Critchlow C, et al: Treatment of primary firstepisode genital herpes simplex virus infections with acyclovir: Results of topical, intravenous and oral therapy. J Antimicrob Chemother 12(suppl b):79, 1983; with permission. suggested that the frequency of long-term recurrences may be decreased in persons treated with oral ACV during their first episode,7 but a second study did not confirm this finding. 36 Herpes Proctitis Rompalo et al 55 recently reported that oral ACV (400 mg five times daily for 10 days) decreased the duration of lesions and viral shedding but not symptoms of herpes proctitis. Many homosexual men with proctitis may be immunocompromised from HIV infection. Thus, it is probably appropriate to use the higher oral ACV dose used by Rompalo et al and in other trials in immunocompromised patients. Episodic Treatment of Recurrent Genital Herpes Indications for episodic treatment of recurrent genital herpes are not as clear as in the case of first-episode genital herpes. Several trials using the 5% ACV ointment available in the United States have failed to demonstrate efficacy, and the ointment is neither licensed nor recommended for treatment of recurrent genital herpes. 34 Episodic treatment with oral ACV (200 mg five times daily for 5 days) is moderately effective. Reichman et al 57 reported that patient-initiated treatment at the first sign of prodrome or lesions was more effective than treatment initiated by the physician after the onset of lesions. However, even with patient-initiated treatment, there was less than a 2-day reduction

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in the duration of viral shedding and lesions, and the mean decrease in the duration of pain of less than 1 day was not statistically significant (Table 3). These clinical benefits should be weighed against the cost and inconvenience of repeated courses of episodic treatment. The cost to the pharmacist is about $13 per course of treatment. I generally reserve episodic treatment for patients who describe infrequent but moderately severe or prolonged episodes or when these episodes are preceded by a prodrome so that therapy may be initiated before onset of lesions. If episodic therapy is used, patients should keep a 5-day supply of ACV at hand and be instructed to start treatment at the first sign of prodrome or lesions. Patients with frequent recurrences generally prefer and benefit more from suppressive than from episodic ACV therapy, regardless of the severity of episodes.40. 41 Suppressive Acyclovir Therapy In patients with frequently recurrent genital herpes, suppressive ACV therapy has been found to be safe and highly effective. Mertz et a1 40. 41 have reported the results of a trial comparing suppressive and episodic treatment in almost 1200 patients who reported a mean of 12 recurrences per year before the study. In the first year of the trial, patients were treated with daily ACV (400 mg twice a day) or placebo; patients whose symptoms recurred were treated with standard episodic treatment with ACV. During Table 3. Effect of Orally Administered Acyclovir on the Course of Recurrent Genital Herpes PHYSICIAN-INITIATED THERAPY

Lesions present at first clinic visit Duration of virus shedding Time to crusting Time to healing All lesions Duration of virus Time to crusting Time to healing Duration of itching Duration of pain Development of new lesions during therapy (%)

PATIENT-INITIATED THERAPY

Acyclovir

Placebo

Acyclovir

Placebo

2.0 ± 0.1*t

3.0 ± 0.3

2.1 ± 0.2t

3.4 ± 0.3

2.1 ± 0.2 6.3 ± 0.3§

2.3 ± 0.2 7.0 ± 0.3

2.4 ± 0.2:j: 5.5 ± 0.311

3.2 ± 0.3 6.5 ± 0.5

± ± ± ± ±

3.1 ± 0.3 2.7 ± 0.2 7.4 ± 0.3 2.9 ± 0.3 3.1 ± 0.3 24.5

2.1 2.4 5.7 2.8 3.0

± ± ± ± ±

3.9 ± 0.3 3.9 ± 0.3 7.2 ± 0.5 3.6 ± 0.3 3.4 ± 0.3 21.7

2.1 2.2 6.3 2.5 2.8

0.2t 0.211 0.3 0.2 0.2 16.0

0.2t 0.2t 0.3 0.3§ 0.3§ 7.3

*Days (mean ± SE M), as measured from the first clinic visit. tDuration significantly less than observed in placebo group (P :50.0(1l) by log-rank test. :j:Duration significantly less than observed in placebo group (P :50.(1) by log-rank test. §Duration not significantly less than observed in placebo group (0.05 :5 P :50.10) by logrank test. IIDuration significantly less than observed in placebo group (P :50.5) by log-rank test. From Reichman RC, Badger Cj, Mertz CL et al: Treatment of recurrent genital herpes simplex infections with oral acyclovir: A controlled trial. JAMA 251:2103, 1984; with permission.

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GENITAL HERPES SIMPLEX VIRUS INFECTIONS

the first year, those treated with suppressive ACV had a mean frequency of 1.8 recurrences and 44% remained free of recurrences; those receiving placebo had a mean frequency of 11.4 recurrences per year, and only 2% remained free of recurrences (Fig. 4). Patients were allowed to choose the form of treatment in the second year, and 89% chose suppressive therapy. Episodes occurring during suppressive therapy are shorter, less severe, and less likely to be associated with viral shedding than untreated episodes. 18 It is not known whether the risk of sexual transmission of genital herpes is decreased in persons receiving suppressive therapy, but some risk of transmission clearly remains. In 1985, when the FDA approved use of oral ACV (200 mg three times a day) for up to 6 months, only results of 3- to 6-month trials were available. Since 1985, the results of studies evaluating the safety and efficacy of a variety of doses and dosing intervals for periods of up to 4 years have been published. 40, 41, 45, 6.1 One early trial raised concerns about ACV resistance in HSV recovered from normal adults on suppressive therapy,65 but larger, long-term studies have found no evidence of emergence of ACV resistance in normal adults on suppressive therapy. 41, 47 Sperm motility and morphology were studied in a placebo-controlled trial in men receiving up to a gram of ACV a day for 6 months, and no effect was found. 19 Nausea has been reported at the onset of suppressive therapy but appears to resolve over time in most patients. 41 No effect on marrow, renal, or hepatic function has been detected in these studies, and there is no clear indication for routine laboratory monitoring of normal adults on suppressive ACV therapy. 50

40

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Episodes of Genital Herpes In 1 V

Figure 4, Frequency of genital herpes episodes in one year among 519 patients receiving continuous suppression (hatched bars) with 400 mg of acyclovir orally twice daily for 1 year and among 431 patients (open bars) receiving placebo (episodic treatment) for 1 year. All patients receive open-laheled acyclovir for 5 days during investigator-confirmed episodes of genital herpes. (From Mertz CL Jones CC, Mills J, et al: Long-term acyclovir suppression of frequently recurring genital herpes simplex virus infection: A multicenter double-blind trial. JAMA 260:201, 1988; with permission.)

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Recently, the FDA approved the use of suppressive ACV for 1 year. Although there is no current evidence that longer periods of continuous suppression are not safe, patients should be encouraged to interrupt treatment periodically to determine whether the frequency of recurrences still justifies suppressive therapy. In addition to the dose of 200 mg three times daily recommended by the FDA, doses of 200 mg two, four, and five times daily, 400 mg once, twice, and three times daily, and 800 mg once daily have been found to be effective (Fig. 5).18. 34. 40. 41. 63. 64 Once-daily treatment with 200 mg appears ineffective and is not recommended. 45 The most effective dosing regimens appear to be 400 mg twice daily and 200 mg four times daily. 41. 45 The former is more convenient to administer, and it is the regimen preferred by the author. Treatment with 200 mg twice daily appears to be almost as effective; patients willing to accept a slight decrease in efficacy in return for decreased cost may prefer this regimen. 18. 45 Neither 400 nor 800 mg once daily appears quite as effective as 200 or 400 mg twice daily, but either could be considered in patients who have difficulty complying with twice-daily dosing. 45 The primary indication for suppressive ACV therapy is frequently recurring genital herpes. There is no absolute cutoff for frequency, but most patients do not derive adequate benefit from suppressive therapy unless they experience six to eight or more recurrences per year. In addition, suppressive therapy is indicated in individuals with recurrent HSV -induced erythema multiforme. 33 U se of Acyclovir in Pregnancy At present, the use of oral or intravenous acyclovir in pregnancy should probably be limited to treatment of women with life-threatening HSV or VZV infections, such as severe varicella pneumonia. 5 Some would consider treatment of primary, first-episode genital herpes in the third trimester because of the apparent adverse impact on the outcome of pregnancy in this setting. 5, 6 However, it is not known whether treatment would alter this outcome. Treatment in the Immunocompromised Host A comprehensive review of treatment of HSV infections in the immunocompromised host is beyond the scope of this article. However, primary care providers should be familiar with routine management of HSV infections in the HIV-infected patient. As with most infectious diseases in HIV-infected patients, HSV infections generally result from reactivation rather than recent acquisition. With a few exceptions, guidelines for treatment are similar to those for episodic or suppressive therapy of genital herpes in the normal host. 34, 58 These exceptions are as follows. First, most studies in the immunocompromised host have used an oral dose of 400 mg five times a day for 10 days for episodic treatment and suppressive doses of 400 mg three or four times daily, and anecdotal experience in HIV-infected patients supports the safety and efficacy of these dosing regimens. 58, 59, 64, 66 Second, although the clinical benefit from episodic treatment is marginal in the normal host, episodic treatment is

1449

GENITAL HERPES SIMPLEX VIRUS INFECTIONS

lO°1at=4.. 200mg qds n=79

90

80 QI

u

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20

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'>0

60

70

80

90

100

Time (days)

Figure 5. Time to first recurrence with different doses of acyclovir. Od, once daily; bd, twice a day; tds, three times a day; qds, four times a day. (From Mindel A, Faherty A, earney 0, et al: Dosage and safety of long-term suppressive acyclovir therapy for recurrent genital herpes. Lancet 1:926, 1988; with permission.)

clearly effective in reducing the duration of viral shedding, lesions, and symptoms in the immunocompromised host. 59 Thus, recurrent HSV episodes in HIV-infected persons should be treated routinely with ACV, particularly if the person has AIDS. Third, once suppressive therapy is initiated in a person with AIDS, it should probably be continued indefinitely. Finally, infection with TK-, ACV-resistant HSV is an infrequent but

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clinically significant problem in persons with AIDS. Acyclovir-resistant HSV should be suspected when lesions fail to improve and remain culturepositive after a week or more of adequate doses of oral or intravenous ACV.2! There are reports of successful treatment of ACV-resistant HSV infections in persons with AIDS with the investigational drug foscarnet, and the AIDS Clinical Trials Croup (ACTC) is conducting a comparison of intravenous therapy with foscarnet versus vidarabine for treatment of ACV-resistant HSV infections. Information about ACTC trials can be obtained by calling 1-800-874-2572. Alternatives to Acyclovir Therapy in the Normal Host At present, there are no safe, effective alternatives to ACV for the treatment of genital herpes infections in the normal host. Intravenous therapy with foscarnet or vidarabine is too toxic and impractical for treatment of genital herpes in the normal host. Topical treatment with foscarnet, vidarabine, idoxuridine (IDU), IDU in dimethyl sulfoxide (DMSO), and ara-A monophosphate have proved ineffective in trials in persons with genital herpes. 34 Neither topical 2-deoxy-D-glucose nor oral lysine has been shown to be effective despite the considerable popularity of these treatments a decade ago. 34 Photodynamic inactivation using neutral red or proflavine dyes was also popular in the past but is no longer recommended. Controlled studies showed it to be ineffective, and in vitro studies showed that HSV treated in this manner could cause cell transformation. Several trials employing either systemic or topical interferons have shown no clear clinical benefit from treatment. 30. 48. 49 Some studies are ongoing, but there is no indication at present for interferon treatment of genital herpes infections. Although isoprinosine is promoted outside the United States for treatment of genital herpes, there are no studies documenting the efficacy of this treatment. Treatment of established HSV infections with inactivated-HSV vaccines available in Europe, BCC, smallpox, and other vaccines is of no proven benefit. Deaths have been reported from disseminated vaccinia, and use of smallpox vaccine should be discouraged. 9 PREVENTION Prevention of transmission of genital herpes will probably require development of an effective vaccine. At present, there is no HSV vaccine available in the United States or elsewhere that has been shown to prevent acquisition of HSV infection in humans. Skinner et al 60 administered an inactivated HSV vaccine free of DNA to sex partners of persons with genital herpes, but the authors' claim of efficacy has been questioned because of the use of a historical control group rather than a randomized, placebocontrolled study design. Mertz et aP5 recently reported that a glycoprotein subunit HSV-2 vaccine failed to provide protection from acquisition of genital HSV infection in a prospective, randomized, placebo-controlled study in sex partners of persons with genital herpes. The vaccine described

GENITAL HERPES SI\1PLEX VIReS INFECTIONS

1451

by Skinner is undergoing further testing, and there are additional vaccines under development. Appropriate use of latex condoms should theoretically reduce the risk of sexual transmission of HSV during periods of asymptomatic viral shedding. Although evidence of clinical benefit is lacking, Nonoxynol-9 inactivates HSV in vitro, and use of spermicides containing Nonoxynol-9 with condoms might further decrease the risk of transmission of HSV. Animal studies suggest that postexposure treatment with ACV might decrease the risk of infection and establishment of latency after exposure to HSV. However, no studies have been performed in humans, and this form of treatment cannot be advocated at present. 34

SUMMARY There has been a dramatic increase in patient visits to physicians for evaluation and treatment of genital herpes infections. This has resulted in part from an increase in genital herpes infections, particularly severe, firstepisode genital herpes infections in adults without prior HSV-l infection. Virus culture remains the most sensitive and specific method for diagnosis, and use of viral cultures is encouraged. Type-specific antibody tests have been employed in studies documenting the role of asymptomatic shedding of HSV in transmission of genital infections, the role of genital HSV in transmission of HIV, the predominance of asymptomatic and unrecognized infections in those infected with HSV-2, and the presence of past asymptomatic or unrecognized acquisition of HSV -2 in 25% of persons presenting with first-episode genital herpes. Unfortunately, commercially available serologic tests do not reliably differentiate between antibody to HSV-l and HSV-2. Recent studies suggest that the annual risk of transmission from a sexual partner with genital herpes is about 10% in heterosexual couples. Currently, promotion of "safe sex" is the only available approach for prevention of transmission. However, ongoing research is focused on the development of an effective vaccine. Acyclovir should be used routinely in persons with first-episode genital herpes, but careful evaluation is needed in persons with recurrent genital herpes to determine whether episodic or suppressive treatment is indicated. Acyclovir should also be used routinely for episodic or suppressive treatment of HSV infections in persons with AIDS. Additional antiviral agents are needed for more effective suppressive therapy and for treatment of ACVresistant HSV infections in the immunocompromised host.

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predict the infant's risk of exposure to herpes simplex virus at delivery. N Engl J Med 315:796, 1986 2. Bernstein Dr, Bryson YJ, Lovett MA: Antibody response to type-common and typeunique epitopes of herpes simplex virus polypeptides. J Med Virol 15:251, 1985

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3. Bernstein DI, Lovett MA, Bryson YJ: Serologic analysis of first-episode nonprimary genital herpes simplex virus infection: Presence of type 2 antibody in acute serum samples. Am J Med 77: 1055, 1984 4. Brock BV, Selke S, Benedetti J, et al: Frequency of asymptomatic shedding of herpes simplex virus in women with genital herpes. JAMA 263:418, 1990 5. Brown ZA: Acyclovir in pregnancy. In Acyclovir Therapy for Herpesvirus Infections. New York, Marcel Dekker, 1989, p 135 6. Brown ZA, Vontver LA, Benedetti J, et al: Effects on infants of a first episode of genital herpes during pregnancy. N Engl J Med 317:1246, 1987 7. Bryson Y, Dillon M, Lovett M, et al: Treatment of first episode genital HSV with oral acyclovir: Long-term follow-up of recurrences. A preliminary report. Scand J Infect Dis (suppl)47:70, 1985 8. Bryson Y, Dillon M, Radolf J, et al: Risk of acquisition of genital HSV-2 in sexual partners of patients with genital HSV: A prospective study [abstract). In Programs and Abstracts of the 28th Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Washington, DC, 1988 9. Centers for Disease Control: Adverse reactions to smallpox vaccinations-1978. MMWR 28:265, 1979 10. Corey L, Adams HG, Brown ZA, et al: Genital herpes simplex virus infection: Clinical manifestations, course, and complications. Ann Intern Med 98:958, 1983 11. Corey L, Ashley R, Benedetti J, et al: The effect of prior HSV -1 infection on the subsequent natural history of genital HSV-2 [abstract). In Programs and Abstracts of the 28th Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Washington, DC, 1988 12. Corey L, Benedetti J, Critchlow C, et al: Treatment of primary first-episode genital herpes simplex virus infections with acyclovir: Results of topical, intravenous and oral therapy. J Antimicrob Chemother 12(suppl B):79, 1983 13. Corey L, Fife KH, Benedetti JK, et al: Intravenous acyclovir for the treatment of primary genital herpes. Ann Intern Med 98:914, 1983 14. Corey L, Holmes KK: Genital herpes simplex virus infections: Current concepts in diagnosis, therapy and prevention. Ann Intern Med 98:973, 1983 15. Corey L, Spear PG: Infections with herpes simplex viruses. Parts 1 and 2. N Engl J Med 314:686, 749, 1986 16. Crumpacker CS, Schnipper LE, Zaia JA, et al: Growth inhibition by acycloguanosine of herpesviruses isolated from human infections. Antimicrob Agents Chemother 15:642, 1979 17. Dorsky DI, Crumpacker CS: Drugs five years later: Acyclovir. Ann Intern Med 107:859, 1987 18. Douglas JM, Critchlow C, Benedetti J, et al: A double-blind study of oral acyclovir for suppression of recurrences of genital herpes simplex virus infection. N Engl J Med 310:1551, 1984 19. Douglas JM, Davis LG, Remington ML, et al: A double-blind placebo-controlled trial of the effect of chronically administered oral acyclovir on sperm production in men with frequently recurrent genital herpes. J Infect Dis 157:588, 1988 20. Elion GB: History, mechanism of action, spectrum and selectiVity of nucleoside analogues. In Antiviral Chemotherapy: New Directions for Clinical Applications and Research. New York, Elsevier Science Publishing, 1986, p 118 21. Erlich KS, Mills J, Chatis P, et al: Acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome. N Engl J Med 320:293, 1989 22. Fife KH, Corey L: Herpes simplex virus. In Sexually Transmitted Diseases, ed 2. New York, McGraw-Hill, 1990, p 941 23. Fowler CL, Mertz GJ: Treatment of first-epsisode genital herpes. In Acyclovir Therapy for Herpesvirus Infections. New York, Marcel Dekker, 1989, p 79 24. Genital herpes infection-United States, 1966-1984. MMWR 35:402, 1986 25. Goldstein LC, Corey L, McDougall JK, et al: Monoclonal antibodies to herpes simplex viruses: Use in antigenic typing and rapid diagnosis. J Infect Dis 147:829, 1983 26. Goodell SE, Quinn TC, Mrktichian E, et al: Herpes simplex virus proctitis in homosexual men. N Engl J Med 308:868, 1983 27. Holmberg SD, Stewart JA, Gerber AR, et al: Prior herpes simplex virus type 2 infection as a risk factor for HIV infection. JAMA 259:1048, 1988

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28. Johnson RE, Nahmias A], Magder LS, et al: A seroepidemiologic survey of the prevalence of herpes simplex virus type 2 infection in the United States. N Engl J Med 321:7, 1989 29. Kinghorn GR, Abeywickreme I, Jeavons M, et al: Efficacy of combined treatment with oral and topical acyclovir in first episode genital herpes. Genitourin Med 62:186, 1986 30. Kuhls TL, Sacher ], Pineda E, et al: Suppression of recurrent genital herpes simplex virus infection with recombinant alpha 2 interferon. J Infect Dis 154:437, 1986 31. Lafferty WE, Coombs RW, Benedetti ], et al: Recurrences after oral and genital herpes simplex virus infection. Influence of site of infection and viral type. N Engl J Med 316: 1444, 1987 32. Lagrew DC, Furlow TG, Hager WD, et al: Disseminated herpes simplex virus infection in pregnancy: Successful treatment with acyclovir. JAMA 252:2058, 1984 33. Leigh IM: Management of non-genital herpes simplex virus infections in immunocompetent patients. Am J Med 85(suppl 2A):34, 1988 34. Mertz GJ: Herpes simplex virus. In Antiviral Agents and Viral Diseases of Man, ed 3. New York, Raven Press, 1990, p 265 35. Mertz G], Ashley R, Burke RL, et al: Double-blind, placebo-controlled trial of a herpes simplex virus type 2 glycoprotein vaccine in persons at high risk for genital herpes infection. J Infect Dis 161:653, 1990 36. Mertz G], Benedetti ], Critchlow C, et al: Long-term recurrence rates of genital herpes infections after treatment of first-episode genital herpes with oral acyclovir. In Herpes Viruses and Virus Chemotherapy. Amsterdam, Elsevier, 1985, p 141 37. Mertz GJ, Coombs RW, Ashley R, et al: Transmission of genital herpes in couples with one symptomatic and one asymptomatic partner: A prospective study. J Infect Dis 157:1169, 1988 38. Mertz GJ, Corey L: Genital herpes simplex virus infections in adults. Urol Clin North Am 11:103, 1984 39. Mertz G], Critchlow CW, Benedetti J, et al: Double-blind placebo-controlled trial of oral acyclovir in first-episode genital herpes simplex virus infection. JAMA 252:1147, 1984 40. Mertz G], Eron L, Kaufman R, et al: Prolonged continuous versus intermittent oral acyclovir treatment in normal adults with frequently recurring genital herpes simplex virus infection. Am J Med 85(suppl 2A):14, 1988 41. Mertz GL Jones CC, Mills J, et al: Long-term acyclovir suppression of frequently recurring genital herpes simplex virus infection. A multicenter double-blind trial. JAMA 260:201, 1988 42. Mertz GL Schmidt 0, Jourden JL, et al: Frequency of acquisition of first-episode genital infection with herpes simplex virus from symptomatic and asymptomatic source contacts. Sex Transm Dis 12:33, 1985 43. Mertz GJ, Skipper BJ, Schaab C, et al: Psychosocial responses to genital herpes infection and other sexually transmitted diseases [abstract 79]. Presented at the VII Annual Meeting of the International Society for STD Research. Atlanta, August 2-5, 1987 44. Meyers JD, Flournoy N, Thomas ED: Infection with herpes simplex virus and cellmediated immunity after marrow transplant. J Infect Dis 142:338, 1980 45. Mindel A, Faherty A, Carney 0, et al: Dosage and safety of long-term suppressive acyclovir therapy for recurrent genital herpes. Lancet 1:926, 1988 46. Mindel A, Kinghorn G, Allason-Jones E, et al: Treatment of first-attack genital herpesacyclovir versus inosine pranobex. Lancet 1:1171, 1987 47. NusinoffLehrman S, Douglas JM, Corey L, et al: Recurrent genital herpes and suppressive oral acyclovir therapy: Relationship between clinical outcome and in vitro drug sensitivity. Ann Intern Med 104:786, 1986 48. Pazin GJ, Armstrong JA, Lam MT, et al: Prevention of reactivated herpcs simplex infection by human leukocyte interferon after operation on the trigeminal root. N Engl J Med 301:225, 1979 49. Pazin Gl, Harger JH, Armstrong JA, et al: Leukocyte interferon for treating first episodes of genital herpes in women. J Infect Dis 156:891, 1987 50. Prober CG, Hensleigh PA, Boucher FD, et al: Use of routine viral cultures at delivery to identify neonates exposed to herpes simplex virus. N Engl J Med 318:887, 1988 51. Prober CG, Sullender WM, Yasukawa LL, et al: Low risk of herpes simplex 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 316:240, 1987

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52. Quinn TC, Corey L, Chaffee RC, et al: The etiology of anorectal infections in homosexual men. Am J Med 71:395, 1981 53. Quinn TC, Stamm WE, Coodell SE, et al: The polymicrobial origin of intestinal infections in homosexual men. N Engl J Med 309:575, 1983 54. Quinnan CV Jr, Masur H, Rook AH, et al: Herpesvirus infections in the acquired immune deficiency syndrome. JAMA 252:72, 1984 55. Rampalo AM, Mertz CJ, Davis LC, et al: Oral acyclovir for treatment of first-episode herpes simplex virus proctitis. JAMA 259:2879, 1988 56. Reeves WC, Corey L, Adams HC, et al: Risk of recurrence after first episodes of genital herpes: Relation to HSV type and antibody response. N Engl J Med 305:315, 1981 57. Reichman RC, Badger CJ, Mertz CJ, et al: Treatment ofrecurrent genital herpes simplex infections with oral acyclovir. A controlled trial. JAMA 251:2103, 1984 58. Saral R: Management of mucocutaneous herpes simplex virus infections in immunocompromised patients. Am J Med 85(suppl 2A):57, 1988 59. Shepp OH, Newton BA, Oandliker PS, et al: Oral acyclovir therapy for mucocutaneous herpes simplex virus infections in immunocompromised marrow transplant recipients. Ann Intern Med 102:783, 1985 60. Skinner CRB, Woodman CB}, Hartley CE, et al: Preparation and immunogenicity of vaccine Ac NFU, (S-) MRC towards the prevention of herpes genitalis. Br J Vener Ois 58:381, 1982 61. Stamm WE, Handsfield HH, Rompalo AM, et al: The association between genital ulcer disease and acquisition of HlV infection in homosexual men. JAMA 260:1429, 1988 62. Straus SE: Clinical and biological differences between recurrent herpes simplex virus and varicella-zoster virus infections. JAMA 262:3455, 1989 63. Straus SE, Croen KO, Sawyer MH, et al: Acyclovir suppression of frequently recurring genital herpes: Efficacy and diminishing need during successive years of treatment. JAMA 260:2227, 1988 64. Straus SE, Seidlin M, Takiff H, et al: Oral acyclovir to suppress recurring herpes simplex virus infections in immunodeficient patients. Ann Intern Med 100:522, 1984 65. Straus SE, Takiff HE, Seidlin M, et al: Suppression of frequently recurring genital herpes: A placebo-controlled double-blind trial of oral acyclovir. N Engl J Med 310:1545, 1984 66. Wade JC, Newton B, Flournoy N, et al: Oral acyclovir for prevention of herpes simplex virus reactivation after marrow transplantation. Ann Intern Med 100:823, 1984 67. Wentworth BB, Alexander ER: Seroepidemiology of infections due to members of the herpesvirus group. Am J Epidemiol 94:496, 1971 68. 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 73:188, 1984

Address reprint requests to Cregory J. Mertz, MD University of New Mexico School of Medicine HSSB 302, Box 608 915 Camino de Salud Albuquerque, NM 87131