THERAPY OF GENITAL HERPES
Few other diseases, except AIDS, have attracted such an enormous amount of media attention as genital herpes. The major consequence of genital herpes infection, excluding the emotional toll, is transmission of the virus from mother to infant during birth. Neonatal herpes simplex virus (HSV) infection is a life-threatening illness that occurs in babies up to 4 to 6 weeks of age. If the mother is known to be infected at the time of delivery, transmission of HSV to the newborn can be prevented by delivering the baby by cesarean section. However, neonatal herpes infection develops in most cases because the disease is unsuspected at the time of delivery, as the mother often has no history of genital herpes virus infection. Serial viral cultures are not indicated for most women during late gestation.
It is estimated that 5 to 20 million persons in the United States suffer from recurrent genital HSV infections. Because this is not a reportable disease, nationwide statistics are unavailable. In one study of residents of Rochester, Minnesota, the overall incidence was 50 cases per 100,000 population, with a peak incidence of 128 cases per 100,000. Approximately 20% of the adult population is positive for HSV-2 antibody.
After the first episode of genital herpes infection, the major morbidity of the disease consists of frequent recurrences. One report shows that most patients with symptomatic recurrent genital herpes have five to eight recurrences yearly. The rate of recurrence of genital herpes varies with the HSV type. Only 14% of patients with genital HSV-1 note a recurrence after their first episode, compared with 60% of patients with HSV-2. The recurrence rate is 77% for patients who present with a prior history of genital herpes. Recurrences occur slightly more frequently in men than in women. The median time to the next recurrence is approximately 40 days in patients with recurrent episodes of genital herpes and about 4 months in patients with first episodes.
Few data are available to define the triggering factors responsible for recurrences. One report noted that the recurrence rate diminished with time for some patients, but another shows no difference in recurrence rate between persons who have had the disease for more than 5 years and those who have had the disease for less than 5 years. Most patients cite emotional stress as a triggering factor, and one study noted that recurrence is more frequent 5 to 12 days before menses. Others find no relationship between recurrences and menses or sexual activity. The majority of recurrences result from the endogenous reactivation of latent virus rather than from reinfection.
First episodes of genital herpes can be divided into primary (absence of neutralizing antibody to HSV-1 or HSV-2) and nonprimary initial episodes (serologic evidence of past HSV infection). About 60% of patients who present with a first episode of genital herpes have primary infection with either HSV-1 or HSV-2. Approximately 30% to 70% of patients with a first episode of genital herpes (nonprimary infection) have preexisting antibody to HSV-2, indicating an earlier, asymptomatic infection. Among homosexual men with HSV-2 antibody, 70% denied any history of genital or rectal herpes infection. Eighty-five percent of first-episode genital herpes lesions are produced by HSV-2 and the remainder by HSV-1. The frequency of oral-genital sex may alter these rates. The incubation period for genital herpes is about 6 days (range, 1 to 45 days).
Primary genital herpes is characterized by both systemic and local symptoms. Constitutional complaints, consisting of low-grade fever, headache, malaise, and myalgias, usually subside after 1 week. Local symptoms include pain, itching, dysuria, tender adenopathy, and genital lesions, which are initially single or multiple small vesicles on an erythematous base; these become intensely painful, ulcerative sores. The lesions persist for 2 to 3 weeks and become crusted before healing. The primary infection may also be asymptomatic. The mean duration of viral shedding is about 12 days.
Nonprimary first-episode genital herpes refers to illness in patients with antibody to HSV (Table 28-1). The disease is milder and of shorter duration than primary genital herpes. Systemic symptoms are generally absent. Recurrent genital herpes is a local disease without systemic complaints. Both the severity and duration of the symptoms are significantly less than in primary or nonprimary first-episode disease. Pain in patients with recurrent herpes usually lasts 3 to 4 days, and the lesions resolve in about 1 week.
Table 28-1. Genital herpes
In the United States, HSV is the most frequent infectious cause of genital ulcers. Laboratory confirmation of the diagnosis is usually based on growing the virus in tissue culture. Isolation of the virus generally requires only 1 to 3 days. Multinucleated giant cells are characteristic of herpesvirus, and these cells can be seen by opening a vesicle with a scalpel and taking a scraping from the base of the lesion. The material is smeared on a slide (Tzanck preparation), fixed in alcohol, and stained with either Wright’s or Giemsa stain. Vesicles are more likely to be positive on viral culture or Tzanck smear than are crusted ulcer lesions. Results of viral culture for herpes are positive in about 80% of cases, and the positivity rate for the Tzanck smear is 50%. Rapid detection of HSV with immunofluorescent staining or enzyme-linked immunosorbent assay (ELISA) is also available for diagnosis. Viral culture is still the best laboratory confirmation. Serology is generally of minimal value in establishing the diagnosis of genital herpes.
The clinician should be aware that the usual laboratory tests do not reliably distinguish between antibodies to HSV-1 and those to HSV-2. The Western blot assay is capable of separating antibodies to HSV-1 and HSV-2. The methods offered by most commercial laboratories are not reliable to distinguish between HSV-1 antibody and HSV-2 antibody, despite claims to the contrary. The polymerase chain reaction (PCR) is a highly sensitive and specific test for identifying HSV in clinical specimens. This diagnostic approach should be commercially available in the near future. A multiplex PCR assay for the simultaneous detection of HSV, Treponema pallidum, and Hae-mophilus ducreyi is under study and appears promising.
Acylovir has been the drug of choice for genital herpes since 1982 and has a record of efficacy and safety. The drug is now available in generic formulations. Two other drugs available for the treatment of genital herpes include famciclovir and valacyclovir; they offer the advantage of less frequent dosing compared with acyclovir. Topical therapy is of limited value for genital herpes and is not indicated if systemic therapy is administered. Rarely, patients may have an acyclovir-resistant HSV infection, and foscarnet is the drug of choice in this situation. Acyclovir inhibits replication of both HSV-1 and HSV-2. Acyclovir is converted to acyclovir triphosphate, an inhibitor of DNA polymerase, by viral thymidine kinase. The presence of viral thymidine kinase is not necessary for foscarnet activity because this drug does not undergo phosphorylation. Three formulations of acyclovir are available: topical, oral, and IV preparations.
Topical acyclovir is available as a 5% ointment in polyethylene glycol. Topical use usually does not result in serum levels of the drug. Intravaginal use should be avoided. Except for some decrease in viral shedding, topical acyclovir has little therapeutic value in recurrent herpes.
IV acyclovir is effective in the treatment of primary genital herpes. The drug is administered for 5 days as 5 mg/kg of body weight given at 8-hour intervals intravenously over 1 hour. Both systemic and local symptoms resolve more rapidly with IV acyclovir in comparison with placebo. Adverse effects are minimal. Bone marrow depression has not been a problem in normal hosts. Rapid bolus injections should be avoided and adequate hydration maintained. No effect on the recurrence rate is noted. The dosage of the drug should be reduced in patients with renal failure. The IV drug is not indicated for recurrent herpes infections.
Orally administered acyclovir has been found to be effective in treating both primary and recurrent genital herpes. For first-episode genital herpes, the drug is given as 200-mg capsules five times daily or 400 mg three times daily for 10 days; for recurrent disease, it is administered as 200-mg capsules five times daily or 400 mg three times daily for 5 days. The drug is effective in decreasing viral shedding and shortening the healing time. Results are more impressive than expected with primary in comparison with nonprimary first-episode or recurrent disease. Self-initiated therapy is more effective than physician-initiated treatment. There are no significant differences in duration of pain or time to subsequent recurrence between treatment with oral acyclovir and placebo in patients with recurrent genital herpes. Oral acyclovir is well tolerated, and adverse effects are uncommon.
Famciclovir is a prodrug of penciclovir and lacks antiviral activity. The drug is well absorbed (70%) following oral administration and rapidly converted to penciclovir. The intracellular half-life of penciclovir triphosphate ranges from 7 to 20 hours, which permits less frequent dosing in comparison with acyclovir. In patients whose renal function is moderately or severely reduced, dose reduction is recommended. An IV preparation is not available.
Valacyclovir, the L-valine ester of acyclovir, is a prodrug of acyclovir. The drug is rapidly converted to acyclovir following oral absorption. The bioavailability of valacyclovir is about 55%, which is far better than that of acyclovir, which is only 15% to 21%. An IV formulation of valacyclovir is not available. However, the area under the curve (AUC) of oral valacyclovir is similar to that of IV acyclovir.
Table 28-2 lists the doses of acyclovir, famciclovir, and valacyclovir for primary disease, recurrent or episodic disease, and suppression. Except for the cost, long-term suppression of recurrent herpes has been well tolerated. The emergence of resistant strains of HSV has not been a problem. Patients should be given a 1- to 2-month drug holiday each year to assess the recurrence rate.
Table 28-2. Genital herpes treatment*
Condoms appear to decrease the transmission of herpesvirus infection, and their use should be promoted. Intercourse should be avoided during symptomatic episodes of HSV infection. There is also a risk of transmitting herpes when patients are asymptomatic. A vaccine for HSV is under study. A vaccine would be useful for both prevention and treatment. A cure for HSV is still eagerly awaited by millions of genital herpes sufferers. (N.M.G.)
Ashley R, et al. Inability of enzyme immunoassays to discriminate between infections with herpes simplex virus types 1 and 2. Ann Intern Med 1991;115:520.
The three licensed enzyme immunoassays provide misleading results in detecting antibodies to HSV-1 and HSV-2 antigens in about 40% of patients.
Boggess KA, et al. Herpes simplex virus type 2 detection by culture and polymerase chain reaction and relationship to genital symptoms and cervical antibody status during the third trimester of pregnancy. Am J Obstet Gynecol 1997;176:443–451.
PCR was more sensitive than culture for detecting asymptomatic genital HSV.
Brock BV, et al. Frequency of asymptomatic shedding of herpes simplex virus in women with genital herpes. JAMA 1990;263:418.
Asymptomatic viral shedding occurs commonly and is not related to the menstrual cycle.
Bryson Y, et al. Risk of acquisition of genital herpes simplex virus type 2 in sex partners of persons with genital herpes: a prospective couple study. J Infect Dis 1993; 167:942–946.
Rate of HSV transmission was about 10% per year. Risk appears to be greater in seronegative women.
Chuang TY, et al. Incidence and trend of herpes progenitalis: a 15-year population study. Mayo Clin Proc 1983;58:436.
Corey L, et al. Genital herpes simplex virus infections: clinical manifestations, course, and complications. Ann Intern Med 1983;98:958.
Review. Twenty-five percent of recurrent episodes were asymptomatic.
Cowan FM, et al. Relationship between antibodies to herpes simplex virus (HSV) and symptoms of HSV infection. J Infect Dis 1996;174:470–475.
The majority of HSV infections are asymptomatic and unrecognized.
Evans RM, Brakl MJ, eds. Genital herpes—a clinician’s guide to diagnosis and treatment. Chicago: American Medical Association, 1997:1–44 (part 1), 1–38 (part 2).
Gold D, Corey L. Acyclovir prophylaxis for herpes simplex virus infection. Antimicrob Agents Chemother 1987;31:361.
Review of prophylaxis. The physician should stop acyclovir after 9 months to see if the recurrence rate warrants continued prophylaxis.
Guinan ME, Wolinsky SM, Reichman RC. Epidemiology of genital herpes simplex virus infection. Epidemiol Rev 1985;7:127.
Disease may affect 20 million persons in the United States, with fewer than 25% of those infected being symptomatic.
Johnson RE, et al. A seroepidemiologic survey of the prevalence of herpes simplex virus type 2 infection in the United States. N Engl J Med 1989;321:7.
The prevalence of HSV-2 antibodies was from less than 1% in the group under 15 years old to 20% for those ages 30 to 44 years.
Koelle DM, et al. Asymptomatic reactivation of herpes simplex virus in women after the first episode of genital herpes. Ann Intern Med 1992;116:433.
Asymptomatic genital shedding occurs more often during the first 3 months after the primary infection than during later periods.
Koutsky LA, et al. Underdiagnosis of genital herpes by current clinical and viral-isolation procedures. N Engl J Med 1992;326:1533.
The history or clinical examination identified only 39% of women with past or current genital HSV infections. That most cases of genital herpes are unrecognized is a factor in the continued spread of this infection.
Mertz GJ, et al. Transmission of genital herpes in couples with one symptomatic and one asymptomatic partner: a prospective study. J Infect Dis 1988;157:1169.
Asymptomatic and unrecognized acquisition of HSV-2 infection was common.
Mertz GJ, et al. Risk factors for the sexual transmission of genital herpes. Ann Intern Med 1992;116:197.
In 69% of patients, transmission occurred from sexual contact during periods of asymptomatic viral shedding. Risk of acquisition of HSV was higher in women than men.
Mertz GJ, et al. Oral famciclovir for suppression of recurrent genital herpes simplex virus infection in women. A multicenter, double-blind, placebo-controlled trial. Arch Intern Med 1997;157:343–349.
The most effective dose of famciclovir for suppression of recurrent genital HSV was 250 mg twice a day. Emergence of resistant strains to penciclovir was not a problem.
Molin L, Ruhnek-Forsbeck M, Svennerholm B. One-year acyclovir suppression of frequently recurring genital herpes: a study of efficacy, safety, virus sensitivity and antibody response. Scand J Infect 1991;80(Suppl 78):33.
Four hundred milligrams of oral acyclovir given twice daily for a year was effective in suppressing disease (87%). After stopping the drug, most (69%) patients relapsed.
Randolph AG, Hartshorn RM, Washington AE. Acyclovir prophylaxis in late pregnancy to prevent neonatal herpes: a cost-effectiveness analysis. Obstet Gynecol 1996;88:603–610.
Based on decision analysis, oral acyclovir prophylaxis in late pregnancy is more cost effective than cesarean section for women with recurrent genital herpes.
Reeves WC, et al. Risk of recurrence after first episodes of genital herpes. N Engl J Med 1981;305:315.
The recurrence rate is 77% for those with a past history of herpes.
Reichman RC, et al. Treatment of recurrent genital herpes simplex infections with oral acyclovir. JAMA 1984;251:2103.
Acyclovir is effective in reducing viral shedding and alleviating symptoms.
Sacks SL, et al. Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes. A randomized, double-blind multicenter trial. JAMA 1996;276;44–49.
Oral famciclovir (125 mg twice daily for 5 days) was effective for recurrent or episodic genital herpes. The intracellular half-life of penciclovir is 10 to 20 hours, compared with 0.7 hours for acyclovir, permitting dosing twice a day.
Schmidt OR, Fife KH, Corey L. Reinfection is an uncommon occurrence in patients with symptomatic recurrent genital herpes. J Infect Dis 1984;149:645.
Recurrences result from endogenous reactivation rather than reinfection.
Scott LL. Perinatal herpes: current status and obstetric management strategies. Pediatr Infect Dis 1995;14:827.
Review. Weekly genital HSV cultures are not indicated. Route of delivery should be based on the presence of identifiable lesions and symptoms.
Scott LL, et al. Acyclovir suppression to prevent cesarean delivery after first-episode genital herpes. Obstet Gynecol 1996;87:69–73.
Use of acyclovir from 36 weeks of gestation until delivery may have a role in reducing the cesarean section rate.
Solomon AR, et al. The Tzanck smear in the diagnosis of cutaneous herpes simplex. JAMA 1984;251:633.
This test has a sensitivity of about 50%.
Spruance SL, et al. A large-scale, placebo-controlled, dose-ranging trial of peroral valacyclovir for episodic treatment of recurrent herpes genitalis. Arch Intern Med 1996;156:1729–1735.
Five hundred milligrams of valacyclovir twice daily for 5 days was effective for recurrent or episodic genital HSV infection. Valacyclovir has the same antiviral activity as acyclovir but superior pharmacokinetics.
Wald A, et al. Virologic characteristics of subclinical and symptomatic genital herpes infection. N Engl J Med 1995;333:770–775.
Most new HSV infections are acquired from partners with unrecognized or subclinical disease. Subclinical viral shedding of HSV-2 is common.
Wald A, et al. Suppression of subclinical shedding of herpes simplex virus type 2 with acyclovir. Ann Intern Med 1996;124:8–15.
Acyclovir suppresses shedding of genital HSV.
Wald A, et al. Frequent genital herpes simplex virus 2 shedding in immunocompetent women. Effect of acyclovir treatment. J Clin Invest 1997;99:1092.
PCR was more sensitive than viral culture in detecting genital HSV-2 shedding, which was noted in 28% of days. Oral acyclovir reduced shedding by 80%.
Whitley RJ, et al. The natural history of herpes simplex virus infection of mother and newborn. Pediatrics 1980;66:489.
Only 20% of mothers of infants infected with HSV gave a history of recurrent genital herpes infection.
Whitley RJ, et al. Herpes simplex viruses. Clin Infect Dis 1998;26:541–555.