WOMEN'S HEALTH

Sexually transmitted diseases in women

Chlamydia trachomatis and herpes simplex infections

Jeffrey T. Kirchner, DO; David H. Emmert, MD

VOL 107 / NO 1 / JANUARY 2000 / POSTGRADUATE MEDICINE

CME learning objectives

• To recognize the clinical manifestations of Chlamydia trachomatis and herpes simplex virus infections in women
• To be familiar with current laboratory techniques used to diagnose these sexually transmitted diseases
• To be aware of the current Centers for Disease Control and Prevention treatment recommendations for these infections

This is the first in a series of articles on women's health coordinated by Jeffrey T. Kirchner, DO, associate director, family practice residency program, department of family and community medicine, Lancaster General Hospital, Lancaster, Pennsylvania. Part 2 of this article, which focuses on diagnosis and treatment of gonorrhea and syphilis, will appear in the February issue.

Preview: The spread and sequelae of sexually transmitted diseases pose a serious public health threat. Chlamydia trachomatis infection, which is often asymptomatic, has surpassed syphilis and gonorrhea in prevalence. Herpes simplex virus types 1 and 2 affect an estimated one third of the world's population. In part 1 of this two-part article, Drs Kirchner and Emmert discuss diagnosis, treatment, and prevention of chlamydial and herpes simplex infections, stressing the importance of discussing sexual issues with patients. Part 2, which focuses on diagnosis and treatment of gonorrhea and syphilis, will appear in the February issue.
Kirchner JT, Emmert DH. Sexually transmitted diseases in women: Chlamydia trachomatis and herpes simplex infections. Postgrad Med 2000;107(1):55-65

Sexually transmitted diseases (STDs) continue to be a significant public health problem in the United States. An estimated 12 million new cases occur yearly at a cost to the healthcare system of $10 billion (1). This does not include monies spent for the care of patients infected with HIV, which total about $7 billion. Although Chlamydia trachomatis infection has surpassed syphilis and gonorrhea in prevalence, viral STDs such as genital herpes, human papillomavirus, and hepatitis B infection are a more burdensome problem in terms of number of individuals infected (1). Moreover, the spread of HIV is closely linked to STD transmission.

For a variety of reasons, including the fact that several STDs are more easily transmissible from male to female, women tend to have more serious complications. Because there may be no symptoms, women are more often victims of the "hidden epidemic," as STDs are referred to in a recent report from the Institute of Medicine (2). According to the report, reasons for the ongoing epidemic include a lack of adequate public health measures and a scarcity of effective systems for prevention and treatment of STDs. In addition, many practicing physicians do not question patients about their sexual behavior. Even among those who do, many physicians may not be diagnosing and treating STDs properly. A recent study by Hessol and colleagues (3) found that 50% of primary care physicians who were managing patients with pelvic inflammatory disease were either unsure of or did not follow the guidelines for treatment of STDs from the Centers for Disease Control and Prevention (CDC) (4). In an era in which the heterosexual transmission of HIV is increasing, it is remarkable that more public health emphasis is not being placed on prevention, as well as on diagnosis and prompt treatment, of all STDs.

In this two-part article, we discuss diagnosis and treatment of four major STDs: chlamydial infection, herpes simplex virus infection, gonorrhea, and syphilis. However, the underlying theme of both parts is the important role of primary care physicians in screening for and diagnosing and treating all STDs (table 1). If we are to make an impact on the long-term sequelae of STDs, which include infertility and the increased spread of HIV, physicians need to become comfortable questioning and counseling all patients about sexual issues and their risks for STDs. Clinicians should also keep up to date as newer diagnostic and treatment regimens become available.

Table 1. Role of the primary care physician in prevention and control of STDs

Education of patients at risk on ways to reduce their risk for STDs Detection in asymptomatic infected patients Detection in symptomatic patients unlikely to seek diagnosis and treatment Effective diagnosis and treatment in infected patients Evaluation, treatment, and counseling of sexual partners of patients infected with STDs Preexposure vaccination of patients at risk for vaccine-preventable STDs Encouraging HIV testing for patients in whom an STD has been diagnosed STD, sexually transmitted disease. Adapted from Centers for Disease Control and Prevention (4).

Chlamydial infection

C trachomatis infection is the most commonly reported STD in the United States. The incidence of chlamydial infection has increased from 182 cases per 100,000 in 1995 to 197 cases per 100,000 in 1997 (5). This translates to more than 4 million cases annually. Of concern for women are the sequelae of C trachomatis infections, which include pelvic inflammatory disease, tubal infertility, and ectopic pregnancy.

Seventy percent to 90% of women with endocervical infections caused by C trachomatis are asymptomatic and may harbor the organism for months to years (6,7). Chlamydial upper genital tract infection that is asymptomatic is believed to occur three times more often than that which is accompanied by symptoms (6).

Chlamydial infection appears to have the highest prevalence in women under 20 years of age who live in urban areas (8). Among women screened at prenatal clinics, the incidence ranges from 5% to 7%, but rates as high as 20% have been reported, depending on the population studied (7). Other risk factors for chlamydial disease include age 15 to 21 years, single marital status, a new sexual partner, and multiple sexual partners.

The immune response to C trachomatis is variable and not well understood. Certain chlamydial strains may be more pathogenic in causing pelvic inflammatory disease (6). In addition, reinfection is the norm rather than the exception for many patients, despite a measurable antibody response.

Clinical manifestations
As already stated, chlamydial infections are usually asymptomatic. Mucopurulent discharge might be seen on examination but is not specific for the disease. Advanced disease can present with a variety of clinical manifestations, including pelvic inflammatory disease and reactive arthritis (table 2).

Table 2. Clinical manifestations of Chlamydia trachomatis infection in women

Acute urethral syndrome Bartholinitis Conjunctivitis Endometritis Mucopurulent cervicitis Perihepatitis (Fitz-Hugh-Curtis syndrome) Reactive arthritis (Reiter's syndrome) Salpingitis (pelvic inflammatory disease) Adapted from Stamm (7).

Diagnosis
Screening is recommended for women in a number of high-risk groups because of the high prevalence and asymptomatic nature of C trachomatis infection. The CDC now recommends that all sexually active adolescents undergo screening for this disease during routine annual pelvic examinations (4). A recent study of inner-city adolescent girls in Baltimore (8) found an incidence of 28 cases per 1,000 person-months. As a result, the investigators recommended that sexually active adolescent girls undergo screening for chlamydial infection every 6 months. The CDC also notes that routine screening of asymptomatic women between 20 and 24 years of age should be considered, particularly for those who have a new sexual partner, have more than one sexual partner, or do not use barrier contraception (4).

Although a variety of laboratory techniques have been developed for the diagnosis of C trachomatis infection, cell culture remains the "gold standard." It has a specificity of nearly 100% but a sensitivity of only 70% to 85% (9). Because C trachomatis is an intracellular pathogen, the organism needs a cell culture system to propagate. Specimens must be collected with use of a cotton-tipped swab or cytological brush and include columnar epithelial cells from the endocervix. Swabs with wooden shafts should not be used because of their toxic effects on cell cultures. For optimal results, meticulous specimen collection and transport and a turnaround time of 3 to 7 days are needed. These requirements have decreased the use of culture, although it is still the standard test for cases of sexual assault or child abuse (9).

A number of nonculture alternatives have been developed over the past 10 years. The first of these involved antigen detection using a swabbed specimen from the urethra or cervix. The most common techniques are direct fluorescent antibody testing and enzyme-linked immunosorbent assay. Compared with cell culture, these tests are easier to perform, yield very specific results, and have a quicker turnaround time. However, an important drawback is the variable sensitivity, which ranges from 50% to 90% (6,9).

Nucleic acid identification and hybridization represent important advances in diagnosis of chlamydial infection. The DNA probe test is a useful technique that can detect both C trachomatis and Neisseria gonorrhoeae with use of a single endocervical specimen. As with antigen detection, the specificity is excellent. Thorough endocervical specimen collection is needed to ensure adequate sensitivity.

Ligase chain reaction (LCR) and polymerase chain reaction (PCR) are techniques that use DNA or RNA amplification. The sensitivity and specificity of PCR and LCR approach 100% (9). A significant advantage of these techniques is that they can be performed on urine specimens or on swabbed vaginal specimens collected by the patient. This obviously facilitates screening for disease in a larger number of patients. Results of multiple studies support the use of urine-based screening for chlamydial infection (10,11). Although the nucleic acid-based tests are more expensive than routine culture, there are data to suggest that the money saved by not doing routine pelvic examinations to screen for chlamydial infection outweighs the added cost of the test (12,13). Moreover, screening with this test would allow for earlier treatment of infection and avoidance of pelvic inflammatory disease and future infertility. Once they become more widely available, PCR, LCR, and comparable nucleic acid amplification tests should become the studies of choice for diagnosing chlamydial infection.

Treatment
In the current CDC treatment guidelines, doxycycline remains an acceptable first-line therapy for C trachomatis infection (table 3) (4). However, azithromycin (Zithromax) is now considered an acceptable alternative, with several clinical trials showing an efficacy of 88% to 100% (14). It is also considered acceptable therapy for pregnant patients with chlamydial infection. Before the publication of several studies that proved the safety and efficacy of azithromycin, amoxicillin (Amoxil, Trimox, Wymox) had been the drug of choice for pregnant women (15,16). The advantage of using azithromycin is that it can be given as a single 1-g dose in tablet form or as a powder dissolved in water. With a single dose, compliance is directly observable. Potential disadvantages, besides higher cost, are gastrointestinal upset and diarrhea, which affect about 3% of patients (14).

Table 3. Treatment regimens for chlamydial infections

Most adults Doxycycline, 100 mg bid x 7 days* or Azithromycin (Zithromax), 1 g in a single dose* or Erythromycin base, 500 mg qid x 7 days or Erythromycin ethylsuccinate (E.E.S., EryPed), 800 mg qid x 7 days or Ofloxacin (Floxin), 300 mg bid x 7 days Pregnant women Azithromycin, 1 g PO in a single dose or Erythromycin base, 500 mg PO qid x 7 days or Amoxicillin (Amoxil, Trimox, Wymox), 500 mg PO tid x 7 days *Recommended treatment. Adapted from Centers for Disease Control and Prevention (4).

Other antimicrobial agents acceptable for treatment of chlamydialcycline, these medications must be given for 7 days, because the organism can reside safely within the confines of epithelial cells for 2 to 3 days. To date, there have been no reports of antimicrobial resistance (6). There are no alternative treatment recommendations for chlamydial infection in patients who also have HIV infection.

Follow-up
A C trachomatis test of cure is often done in high-risk clinic populations, although the CDC does not recommend that this be done routinely (4). Follow-up testing should be done in pregnant women and probably should be done if a patient's symptoms persist or if there is concern about reinfection. Testing should not be done until at least 3 weeks after the completion of antibiotic therapy (4). Retesting too early, especially with the nonculture methods discussed previously, may result in false-positive results owing to continued excretion of dead organisms.

Ideally, all women with chlamydial infection should notify their sexual partners and encourage them to be tested and treated. Notification should include anyone who had sexual contact with the patient within 60 days of onset of symptoms or diagnosis of chlamydial infection (4). Some physicians may consider empirical treatment of the partners if there is concern about adequate follow-up, although this approach is controversial. Sexual abstinence is recommended until both persons have been appropriately treated. Testing for HIV is also strongly encouraged.

Herpes simplex virus

Herpes simplex virus (HSV) exists as two separate types, HSV-1 and HSV-2, which together infect more than one third of the world's population (17). HSV-2 is responsible for the majority of cases of genital herpes, although HSV-1 can also cause genital infections. HSV is a double-stranded DNA virus that first targets epithelial cells and then is transported via neural tissue to sensory ganglia, where lifelong latent infection is established (17). Local or systemic stimuli such as immunodeficiency, trauma, fever, menstruation, ultraviolet light, and sexual intercourse can trigger viral reactivation (18). While most sources also attribute a causative role to emotional stress, a recent review (19) found no convincing evidence that stress causes recurrences.

More than 20% of all Americans 12 years of age or over have serologic evidence of HSV-2 infection (20), and this number is growing. Most infected patients are not aware of their disease (4). Genital infection with HSV usually occurs through sexual contact, and independent risk factors include lifetime number of sexual partners, age under 30, African American race, female sex, low socioeconomic status, and HIV-positive status (17,18,20).

Clinical presentation
Initial episodes of genital herpes infection cause more severe and longer-lasting symptoms than do recurrences. After an incubation period of several days, the patient may notice a prodrome of itching, burning, or erythema. The classic vesicles are usually quite painful and appear on the cervix, vagina, vulva, perineum, and surrounding skin. The vesicles typically rupture, leading to ulceration and crusting by 14 to 21 days after their initial appearance. Systemic symptoms are common with the initial infection and include fever, headache, malaise, abdominal pain, and myalgias (18).

Transmission of HSV-2 may occur whenever visible lesions or symptoms are present, but it is well documented that shedding of viral particles also takes place during asymptomatic periods. Immunocompetent patients with HSV shed virus up to 5% of the time they are asymptomatic, and recently infected patients and those with HIV infection shed even more often (17,21,22).

Diagnosis
The diagnosis of genital herpes infection is made clinically by recognition of the characteristic multiple, shallow, and tender ulcerations or vesicles on or around the genitalia. Laboratory confirmation is recommended only for patients presenting for the first time with initial or suspected recurrent infection. In addition, all patients who have genital ulcers should have a serologic test for syphilis and testing for HIV (4).

The "gold standard" for laboratory diagnosis of HSV is viral isolation by tissue culture (17), although this can take up to 5 days and sensitivity is only 70% to 80%. Despite these limitations, viral culture is still the diagnostic test of choice for HSV skin infections. Antigen detection and Tzanck tests, while helpful if results are abnormal, have lower sensitivities (17,18). Serologic studies are not helpful during primary illness because of the delay in development of antibodies (17). PCR is sensitive (96%) and specific (99%), but its high cost and limited availability have relegated current use to diagnosis of HSV infections of the central nervous system. However, it may later prove to be clinically useful for outpatient management.

Treatment
Acyclovir (Zovirax), an acyclic analog of guanosine, binds viral DNA polymerase and ends replication. Because HSV replication may end as soon as 48 hours into a recurrence, acyclovir and the newer antiviral drugs must be administered early in the course of the illness. The oral bioavailability of acyclovir is only 15% to 30%. The half-life of this agent is about 2 1/2 hours, and dosage must be adjusted in patients who have renal failure. Since its introduction almost 20 years ago, acyclovir has been found to be a safe and well-tolerated drug. Its side effects include mild nausea, vomiting, rash, and headache. Toxicity is rare, but elevated creatinine levels have been seen in patients with poor renal function (23). Use during pregnancy is recommended only for severe infections, although a registry has found no adverse outcomes among more than 850 women who took the drug because of herpes simplex infection during their pregnancies (4,24).

Valacyclovir hydrochloride (Valtrex), a new antiviral agent, is the l-valine ester prodrug of acyclovir and is easily absorbed and then converted to acyclovir. Famciclovir (Famvir), another recently approved antiviral medication, is the oral form of penciclovir, a purine analog similar to acyclovir. These two drugs boast higher oral bioavailability and less frequent dosing regimens than acyclovir, and they have good safety records in the few years since their release (18). The costs, however, can be significantly higher than the cost of generic acyclovir, and there is no current evidence that proves greater efficacy.

Antiviral therapy is recommended for initial episodes of genital herpes infection, especially for patients who have systemic symptoms or are immunocompromised (4,18). Oral acyclovir is effective in shortening the duration of lesions and making the symptoms less severe and it is the treatment of choice (table 4) (4,18). Intravenous administration may be required for immunocompromised patients and in cases of severe disseminated infection. Topical acyclovir and penciclovir (Denavir) are less effective (4,18). Both drugs purport to shorten the duration of lesions and make the symptoms less severe, although the differences in duration noted in clinical trials have amounted to less than 24 hours.

Table 4. Treatment regimens for initial episodes of genital HSV infection
Drug	Dosage
Acyclovir* (Zovirax)	200 mg PO 5 times a day x 10 days or 400 mg PO tid x 10 days
or
Famciclovir* (Famvir)	250 mg PO tid x 10 days
or
Valacyclovir HCl (Valtrex)	1 g PO bid x 10 days
HSV, herpes simplex virus. *Treatment may be extended if healing is incomplete after 10 days of therapy. Adapted from Centers for Disease Control and Prevention (4).

Treatment with acyclovir does not influence the frequency or number of recurrences. It cannot eradicate latent virus and does not affect the long-term natural history of the infection (17). Fortunately, in immunocompetent patients most recurrences are mild and infrequent and require no treatment. For patients who desire therapy for recurrences because of the severity, frequency, or personal impact of the episodes, two long-term options are available: suppressive therapy and episodic treatment.

Daily antiviral therapy effectively suppresses recurrences, but because of the high cost and inconvenience, it is usually reserved for patients with more than six recurrences per year. Suppressive therapy decreases asymptomatic shedding by 95% but has not yet been shown to decrease the transmission of HSV to sexual partners (25).

Suppressive regimens of antiviral medication decrease the frequency of genital herpes recurrences by up to 80% (23,26,27). Suppression may continue indefinitely without adverse effects (23), but such therapy should be discontinued annually to assess whether it is needed. In addition, cost and compliance should be discussed with the patient. All three drugs appear to have equal efficacy for suppression (table 5). Valacyclovir has the advantage of once-daily dosing (26). Famciclovir and acyclovir must be given twice daily to be effective (27).

Table 5. Antiviral regimens for suppressive treatment of HSV infection
Drug	Dosage
Acyclovir (Zovirax)	400 mg PO bid
or
Famciclovir (Famvir)	250 mg PO bid
or
Valacyclovir HCl (Valtrex)	500 mg PO qd or 250 mg PO bid* or 1 g PO qd if >10 episodes yearly
HSV, herpes simplex virus. *A 250-mg pill is currently not available. The 500-mg tablet for valacyclovir is unscored. Adapted from Centers for Disease Control and Prevention (4).

Episodic treatment of genital herpes infections is not intended to decrease the frequency of recurrences, but rather to influence the symptoms after onset of a recurrence. Acyclovir, given within minutes to hours after the prodrome begins, exerts a statistical, albeit minimal, effect on recurrent infections (28). Famciclovir and valacyclovir appear to be slightly more effective for recurrences (table 6).

Table 6. Antiviral regimens for episodic treatment of HSV infection
Drug	Dosage
Acyclovir (Zovirax)	200 mg PO 5 times a day x 5 days or 400 mg PO tid x 5 days or 800 mg PO bid x 5 days
or
Famciclovir (Famvir)	125 mg PO bid x 5 days
or
Valacyclovir HCl (Valtrex)	500 mg PO bid x 5 days
HSV, herpes simplex virus. Adapted from Centers for Disease Control and Prevention (4).

The clinical benefit of episodic therapy is relatively small, and its utility has been questioned (29). Patients who have frequent recurrences overwhelmingly choose suppressive therapy over episodic therapy (27,30). Patients should be encouraged to participate in decisions about such therapy.

Patient education
Because genital herpes cannot be cured, prevention of disease is critical. Limiting the number of sexual partners is essential. Condom use is somewhat effective in preventing transmission, but it is not completely effective, since ulcers can occur on uncovered skin near genitalia (4,20). Patient education about viral shedding can decrease transmission through avoidance of high-risk situations. Patients should specifically be instructed not to engage in sexual activity when ulcers or symptoms are present, and they should know that even when they have no symptoms, it is still possible to transmit the infection. For these reasons, discordant couples (in which one person is infected and the other is not) present a unique problem for physicians who are counseling about sexual activity and HSV transmission.

Female patients who have genital herpes should be warned that HSV can cause devastating disease in newborns and that if they become pregnant, they need to inform their doctor about their history of genital herpes. Some circumstances warrant treatment during pregnancy; however, cesarean section is indicated only if lesions are active at the time of labor (4). Some clinicians prescribe suppressive therapy for women who are in the last 4 weeks of pregnancy, although there are no data from clinical trials to support this practice. In the future, vaccines based on mucosal immunity may become feasible (31). Currently, however, the best therapy for genital herpes is to avoid becoming infected.

Summary

C trachomatis infection is the most commonly reported STD in the United States, and the majority of women infected are asymptomatic. Screening is recommended for those at high risk, including women who are between 15 and 21 years of age, live in urban areas, are single, or have new or multiple sexual partners. The "gold standard" for diagnosis is chlamydial culture; however, techniques that use DNA and RNA amplification are nearly 100% sensitive and specific and may prove cost-effective. Doxycycline is a recommended first-line therapy, but certain other antibiotics may also be effective.

Herpes simplex virus affects more than one third of the world's population. It is diagnosed by observation of shallow, tender ulcerations around the genitalia and by viral isolation using tissue culture. Initial treatment is with antiviral drugs, which may also be necessary episodically or as a suppressive regimen for recurrences.

Patient education about prevention of these and other STDs, as well as the impact of such disease on sexual partners, is critical. Physicians should therefore become comfortable questioning and counseling patients about sexual issues and risks for STDs.

References

1. Gunn RA, Rolfs RT, Greenspan JR, et al. The changing paradigm of sexually transmitted disease control in the era of managed health care. JAMA 1998;279(9):680-4
2. Institute of Medicine Committee on Prevention and Control of Sexually Transmitted Diseases. The hidden epidemic: confronting sexually transmitted diseases. Washington, DC: National Academy Press, 1996
3. Hessol NA, Priddy FH, Bolan G, et al. Management of pelvic inflammatory disease by primary care physicians: a comparison with Centers for Disease Control and Prevention guidelines. Sex Transm Dis 1996;23(2):157-63
4. Centers for Disease Control and Prevention. 1998 guidelines for treatment of sexually transmitted diseases. MMWR 1998;47(RR-1):1-111
5. Centers for Disease Control and Prevention. Summary of notifiable diseases. United States, 1997. MMWR 1997;46(54):73
6. Stamm WE. Chlamydia trachomatis infections: progress and problems. J Infect Dis 1999;179(Suppl 2):S380-3
7. Stamm WE. Chlamydia trachomatis infections of the adult. In: Holmes KK, Sparling PF, Mardh PA, et al, eds. Sexually transmitted diseases. 3d ed. New York: McGraw-Hill, 1999:407-19
8. Burstein GR, Gaydos CA, Diener-West M, et al. Incident Chlamydia trachomatis infections among inner-city adolescent females. JAMA 1998;280(6):521-6
9. Black CM. Current methods of laboratory diagnosis of Chlamydia trachomatis infections. Clin Microbiol Rev 1997;10(1):160-84
10. Gaydos CA, Howell MR, Pare B, et al. Chlamydia trachomatis infections in female military recruits. N Engl J Med 1998;339(11):739-44
11. Lee HH, Chernesky MA, Schachter J, et al. Diagnosis of Chlamydia trachomatis genitourinary infection in women by ligase chain reaction assay of urine. Lancet 1995;345(8944):213-6
12. Howell MR, Quinn TC, Brathwaite W, et al. Screening women for Chlamydia trachomatis in family planning clinics: the cost effectiveness of DNA amplification assays. Sex Transm Dis 1998;25(2):108-17
13. Howell MR, Quinn TC, Gaydos CA. Screening for Chlamydia trachomatis in asymptomatic women attending family planning clinics: a cost-effectiveness analysis of three strategies. Ann Intern Med 1998;128(4):277-84
14. Alvarez-Elcoro S, Enzler MJ. The macrolides: erythromycin, clarithromycin, and azithromycin. Mayo Clin Proc 1999;74:613-34
15. Wehbeh HA, Ruggeirio RM, Shahem S, et al. Single-dose azithromycin for Chlamydia in pregnant women. J Reprod Med 1998;43(6):509-14
16. Adair CD, Gunter M, Stovall TG, et al. Chlamydia in pregnancy: a randomized trial of azithromycin and erythromycin. Obstet Gynecol 1998;91(2):165-8
17. Whitley RJ, Kimberlin DW, Roizman B. Herpes simplex virus. Clin Infect Dis 1998;26:541-55
18. Oxman MN. Genital herpes. In: Gorbach SL, Bartlett JG, Blacklow NR, eds. Infectious diseases. 2d ed. Philadelphia: Saunders, 1998:986-1007
19. Green J, Kocsis A. Psychological factors in recurrent genital herpes. Genitourin Med 1997;73(4):253-6
20. Fleming DT, McQuillan GM, Johnson RE, et al. Herpes simplex virus type 2 in the Unites States, 1976 to 1994. N Engl J Med 1997;337(16):1105-11
21. Wald A, Zeh J, Selke S, et al. Virologic characteristics of subclinical and symptomatic genital herpes infections. N Engl J Med 1995;330:770-5
22. Augenbraun M, Feldman J, Chirgwin K, et al. Increased genital shedding of herpes simplex virus type 2 in HIV-seropositive women. Ann Intern Med 1995;123(11):845-7
23. Whitley RJ, Gnann JW Jr. Acyclovir: a decade later. N Engl J Med 1992;327(11):782-9
24. American College of Obstetricians and Gynecologists. Washington, DC: ACOG, 1998; ACOG Educational Bulle-tin No. 245:7
25. Wald A, Zeh J, Barnum G, et al. Suppression of subclinical shedding of herpes simplex virus type 2 with acyclovir. Ann Intern Med 1996;124(2 Pt 1):8-15
26. Reitano M, Tyring S, Lang W, et al. Valacyclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dose range-finding study. J Infect Dis 1998;178:603-10
27. Diaz-Mitoma F, Sibbald RG, Shafran SD, et al. Oral famciclovir for the suppression of recurrent genital herpes. JAMA 1998;280(10):887-92
28. Reichman RC, Badger GJ, Mertz GJ, et al. Treatment of recurrent genital herpes simplex infections with oral acyclovir: a controlled trial. JAMA 1984;251(16):2103-7
29. Kroon S. Genital herpes--when and how to treat. Semin Dermatol 1990;9(2):133-40
30. Mertz GJ, 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 1988;85(2A):14-9
31. Langenberg AG, Burke RL, Adair SF, et al. A recombinant glycoprotein vaccine for herpes simplex virus type 2: safety and immunogenicity. Ann Intern Med 1995;122(12):889-98 [Erratum: Ann Intern Med 1995;123(5):395]

Dr Kirchner, coordinator of this series, is associate director, family practice residency program, department of family and community medicine, Lancaster General Hospital, Lancaster, Pennsylvania. Dr Emmert is a member, department of family and community medicine, and a clinical affiliate faculty member in the residency program, Lancaster General Hospital. Correspondence: Jeffrey T. Kirchner, DO, Department of Family and Community Medicine, Lancaster General Hospital, 555 N Duke St, PO Box 3555, Lancaster, PA 17604-3555. E-mail: jkirchner@desupernet.net.