Serologic testing for herpes simplex virus: Ready for prime time?

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cme² designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

TARGET AUDIENCE
Obstetrician/gynecologists and women's health practitioners.

EDUCATIONAL OBJECTIVES
After completing the following CME activity, the reader should be able to:

• Recognize the reasons for the genital herpes epidemic in the United States and the prevalence of genital HSV-2 and HSV-1 cases.
• Identify who should have HSV serologic testing and the recommended HSV serologic tests as well as when to consider confirmatory tests.
• Summarize the strategies for HSV diagnosis in women with lesions and in women without lesions or with a history of lesions.
• Recognize the need to distinguish between HSV-1 and HSV-2, correctly interpret type-specific serology results, and identify the points to cover in counseling serodiscordant couples to avoid HSV transmission.

TO EARN CREDIT FOR THIS ACTIVITY
Participants should study the article, log onto http://www.modernmedicine.com, click on the "CME/CE Center" tab at the top of the page and type in keyword: COG102007. Participants will be taken to the activity, where they must pass a post-test and complete an online evaluation. After passing the post-test and completing the online evaluation, a CME certificate will be automatically generated. The release date for this activity is October 1, 2007. The expiration date is October 1, 2008.

DISCLOSURES
Editors Elizabeth A. Nissen, Paul L. Cerrato, and Julia Talsma, and Instructional Design Consultant Richard Currier, PhD, disclose that they do not have any financial relationships with any manufacturer in this area of medicine.

The manuscript reviewer discloses that she has no financial relationships with any manufacturer in this area of medicine.

Dr. Gardella discloses that she has no financial relationships with any manufacturer in this area of medicine. Dr. Brown discloses that he is on the Speakers' Bureau of GlaxoSmithKline.

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UNAPPROVED/OFF-LABEL USE DISCUSSION
Faculty may discuss information about pharmaceutical agents, devices, or diagnostic products that are outside of FDA-approved labeling. This information is intended solely for CME and is not intended to promote off-label use of these medications. If you have questions, contact the medical affairs department of the manufacturer for the most recent prescribing information. Faculty are required to disclose any off-label discussion.

Underdiagnosis and lack of symptoms are fueling the genital herpes crisis in the United States. Of the 1.6 million new cases of genital herpes in this country each year, most are transmitted by persons who are unaware that they're even infected-because their infections are subclinical or undiagnosed. But accurate serologic tests to detect HSV antibodies and distinguish between HSV-1 and HSV-2 infection exist and in our opinion should be used routinely to diagnose herpes infections in symptomatic persons and in asymptomatic persons at risk for having or acquiring the infection.

How huge an epidemic?

At least 45 million people older than age 12 are infected with genital herpes, by current estimates. Put another way, one out of five adolescents and adults are infected, with the prevalence higher in women than men. Recent NHANES data suggest a drop in the prevalence of HSV-2 for the first time since the survey began in the 1980s.¹ However, with more than 1 million Americans acquiring genital HSV-2 every year, the epidemic is expected to continue in the near future. Furthermore, there's been a concomitant increase in genital herpes caused by HSV-1. Among college students with newly diagnosed genital herpes, 80% were from HSV-1.² The rise in genital HSV-1 is likely due to increased practice of orogenital sex, perceived by people in this age group as a safe alternative to genital-genital sex.^3,4

Although one in five persons has genital herpes, it bears repeating that most people with it don't know they carry the virus.¹ Lack of diagnosis of the infection is therefore a key contributor to the epidemic. Seventy percent of genital herpes infections are transmitted by people who either have no symptoms or are unaware of their infections.⁵

Diagnosis in women with lesions

Strategies to increase testing and diagnosis of genital herpes infections are important. The Centers for Disease Control and Prevention recommends laboratory confirmation of genital herpes because the clinical diagnosis is neither sensitive nor specific.⁶ Up to 20% of patients with symptoms are incorrectly diagnosed as having HSV when they do not.⁷

VIRAL CULTURE APPROACH. For women who present with a genital lesion, a specimen for viral culture can be collected and viral typing performed. The main disadvantages of viral culture are difficulty in handling and the high false-negative rate. Up to 75% of viral cultures from recurrent lesions are negative.

PCR APPROACH IS GAINING GROUND. Alternatively, polymerase chain reaction (PCR) detects HSV DNA in lesions or from genital secretions. Not only is it three to four times more sensitive than viral culture, but the specimen requires significantly less fastidious handling. At present, though, PCR is more expensive than viral culture.⁸ PCR is expected to replace viral culture in the near future as it becomes more readily available for routine clinical use.

Whenever the virus is detected, either by culture or PCR, the specimen always should be typed to determine if it is HSV-1 or HSV-2. This will facilitate safer-sex counseling and provide a prognosis for the clinical course. Genital reactivation of the virus is much less frequent with HSV-1, which rarely recurs with or without symptoms after the first year of infection.⁹ In contrast, genital HSV-2 continues to recur, often quite often, for many years.¹⁰

Diagnosis in women without lesions

In women who present without genital lesions, or with a history of lesions but none at the time of the clinical examination, serologic evaluation is the preferred diagnostic method. Only glycoprotein G (gG)-based type-specific antibody tests should be used so that HSV-1 and HSV-2 antibodies can be distinguished (Table 1). There are many HSV serologic tests commercially available that are not gG-based and are therefore not type specific.¹¹ Therefore, we believe that it's important to order the test by name or confirm that your lab is using a gG-based test. Table 1 provides gG-based tests that are FDA approved and commercially available, while Table 2 lists currently available tests that we do not recommend.

HIGH SENSITIVITY/SPECIFICITY. All recommended tests have high sensitivity, especially for HSV-2, and acceptable specificity, particularly when a high cut-off value is used for Focus ELISA tests (Focus Diagnostics, Inc.).¹² In cases for which results of the Focus ELISA are "low positive," a confirmatory test such as the Biokit can be used. For the Focus HSV-2 ELISA test, an index value below 0.9 is considered negative; 0.9 to 1.1 is indeterminate; and greater than 1.1 is positive. However, we recommend confirmatory testing with Biokit for all sera with Focus ELISA values between 1.1 and 3.5. The time to seroconversion is a median of 20 days for Focus and less than 20 days for the Biokit HSV-2 test.¹³

Interpreting IgM tests can be problematic because IgM levels can increase in HSV reactivation, so we do not recommend them. It usually requires 6 to 8 weeks for HSV seroconversion to occur but can take up to 12 weeks or longer.

HSV-2 serology is also useful for patients with recurrent, undiagnosed, or complicated genitourinary symptoms, as well as for patients with culture-negative lesions or women who have a clinical diagnosis of genital herpes without laboratory confirmation.

WHO SHOULD HAVE HSV SEROLOGIC TESTING? All women requesting sexually transmitted infection screening or requesting herpes testing, as well as any woman with a current or past sex partner with genital herpes (Table 3). We also recommend HSV serologic testing in all patients with HIV infection due to interactions between these viruses that may facilitate HIV transmission. Along with some other experts, we advocate routine HSV serologic testing in pregnancy to prevent acquisition in the third trimester and subsequent neonatal herpes. The issues of cost and psychosocial impact are still being evaluated.

Interpreting serologic test results

When interpreting test results, it's important to distinguish between HSV-1 and HSV-2 for prognosis and to distinguish between new versus established infection. This is particularly important in pregnant patients, because the risk of transmission to the baby is high only in new infections acquired in the third trimester.¹⁴ If a woman is seronegative for the type identified on culture or PCR, assume it's a new infection.

Table 4 shows how to interpret type-specific serology results. A patient with a positive HSV-2 serology should be told that she has genital herpes. Virtually all HSV-2 seropositive women will shed HSV-2 from the genital tract at some point.¹⁵ A patient whose HSV-1 serology is positive but asymptomatic at oral and genital sites is considered to have an HSV-1 infection of unknown site. If a new exposure occurred recently or she has had symptoms, repeat an HSV-2 serology in 8 weeks to allow time for seroconversion. Again, if the woman is HSV seronegative, you can repeat serology in 8 weeks or re-swab genital lesions to establish definitive diagnosis.

Using viral typing and type-specific serology, symptomatic genital herpes can be classified in one of three ways:

1 Primary;
2 Nonprimary first episode (NPFE); or
3 Recurrent.

Primary infection is defined as isolation of HSV-1 or HSV-2 from genital secretions in the absence of HSV antibodies in serum. NPFE disease is characterized by isolation of HSV-2 from genital secretions in the presence of HSV-1 antibodies in serum. Finally, recurrent disease is characterized by isolation of HSV-1 or HSV-2 from the genital tract in the presence of HSV antibodies of the same serotype as the isolate. Patients with NPFE tend to have clinically milder presentation because the clinical presentation is attenuated by the HSV-1 antibody. Notably, about 25% of patients with first episode lesions will have recurrent disease by test results.

Prevention of transmission among serodiscordant couples

Based on the unpredictable and largely asymptomatic nature of genital shedding of HSV, prevention of transmission can be challenging. However, we now have several proven methods to prevent transmission. Key factors to prevent genital herpes transmission include disclosure to sexual partners, condom use, and antiviral suppressive therapy in the infected partner, each of which half the risk of HSV transmission.^16-19 Therefore, we advise patients to disclose that they have genital herpes before initiating sexual activity and use condoms regardless of signs or symptoms of genital herpes, and that the source partner receive antiviral suppressive therapy.

Type-specific serologic tests for HSV-2 are available. Despite some limitations, they offer much more accurate diagnosis than clinical acumen or viral detection tests, or both. Identification of women at risk for acquiring HSV and identification of patients at risk for transmitting the virus are the first steps toward controlling the spread of genital herpes. Once identified, counsel serodiscordant couples to avoid sex during symptomatic outbreaks, to use condoms, and to consider having the infected partner take suppressive antiviral therapy to decrease the risk of transmission. Encourage those newly diagnosed with herpes to disclose their diagnosis to sex partners.

DR. GARDELLA is Assistant Professor in the Division of Women' Health, and DR. BROWN is Professor in the Division of Perinatology, Department of Obstetrics and Gynecology, Division of Women' Health, University of Washington, Seattle, Wash.

REFERENCES

1. Xu F, Sternberg MR, Kottiri BJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA. 2006;296:964-973.

2. Roberts CM, Pfister JR, Spear SJ. Increasing proportion of herpes simplex virus type 1 as a cause of genital herpes infection in college students. Sex Transm Dis. 2003;30:797-800.

3. Lafferty WE, Downey L, Celum C, et al. Herpes simplex virus type 1 as a cause of genital herpes: impact on surveillance and prevention. J Infect Dis. 2000;181:1454-1457.

4. Roberts C. Genital herpes in young adults: changing sexual behaviours, epidemiology and management. Herpes. 2005;12:10-14.

5. Mertz GJ, Benedetti J, Ashley R, et al. Risk factors for the sexual transmission of genital herpes. Ann Intern Med. 1992;116:197-202.

6. Centers for Disease Control and Prevention, Workowski KA, Berman SM. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep. 2006;55(RR-11):1-94.

7. Langenberg A, Corey L, Ashley R, et al. A prospective study of new infections with herpes simplex virus type 1 and type 2. Chiron HSV Vaccine Study Group. N Engl J Med. 1999;341:1432-1438.

8. Wald A, Huang ML, Carrell D, et al. Polymerase chain reaction for detection of herpes simplex virus (HSV) DNA on mucosal surfaces: comparison with HSV isolation in cell culture. J Infect Dis. 2003;188:1345-1351.

9. Engelberg R, Carrell D, Krantz E, et al. Natural history of genital herpes simplex virus type 1 infection. Sex Transm Dis. 2003;30:174-177.

10. Wald A, Corey L, Cone R, et al. Frequent genital herpes simplex virus 2 shedding in immunocompetent women. Effect of acyclovir treatment. J Clin Invest. 1997;99:1092-1097.

11. Morrow RA, Friedrich D. Inaccuracy of certain commercial enzyme immunoassays in diagnosing genital infections with herpes simplex virus type 1 or 2. Amer J ClinPathol. 2003;120:839-844.

12. Ashley-Morrow R, Nollkamper J, Robinson NJ, et al. Performance of focus ELISA tests for herpes simplex virus type 1 (HSV-1) and HSV-2 antibodies among women in ten diverse geographical locations. Clin Microbiol Infect. 2004;10:530-536.

13. Morrow RA, Friedrich D, Meier A, et al. Use of "biokit HSV-2 Rapid Assay" to improve the positive predictive value of Focus HerpeSelect HSV-2 ELISA. BMC InfectDis. 2005;5:84.

14. Brown ZA, Wald A, Morrow RA, et al. Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA. 2003;289:203-209.

15. Wald A, Zeh J, Selke S, et al. Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N Engl J Med. 2000;342:844-850.

16. Wald A, Krantz E, Selke S, et al. Knowledge of partners' genital herpes protects against herpes simplex virus type 2 acquisition. J Infect Dis. 2006;194:42-52.

17. Wald A, Langenberg A, Link K, et al. Effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women. JAMA. 2001;285:3100-3106.

18. Gottlieb SL, Douglas JM Jr, Foster M, et al. Incidence of herpes simplex virus type 2 infection in 5 sexually transmitted disease (STD) clinics and the effect of HIV/STD risk-reduction counseling. J Infect Dis. 2004;190:1059-1067.

19. Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004;350:11-20.