Common misperceptions about HSV in the healthcare community can compromise the diagnosis and care of patients, their partners and their unborn children.

As a frequent speaker on the diagnosis and treatment of HSV to healthcare professionals, I routinely hear the same reasons why patients are not tested for HSV infection.

• "I don’t see those kinds of patients."
  • Although there are differences by race, gender, economic status - no one is immune to HSV-2.
  • There are up to one million new cases of HSV each year.

• "If they don’t have symptoms, I don’t test for it."
  • More than 1 out of every 5 adults in the US is infected
    with the herpes simplex virus.
  • Up to 90% of all HSV infections go undiagnosed.⁽⁵⁾
  • HSV infection is often asymptomatic and transmissible without active lesions.⁽³⁾ Asymptomatic patients may unknowingly transmit infection to their partner or to their unborn baby.⁽⁵⁾

• "Counseling patients with HSV infection requires time and resources that I don’t have in my busy practice.
  • There are many excellent resources available to assist the healthcare provider with answers to frequently asked questions and counseling for patients on how to deal with the emotional issues and life choices associated with a positive diagnosis.
  • CDC, ACOG, ASHA and Valtrex.com are great resources for patient literature and counseling material.

HSV testing needs to become a routine part of caring for a patient’s sexual and reproductive health.

Patients with high-risk lifestyles need to be diagnosed and made aware of the added threat of HIV infection if they are HSV-2 positive.

ACOG and CDC recommend discussing sexual history with pregnant women to decrease the risk of transmission to neonates.

A Herpes infection is life long and commonly misdiagnosed.

CDC guidelines state that serologic type-specific glycoprotein G (gG)-based assays should be specifically requested when serology is performed.

You must use the right serology test to get type-specific information.

The HerpeSelect products from Focus Diagnostics are offered by many commercial laboratories in the U.S. If you are a Quest Diagnostics client, you have HerpeSelect available on the OB/GYN requisition form.

Recently, Focus Diagnostics has made available the HerpeSelect® Express™ rapid point of care device for accurate HSV-2 serology results from a finger stick blood sample in about 15 minutes.

Meet Your Host
Gary A. Richwald, MD, MPH

Dr. Richwald received his engineering degree from Cornell University, his medical degree from the Mt. Sinai School of Medicine in New York, and his Masters in Public Health at UCLA. Dr. Richwald completed his specialty and subspecialty training in internal medicine, communicable diseases, preventive medicine, and geriatrics at the University of Michigan, UCLA Medical Center, and the VA Wadsworth Medical Center, and was a Robert Wood Johnson Foundation Clinical Scholar at UCLA.

From 1989 to 2000, Dr. Richwald served as the Director and Chief Physician of the Los Angeles County STD Program, the largest provider of sexual health and disease-related services in the United States. Prior to this appointment, he was a full-time member of the UCLA faculty and currently co-teaches the graduate course on sexually transmitted infections. He is currently a consultant to the America Social Health Association in the area of viral diseases.

Herpes Facts

The Herpes Virus Family

There are eight herpes viruses currently known to infect humans. These include; herpes simplex virus type-1 (HSV-1), commonly associated with cold sores or fever blisters; HSV-2, most commonly associated with genital herpes; varicella zoster virus, which causes chickenpox and shingles; cytomegalovirus (CMV), associated with retinitis and pneumonia in immunocompromised people; Epstein-Barr virus, which causes infectious mononucleosis; human herpes virus 6 (HHV6), causing childhood roseola; HHV7, which results in infectious mononucleosis in children; and HHV8, associated with Kaposi’s sarcoma. Despite the extensive range of symptoms of herpes virus infections, all are characterized by the establishment of latent infection and all have the potential to reactivate from latency.

Herpes simplex virus type-1: commonly causes herpes labialis (also called oral herpes, cold sores or fever blisters), which are highly infectious open sores that crust over before healing. Although less probable, HSV-1 can also cause genital herpes.

Herpes simplex virus type-2: a contagious sexually transmitted viral infection primarily causing genital herpes in men and women. The telltale signs of genital herpes include recurrent clusters of blisters, bumps and rashes in the genital areas and rectal lesions. HSV-2 can also be responsible for herpes labialis, although less often than HSV-1.

Structure of the Virus

The HSV-1 and HSV-2 viruses look identical by the electron microscope.

Genital Herpes Symptoms

Most people with genital herpes are unaware that they have the disease because they never have symptoms or do not recognize them. When they do occur, the symptoms (and severity) of genital herpes vary from person to person. First episode symptoms of genital herpes can appear within 2 to 10 days of infection and last an average of 2 to 3 weeks. In many people, the first infection may be so mild that it goes unnoticed. In other people, painful sores may appear at the site of infection.

Other symptoms can include:

• tingling
• itching or burning sensation
• pain in the thighs, buttocks, or genital area
• vaginal discharge
• a feeling of pressure in the abdominal area
• flu-like symptoms (which may include swollen glands, headache, muscle ache or fever;)
• and painful or difficult urination.

Genital herpes symptoms are sometimes mistaken for:

• Vaginitis
• Yeast infection
• Ingrown hair
• UTI/Bladder infection

• Zipper burn
• Jock itch
• Ingrown hair
• Hemorrhoids

Transmission

HSV-1 and HSV-2 is released from the sores that the viruses cause, but they also are released between episodes from skin that does not appear to be broken or to have a sore. A person almost always gets HSV-2 infection during sexual contact with someone who has a genital HSV-2 infection. A person can get HSV-1 by coming into contact with the saliva of an infected person. HSV-1 infection of the genitals is caused by oral-genital sexual contact with a person who has the oral HSV-1 infection or genital contact with a person who has genital HSV-1 infection.

Increased risk of HIV with HSV-2 infection

There is significant evidence that there is synergism between HSV-2 and HIV-1. These findings are bringing about a fundamental change in physicians views about the importance of Herpes testing. The paradigm shift means that concerns of physicians and health officials are in concert with those of patients with known genital herpes infections who have been concerned about transmission of the disease. Almost all new cases of genital herpes are transmitted by a person who is unaware of their HSV-2 status. Type specific testing is important so treatment can be instituted. 

To date, there have been over 30 studies that have determined the risk for HIV acquisition among persons with HSV-2 is fairly high. In international studies, there is the establishment of linkage.

HSV-2 has a different natural history among HIV-infected persons. Those individuals that have both infections have more frequent HSV-2 activations, at much higher rates of viral shedding. Finally, there are some data that HSV-2 is associated with increased HIV plasma levels in people who have both infections. HSV-2 may be one of the core factors to determine the progression and natural history of HIV disease. There are some early indications that suggest that treatment for HSV may be associated with reductions in plasma HIV levels.

Pregnancy

Women with herpes can have healthy babies. However, the risk of transmission of genital herpes from an infected mother to the baby is high among women who acquire the infection near the time of delivery. The risk is lower among women with recurrent herpes at term or who acquire the infection during the first half of pregnancy. Prevention of neonatal HSV infection depends on preventing the mother from acquiring genital herpes infection during late pregnancy and avoiding exposure of the baby to herpes lesions during delivery. Type-specific serologic testing may be useful to identify women at risk of acquiring HSV when their partner has known or suspected genital herpes.

Recurrences

After infection, the herpes virus remains inside nerve cells in an inactive, latent state. In most people, the virus reactivates from time to time and can cause new lesions to appear near the site of the original outbreak. The virus can also reactivate without causing any visible symptoms. During this time, small amounts of virus can be shed and can infect a partner (asymptomatic viral shedding.) Symptoms of recurrent episodes are usually milder than initial outbreaks and usually of shorter duration. The frequency and severity of recurrences varies greatly.

Diagnosis Guidelines

Any person who has been sexually active may have contracted genital herpes. Diagnosis should be strongly considered in those with:

• More than five lifetime sexual partners
• A partner with known genital herpes
• Any recurrent lesions or symptoms in the area of the sacral dermatomes
• A history of STD or HIV infection.

2006 CDC STD Treatment Guidelines excerpt:

"Both virologic and type-specific serologic tests for HSV should be available in clinical settings that provide patient care for patients with STDs or those at risk for STDs."

> Click here to print the Diagnostic Algorithm chart below.

CDC Sexually Transmitted Diseases Treatment Guidelines
(as printed in the Morbidity and Mortality Weekly Report)

CDC Guidelines excerpts*:

"... the clinical diagnosis of genital herpes should be confirmed by laboratory testing. Both virologic tests and type-specific serologic tests for HSV should be available in clinical settings ..."

"Because false-negative HSV cultures are common, especially in patients with recurrent infection or with healing lesions, type-specific serologic tests are useful ..."

"... older assays that do not accurately distinguish HSV-1 from HSV-2 antibody, despite claims to the contrary remain on the market."

"... serologic type-specific gG-based assays should be specifically requested when serology is performed."

The MMWR series of publications is published by the Epidemiology Program Office, Centers for Disease Control and Prevention (CDC), US Department of Health and Human Services, Atlanta GA 3033.

*Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2006. MMWR 2006;55(No. RR-11):[page 16].

To view the complete report, please go to:
> http://www.cdc.gov/STD/treatment/2006/rr5511.pdf

Summary Guidelines for the Use of Herpes Simplex Virus (HSV) type-2 Serologies
(published by the California STD Controllers Association and California Department of Health Services, 2004)

California Guidelines Summary:

Recommended Use of HSV-2 Serologies For Diagnosis and Screening

• Diagnosis of genital lesions/symptoms: type-specific serology tests should be available for diagnostic purposes in conjunction with virologic tests at any setting where patients are evaluated for STDs.
• Screening in patients at-risk for STD/HIV (Current STD, recent STD, high-risk behaviors): shoud be offered to select patients. 
• Screening in HIV-positive patients: should be generally offered.
• Universal screeing in pregnancy: should generally not be offered.
• Screening in general population: should generally not be offered.
• Herpes education and prevention/transmission counseling is necessary for all people being tested or screened for HSV-2.

Laboratory Tests

As the clinical diagnosis of genital herpes is both insensitive and non-specific, laboratory testing should be used to help diagnosis. Most clinical laboratories offer both virus detection tests and antibody detection tests.

Virus Detection

Virus detection tests begin by vigorously swabbing lesion sites to collect a viral sample. Viral detection tests include:

Culture (viable virus)

Isolation of HSV in cell culture is the preferred virologic test of most healthcare providers. Cell culture requires the collection of live virus samples that require special care in transport to the laboratory to retain viability. When viable samples are used, culture can be highly specific (if typing is performed) and positive results are generally reliable. The sensitivity of culture declines rapidly as lesions begin to heal and for this reason frequently non-positive results are falsely negative.

Antigen Detection (virus antigen)

The common methods used for antigen detection areThe common methods used for antigen detection are immunofluorescence or enzyme immunoassays. These tests are inexpensive and rapid, but have relatively low specificity and lack usefulness in asymptomatic patients.

PCR assays for HSV DNA are highly sensitive but expensive to perform.

Antibody Detection

Antibody detection or serology tests involve the detection of antibodies to HSV in the blood. Both type-specific and nonspecific antibodies to HSV develop during the first several weeks following infection and remain in the blood indefinitely. Serology tests an important adjunct to virus detection method in patients with no obvious symptoms. The following tests are in this category:

Type-common (crude antigen) serology tests measure HSV antibodies in the blood but are unable to distinguish between HSV-1 and HSV-2 infection. Most adults have HSV-1 antibodies, so crude antigen tests ability to detect HSV-2 infections is questionable.

Type-specific serology tests distinguish between HSV-1 and HSV-2 antibodies.

There are ELISA (enzyme immunoassay) tests commercially available that are type-specific assays for HSV antibodies. These tests should be based on the HSV-specific glycoprotein G2 (gG2) for HSV-2 and with glycoprotein G1 (gG1) to for HSV -1.

The HerpeSelect® tests from Focus Diagnostics are available in four formats for detecting type-specific HSV IgG antibodies.

2. HerpeSelect® ELISA consists of two micro-plate assays, one for detecting antibodies to HSV-1 (gG1), and the other for antibodies to HSV-2 (gG2).

3. Plexus™ HerpeSelect® provides both HSV-1 and HSV-2 from a single specimen using Luminex®xMAP® technology.

4. HerpeSelect® Express™ rapid HSV-2, a point-of-care device providing an HSV-2 serology result from a finger stick in about 15 minutes. (pending CLIA waiver).

All HerpeSelect assays are intended for testing sexually active adults and expectant mothers.

The Western Blot assay for HSV is highly accurate in differentiating HSV-1 and HSV-2 antibodies when used with a step to cross-adsorb antibodies to HSV-1 and HSV-2 antigens. However, it is expensive to perform, takes several days, and is not commercially available. The provider of Western blot testing services is the University of Washington.

Serological tests for HSV only indicate presence or absence of infection and do not identify the site of infection. These tests may give false-negative results in the early stages of infection because antibodies may not reach detectable levels. Repeat testing may be indicated in settings with a positive predictive value. False-positive results can also occur in patients with low likelihood of HSV infection. Repeat testing or a confirmatory test may be indicated in some cases.

Physicians can review the testing and counseling guidelines from the STD/HIV prevention programs to aid in the implementation of HSV serology testing and talking with patients.

http://depts.washington.edu/nnptc/

or

http://www.stdptc.org/

HerpeSelect® Tests

Ask for it by Name

HerpeSelect is the brand name of the diagnostic test kits manufactured by Focus Diagnostics. HerpeSelect tests utilize highly purified preparations of the HSV type-specific antigens glycoprotein G1 and glycoprotein G2. These antigens are used to detect HSV type-specific antibodies.

• Sexually active adults, with or without symptoms, who could transmit the virus to a sexual partner.
• Expectant mothers, to reduce the risk acquiring an infection near labor and transmitting the infection during labor.

The selection of assay options on the HerpeSelect product menu makes it easy for a physician or laboratory to provide testing that is right for them and their patients.

Serology can aid in diagnosis when:

• Culture results are negative
• No symptoms are present but patient states that previous symptoms may have been undiagnosed herpes

Type-specific serology tests provide physicians with the information they need to establish treatment options and provide appropriate patient counseling.

• Type-specific serology can differentiate HSV-1 from HSV-2. Both HSV -1 and HSV-2 can cause genital herpes infection.
• During pregnancy, type-specific serology can identify women at risk of acquiring genital HSV-1 or HSV-2 infections close to labor.
• Treatment recommendations may vary based upon type-specificity as outbreak frequency is often higher with HSV-2 genital infections than with HSV-1 infections.
• Patient counseling may vary based upon type-specificity:
• prognosis and status of sexual health
• risk of transmission to partner
• risk of acquiring genital herpes during pregnancy/transmission to baby
• behavior modification

1. HerpeSelect® Immunoblot – blot test for detecting HSV-1 or HSV-2.

2. HerpeSelect® ELISA consists of two micro-plate assays, one for detecting antibodies to HSV-1 (gG1), and the other for antibodies to HSV-2 (gG2).

4. HerpeSelect® Express™ rapid HSV-2, a point-of-care device providing an HSV-2 serology result from a finger stick in about 15 minutes. (pending CLIA waiver).

Availability

Many laboratories offer HerpeSelect assays for type-specific testing, however others offer the test under a more generic methodology name such as HSV-1 IgG or HSV-2 IgG ELISA. To make it easy, Quest Diagnostics OB/GYN clients have the HerpeSelect name on the laboratory requisition form. Be sure to contact your laboratory to ensure they utilize an FDA-cleared glycoprotein-G based assay.

HerpeSelect Express HSV-2 Rapid Test is now available through Focus Diagnostics for use in CLIA moderately complex sites. CLIA moderately complex laboratories can contact Focus Diagnostics for a distributor in their area.

You can contact Focus Diagnostics online at www.focusdx.com.

Diagnostic Use in the United States

HerpeSelect HSV type-specific serology tests for both HSV-1 and HSV-2 are for in vitro diagnostic use for both sexually active adults and expectant mothers.

HerpeSelect Express is for in vitro diagnostic use in CLIA moderately complex laboratories and is pending CLIA waived status.

HerpeSelect Immunoblot is for in vitro diagnostic use in CLIA moderately complex laboratories.

Treatment

While there is no cure for genital herpes, there are treatment options available.

Treatment with antiviral medication can help control the infection in one of three ways:

• First episode: a 7 to 10 day course of oral antiviral medication, such as acyclovir, can dramatically shorten the duration of the first episode and lessen the severity of symptoms.
  
• Episodic therapy: when taken at the first sign of a recurrence, oral antiviral medication can help reduce the duration of the symptoms and discomfort of an outbreak.
  
• Suppressive therapy: continuous daily treatment with smaller doses of oral antiviral medication can suppress the virus’ activity and reduce the number of recurrences.

Medications: Medications: acyclovir [ZOVIRAX®] and valiciclovir [VALTREX®] made by GlaxoSmithKline; and famiciclovir [FAMVIR®] made by Novartis.

For more information, please visit:

• www.gsk.com
• www.famvir.com

Links & References

The following websites and support materials are provided as a convenient resource only and should not be considered a complete list.  The information contained in these websites is neither endorsed nor controlled by Focus Diagnostics.

Websites

American Herpes Foundation
www.herpes-foundation.org

The website of the American Herpes foundation (AHF), a non-profit organization committed to improving the management and prevention of herpes virus infections through research and education. The site contains both patient and physician information. The site is supported by educational grants from GlaxoSmithKline and Merck.

American Social Health Association (ASHA)
www.ashastd.org/hrc

This website for the American Social Health Association (ASHA), a non-profit organization dedicated to stopping sexually transmitted diseases and their harmful consequences to individuals, families, and community. The site provides information about support groups, the range of hotlines operated by ASHA, and STD news.

For more information, send a self-addressed, stamped envelope to:
National Herpes Resources Center
American Social Health Association
P.O. Box 1327
Research Triangle Park, NC 27709

Herpes Hotline
(919) 361-8488

Centers for Disease Control and Prevention:
http://www.cdc.gov/std/Herpes/STDFact-Herpes.htm

The facts about herpes as presented by The Centers for Disease Control and Prevention (CDC), the recognized lead federal agency for protecting the health and safety of people at home and abroad.

Herpes Diagnosis
www.herpesdiagnosis.com

This website was designed by Drs. Lawrence Corey, Rhoda Ashley and Gray Davis. These 3 individuals have spent over 25 years working in the field of genital herpes and have been instrumental in the development of antiviral therapy for the disease as well as developing the current western blot and PCR based assays for diagnosing this infection.

International Herpes Management Forum (IHMF)
www.ihmf.com

The website for the International Herpes Management Forum (IHMF). The site provides information that can be downloaded and educational guidelines for doctors and patients on the management of herpes virus infection. The site offers global links on herpes management, listing of meetings, and a library of posters and slide presentations on herpes.

International Herpes Alliances
www.herpesalliance.org

The website for the International Herpes Alliance (IHA), a newly formed organization that aims to offer support and information to those with genital herpes, those helping to manage the disease, and national patient support groups worldwide. A non-profit association run by patients, medical professionals and support group leaders. Sponsored by educational grant from GlaxoSmithKline.

Novartis/FAMVIR
www.healthandhope.com
www.famvir.com
www.genitalherpes.com

A website of genital herpes resources information. Includes a game to tests herpes knowledge along with treatment information.

GlaxoSmithKline/VALTREX
www.herpeshelp.com
www.valtrex.com
www.gsk.com

Facts about genital herpes, cold sores, and varicella zoster virus. Sponsored by GlaxoSmithKline.

HealthCheck USA
www.healthcheckusa.com

Developed to assist in the prevention of disease by offering health screening services to the public. HealthCheck USA provides health awareness screening to customers throughout the USA by providing patients with direct access to testing services from the country's major fully accredited medical reference laboratories.

Booklets

"Four Tough Questions about Genital Herpes in the US" from American Social Health Association, 2000

"A Clinicians Guide to Diagnosis and Treatment of Genital Herpes" from AMA, November 2002 (funded by GlaxoSmithKline)

"Genital Herpes" authored by Hunter Handsfield, MD, 2001, McGraw-Hill

"You May Think You Don’t See Herpes, but…You May Only see the Tip of the Iceberg", 2001 (funded by GlaxoSmithKline)

Scientific Papers

Inaccuracy of Certain Commercial Enzyme Immunoassays in Diagnosing Genital Infections With Herpes Simplex Virus Types 1 or 2”, by Rhoda Ashley Morrow, American Journal of Clinical Pathology, Vol. 120, No.6 (December 2003)

"Sorting Out the New HSV Type-Specific Antibody Tests", by Dr. Rhoda Ashley, PhD, Sexually Transmitted Infections, Vol. 77, p. 232-237( August 2001)

"Evaluation of Enzyme Immunoassay System for Measuring Herpes Simplex virus type-1 and type-2 Type Specific IgG Antibodies" by Harry Prince, PhD, Journal of Clinical Laboratory Analysis 14:13-16 (2000)

“Time Course of Seroconversion by HerpeSelect ELISA After Acquisiton of Genital Herpes Simplex Virus type-1 (HSV-1) or HSV-2, by Rhoda Ashley-Morrow, Sexually Transmitted Diseases, Vol. 30 No.4 pp 310-314 (April 2003)

"Reactivation of Genital Herpes Simplex Virus type-2 Infection in Asymptomatic Seropositive Persons", by Anna Wald, MD, New England Journal of Medicine, Vol. 342, Number 12; 844-850 (March 2000)

"Risk of Human Immunodefiency Virus Infection in Herpes Simplex Virus type-2 Seropositive Persons-A Meta Analysis", by Anna Wald, MD, The Journal of Infectious Diseases, 185: 45-52 (2002)

“Once-Daily Valacyclovir to Reduce the Risk of Transmission of Genital Herpes”, by Lawrence Corey,The New England Journal of Medicine, Vol. 350,No.1, pp 11-20 (Jan 2004)

Additonal Scientific References for Herpes Simplex Virus

References

1. Flemming DT, McQuillan GM, Johnson RE, et al. Herpes simplex virus type-2 in the United States, 1976 to 1994. N Engl J Med. 1997;337:1105-1111.

2. CDC. Sexually Transmitted Diseases Treatment Guidelines 2006. MMWR 2006; 55(No.RR-11); 16-21

3. Mertz et al, Ann Internal Med 1992: 116:197-202.

4. Mertz GJ et al. Transmission of genital herpes in couples with one symptomatic and one asymptomatic partner: a prospective study. J Infect Dis. 1988 Jun;157(6):1169-77.

5. Gupta, Warren, Wald et al, The Lancet 2007; 370: 2127-37

6. Corey, L. Clinical Tools for Preventing Transmission of Genital Herpes. Medscape Infectious Diseases 6(1) 2004

7. Freeman EE, Weiss HA, Glynn JR, et al. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS. 2006; 20: 73-83.

8. S.L. Gottlieb et al. Seroprevalance and Correlates of Herpes Simplex Virus Type 2 Infection in Five Sexually Transmitted-Disease Clinics. Journal of Infectious Disease 2002: 186: 1381-1389.

9. 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; 296L 964-973.

10. Page J, Taylor J, Tideman RL, Seifert C, Marks C, Cunningham A, Mindel A, et al. Sex Transm Infect 2003; 79: 276-279.

11. Benedetti J, Corey L, Ashley R, et al. Annals of Internal Medicine 1994; 121: 847-854.