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."
  • The herpes simplex virus does not discriminate by
    socioeconomic status, sex or race.
    > Click here to read a CDC Trends 2000 Report
• "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.
  • HSV infection is often asymptomatic and transmissible without active lesions. Asymptomatic patients may unknowingly transmit infection to their partner or to their unborn baby.
• "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.

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 risk of HSV type-2 infection.

The clinical diagnosis of HSV (visual) is both insensitive and nonspecific and often does not provide an accurate diagnosis. Culture is the gold standard method of testing for herpes infection and although positive culture results are generally reliable, 50% to 70% of non-positive results are falsely negative in recurrent episodes.

A Herpes infection is life long, but a positive culture is only intermittent.

Serology (blood) tests are a must in detecting herpes infection in patients who have no symptoms or active lesions.

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

Until recently, accurate serology tests for herpes were not available. HSV type-1 and HSV type-2 type-specific information can aid in diagnosis, developing a treatment plan, patient and partner counseling and evaluating prognosis for future outbreaks. There are currently only two FDA-cleared type-specific glycoprotein-G based serology tests on the market for HSV type-1 and HSV type-2. The HerpeSelect test from FOCUS Diagnostics has been available for several years. A newly released test called CAPTIA™ is now available from Trinity Biotech. A third test, the POCKit® HSV type-2 Rapid Test from Diagnology, not currently sold in the US, is FDA-cleared for HSV type-2 testing only.

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.

> Back to Top

Herpes Facts

The Herpes Virus Family

There are eight herpes viruses currently known to infect humans. These include; herpes simplex virus type-1 (HSV type-1), commonly associated with cold sores or fever blisters; HSV type-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 herpesvirus 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 type-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 type-2 can also be responsible for herpes labialis, although less often than HSV type-1.

--------------------------------------------------------------------------------

Structure of the Virus

The HSV type-1 and HSV type-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, an 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 simple skin irritation, jock itch, razor burn, or a yeast infection.

--------------------------------------------------------------------------------

Transmission

HSV type-1 and HSV type-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 type-2 infection during sexual contact with someone who has a genital HSV type-2 infection. A person can get HSV type-1 by coming into contact with the saliva of an infected person. HSV type-1 infection of the genitals is caused by oral-genital sexual contact with a person who has the oral HSV type-1 infection or genital contact with a person who has genital HSV type-1 infection.

Increased risk of HIV with HSV type-2 infection

There is significant evidence that there is synergism between HSV type-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 type-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 type-2 is fairly high. In international studies, there is the establishment of linkage.

HSV type-2 has a different natural history among HIV-infected persons. Those individuals that have both infections have more frequent HSV type-2 activations, at much higher rates of viral shedding. Finally, there are some data that HSV type-2 is associated with increased HIV plasma levels in people who have both infections. HSV type-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.

> Back to Top

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.

--------------------------------------------------------------------------------

Facts and Statistics

Transmission of the disease:

• 1 in 6 people worldwide have genital herpes caused by HSV type-2.
• HSV type-2 infects more than 1 of every 5 people in the US
• About 70% of people contracting herpes get it from a partner who is unaware they have it at the time they transmit the disease.
• Both HSV type-1 and HSV type-2 can cause genital infection.
• Genital herpes can be transmitted by genital or oral sex (cold sores).
• Viral shedding in the absence of symptoms can transmit infection.
• Transmission of herpes can occur within committed long-term relationships and in people who have never had penetrative sex through close genital contact or oral-genital contact.
• Condoms reduce the risk of transmission, but it is also advisable to avoid skin to skin contact when lesions are present.
• HSV type-2 infection increases the risk of HIV infection.

Diagnosis:

• Up to 90% of all HSV type-2 infections go unnoticed or undiagnosed because of mild or absent symptoms.
• Up to 20% of first episodes are actually reactivation of previously latent infection rather than recently acquired primary infection.
• HSV culture can frequently give false negative results.
• Accurate, type-specific serology tests can detect asymptomatic infection.

Recurrences:

• People who experience a first episode will get better. Lesions will heal and recurrences will usually be less severe.
• HSV type-2 may reactivate more frequently than HSV type-1.
• Antiviral treatment can minimize and/or prevent HSV outbreak.

Pregnancy:

• Genital herpes does not cause cervical cancer or affect fertility.
• First episode genital maternal HSV infection poses a threat to the baby.
• Neonatal herpes is serious but rare.
• Women with genital herpes can have a safe pregnancy and vaginal delivery.
• New infections need close medical follow-up.

Laboratory Tests

The clinical diagnosis of genital herpes is both insensitive and non-specific. Therefore the clinical diagnosis of genital herpes should be confirmed by laboratory testing. Clinical laboratories should 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. Type-specific serology tests should be used in these cases to confirm a clinical diagnosis of genital herpes.

Antigen Detection (virus antigen)
The 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.

Polymerase Chain Reaction or PCR
PCR assays for HSV DNA are highly sensitive but expensive to perform and therefore, not suited for routine use.

--------------------------------------------------------------------------------

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 type-1 and HSV type-2 infection. Detection of antibodies can be useful to diagnose HSV infection when culture, virus antigen detection or PCR yield negative results, but are not helpful in making a definitive diagnosis of genital herpes in a patient with prior oral HSV type-1 infection.

Type-specific serology tests are those that accurately distinguish between HSV type-1 and HSV type-2 antibodies.

The Western Blot assay for HSV is highly accurate in differentiating HSV type-1 and HSV type-2 antibodies when used with a step to cross-adsorb antibodies to HSV type-1 and HSV type-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.

There are several type-specific ELISA (enzyme immunoassay) tests commercially available that are relatively easy to perform in the laboratory and give results quickly. Type-specific assays for HSV antibodies must be based on the HSV-specific glycoprotein G2 to accurately diagnose infection with HSV type-2 and with glycoprotein G1 to accurately diagnose HSV type-1.

HerpeSelect, from Focus Diagnostics offers two FDA-cleared lab-based assay formats for detecting type-specific HSV IgG antibodies: HerpeSelect immunoblot uses purified recombinant type-specific gG-1 and gG-2 antigens, and native HSV common antigens immobilized on nitrocellulose membranes. HerpeSelect ELISA consists of two micro-plate assays, one for detecting antibodies to HSV type-1 (gG1), and the other for antibodies to HSV type-2 (gG2). Both assay formats had sensitivity and specificity values ranging from 91-100% in clinical trials with sexually active adults and pregnant women.

Other FDA-cleared gG-based type-specific assays are available. Trinity Biotech manufactures HSV type-1 and type-2 kits, which have recently received FDA clearance. A type-specific HSV-2 assay, formerly available from Diagnology (POCkit^®), is expected to be reintroduced soon by another manufacturer.

Serological tests for HSV only indicate prior 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 for 8 weeks or longer. 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.

HerpeSelect

Description

HerpeSelect is the brand name of two FDA-cleared 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. HerpeSelect test kits come in two assay formats.

For type-specific HSV testing in higher volume laboratories:
HerpeSelect ELISA system consists of two micro-plate assays, one for detecting HSV type-1 (gG1) IgG antibodies, and the other for HSV type-2 (gG2) IgG antibodies.

For differentiating type-1 and type-2 in a single specimen (low volume testing):
HerpeSelect Immunoblot is a nitrocellulose strip that contains gG1 and gG2 antigens protein stripe, along with a HSV common antigen strip, (resembles a Western Blot).

--------------------------------------------------------------------------------

Performance Characteristics

HerpeSelect assays are designed to:

• Identify individuals, including pregnant women, at risk for infection,
• Aid in the diagnosis of infected expectant mothers who could transmit virus during labor and,
• Aid in the diagnosis of individuals, with or without typical genital symptoms,
  who could transmit virus to a sexual partner.

Both assay formats had sensitivity and specificity values ranging from 91-100% in clinical trials with sexually active adults and pregnant women.

--------------------------------------------------------------------------------

Availability

HerpeSelect test kits are used in commercial and hospital laboratories throughout the US. Although many labs offer these assays under the brand name HerpeSelect others utilize the HerpeSelect test kit but offer the test under a more generic methodology name such as HSV type-1 or HSV type-2 type-specific ELISA. Make certain that your laboratory utilizes an FDA-cleared glycoprotein-G based assay that accurately discriminates IgG antibodies from HSV type-1 and HSV type-2 infections.

For further information about what labs offer HerpeSelect testing, please contact Focus Diagnostics’ HSV Information Center at (800) 505-0536. For information about testing at Focus Diagnostics please call Client Service at (800) 445-4032 (within the US), (714) 220-1900 or fax us at (714) 220-1820. You can contact Focus Diagnostics online at www.focusdx.com.

--------------------------------------------------------------------------------

FDA Clearance

HerpeSelect HSV type-specific serology tests for both HSV type-1 and HSV type-2 are FDA-cleared for both sexually active adults and expectant mothers.

--------------------------------------------------------------------------------

Frequently Asked Questions

What differentiates HerpeSelect from other methods?

Many laboratories offer HSV type-1 or HSV type-2 IgG antibody testing, but their tests are not able to deliver reliable type-specific results. Reactivity with shared, type-common antigens is almost always present to some degree, causing inaccurate results to be reported in up to 70% of positive patients. HerpeSelect 1 and 2 kits use glycoprotein G antigens -- gG1 (from HSV type-1) and gG2 (from HSV type-2) – the major antigens known to elicit type-specific antibody responses. HerpeSelect HSV type-1 and HSV type-2 type-specific tests are FDA-cleared.

What is the difference between HerpeSelect ELISA and HerpeSelect Immunoblot?

HerpeSelect ELISA system consists of two micro-plate assays, one for detecting HSV type-1 (gG1) IgG antibodies, and the other for HSV type-2 (gG2) IgG antibodies. These tests are appropriate for high- volume testing on automated platforms and individual antibody type testing.

HerpeSelect HSV type-1 and HSV- 2 Immunoblot is like a simplified Western Blot with gG1 and gG2 bands, a type-common HSV band, and a serum control band all arrayed on a single strip. The test is read visually for HSV type-1 and HSV type-2 results so that instrumentation is not required. It is well suited for lower volume laboratory testing.

Is HerpeSelect immunoblot a confirmatory test for HerpeSelect ELISA?

No. Both formats exhibit sensitivity and specificity values ranging from 91-100% in clinical trials with sexually active adults and pregnant women.

How long after infection will HerpeSelect detect IgG antibodies?

Recent studies show that HerpeSelect can detect HSV IgG antibodies as quickly as 3 weeks after onset of symptoms.

What about HSV IgM testing?

The presence of IgM antibodies in HSV infections is difficult to interpret and may be confusing because, unlike IgG, IgM is not type-specific. The presence of IgM may indicate a true primary infection, a super-infection with the other serotype, or reactivation of a latent HSV infection (HSV type-1 or -2). For this reason, IgM testing is not recommended as a differential diagnostic tool, but may offer information about a particular patient’s antibody response.

How long does it take to perform HerpeSelect testing?

Both tests are performed in less than 3 hours.

Is HerpeSelect reimbursed by payors?

An example of reimbursement is:

Medicare Part B, 2004 Fee Schedule:
HSV type-1    CPT Code 86695    $18.91
HSV type-2    CPT Code 86696    $27.75

How do I know if the laboratory I use offers the HerpeSelect test?

Many laboratories throughout the US use the HerpeSelect test. Many labs offer the test using the HerpeSelect brand name. Other laboratories offer the test using a more generic method name such as HSV type-1 or HSV type-2 type-specific ELISA. Ask to speak to the director of the infectious disease laboratory to verify that their type-specific serology meets these specifications:

• Type-specific for HSV type-1 and HSV type-2 .
• Kit insert specifies glycoprotein-G based technology versus crude antigen.
• FDA-cleared for use in sexually active adults and pregnant women.

For the names of laboratories that are currently using HerpeSelect contact Focus Diagnostics’ HSV Information Center at (800) 505-0536.

How much does a HerpeSelect test cost?

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 type-1) or HSV type-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