Draft Recommendation Statement
Genital Herpes Infection: Serologic Screening
This opportunity for public comment expired on August 29, 2016 at 8:00 PM EST
Note: This is a Draft Recommendation Statement. This draft is distributed solely for the purpose of receiving public input. It has not been disseminated otherwise by the USPSTF. The final Recommendation Statement will be developed after careful consideration of the feedback received and will include both the Research Plan and Evidence Review as a basis.
Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Draft: Recommendation Summary
Genital herpes is a prevalent sexually transmitted infection (STI) in the United States; the Centers for Disease Control and Prevention (CDC) estimates that almost one in six persons ages 14 to 49 years have genital herpes.1 Genital herpes infection is caused by two subtypes of HSV (HSV-1 and HSV-2). Unlike other infections for which screening is recommended, HSV infection may not have a long asymptomatic period during which screening, early identification, and treatment might alter its course. Antiviral medications may provide symptomatic relief from outbreaks; however, they do not cure HSV infection. Although vertical transmission can occur between an infected pregnant woman and her infant during vaginal delivery, interventions can help limit transmission. Neonatal herpes infection, while uncommon, can result in substantial morbidity and mortality.
In the United States, most cases of genital herpes historically have been caused by infection with HSV-2. There is adequate evidence that the most widely used currently available serologic screening test for HSV-2 approved by the U.S Food and Drug Administration is not suitable for population-based screening due to its low specificity, lack of widely available confirmatory testing, and high false-positive rate. Rates of genital herpes due to HSV-1 infection in the United States may be increasing. There is no serologic screening test for genital herpes resulting from HSV-1 infection.
Benefits of Early Detection and Intervention
Based on limited evidence from a small number of trials on the potential benefit of screening and interventions among asymptomatic populations and an understanding of the natural history and epidemiology of genital HSV infection, the USPSTF concluded that the evidence is adequate to bound the potential benefits of screening in asymptomatic adolescents and adults, including those who are pregnant, to be no greater than small.
Harms of Early Detection and Intervention
Based on evidence on potential harms from a small number of trials, the high false-positive rate, and the potential anxiety and disruption of relationships related to diagnosis, the USPSTF found that the evidence is adequate to bound the potential harms of screening in asymptomatic adolescents and adults, including those who are pregnant, as at least moderate.
The USPSTF concludes with moderate certainty that the harms outweigh the benefits for population-based screening in asymptomatic adolescents and adults, including those who are pregnant.
Draft: Clinical Considerations
Patient Population Under Consideration
This recommendation statement applies to asymptomatic adolescents and adults, including those who are pregnant, without a history of genital HSV infection.
The USPSTF does not recommend serologic screening for genital HSV infection in asymptomatic persons.
The CDC provides guidance for the diagnosis and management of genital HSV infection (available at http://www.cdc.gov/std/tg2015/herpes.htm).
Additional Approaches to Prevention
The USPSTF recommends intensive behavioral counseling interventions to reduce the likelihood of acquiring an STI for all sexually active adolescents and for adults at increased risk.2
Draft: Other Considerations
Research Needs and Gaps
There are many areas in need of research to better understand the detection and management of asymptomatic genital HSV infection, including:
- Improved epidemiologic data on the true prevalence and natural history of asymptomatic genital HSV infection in the United States.
- Development of screening and diagnostic tests with higher specificity and that detect both asymptomatic HSV-1 and HSV-2 genital infections.
- Behavioral interventions to reduce the transmission of genital HSV infection, including interventions to reduce the risk of transmission to uninfected pregnant women.
- Potential effectiveness of antiretroviral medications as pre- or postexposure prophylaxis.
- More data on the potential harms of screening in asymptomatic persons, including psychological distress and the disruption of relationships.
- Increased understanding of the potential role of HSV infection in increasing the risk of HIV infection and the management of co-infection with HSV and HIV.
In addition, research to develop a cure for genital HSV infection and a vaccine to prevent genital HSV infection should continue.
Burden of Disease
Genital herpes is an STI caused by two related viruses, HSV-1 and HSV-2. In adolescents and adults, genital herpes infection often results in outbreaks of blisters (vesicles) in the area in and around the genitals and rectum. These blisters break and leave sores (ulcers) that are often painful. The first outbreak of genital herpes is usually the most painful and may be accompanied by flu-like symptoms, including fever, achiness, and swollen glands. Seventy to 90% of persons who have a symptomatic first outbreak will have at least one additional symptomatic outbreak within the first year, with an average of four outbreaks.7, 8 Repeat outbreaks are usually shorter and less severe than the initial outbreak. Although the risk of transmission is higher during a symptomatic outbreak, persons with genital herpes can spread the infection to sexual partners when they are asymptomatic. Studies suggest that up to 85% of persons who are found to be infected with HSV-2 and who report no prior symptoms of genital herpes have a symptomatic outbreak within 6 months of being tested. Some experts believe that persons who receive education about genital herpes are more likely to recognize and report its symptoms. If true, this suggests that some persons who are thought of as "asymptomatic" may have experienced symptoms but not identified them as genital herpes.
There is currently no cure for genital herpes; once infected, the virus remains in a person for life. For this reason, the prevalence of infection increases with age. Data from the National Health and Nutrition Examination Survey (2005–2008) indicate that the prevalence of HSV-2 infection ranged from 1.4% among teens ages 14 to 19 years to 26.1% among adults ages 40 to 49 years.9 Overall, 15.5% of persons ages 14 to 49 years in the United States tested positive for HSV-2 between 2005 and 2008.9 These estimates, however, should be interpreted with caution; because of a lack of confirmatory testing, these data likely overestimate the prevalence of HSV-2 infection. These data also do not account for genital herpes caused by HSV-1, for which there is no serologic test. In the National Health and Nutrition Examination Survey, women were almost twice as likely to be infected with HSV-2 as men (20.9% vs. 11.5%), likely because of anatomic factors that predispose women to infection.9 Rates of HSV-2 infection also vary by race/ethnicity and geographical region and are higher among men who have sex with men.9
HSV infection may be transmitted from mother to infant during vaginal delivery. Among women who have a prior history of symptomatic genital herpes, nearly 75% will have at least one recurrence during pregnancy and about 14% will have symptoms or clinical recurrence at delivery.10, 11 Evidence shows, however, that vertical transmission and subsequent severe neonatal HSV infection are most likely in pregnant women who develop the initial genital HSV infection during pregnancy.12, 13 The overall incidence of neonatal herpes is low.12, 14 Older data from a 2006 study using a multistate pediatric inpatient discharge database estimated the incidence of neonatal HSV infection to be 9.6 cases per 100,000 births (95% confidence interval [CI], 4.3 to 12.0).14 The most recent estimate of neonatal herpes incidence comes from a large study in New York City of cases reported between 2006 and 2010. Using a clinical laboratory system, this study found 76 cases of neonatal HSV infection and estimated an incidence rate of 13.3 cases per 100,000 live births.15 The study also found that of the 72% of cases for which HSV typing was done, infections were approximately equally caused by HSV-1 and HSV-2 (28 vs. 27 cases).15 Incidence rates are thought to vary by geographic region and race/ethnicity, and in the multistate study, were substantially higher among women with Medicaid (15.1 cases per 100,000 live births) compared with women with private insurance (5.4 cases per 100,000 live births).14, 16
Approximately 45% of infants with neonatal HSV infection develop relatively mild skin, eye, or mucous membrane infections; 30% develop a central nervous system infection; and 25% develop disseminated disease.17 Four percent of infants with a central nervous system infection and 30% of infants with disseminated disease may die as a result.18
Scope of Review
The USPSTF commissioned a systematic evidence review to examine the evidence on the accuracy, benefits, and harms of serologic screening for HSV-2 infection in asymptomatic adolescents and adults, including those who are pregnant.19 The evidence review also considered the effectiveness and harms of preventive medications and behavioral counseling interventions in asymptomatic populations to reduce future symptomatic episodes and transmission to susceptible sexual partners and infants.
Accuracy of Screening Tests
HerpeSelect® (Focus Diagnostics, Cypress, CA), the most widely available serologic test for genital HSV-2 infection approved by the U.S. Food and Drug Administration, has a pooled estimate of sensitivity of 99% (95% CI, 97 to 100) and a pooled estimate of specificity of 83% (95% CI, 72 to 91).19 A second test, the Biokit HSV-2 Rapid Test (Biokit USA, Lexington MA), has a joint estimate of sensitivity of 84% (95% CI, 73 to 91) and specificity of 95% (95% CI, 93 to 97).19 In the general U.S. population, the positive predictive value of the Biokit test may be as low as 75% and as low as 50% for HerpeSelect. Western blot is considered the gold standard for the serologic diagnosis of herpes. Western blot test results can be obtained by sending a blood sample to a single research laboratory (the University of Washington Clinical Virology Laboratory); however, it is not widely available as a screening or confirmatory test for persons who screen positive for HSV-2 on one of the less specific commercially available serologic tests. No studies have examined the screening accuracy of serologic HSV tests in pregnant women. Serologic HSV tests may be clinically useful for persons with persistent undiagnosed genital complaints and in other diagnostic settings.
Effectiveness of Early Detection and Treatment
Currently, there is no cure for genital HSV infection. Antiviral medications are generally used for the management of symptomatic outbreaks and for the prevention of outbreaks in patients with a history of frequent symptomatic outbreaks. In studies, many persons identified with asymptomatic genital herpes (meaning they have been infected with HSV-2 and report having never experienced symptoms) experience a symptomatic outbreak within 6 months of testing. The increasing percentage of genital herpes cases caused by HSV-1, for which there is no serologic test, also limits the potential benefit of serologic screening in asymptomatic persons. While HSV-1 infection can be detected through serologic tests, these tests cannot determine the site of HSV infection. Since HSV-1 can cause both oral and genital herpes infections, and oral herpes infection is very common, serologic tests for HSV-1 cannot be used to screen for asymptomatic genital herpes infection. The USPSTF found that the evidence is inadequate to determine if suppressive antiviral therapy reduces transmission of genital HSV infection between serodiscordant couples with an asymptomatic partner.
Adolescents and women with new or known history of genital HSV infection are carefully observed during pregnancy. In order to reduce the chance of HSV transmission to the infant during delivery, women with active genital HSV lesions are usually offered the option of cesarean delivery. The effectiveness of antiviral therapy to decrease the risk for HSV transmission to pregnant women by infected partners has not been studied.
Potential Harms of Screening and Treatment
Serologic screening in asymptomatic persons is expected to result in a large number of false-positive results. Given the limitations of currently available tests, 1 out of 2 positive results may be false. Given the test characteristics of the most widely used serologic screening test for HSV-2 and a population infection prevalence of 15%, screening 10,000 persons would result in approximately 1,485 true-positive and 1,445 false-positive results. Confirmatory testing is not currently widely available and is only performed at a single research laboratory. There are social and emotional harms of receiving a false-positive result, in addition to the potential harms of unnecessary treatment with preventive antiviral medications.20, 21 However, it is generally thought that antiviral medications have few harms in nonpregnant adults.19
Estimate of Magnitude of Net Benefit
Based on the natural history of HSV infection, its epidemiology, and studies on the accuracy of serologic screening tests, the USPSTF found adequate evidence to bound the potential benefits and harms and conclude with moderate certainty that the harms outweigh the benefits of serologic screening for genital HSV infection in asymptomatic adolescents and adults, including those who are pregnant.
Draft: Update of Previous USPSTF Recommendation
This recommendation is consistent with and updates the 2005 USPSTF recommendation. This recommendation is based on substantial new evidence on the accuracy of serologic screening tests for genital HSV-2 infection and limited new evidence on the benefits and harms of screening.
Draft: Recommendations of Others
The American Academy of Family Physicians, the American College of Obstetricians and Gynecologists (ACOG), and the CDC do not recommend routine serologic screening for genital HSV infection in asymptomatic adolescents or adults.22, 24 Diagnostic testing, however, in persons with recurrent atypical genital symptoms may be helpful. The CDC recommends consideration of serologic testing for HSV-2 in persons presenting for STI evaluation and for persons living with HIV infection.24 The CDC also recommends consideration of screening for HSV infection in men who have sex with men and are at high risk for HIV infection.24
The American Academy of Family Physicians, ACOG, and the CDC do not recommend routine serologic screening for genital HSV infection in pregnant adolescents and women.22, 24, 25 The CDC and ACOG recommend asking pregnant women about history of genital HSV infection and consideration of cesarean delivery for women with prodromal symptoms or active genital lesions during labor to reduce the risk of neonatal HSV infection.24, 25
- Centers for Disease Control and Prevention. Genital herpes: CDC fact sheet. http://www.cdc.gov/std/herpes/stdfact-herpes.htm. Accessed July 12, 2016.
- U.S Preventive Services Task Force. Behavioral counseling interventions to prevent sexually transmitted infections: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;161(12):894-901.
- U.S Preventive Services Task Force. Screening for chlamydia and gonorrhea: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;161(12):902-10.
- U.S. Preventive Services Task Force. Screening for hepatitis B virus infection in nonpregnant adolescents and adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;161(1):58-66.
- U.S. Preventive Services Task Force. Screening for HIV: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;159(1):51-60.
- U.S. Preventive Services Task Force. Screening for syphilis infection in nonpregnant adults and adolescents: U.S. Preventive Services Task Force recommendation statement. JAMA. 2016;315(21):2321-7.
- Patel R, Rompalo A. Genital herpes infections. In: Zenilman JM, Shahmahnesh M, eds. Sexually Transmitted Infections: Diagnosis, Management, and Treatment. Burlington, MA: Jones & Bartlett; 2012.
- Benedetti JK, Zeh J, Corey L. Clinical reactivation of genital herpes simplex virus infection decreases in frequency over time. Ann Intern Med. 1999;131(1):14-20.
- Centers for Disease Control and Prevention (CDC). Seroprevalence of herpes simplex virus type 2 among persons aged 14-49 years—United States, 2005-2008. MMWR Morb Mortal Wkly Rep. 2010;59(15);456-9.
- Watts DH, Brown ZA, Money D, et al. A double-blind, randomized, placebo-controlled trial of acyclovir in late pregnancy for the reduction of herpes simplex virus shedding and cesarean delivery. Am J Obstet Gynecol. 2003;188(3):836-43.
- Sheffield JS, Hollier LM, Hill JB, Stuart GS, Wendel GD. Acyclovir prophylaxis to prevent herpes simplex virus recurrence at delivery: a systematic review. Obstet Gynecol. 2003;102(6):1396-403.
- 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(2):203-9.
- ACOG practice bulletin. Management of herpes in pregnancy. Number 8 October 1999. Clinical management guidelines for obstetrician-gynecologists. Int J Gynaecol Obstet. 2000;68(2):165-73.
- Flagg EW, Weinstock H. Incidence of neonatal herpes simplex virus infections in the United States, 2006. Pediatrics. 2011;127(1):e1-8.
- Handel S, Klingler EJ, Washburn K, Blank S, Schillinger JA. Population-based surveillance for neonatal herpes in New York City, April 2006-September 2010. Sex Transm Dis. 2011;38(8):705-11.
- Mahnert N, Roberts SW, Laibl VR, Sheffield JS, Wendel GD Jr. The incidence of neonatal herpes infection. Am J Obstet Gynecol. 2007;196(5):e55-6.
- Hollier LM, Wendel GD. Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection. Cochrane Database Syst Rev. 2008(1):CD004946.
- Kimberlin DW, Rouse DJ. Clinical practice. Genital herpes. N Engl J Med. 2004;350(19):1970-7.
- Feltner C, Grodensky CA, Middleton JC, et al. Serologic Screening for Genital Herpes Infection: An Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 149. AHRQ Publication No. 15-05223-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2016.
- Melville J, Sniffen S, Crosby R, et al. Psychosocial impact of serological diagnosis of herpes simplex virus type 2: a qualitative assessment. Sex Transm Infect. 2003;79(4):280-5.
- Rosenthal SL, Zimet GD, Leichliter JS, et al. The psychosocial impact of serological diagnosis of asymptomatic herpes simplex virus type 2 infection. Sex Transm Infect. 2006;82(2):154-7; discussion 157-8.
- American Academy of Family Physicians. Clinical preventive service recommendation: genital herpes simplex virus infection. http://www.aafp.org/patient-care/clinical-recommendations/all/genital-herpes.html. Accessed July 12, 2016.
- American College of Obstetricians and Gynecologists. ACOG-endorsed documents. http://www.acog.org/Resources-And-Publications/Endorsed-Documents. Accessed July 12, 2016.
- Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015: genital HSV infections. http://www.cdc.gov/std/tg2015/herpes.htm. Accessed July 12, 2016.
- ACOG Committee on Practice Bulletins. ACOG practice bulletin. Clinical management guidelines for obstetrician-gynecologists. No. 82 June 2007. Management of herpes in pregnancy. Obstet Gynecol. 2007;109(6):1489-98.
Internet Citation: Draft Recommendation Statement: Genital Herpes Infection: Serologic Screening. U.S. Preventive Services Task Force. December 2016.