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Genital Herpes Infection, Serologic Screening, 2016

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Recommendations: Serologic Screening for Genital Herpes Infection

Discussion:

Burden of Disease

Genital herpes is an STI caused by 2 related viruses, HSV-1 and HSV-2. In adolescents and adults, genital 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, body aches, and swollen glands. Among persons who have a symptomatic first outbreak, 70% to 90% will have at least 1 more symptomatic outbreak within the first year, with an average of 4 outbreaks.89 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 even 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. According to some experts, persons who receive education about genital herpes may be more likely to recognize and report its symptoms. If this is true, some persons who are considered “asymptomatic” may have actually experienced symptoms but not identified them as genital herpes.

There is currently no cure for genital herpes; once infection has occurred, the virus remains in a person for life. For this reason, the prevalence of infection increases with age. Data from the 2005–2010 National Health and Nutrition Examination Survey indicate that the prevalence of HSV-2 infection ranged from 1.2% in adolescents aged 14 to 19 years to 25.6% in adults aged 40 to 49 years.10 Overall, 15.7% of persons aged 14 to 49 years in the United States tested positive for HSV-2 infection between 2005 and 2010.10 These estimates, however, should be interpreted with caution; because of a lack of confirmatory testing, these data may overestimate the prevalence of HSV-2 infection. These data also may underestimate the overall prevalence of genital herpes, as they do not account for herpes infection caused by HSV-1. 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%), in part because of anatomical factors that predispose women to infection.11 Rates of HSV-2 infection also vary by race/ethnicity and geographical region and are higher in men who have sex with men.10

The herpes simplex virus may be transmitted from mother to infant during vaginal delivery. Among women with a prior history of symptomatic genital herpes, nearly 75% will have at least 1 recurrence during pregnancy and about 14% will have symptoms or clinical recurrence at the time of delivery.1213 Evidence shows, however, that vertical transmission and subsequent severe neonatal HSV infection are most likely in pregnant women who develop the initial genital infection during pregnancy.1415 The overall incidence of neonatal herpes is low.1416 Older data from a 2006 study using a multistate pediatric inpatient discharge database estimated the incidence of neonatal HSV infection as 9.6 cases per 100,000 births (95% CI, 4.3 to 12.0).16 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, that study found 76 cases of neonatal HSV infection among approximately 571,000 infants—an estimated incidence rate of 13.3 cases per 100,000 live births.17 The study also found that of the 72% of cases for which HSV typing was done, infections were almost equally caused by HSV-1 and HSV-2 (28 vs 27 cases).17 Incidence rates are thought to vary by geographic region and race/ethnicity. In the multistate study, incidence rates were substantially higher in infants born to women covered by Medicaid (15.1 cases per 100,000 live births) vs private insurance (5.4 cases per 100,000 live births).1618

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.19 Four percent of infants with a central nervous system infection and 30% of infants with disseminated disease may die as a result.20

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.2122 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), the most widely available serologic test for genital HSV-2 infection approved by the US 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).22 A second test, the Biokit HSV-2 Rapid Test (Biokit USA), has a pooled estimate of sensitivity of 84% (95% CI, 73 to 91) and specificity of 95% (95% CI, 93 to 97).22 In the general US population, the positive predictive value of may be as low as 75% for the Biokit test and as low as 50% for HerpeSelect. Western blot is considered to be 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 (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 symptoms 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 prevention in patients with a history of frequent symptomatic outbreaks. In studies, many persons identified with asymptomatic genital herpes (ie, they have been infected with HSV-2 and have never experienced symptoms) have a symptomatic outbreak within 6 months of testing. The increasing percentage of genital herpes cases caused by HSV-1 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 evidence is inadequate to determine if suppressive antiviral therapy reduces transmission of genital HSV infection between serodiscordant couples with an asymptomatic partner.

Pregnant adolescents and women with new or known history of genital HSV infection should be carefully observed during pregnancy. To reduce the chance of HSV transmission to the infant during delivery, women with active genital HSV lesions at the time of birth are usually offered the option of cesarean delivery. No studies have examined the effectiveness of antiviral therapy to decrease the risk for HSV transmission to pregnant women by an infected partner.

Potential Harms of Screening and Treatment

Serologic screening in asymptomatic persons will likely result in a large number of false-positive results. Given the limitations of currently available tests, 1 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 1485 true-positive and 1445 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.2324 However, antiviral medications are generally considered to have few harms in nonpregnant adults.21

Estimate of Magnitude of Net Benefit

Based on the natural history of HSV infection, its epidemiology, and the available evidence 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.

Response to Public Comment

A draft version of this recommendation statement was posted for public comment on the USPSTF website from August 2 to August 29, 2016. The USPSTF reviewed and considered all comments received during this period. Several comments supported the USPSTF's analysis and conclusions; some comments noted that the recommendation is consistent with current clinical practice and advice from other organizations, including the CDC and the American College of Obstetricians and Gynecologists (ACOG). A few comments expressed concern that persons with asymptomatic genital herpes infection can (unknowingly) transmit the infection to sexual partners. While the USPSTF understands this concern, given the current lack of accurate, widely available serologic screening tests and the expected high rate of false-positive results that would occur with widespread screening in asymptomatic persons, the USPSTF continues to recommend against routine serologic screening in asymptomatic adolescents and adults. In addition, the USPSTF clarified its language about HSV-1 infection, noting that while HSV-1 infection can be identified by serologic tests, the tests cannot determine if the site of infection is oral or genital.

Other Sections:

Other Considerdations

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 that detect both asymptomatic genital HSV-1 and HSV-2 infections
  • Behavioral interventions to reduce the transmission of genital HSV infection, including interventions to reduce the risk of transmission to uninfected pregnant women
  • Further interventions to prevent and treat neonatal herpes infection
  • Potential effectiveness of antiretroviral medications, including topical gels, as preexposure or postexposure prophylaxis
  • More data on the potential harms of screening in asymptomatic persons, including psychological distress and the disruption of personal relationships
  • Increased understanding of the potential role of HSV infection in increasing the risk of HIV infection and the management of coinfection with HSV and HIV

Research to develop a cure for genital HSV infection and a vaccine to prevent genital HSV infection should continue.

 

Recommendations of Others

The American Academy of Family Physicians,26 ACOG,27 and the CDC2 do not recommend routine serologic screening for genital HSV infection in asymptomatic adolescents or adults. 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.2 The CDC also recommends consideration of screening for HSV infection in men who have sex with men and who are at high risk for HIV infection.2

The American Academy of Family Physicians,26 ACOG,28 and the CDC2 do not recommend routine serologic screening for genital HSV infection in pregnant adolescents and women. The CDC2 and ACOG28 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. The CDC recommends that women with recurrent genital herpes during pregnancy be offered suppressive therapy at 36 weeks of gestation.2

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