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# **HHS Public Access**

Author manuscript JAMA Dermatol. Author manuscript; available in PMC 2024 April 01.

Published in final edited form as:

JAMA Dermatol. 2023 April 01; 159(4): 371–373. doi:10.1001/jamadermatol.2022.6236.

## **Renewed USPSTF Recommendation Against Serologic Screening for Genital Herpes: Empowering Clinicians and Reducing Potential Harm**

**Howa Yeung, MD MSc**1,2,3, **Anandi N. Sheth, MD MSc**3,4, **Lauren F. Collins, MD MSc**3,4

1Department of Dermatology, Emory University School of Medicine, Atlanta, GA

2Clinical Resource Hub, Veterans Integrated Service Network (VISN) 7 Southeast Network, Decatur, GA

3Ponce de Leon Center, Grady Health System, Atlanta, GA

4Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA

> The United States Preventive Services Task Force renewed its 2016 recommendation against population-based serologic genital herpes screening in asymptomatic adults and adolescents, including pregnant persons (Grade D).1 With little new data identified in a focused evidence update (i.e., zero eligible studies were included), the current 2023 recommendation reaffirmed with moderate certainty that the potential harms of serologic screening for genital herpes simplex virus (HSV)-2 infection in asymptomatic individuals outweigh potential benefits.1 This recommendation aligns with corresponding guidelines from the Centers of Disease Control and Prevention (CDC)2 and the American College of Obstetrics and Gynecology (ACOG).3

Screening in asymptomatic individuals must first be distinguished from diagnostic testing in patients presenting with genital lesions or symptoms. HSV-1 and HSV-2 serologic tests are generally of limited utility in diagnosing active genital herpes, as serologic tests cannot distinguish between current and past HSV infection or between oropharyngeal versus genital infection.2 Genital herpes diagnosis should be confirmed by type-specific nucleic acid amplification tests (NAAT) or viral culture. Type-specific NAAT, i.e., polymerase chain reaction testing for HSV-1 and HSV-2, display high sensitivity (range, 90.9-100%) and specificity (98.1-100%) for active infections, while viral culture may facilitate phenotypic sensitivity testing of acyclovir resistance in treatment-refractory disease.2,4 Herein, our discussion focuses on the recommendation against screening in individuals with no history or symptoms of genital herpes.

**Correspondence:** Howa Yeung, MD MSc. Department of Dermatology, Emory University School of Medicine, 1525 Clifton Road NE, Atlanta, GA 30322. Phone: (404) 778-3333. Fax: (404) 727-4920. howa.yeung@emory.edu.

2) All other relationships:

The authors have no additional conflicts of interest to disclose.

**Disclaimer:** The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Department of Veterans Affairs.

#### **High Bar to Achieve Screening Benefits**

To contextualize the recommendation against screening, it is important to understand that the bar to recommend routine screening in asymptomatic, otherwise healthy individuals is high — there must be substantial net benefit over harm. Most people with genital HSV-1 or HSV-2 infections are asymptomatic and, given the lack of clinical disease, are not diagnosed with genital herpes. In the 1988-2010 National Health and Nutrition Examination Surveys (NHANES), 87-91% of HSV-2 seropositive participants reported never being diagnosed with genital herpes.5 Further, a prospective cohort study of 3,438 HSV-seronegative women revealed that 74% and 63% of incident HSV-1 and HSV-2 seroconversions, respectively, occurred without recognized signs or symptoms of herpes disease.6 Thus, for genital herpes screening in asymptomatic individuals to yield net benefit, it must be capable of diagnosing latent infection prior to clinical disease onset and facilitating interventions that alter the natural history of genital herpes. Such interventions, including early behavioral counseling and/or antiviral medications, would aim to prevent HSV outbreaks, diminish HSV symptoms, or reduce viral shedding and transmission with minimal potential harms.

To date, there are no population-based studies demonstrating benefits of genital herpes screening in asymptomatic individuals.1 Unfortunately, no cure currently exists for genital herpes. Asymptomatic viral shedding is common after the first clinical outbreak of genital herpes.7,8 However, data are lacking on viral shedding frequency and transmission likelihood among individuals without prior history of clinical disease. In small studies of asymptomatic HSV-2 seropositive individuals, valacyclovir (but not famciclovir) reduced viral shedding and symptomatic genital lesions over 6-8 weeks of follow-up.9,10 However, larger studies with longer follow-up are needed to confirm and assess the durability of potential treatment benefits in asymptomatic HSV-seropositive individuals. It must also be considered that individuals may face psychosocial harms and/or receive unnecessary antiviral treatments if an inaccurate diagnosis of genital herpes is made due to false-positive screening results.

## **Screening Implications of Decreasing Epidemiologic Trends of Herpes Infection**

Both HSV-1 and HSV-2 infections can cause genital herpes.2 In the United States, seroprevalence of HSV-1 and HSV-2 have been consistently decreasing. From 1999-2000 to 2015-2016, the seroprevalence among persons aged 14-49 years decreased from 59.4% to 48.1% for HSV-1 and from 18.0% to 12.1% for HSV-2.11 At the time of the 2016 USPSTF recommendation, HSV-2 seroprevalence in the U.S. was estimated to be 16% and the sensitivity and specificity of commonly available serologic tests ranged from 84-99% and 83-95%, respectively.12 Taken together, the positive predictive value of commercially available HSV-2 serologic tests was estimated at that time to be as low as 50-75%.13 As the population prevalence of HSV-2 infection has since decreased,11 and no new highquality data were identified to suggest substantial changes in test characteristics,1 the current positive predictive value of HSV serologic testing is expected to be even lower than prior

JAMA Dermatol. Author manuscript; available in PMC 2024 April 01.

estimates. Unfortunately, this has the potential to exacerbate possible harms of routine genital herpes screening in asymptomatic individuals.

#### **Potential Harms of Positive Screening Tests**

Stigma associated with genital herpes is widely prevalent and leads to high levels of emotional, social, relational, and sexual distress, particularly among individuals at the time of initial diagnosis.14 Occurrence of genital herpes has been associated with harmful emotional impacts on the individual diagnosed, including negative moral connotations of sexual promiscuity; retreat from, fear of, and/or loss of interest in sexuality; internalized stigma of genital herpes as a personal fault or loss of self; and anger as a result of contracting genital herpes from prior sex partners.14 For individuals diagnosed with genital herpes, interpersonal relationships are at risk of becoming strained, as mediated by personal feelings of anxiety, guilt, loneliness, fear, and isolation around disclosure as well as considerations involving sexual and non-sexual means of herpes transmission.14 While the impact of false-positive diagnoses has not been specifically examined, routine genital herpes screening in asymptomatic individuals may create substantial psychosocial harm for patients by the potential compounding of pervasive internal and social stigma around genital herpes infections. Future research should consider addressing the direct impact of false positive genital herpes testing on psychosocial health and health-related quality of life.

#### **Exceptions to the Rule**

There are uncommon scenarios in which HSV serology may help inform clinical care among asymptomatic patients, i.e., those without signs, symptoms, or prior history of genital herpes. First is the case of serodiscordant couples, in which one partner is known to have genital herpes infection and the other partner does not. Serologic screening of the partner without known infection may guide efforts to decrease transmission risks, such as counseling on consistent condom use, avoiding sexual activities during active outbreaks, and/or using prophylactic antiviral treatment. Among serodiscordant, heterosexual couples at two university-based research clinics, transmission occurred in 9.7% of couples over a median of 334 days.15 Importantly, the risk of HSV transmission differed by sex, observed in 16.9% versus 3.8% of couples with male versus female source partners, respectively, a finding supported by additional literature.15,16 A separate study found that daily valacyclovir treatment of seropositive partner decreased the risk of HSV-2 acquisition in the susceptible partner from 3.6% to 1.9% over 32 weeks.17 Similarly, serologic testing may be considered in pregnant persons with a prior history suggestive of genital herpes or whose partners are known to have genital herpes. If the pregnant patient is seronegative, they should be counseled to avoid vaginal or receptive oral intercourse during the third trimester of pregnancy with partners known or suspected to have herpes to decrease the risks of perinatal transmission of herpes infection.2

Second, during the initial evaluation of persons living with HIV, particularly among individuals with history suggestive of genital herpes but without active symptoms, serologic testing may help evaluate prior HSV exposure and potential risk of developing clinical disease.2 An ensuing informed risk-benefits discussion between patient and provider could

JAMA Dermatol. Author manuscript; available in PMC 2024 April 01.

be considered on use of suppressive antiviral medications to prevent severe outbreaks, such as during the first 6 months after antiretroviral therapy initiation, particularly in individuals with CD4 <200 cells/mm3 . 18 Overall, these scenarios are uncommon and routine genital herpes screening in asymptomatic persons, including pregnant persons, are not recommended.1

## **De-implementation of serologic screening for genital herpes in the general population**

What does this updated – and unchanged – recommendation aim to achieve? It should empower providers and patients to avoid most cases of HSV serologic testing in individuals without clinical symptoms of genital herpes. It will hopefully remind patients, clinicians, and programs that ordering HSV-1 and HSV-2 serologic tests as part of asymptomatic screening for sexually transmitted infections is not indicated based on available evidence. This is increasingly relevant with the expansion of telemedicine and at-home laboratory testing, as HSV-2 serologic tests have been marketed to patients either directly or as part of bundled testing for sexually transmitted infections.

Trends in HSV serologic test utilization in the general population should be examined, as part of an ongoing research agenda focused on refining tools and strategies for the screening, evaluation, and management of HSV infection. Additional investigation should prioritize assessment of who orders HSV serologic tests and in which populations, and how testing characteristics and associated implications may impact special populations including pregnant persons and persons living with HIV. Research on the impact of HSV infection on outcomes among pregnant persons and among those with or at-risk of HIV is urgently needed. Also, how can we as a health community rally to discourage serologic screening for genital herpes in asymptomatic persons to minimize potential psychosocial harms associated with false-positive diagnoses? How should programmatic and laboratory leadership uncouple HSV-2 serologic tests from routine sexually transmitted infection screening panels? The reaffirmed USPSTF recommendation against serologic screening for genital herpes in asymptomatic persons should inspire patients, clinicians, and healthcare leaders to campaign against unnecessary testing in the spirit of "do no harm."

### **Funding**

Dr. Yeung is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases under award numbers L30AR076081 and K23AR075888. Dr. Collins is supported by the National Center for Advancing Translational Sciences (NCATS) of the NIH (award numbers UL1TR002378 and KL2-TL1TR002381) and the Program for Retaining, Supporting, and EleVating Early-career Researchers at Emory (PeRSEVERE) from Emory University School of Medicine, a gift from the Doris Duke Charitable Foundation.

#### **Role of the Funder/Sponsor:**

The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

## **References**

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JAMA Dermatol. Author manuscript; available in PMC 2024 April 01.

JAMA Dermatology

Serologic screening for genital herpes infection: US Preventive Services Task Force reaffirmation recommendation statement.

JAMA

Serologic screening for genital herpes: updated evidence report and systematic review for the US Preventive Services Task Force.

Management of genital herpes in pregnancy: ACOG Practice Bulletin, number 220.

Obstet Gynecol

Automated processing, extraction and detection of herpes simplex virus types 1 and 2: a comparative evaluation of three commercial platforms using clinical specimens.

J Clin Virol

Trends in seroprevalence of herpes simplex virus type 2 among non-Hispanic blacks and non-Hispanic whites aged 14 to 49 years—United States, 1988 to 2010.

Sex Transm Dis

Epidemiology, clinical presentation, and antibody response to primary infection with herpes simplex virus type 1 and type 2 in young women.

Clin Infect Dis

Viral shedding 1 year following first-episode genital HSV-1 infection.

Genital shedding of herpes simplex virus among symptomatic and asymptomatic persons with HSV-2 infection.

Famciclovir reduces viral mucosal shedding in HSV-seropositive persons.

The effect of daily valacyclovir suppression on herpes simplex virus type 2 viral shedding in HSV-2 seropositive subjects without a history of genital herpes.

Prevalence of herpes simplex virus type 1 and type 2 in persons aged 14-49: United States, 2015-2016.

NCHS Data Brief

Serologic screening for genital herpes infection: US Preventive Services Task Force recommendation statement.

Serologic screening for genital herpes: an updated evidence report and systematic review for the US Preventive Services Task Force.

Impact of primary and recurrent genital herpes on the quality of life of young people and adults: a mixed methods systematic review.

JBI Evid Synth

Risk factors for the sexual transmission of genital herpes.

Ann Intern Med

Effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women.

Once-daily valacyclovir to reduce the risk of transmission of genital herpes.

N Engl J Med

Reactivation of herpes simplex virus type 2 after initiation of antiretroviral therapy.

J Infect Dis

Reaffirmed USPSTF Recommendation Against Serologic Screening for Genital Herpes: Empowering Clinicians and Reducing Potential Harm.

Reaffirmed USPSTF Recommendation Against Serologic Screening for Genital Herpes

Reaffirmed USPSTF Recommendation Against Serologic Screening for Genital Herpes

Clinical Summary

What was studied

Key findings

Study limitations

Clinical implications

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