Final Research Plan
Genital Herpes Infection: Serologic Screening
December 02, 2021
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.
*Studies that screen using an HSV-2 serologic test alone or type-specific HSV-1 and HSV-2 serologic tests in combination will be included if they meet other eligibility criteria; however, only the accuracy of test characteristics related to HSV-2 serological tests will be evaluated.
**KQ 7 will only be addressed if there is insufficient literature for KQs 1 and 5 but sufficient literature for KQ 4.
Abbreviations: HSV=herpes simplex virus; KQ=key question.
- Does serologic screening for herpes simplex virus type 2 (HSV-2) or type-specific testing for herpes simplex virus type 1 (HSV-1) and 2 in combination in asymptomatic adolescents and adults reduce future symptomatic episodes and transmission of genital herpes, including vertical transmission among pregnant persons?
- What is the accuracy of serologic screening for HSV-2 in asymptomatic adolescents, adults, and pregnant persons?
- What are the harms of serologic screening for HSV-2 or combined type-specific testing for HSV-1 and HSV-2 in asymptomatic adolescents, adults, and pregnant persons?
- How effective are antiviral medications in reducing genital HSV-2 viral shedding in asymptomatic adolescents, adults, and pregnant persons?
- How effective are antiviral medications and behavioral counseling interventions in reducing future symptomatic episodes and transmission of genital herpes in asymptomatic adolescents and adults, including vertical transmission among pregnant persons?
- What are the harms of antiviral medications and behavioral counseling interventions for reducing future symptomatic episodes and transmission of genital herpes in asymptomatic adolescents and adults, including vertical transmission among pregnant persons?
- What is the evidence supporting an association between subclinical genital HSV-2 viral shedding and health outcomes in asymptomatic adolescents, adults, and pregnant persons who are seropositive for HSV-2?
Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.
- What proportion of asymptomatic adolescents, adults, and pregnant persons who are identified as being seropositive for HSV-2, HSV-1, or both will have a recognized symptomatic episode of genital herpes?
- Are externally validated, reliable risk stratification tools available that distinguish persons who are more or less likely to have genital herpes?
The Research Approach identifies the study characteristics and criteria that the Evidence-based Practice Center will use to search for publications and to determine whether identified studies should be included or excluded from the evidence review. Criteria are overarching as well as specific to each of the key questions (KQs). The limited systematic review update for this topic will be conducted using synthesis procedures described in Section 4.7 (Reaffirmation Evidence Update Process) of the U.S. Preventive Services Task Force (USPSTF) Procedure Manual (available at https://uspreventiveservicestaskforce.org/uspstf/about-uspstf/methods-and-processes).
|Populations||All KQs: Asymptomatic* sexually active adolescents or adults with no clinical history of genital herpes†, including asymptomatic partners of persons with known genital herpes (i.e., discordant couples) and pregnant persons
KQ 2: Asymptomatic persons or populations unselected based on symptoms or diagnosis of genital herpes
KQs 4–7: Asymptomatic persons who are HSV-2 seropositive
KQs 5, 6: Asymptomatic pregnant persons who are HSV-2 seronegative are also eligible
|All KQs: Children (age <13 years), persons with HIV infection or other immunosuppressive disorders
KQs 1, 3–7: Persons with current symptoms (e.g., genital ulcers) or previously diagnosed with genital herpesKQ 2: Studies limited to persons with current symptoms of genital herpes or previously diagnosed with genital herpes
|Screening||KQs 1–3: FDA-approved serologic tests for HSV-2 or “paired testing” for HSV-1 and HSV-2‡||KQs 1–3: Serologic tests for HSV-2 that are not commercially available or approved by the FDA; nonserologic tests indicated for the diagnosis of HSV in persons with genital lesions (e.g., cell culture or PCR-based testing); HSV serologic tests that are not type specific|
|Interventions||KQs 4–6: FDA-approved antiviral medications (acyclovir, famciclovir, or valacyclovir) to prevent symptomatic episodes of genital herpes or reduce risk for transmission
KQs 5, 6: Behavioral counseling interventions, including patient education or counseling, partner notification, barrier protection (e.g., condoms), or combinations of these components; behavioral counseling interventions for seronegative pregnant persons that aim to prevent primary genital HSV infection during pregnancy
|KQs 4–6: Vaccinations, pharmacotherapy not approved by the FDA for genital herpes
KQs 5, 6: Routine periodic pelvic examinations to screen for gynecologic conditions (e.g., external inspection for genital ulcers)
|Comparisons||KQ 1: Screened versus nonscreened groups
KQ 2: FDA-approved HSV-2 serologic tests vs. HSV Western blot
KQ 3 (psychosocial outcomes): Any (or no) comparator
KQ 3 (cesarean delivery rate): Screened vs. nonscreened groups
KQs 4–6: Antiviral medications vs. placebo or no intervention
KQs 5 and 6: Behavioral counseling interventions vs. attention controls or usual care care (e.g., provision of a patient handout on genital herpes)
KQ 7: Higher vs. lower rates (or frequency) of subclinical viral shedding (e.g., percentage of days of subclinical viral shedding)
|KQs 1, 2, 4–7: No comparison; nonconcordant historical controls; comparative studies of various interventions (e.g., comparing two antiviral drugs or two different type-specific HSV-2 serologic tests)|
|Outcomes||KQs 1, 5, 7: Reduced rates of symptomatic genital herpes, reduced rates of genital herpes transmission measured by partner symptom recognition (or clinician diagnosis) or HSV seroconversion, reduced rates of neonatal HSV infection, and reduced rates of symptomatic genital herpes at delivery
KQ 2: Sensitivity, specificity, positive predictive value, and negative predictive value
KQ 3: Labeling, anxiety, or false-positive results leading to unnecessary treatment, partner discord, or distress or anxiety around the meaning of HSV-1 results when screening involves a “paired test” (HSV-1 and HSV-2 results reported together) or other psychosocial harms; increased rates of cesarean delivery (in persons with no evidence of active genital lesions at the time of delivery)
KQ 4: Reduced rates (or frequency) of subclinical HSV-2 viral shedding
KQ 6: Treatment-related adverse events (e.g., adverse drug reactions related to antiviral medications); psychosocial harms related to counseling or behavioral interventions
|All KQs: Cost-effectiveness or cost-related outcomes, transmission of other sexually transmitted infections (e.g., HIV)
KQ 3: Acceptability of HSV serologic testing
|Study designs||KQs 1, 4, 5: RCTs
KQs 2 and 3: Good-quality, recent (within 5 years) systematic reviews§; trials or observational studies published since the most recent review
KQ 6: RCTs and multi-institution antiviral medication pregnancy exposure registries
KQ 7: Treatment studies included in KQs 4–6 reporting both change in HSV-2 viral shedding and change in a health outcome; prospective cohort studies that follow participants for at least 1 year
|All other designs|
|Setting||All KQs: Primary care outpatient settings (or similar settings that are applicable to primary care)
KQs 1, 3–7:Countries categorized as “Very High” on the Human Development Index (as defined by the United Nations Development Programme 2020 Human Development Report)KQ 2: Any category of country on the Human Development Index
|All other settings|
|Language||English||Languages other than English|
* “Asymptomatic” refers to persons who have never had clinical symptoms of genital herpes (e.g., genital ulcers), not persons with genital herpes who have symptom-free periods between symptomatic recurrences.
† Eligible studies with mixed populations (e.g., studies that enroll a subset of participants who are seropositive for HSV without a clinical history of genital herpes) will be included when results are provided separately or can be obtained from the authors.
‡ Studies that test for both HSV-1 and HSV-2 (simultaneously) will be included if they meet other eligibility criteria; however, only the accuracy of test characteristics related to HSV-2 serologic tests will be evaluated.
§ Previous systematic reviews will be included if they are recent (published within 5 years), of good quality, and are similar in scope to our review. Initial database searches will not be limited by date of publication for these KQs. If no recent, good-quality systematic reviews are identified, all eligible primary studies that address the KQs will be included.
Abbreviations: FDA=U.S. Food and Drug Administration; HIV=human immunodeficiency virus; HSV=herpes simplex virus; KQ=key question; PCR=polymerase chain reaction; RCT=randomized, controlled trial
The draft Research Plan was posted for public comment on the USPSTF website from July 8, 2021, to August 4, 2021. In response to comments, the USPSTF revised its terminology related to simultaneous serologic testing for HSV-1 and HSV-2 from “paired testing” or “combined testing” to “type-specific testing.” The USPSTF clarified the role of HSV-1 in genital herpes infections and its rationale for focusing on HSV-2. The USPSTF also clarified its use of the term “asymptomatic” to refer to populations who had never experienced or recognized having symptoms of genital herpes. Finally, several comments highlighted the role of behavioral change in modifying the spread of HSV. The USPSTF plans to review behavioral counseling interventions, as listed in the Analytic Framework. Additionally, the USPSTF has a separate recommendation on “Behavioral Counseling Interventions to Prevent Sexually Transmitted Infections,” which includes herpes simplex infections.