Draft Research Plan
Genital Herpes Infection: Serologic Screening
July 08, 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 a “paired” (HSV-1 and HSV-2) serologic test 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.
**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 combined testing for herpes simplex virus type 1 (HSV-1) and 2 in asymptomatic adolescents and adults reduce future symptomatic episodes and transmission of genital herpes, including vertical transmission for 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 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 for 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 for 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?
These 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 proposed 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 USPSTF Procedure Manual (available at https://uspreventiveservicestaskforce.org/uspstf/about-uspstf/methods-and-processes/procedure-manual).
| Include | Exclude | |
|---|---|---|
| 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 |
All KQs: Children (younger than 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 herpes KQ 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 the following: 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, 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, 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 KQ 2: Any country categorized 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