Final Research Plan
Genital Herpes Infection: Serologic Screening
August 06, 2015
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 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: KQ=key question; HSV=herpes simplex virus.
The figure is an analytic framework that depicts the seven key questions described in the research plan. In general, it illustrates the overarching questions of whether serologic screening in asymptomatic sexually active adults, adolescents, and pregnant women with no clinical history of genital herpes leads to improved health outcomes or potential harms. It also illustrates the intermediate steps and key questions about the accuracy of serologic screening tests for early detection of genital herpes. Finally, it illustrates whether treatment of genital herpes leads to improved health outcomes or potential harms.
1a. Does serologic screening for herpes simplex virus type 2 (HSV-2) or paired testing for herpes simplex virus type 1 (HSV-1) and 2 in asymptomatic nonpregnant adults and adolescents reduce future symptomatic episodes and transmission of genital herpes?
1b. Does serologic screening for HSV-2 or paired testing for HSV-1 and HSV-2 in pregnant women reduce neonatal HSV infection and symptomatic episodes of genital herpes at delivery?
2. What is the accuracy of serologic screening for HSV-2 in asymptomatic adults, adolescents, and pregnant women?
3a. What are the harms of serologic screening for HSV-2 or paired testing for HSV-1 and HSV-2 in asymptomatic nonpregnant adolescents and adults?v 3b. What are the harms of serologic screening for HSV-2 or paired testing for HSV-1 and HSV-2 in asymptomatic pregnant women?
4. How effective are oral antiviral medications in reducing genital HSV-2 viral shedding in asymptomatic adolescents, adults, and pregnant women?
5a. How effective are preventive medications and behavioral counseling interventions in reducing future symptomatic episodes and transmission of genital herpes in asymptomatic nonpregnant adults and adolescents?
5b. How effective are preventive medications and behavioral counseling interventions in reducing neonatal HSV infection and symptomatic episodes of genital herpes at delivery in pregnant women?
6a. What are the harms of preventive medications and behavioral counseling interventions for reducing future symptomatic episodes and transmission of genital herpes in asymptomatic nonpregnant adults and adolescents?
6b. What are the harms of preventive medications and behavioral counseling interventions for reducing neonatal HSV infection and symptomatic episodes of genital herpes at delivery in asymptomatic pregnant women?
7. What is the evidence supporting an association between subclinical genital HSV-2 viral shedding and health outcomes in asymptomatic adults, adolescents, and pregnant women 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 adults, adolescents, and pregnant women who are identified as being seropositive for HSV-2, HSV-1, or both will have a recognized symptomatic episode of genital herpes?
- Among asymptomatic adults, adolescents, and pregnant women who are identified as being seropositive for one virus subtype (HSV-1 or HSV-2), what proportion of recognized symptomatic episodes is due to a new (incident) HSV infection with a different subtype (i.e., nonprimary infection) versus a recurrent infection?
- What is the estimated incidence rate of neonatal HSV infection in the United States?
- What proportion of neonatal HSV infections in the United States is attributed to HSV-1 and HSV-2?
- Are externally validated, reliable risk stratification tools available that distinguish persons who are more or less likely to have genital herpes?
- What populations are at higher risk for genital herpes infection?
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).
|Populations||All KQs: Asymptomatic* sexually active adults or adolescents with no clinical history of genital herpes†, including asymptomatic partners of persons with known genital herpes (i.e., discordant couples)
KQs 1b, 3b, 5b, 6b: Asymptomatic pregnant women only
KQ 2: Asymptomatic persons or persons previously diagnosed with genital herpes
|All KQs: Children (age <13 years); persons with HIV infection or other immunosuppressive disorders
KQs 1, 3–7: Persons previously diagnosed with genital herpes or with current symptoms (e.g., genital ulcers)
|Screening||KQs 1–3: FDA-approved serologic tests for HSV-2 or “paired testing” for HSV-1 and HSV-2‡||KQs 2b, 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 oral 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 componentsKQ 5b: Behavioral counseling interventions for seronegative pregnant women that aim to prevent primary genital HSV infection during pregnancy
|KQs 4–6: Vaccinations; non–FDA-approved pharmacotherapy
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
KQs 3 a, b (psychosocial outcomes): Any (or no) comparator
KQ 3b (Cesarean delivery rate): Screened vs. nonscreened groups
KQs 4–6a: Oral antiviral medications vs. placebo
KQ 6b: Oral antiviral medications vs. placebo or no intervention
KQs 5, 6: Behavioral counseling interventions vs. attention controls or usual 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 1a, 5a, 7: Reduced rates of symptomatic genital herpes; reduced rates of genital herpes transmission measured by partner symptom recognition (or clinician diagnosis) or HSV seroconversion
KQs 1b, 5b: Reduced rates of neonatal HSV infection; reduced rates of 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
KQ 3b: Increased rates of Cesarean delivery (in women 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, 4–6a: Randomized, controlled trials
KQs 2, 3: Good-quality, recent (within 5 years) systematic reviews§; trials or observational studies published since the most recent review
KQ 6b: Randomized, controlled trials 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||Primary care outpatient settings (or similar settings that are applicable to primary care)||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 not be excluded if they meet the 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; PCR = polymerase chain reaction.
The draft Research Plan was posted for public comment on the USPSTF Web site from April 30 to May 27, 2015. In response, the USPSTF revised its terminology related to study outcomes from genital herpes “outbreaks” to “symptomatic episodes.” The USPSTF also added four new Contextual Questions to explore issues related to the epidemiology of neonatal HSV infection in the United States and risk factors associated with genital herpes infection. The USPSTF clarified its inclusion criteria for populations, screening tests, and behavioral counseling interventions. Specifically, the USPSTF clarified that paired tests (i.e., serologic tests that screen for HSV-1 and HSV-2 simultaneously) would not be excluded from the evidence review. The USPSTF also clarified that studies enrolling discordant couples would be considered, and that there are no exclusion criteria for the date of publication for eligible studies for KQs 2 and 3. However, for systematic reviews, only recent (published within the past 5 years) reviews rated as good quality and of similar scope to the current review will be included. If a recent good-quality systematic review is identified, relevant primary studies published since the review will be identified and included. Finally, the USPSTF eliminated geographic setting as an inclusion criterion for all KQs.