Draft Research Plan
Genital Herpes Infection: Serologic Screening
April 30, 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.
Abbreviations: KQ = key question; HSV-2 = herpes simplex virus type 2.
* KQ 7 will only be addressed if there is insufficient literature for KQs 1 and 5 but sufficient literature for KQ 4.
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) in asymptomatic nonpregnant adults and adolescents reduce outbreaks* and transmission of genital herpes?
1b. Does serologic screening for HSV-2 in pregnant women reduce neonatal HSV infection and outbreaks 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 in asymptomatic nonpregnant adolescents and adults?
3b. What are the harms of serologic screening for 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 in reducing outbreaks and transmission of genital herpes in asymptomatic nonpregnant adults and adolescents?
5b. How effective are preventive medications and behavioral counseling in reducing neonatal HSV infection and outbreaks of genital herpes at delivery in pregnant women?
6a. What are the harms of preventive medications and behavioral counseling for reducing outbreaks and transmission of genital herpes in asymptomatic nonpregnant adults and adolescents who are seropositive for HSV-2?
6b. What are the harms of preventive medications and behavioral counseling for reducing neonatal HSV infection and outbreaks of genital herpes at delivery in asymptomatic pregnant women who are seropositive for HSV-2?
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.
1a. What proportion of asymptomatic adults, adolescents, and pregnant women who are identified as being seropositive for HSV-2, HSV type 1 (HSV-1), or both will have a recognized outbreak of genital herpes?
1b. What proportion of these outbreaks is due to a new (incident) HSV infection (i.e., nonprimary infection) versus a recurrent infection?
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).
|Populations||All KQs: Asymptomatic* sexually active adults or adolescents with no clinical history of genital herpes†
KQs 1b, 3b, 5b, 6b: Asymptomatic pregnant women onlyKQ 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 2, 3: FDA-approved serologic tests for 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 outbreaks of genital herpes or reduce risk for transmission
KQs 5, 6: Patient education or counseling; partner notification; barrier protection (e.g., condoms)
|KQs 4–6: Vaccinations; non–FDA-approved pharmacotherapy
KQs 5, 6: Screening pelvic examination (e.g., external inspection for genital ulcers)
|Comparisons||KQ 1: Screened versus nonscreened groups
KQ 2: FDA-approved HSV-2 serologic tests compared with HSV Western blot
KQ 3: Any (or no) comparator
KQs 4, 5, 6a: Oral antiviral medications compared with placebo
KQ 6b: Oral antiviral medications compared with placebo or no intervention
KQs 5, 6: Behavioral counseling interventions compared with attention controls or usual care
KQ 7: Higher versus 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 genital herpes outbreaks; reduced rates of genital herpes transmission measured by partner symptom recognition (or clinician diagnosis) or HSV-2 seroconversion
KQs 1b, 5b: Reduced rates of neonatal HSV infection; reduced rates of genital herpes outbreaks at delivery
KQ 2: Sensitivity, specificity, positive predictive value, negative predictive value
KQ 3: Labeling, anxiety, false-positive results leading to unnecessary treatment, partner discord 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, 5: Randomized, controlled trials
KQ 2: Good-quality, recent (within 5 years) systematic reviews; trials or observational studies that compare an FDA-approved HSV-2 serologic test with HSV Western blot (in asymptomatic persons)
KQ 3: Good-quality, recent (within 5 years) systematic reviews to identify previous studies; bridge searches will be performed to identify trials or observational studies published since the review and to determine whether they are consistent with the review
KQ 6a: Randomized, controlled trials
KQ 6b: Randomized, controlled trials and multi-institution antiviral medication pregnancy exposure registries
KQ 7: Treatment studies included in KQs 4, 5, or 6 reporting both change in HSV 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); studies conducted in countries categorized as “Very High” on the Human Development Index, as defined by the United Nations Development Programme||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 recurrent outbreaks.
† 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.
Abbreviations: FDA = U.S Food and Drug Administration; PCR = polymerase chain reaction.