Final Research Plan

Hepatitis C Virus Infection in Adolescents and Adults: Screening

December 21, 2017

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.

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Panel 1

The final Research Plan will be used to guide a systematic review of the evidence by researchers at an Evidence-based Practice Center. The resulting Evidence Review will form the basis of the USPSTF Recommendation Statement on this topic.

The draft Research Plan was available for comment from September 21 until October 18, 2017 at 5:00 p.m., ET.

The analytic framework depicts the relationship between the populations, interventions, outcomes, and harms of screening for hepatitis C virus (HCV) infection. The far left of the framework describes the target population for screening as asymptomatic, nonpregnant and pregnant adults and adolescents. To the right of the population is a line that represents HCV screening, and the yield of new diagnoses when comparing one-time vs. repeat screening (key question 3), that leads to either HCV-positive or HCV-negative populations. A subsequent arrow indicates assessment of harms of screening (key question 4). From the HCV-positive population, an arrow leads to disease staging and, in pregnancy, represents the effectiveness of interventions in HCV-positive persons during labor and delivery or in the perinatal period on risk of vertical transmission of HCV infection (key question 5). This line also represents the effectiveness of antiviral treatment in improving mortality, morbidity, and quality of life (key question 6) and in improving the intermediate outcome of SVR rates (key question 7), as well as harms associated with antiviral treatments (key question 8). A dotted line represents the association between SVR rates and the reduction in risk of adverse health outcomes associated with HCV infection (key question 9). An overarching arrow symbolizing key question 1 spans directly from screening to the health outcomes mentioned previously. In addition, this line represents the effectiveness of different risk- or prevalence-based methods for screening for HCV infection on health outcomes (key question 2).

Abbreviations: HCV=hepatitis C virus; SVR=sustained virologic response.

* Includes persons without known liver function test abnormalities. Adolescents are defined as those ages 12 to 17 years. Excludes persons living with HIV, transplant recipients, and patients with renal failure.
† Defined as HCV antibody testing with confirmatory HCV RNA testing as indicated.
‡ Includes interventions that may affect vertical transmission of HCV, such as cesarean delivery, amniocentesis, and fetal monitoring, as well as antiviral treatment.

1a.  Does screening for hepatitis C virus (HCV) infection in pregnant and nonpregnant adolescents and adults without known abnormal liver enzyme levels reduce HCV-related mortality and morbidity or affect quality of life?
1b.  Does prenatal screening for HCV infection reduce risk of vertical transmission of HCV infection?
2.    What is the effectiveness of different risk- or prevalence-based methods for screening for HCV infection on clinical outcomes?
3.    What is the yield (number of new diagnoses per tests performed) of one-time versus repeat screening for HCV infection, and how does the screening yield vary in different risk groups?
4.    What are the harms of screening for HCV infection (e.g., anxiety and labeling)?
5.    What are the effects of interventions during labor and delivery or the perinatal period on risk of vertical transmission of HCV infection?
6.    What is the effectiveness of currently recommended antiviral treatments in improving health outcomes in patients with HCV infection?*
7.    What is the effectiveness of currently recommended antiviral treatments in achieving a sustained virologic response in patients with HCV infection?*
8.    What are the harms of currently recommended antiviral treatments?*
9.    What is the association between improvement of sustained virologic response following antiviral treatment and reduction in risk of HCV-related adverse health outcomes?

* Subpopulations of interest for Key Questions (KQs) 6, 7, and 8 include those defined by age, race/ethnicity, sex, drug use, receipt of maximally assisted therapy, stage of disease, HCV genotype, and pregnancy status (including nonpregnant women of childbearing age).

Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.

  1. Based on population level estimates, what are recent trends in the epidemiology, prevalence, and incidence of HCV infection in the United States, including in primary care settings, over the past 5 to 10 years?
  2. What are the effects of different risk- or prevalence-based methods for screening for HCV infection in modeling studies?
  3. What is the effect of antiviral treatments on behavioral outcomes?

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 KQs.

The evidence review will focus on screening in asymptomatic persons without known liver function test abnormalities. Patients who are coinfected with the hepatitis B virus or HIV will be excluded from the review, since management of these conditions may include evaluation for HCV infection. Older antiviral regimens that are no longer recommended will also be excluded. For KQs related to screening, the focus will be on settings applicable to U.S. primary care and emergency departments. Studies of screening conducted in specialty settings and geographic areas in which the epidemiology and management of HCV infection differ substantially from U.S. primary care settings will be excluded.

  Included Excluded
Screening in nonpregnant adolescents and adults (KQs 1a, 2–4)
Populations Asymptomatic, nonpregnant adolescents (ages 12 to 17 years) and adults without prior HCV infection Persons with known abnormal liver function tests, hepatitis B virus infection, or HIV infection; children age <12 years
Interventions Screening Other interventions
Comparisons Screening vs. no screening, one screening method vs. another, screening interval comparisons Other comparisons
Outcomes Mortality, morbidity (e.g., cirrhosis, hepatic decompensation, liver transplant, extrahepatic manifestations of HCV infection), quality of life, HCV transmission, harms (e.g., labeling, anxiety, drug-related harms), screening yield (number of new diagnoses per tests performed) (KQ 3) Other outcomes, including intermediate outcomes
Setting U.S. primary care, obstetrics/gynecology, emergency department, and primary care–applicable settings, including settings that offer integrated services for primary care and behavioral health care (e.g., substance use treatment clinics)  
Study design RCTs, controlled observational studies Uncontrolled studies
Screening in pregnant adolescents and adults (KQs 1–4)
Populations Asymptomatic pregnant adolescents (ages 12 to 17 years) and adults without prior HCV infection Persons with known abnormal liver function tests, hepatitis B virus infection, or HIV infection
Interventions Screening Other interventions
Comparisons Screening vs. no screening, one screening method vs. another, screening interval comparisons Other comparisons
Outcomes Perinatal transmission, mortality, morbidity, quality of life, harms (e.g., labeling, anxiety, drug-related harms), screening yield (number of new diagnoses per tests performed) (KQ 3) Other outcomes
Setting U.S. primary care, obstetrics/gynecology, emergency department, and primary care–applicable settings, including settings that offer integrated services for primary care and behavioral health care (e.g., substance use treatment clinics)  
Study design RCTs, controlled observational studies Uncontrolled studies
Labor and delivery and perinatal interventions (KQ 5)
Populations Pregnant adolescents and adults with HCV infection Other populations
Interventions Mode of delivery, labor management strategies, breastfeeding practices Other interventions
Comparisons Elective cesarean delivery vs. vaginal or emergency cesarean delivery, internal fetal monitoring vs. no monitoring, longer vs. shorter duration of rupture of membranes, breastfeeding vs. no breastfeeding Other comparisons
Outcomes Perinatal transmission of HCV infection Other outcomes
Settings U.S. labor and delivery settings  
Study design RCTs, controlled observational studies Case reports, studies not reporting original data
Antiviral treatment (KQs 6–8)
Populations Persons with screen-detected or asymptomatic HCV infection (patients with a METAVIR fibrosis stage of 0–3, if symptom status is not reported); persons with no prior antiviral treatment; includes pregnant women Persons who are coinfected with the hepatitis B virus or HIV, transplant patients, persons with renal failure
Interventions Currently recommended direct-acting antiviral regimens Interferon-based treatment and other nonrecommended regimens
Comparisons Another direct-acting antiviral regimen or older antiviral regimen; includes clinical trials without a comparison group  
Outcomes Sustained virologic response (KQ 6); morbidity (e.g., cirrhosis, hepatic decompensation, liver transplant, extrahepatic manifestations of HCV infection), mortality, quality of life, HCV transmission (KQ 5), harms of treatment (KQ 7); behavioral outcomes will be included for Contextual Question 3 Histologic outcomes, liver function tests
Setting Clinical settings in which HCV antiviral treatments are prescribed  
Study design RCTs and uncontrolled clinical trials; for harms, will also include large cohort and case-control studies; will consider good-quality systematic reviews of clinical trials Case reports, studies not reporting original data
Association between improvements in sustained virologic response and clinical outcomes (KQ 9)
Populations Persons with HCV infection being treated with antiviral therapy Persons who are coinfected with the hepatitis B virus or HIV, transplant patients, persons with renal failure
Interventions Direct-acting antiviral regimens or other antiviral treatment  
Comparisons Persons who experience a sustained virologic response vs. those who do not  
Outcomes Morbidity (e.g., cirrhosis, hepatic decompensation, liver transplant), mortality Histologic outcomes, liver function tests
Setting Clinical settings in which HCV antiviral treatments are prescribed  
Study design Cohort studies Case-control studies, case reports, studies not reporting original data

Abbreviations: HCV=hepatitis C virus; KQ=key question; RCT=randomized, controlled trial.

The draft Research Plan was posted for comment on the USPSTF Web site from September 21, 2017 through October 18, 2017. After reviewing public comments, the USPSTF revised the Research Plan to clarify the following: screening settings include emergency departments and settings that offer integrated services for primary care and behavioral health care; subpopulations of interest include drug use, persons using medication-assisted therapies, and nonpregnant women of childbearing age; morbidity outcomes include extrahepatic manifestations of HCV infection, such as depression and diabetes; health outcomes include perinatal HCV transmission; and the population for antiviral treatment includes persons with a METAVIR fibrosis stage of 0 to 3. The USPSTF also added a KQ on the yield of repeat HCV screening and revised Contextual Question 3 to address the effects of antiviral treatment on both positive and negative behaviors pertaining to HCV risk.