Final Research Plan
Final Research Plan for Hepatitis B Virus Infection in Nonpregnant Adolescents and Adults: Screening
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.
The final Research Plan is 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 November 29, 2018 until January 2, 2019 at 8:00 p.m., ET.
Note: “Screening” is defined as testing for anti-HBs and HBsAg, with or without testing for anti-HBc.
* “Chronic HBV infection” is defined by a positive HBsAg test result. Chronic HBV infection should be staged by assessment for hepatitis fibrosis/inflammation, HBV viral load, HBeAg status, anti-HBe status, and liver function tests. Appropriate interventions depend on disease stage.
† “Evidence of HBV immunity” is defined as positive anti-HBs, negative HBsAg, and positive (cleared infection) or negative (seroprotection due to vaccination) anti-HBc test results. Patients who have positive anti-HBc test results may benefit from education regarding risk of reactivation.
‡ “Isolated anti-HBc positive” is defined as positive anti-HBc test results but negative anti-HBs and HBsAg test results and indicates prior HBV exposure. Patients who have positive isolated anti-HBc test results may benefit from education regarding risk of reactivation. HBV vaccination is recommended for patients with positive isolated anti-HBc test results who are from countries with low prevalence of HBV infection (such as the United States) or who are immunocompromised.
§ “Never exposed to HBV” is defined as negative anti-HBs, anti-HBc, and HBsAg test results.
Abbreviations: anti-HBc = antibody to the hepatitis B core antigen; anti-HBe = antibody to the hepatitis B e antigen; anti-HBs = hepatitis B surface antibody; HBeAg = hepatitis B e-antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; KQ = key question.
This figure depicts the research approach that will guide the evidence review outlined in this research plan. The target population is asymptomatic, nonpregnant adolescents and adults. To the right of the population is an arrow that represents the yield and sensitivity of alternative HBV screening strategies (Key Question 3), and a subsequent arrow indicates assessment of harms of screening (Key Question 2). Screening leads to populations that fall into one of the four following categories: chronic HBV infection, evidence of HBV, isolated anti-HBc positive, or never exposed to HBV. An arrow to the right of the chronic HBV infection population leads to the provision of education or behavior change counseling, and another arrow leads to provision of antiviral medications. To the right of antiviral medications, one arrow leads to intermediate outcomes of virologic improvement, histologic improvement, clearance of HBeAg, and clearance of HBsAg clearance (Key Question 4), and a second arrow leads to clinical health outcomes, including mortality, cirrhosis, extrahepatic manifestations of HBV, hepatocellular cancer, quality of life, and disease transmission (Key Question 5). A third arrow to the right of antiviral medications indicates assessment of harms associated with antiviral treatment (Key Question 6). A dotted line represents the examination of the association between improvements in intermediate outcomes as a result of antiviral treatment and reduction in risk of HBV-related adverse health outcomes (Key Question 7). An overarching arrow that extends from the screened population of asymptomatic, nonpregnant adolescents and adults to the clinical health outcomes symbolizes Key Question 1 about the direct benefits of screening on clinical health outcomes.
Key Questions to Be Systematically Reviewed
- What are the benefits of screening for hepatitis B virus (HBV) infection in asymptomatic, nonpregnant adolescents and adults on morbidity, mortality, and disease transmission?
- What are the harms of screening for HBV infection in asymptomatic, nonpregnant adolescents and adults (e.g., labeling or anxiety)?
- What is the yield (number of new diagnoses per tests performed) and sensitivity of alternative HBV screening strategies (e.g., universal vs. targeted screening or screening strategies based on alternative risk factors)?
- How effective is antiviral treatment in improving intermediate outcomes among nonpregnant adolescents and adults with chronic HBV infection, including virologic or histologic improvement, clearance of hepatitis B e-antigen (HBeAg) (as indicated by loss of HBeAg or acquisition of the antibody to HBeAg [anti-HBe]), or clearance of hepatitis B surface antigen (HBsAg) (as indicated by loss of HBsAg or acquisition of hepatitis B surface antibody [anti-HBs])?*
- How effective is antiviral treatment in improving health outcomes among nonpregnant adolescents and adults with chronic HBV infection?*
- What are the harms associated with antiviral treatment in nonpregnant adolescents and adults with chronic HBV infection?*
- What is the association between improvements in intermediate outcomes as a result of antiviral treatment of chronic HBV infection and reduction in risk of HBV-related adverse health outcomes?
*Subpopulations of interest for Key Questions 4, 5, and 6 include those defined by age, race/ethnicity, sex, injection drug use status, HBV genotype, HBeAg status, fibrosis stage, alanine transaminase level, presence of nonalcoholic steatohepatitis, HBV DNA level, and hepatitis D virus status.
Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.
- What are the effects of different risk- or prevalence-based methods for screening for HBV infection in modeling studies?
- What is the accuracy of tools for identifying persons with chronic HBV infection?
- In persons with serologic evidence of HBV infection (positive test results for the antibody to hepatitis B core antigen or for HBsAg), what is the likelihood of reactivation following exposure to immunosuppressant therapy, and what is the effectiveness of interventions to improve clinical outcomes associated with reactivation?
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).
|Definition of Disease||Chronic HBV infection, defined as detectable HBsAg in blood for >6 months||Acute HBV infection|
|Populations||KQs 1–3: Nonpregnant adolescents (ages 13 to <18 years) and adults (age ≥18 years) with no signs or symptoms of HBV infection
KQs 4–7: Nonpregnant adolescents and adults with chronic HBV infection
|KQs 1–3: Symptomatic patients, children age <13 years, pregnant women, persons living with HIV or hepatitis C virus infection, persons who have been previously treated for HBV infection, and other special populations (e.g., persons undergoing hemodialysis or an organ transplant)|
|Interventions||KQs 1–3: Screening, including alternative screening strategies (KQ 3)
KQs 4–7: Antiviral treatments approved by the FDA for patients who have never been treated for HBV infection. Therapies will be classified as:
|KQs 4–7: Antiviral treatments not approved by the FDA; combination therapy|
|Comparators||KQs 1, 2: No screening
KQ 3: One screening strategy vs. an alternative screening strategy
KQs 4–6: No treatment; preferred vs. nonpreferred antiviral therapiesKQ 7: Effects on intermediate outcome (HBV DNA level, HBeAg status, alanine transaminase level, fibrosis) as a result of antiviral therapy vs. no effects on intermediate outcome
|Outcomes||KQs 1, 5, 7:
KQ 2: Labeling, anxiety, and stigma
KQ 3: Yield (number of new diagnoses per number of persons screened) and sensitivity (number of diagnoses of HBV infection per number of total HBV diagnoses)
|KQ 4: Drug resistance; development of mutations or antibodies to drugs|
|Setting||All KQs: Primary care and primary care–referable settings (e.g., correctional settings, community care settings serving persons who inject drugs, men who have sex with men, or persons with sexually transmitted diseases)
KQs 1–3: United States and countries with similar HBV prevalence
KQs 4–7: All countries
|Study Designs||KQs 1–3: Randomized, controlled trials; cohort studies; and case-control studies; cross-sectional studies (KQ 3 only)
KQs 4–6: Randomized, placebo-controlled trials; head-to-head trials of preferred vs. nonpreferred antiviral therapies approved by the FDA
KQ 5: Cohort studies for long-term (>5 years) clinical outcomes that report adjusted risk estimates
KQ 6: All of the above study designs, plus cohort studies of harms not adequately evaluated in randomized trialsKQ 7: Cohort studies examining the association between intermediate and clinical outcomes after antiviral treatment that report adjusted risk estimates
|KQs 1–3: Uncontrolled studies (e.g., case studies, treatment series)|
Abbreviations: anti-HBe = antibody to the hepatitis B e-antigen; anti-HBs = hepatitis B surface antibody; DNA = deoxyribonucleic acid; FDA = U.S. Food and Drug Administration; HBeAg = hepatitis B e-antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; KQ = key question.
Response to Public Comment
The draft Research Plan was posted for comment on the USPSTF Web site from November 29, 2018 through January 2, 2019. After reviewing public comments, the USPSTF revised the Research Plan as follows: clarified the meaning of the “staging” step for HBV infection, removed the “low-risk” and “high-risk” stratification, removed “testing” and clarified the meaning of screening, and added a separate group for persons with a positive isolated anti-HBc test result. In addition, the USPSTF added injection drug use status and nonalcoholic steatohepatitis as subgroup characteristics of interest, added extrahepatic manifestations to health outcomes, removed harms of liver biopsies, and expanded the study design criteria to include cohort studies of treatment versus no treatment for long-term clinical outcomes.
Internet Citation: Final Research Plan: Hepatitis B Virus Infection in Nonpregnant Adolescents and Adults: Screening. U.S. Preventive Services Task Force. March 2019.