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Draft Research Plan

Draft Research Plan for Hepatitis B Virus Infection: Screening in Nonpregnant Adolescents and Adults

This opportunity for public comment expired on January 2, 2019 at 8:00 PM EST

Note: This is a Draft Research Plan. This draft is distributed solely for the purpose of receiving public input. It has not been disseminated otherwise by the USPSTF. 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.

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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In an effort to maintain a high level of transparency in our methods, we open our draft Research Plans to a public comment period before we publish the final version.

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Draft: Proposed Analytic Framework

The analytic framework depicts the relationship between the populations, interventions, outcomes, and harms of screening for hepatitis B virus (HBV) infection. The far left of the framework describes the target population as asymptomatic, nonpregnant adolescents and adults. An overarching arrow that extends from the target population to the clinical health outcomes symbolizes the direct benefits of screening on clinical health outcomes (Key Question 1). To the right of the population is an arrow that represents HBV screening, including the harms of screening (Key Question 2) and the yield and sensitivity of alternative HBV screening strategies (Key Question 3. An arrow to the right of the high-risk population represents testing that further separates this population into persons with chronic HBV infection, evidence of HBV immunity, or no evidence of HBV immunity. To the right of the population with no evidence of immunity, an arrow depicts HBV vaccination. To the right of vaccination, an arrow leads to clinical health outcomes. To the right of the population with chronic HBV infection, an arrow leads to the process of staging chronic HBV infection. To the right of staged HBV infection, two arrows depict outcomes for different interventions: the first arrow leads to provision of education or behavior change counseling and the second 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 hepatitis B e-antigen, acquisition of antibody to hepatitis B e-antigen, clearance of hepatitis B surface antigen, and acquisition of antibody to hepatitis B surface antigen (Key Question 4). A second arrow leads to clinical health outcomes, including mortality, cirrhosis, 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 for HBV infection (Key Question 6). A dotted line represents the examination of the association between improvements in intermediate outcomes as a result of antiviral treatment for chronic HBV infection and reduction in risk of HBV-related adverse health outcomes (Key Question 7).

Abbreviations: anti-HBe = antibody to hepatitis B e-antigen; anti-HBs = hepatitis B surface antibody; HBeAg = hepatitis B e-antigen; HBsAg = hepatitis B surface antigen; KQ=key question.

Draft: Proposed Key Questions to Be Systematically Reviewed

  1. What are the benefits of screening for hepatitis B virus (HBV) infection in asymptomatic, nonpregnant adolescents and adults on morbidity, mortality, and disease transmission?
  2. What are the harms of screening for HBV infection (e.g., labeling, anxiety, and harms of confirmatory tests, including biopsy)?
  3. 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)?
  4. How effective is antiviral treatment at improving intermediate outcomes in 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 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])?*
  5. How effective is antiviral treatment at improving health outcomes in nonpregnant adolescents and adults with chronic HBV infection?*
  6. What are the harms associated with antiviral treatment of chronic HBV infection in nonpregnant adolescents and adults?*
  7. 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, HBV genotype, HBeAg status, fibrosis stage, alanine transaminase level, and HBV deoxyribonucleic acid (DNA) level.

Draft: Proposed Contextual Questions

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

  1. What are the effects of different risk- or prevalence-based methods for screening for HBV infection in modeling studies?
  2. What is the accuracy of tools for identifying persons with chronic HBV infection?
  3. In persons with serologic evidence of HBV infection (positive for antibody to hepatitis B core antigen or positive 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?

Draft: Proposed Research Approach

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).

  Included Excluded
Definition of Disease Chronic HBV infection, defined as detectable HBsAg in blood serum for >6 months Acute HBV infection
Populations KQs 1–3: Nonpregnant adults (age ≥18 years) and adolescents (ages 13 to <18 years) with no signs or symptoms of HBV infection

KQs 4–7: Nonpregnant adults and adolescents 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:

  • Preferred: Pegylated interferon (adults), nonpegylated interferon (children ages 13 to 17 years), entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide
  • Nonpreferred: Lamivudine, adefovir, and telbivudine
 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 therapies

KQ 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:
  • Mortality
  • Cirrhosis
  • Hepatocellular cancer
  • Quality of life
  • Disease transmission

KQ 2:

  • Labeling, anxiety, and stigma
  • Harms from liver biopsy

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:

  • Virologic improvement
  • Histologic improvement
  • HBeAg clearance (loss of HBeAg or acquisition of anti-HBe)
  • HBsAg clearance (loss of HBsAg or acquisition of anti-HBs)

KQ 6:

  • Harms of antiviral medications
  • Withdrawals due to adverse events
  • Serious adverse events
 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; will also include cross-sectional studies for KQ 3

KQs 4–6:

  • Randomized, placebo-controlled trials
  • Head-to-head trials of preferred vs. nonpreferred antiviral therapies approved by the FDA

KQ 6: All of the above study designs, plus cohort studies of harms

KQ 7: Cohort studies examining the association between intermediate and clinical outcomes after antiviral treatment		 KQs 1–3: Uncontrolled studies (e.g., case studies, treatment series)

Abbreviations: anti-HBe = antibody to 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.

Current as of: November 2018

Internet Citation: Draft Research Plan: Hepatitis B Virus Infection: Screening in Nonpregnant Adolescents and Adults. U.S. Preventive Services Task Force. November 2018.
https://www.uspreventiveservicestaskforce.org/Page/Document/draft-research-plan/hepatitis-b-virus-infection-screening-nonpregnant

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