Screening for Hepatitis B Virus Infection in Adolescents and Adults: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation

In 2008, an estimated 704000 persons in the United States were chronically infected with hepatitis B virus (HBV) (1). Potential long-term sequelae of chronic HBV infection include cirrhosis, hepatic decompensation, and hepatocellular carcinoma (2). In 2010, deaths associated with HBV infection were estimated at 0.5 per 100000 persons (3). In the United States, persons born in countries with a prevalence of HBV infection of 2% or greater account for 47% to 95% of chronically infected persons (47). Persons at high risk for HBV infection include household contacts or sexual partners of persons with HBV infection, men who have sex with men, injection drug users, and HIV-positive persons. The number of reported acute cases of HBV infection in the United States decreased from more than 20000 annually in the mid-1980s to 2890 in 2011 (the actual number of new cases is estimated at 6.5 times the number of reported cases) (3). Globally, incidence of HBV infection has markedly decreased, particularly among younger persons, after the implementation of universal vaccination programs (1, 8). Screening for HBV infection could identify chronically infected persons who might benefit from antiviral therapies, surveillance to diagnose hepatocellular carcinoma, or interventions to reduce behaviors associated with progression of liver disease (for example, alcohol use) or transmission and to identify persons without HBV immunity who could benefit from vaccination (9). However, in 2004, the U.S. Preventive Services Task Force (USPSTF) recommended against screening asymptomatic persons for HBV infection (D recommendation) on the basis of a lack of evidence that screening improves clinical outcomes and the low prevalence of HBV infection in the general population (10). Other groups recommend screening high-risk persons (7, 9). The purpose of this report is to review the current evidence on screening for HBV infection in asymptomatic adolescents and adults, excluding pregnant women. This report differs from the previous USPSTF review (11) by including additional key questions on the benefits and harms of antiviral treatment and the association between improvements in intermediate outcomes after antiviral therapy and subsequent clinical outcomes. Methods Scope of the Review We developed a review protocol and analytic framework (Appendix Figure 1) that included the following key questions. Appendix Figure 1. Analytic framework. HBeAg = hepatitis B e antigen; HBV = hepatitis B virus; KQ = key question. * The full report (12) addresses this KQ. 1. What are the benefits of screening for HBV infection versus no screening in asymptomatic adolescents and adults on morbidity, mortality, and disease transmission? 2. What are the harms of screening for HBV infection? 3. How well do different screening strategies identify persons with HBV infection? 4. In persons without evidence of HBV immunity, how effective is HBV vaccination at improving clinical outcomes? 5. How effective is antiviral treatment at improving intermediate outcomes? 6. How effective is antiviral treatment at improving health outcomes? 7. What are the harms associated with antiviral treatment for HBV infection? 8. Are improvements in intermediate outcomes after antiviral therapy associated with improvements in health outcomes? The full report (12) contains detailed methods and data, including search strategies, inclusion criteria, abstraction and quality rating tables, an additional key question on the effects of behavior change counseling and education, and results related to biochemical and composite intermediate outcomes. The protocol was developed by using a standardized process with input from experts and the public. The analytic framework focuses on direct evidence that screening for HBV infection improves important health outcomes versus not screening and the chain of indirect evidence linking screening to improved health outcomes. Links in the chain of indirect evidence include the yield and performance of testing strategies for identifying persons with HBV infection and benefits and harms from subsequent treatments. We did not re-review the accuracy of HBV serologic testing, which the USPSTF previously determined to be accurate (sensitivity and specificity >98%) (13). We also did not evaluate prenatal screening, which the USPSTF is not currently addressing. Data Sources and Searches A research librarian searched MEDLINE (1946 through January 2014), the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and PsycINFO. We supplemented electronic searches by reviewing reference lists of retrieved articles. Study Selection At least 2 reviewers independently evaluated each study to determine inclusion eligibility. For screening, we included randomized trials and observational studies that compared different screening strategies in asymptomatic adults without known abnormal liver enzyme levels. We also reported clinical outcomes or the sensitivity and number needed to screen (NNS) to identify 1 HBV-infected person or provided the data to calculate these variables. For treatment, we included placebo-controlled trials of vaccination of adolescents and adults without known immunity to HBV and relevant systematic reviews. For antiviral therapy, we included trials of monotherapy with a medication approved by the U.S. Food and Drug Administration versus placebo or no treatment or first-line antiviral therapies (entecavir, tenofovir, or pegylated interferon-2a) (9) versus other approved therapies (adefovir, nonpegylated interferon, lamivudine, or telbivudine) that reported clinical outcomes (mortality, cirrhosis, hepatic decompensation, hepatocellular carcinoma, need for transplantation, or disease transmission), intermediate outcomes (histologic, virologic, or serologic), or harms (withdrawals due to adverse events, serious adverse events, or overall adverse events). We included trials of interferon-2a (not approved for HBV infection) that reported clinical outcomes because evidence for interferon-2b and pegylated interferon was limited. For the association between achieving an intermediate outcome after antiviral treatment and subsequent clinical outcomes, we included cohort studies that reported adjusted risk estimates. We included only English-language articles and excluded studies published only as abstracts. We excluded trials of persons who did not respond to prior antiviral therapy or those who had virologic relapse and did not evaluate drug resistance as an outcome. We excluded studies of patients co-infected with HIV or hepatitis C virus, transplant recipients, and patients receiving hemodialysis. We excluded systematic reviews of antiviral therapies unless we were unable to abstract the primary studies because they were in a foreign language. Appendix Figure 2 shows the summary of evidence search and selection. Appendix Figure 2. Summary of evidence search and selection. * Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews. Reference lists of relevant articles. Some studies are included for >1 key question. The full report (12) addresses this key question. Data Abstraction and Quality Rating One investigator abstracted details about the study design, patient population, setting, screening method, interventions, analysis, follow-up, and results. A second investigator reviewed data for accuracy. Two investigators independently applied criteria developed by the USPSTF (14, 15) to rate the quality of each study as good, fair, or poor. Discrepancies were resolved through consensus. Data Synthesis and Analysis We assessed the aggregate internal validity (quality) of the body of evidence for each key question (good, fair, or poor) on the basis of the number, quality, and size of studies; consistency of results; and directness of evidence (14, 15). For antiviral therapy and vaccination, we conducted meta-analyses to calculate relative risks using the DerSimonianLaird random-effects model (Review Manager, version 5.2, Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark). Primary analyses for antiviral therapy were based on total follow-up (including events after discontinuation of treatment), although we conducted sensitivity analyses of events during antiviral therapy. For harms, we analyzed events that occurred during antiviral therapy. For all analyses, we stratified results by antiviral drug. Statistical heterogeneity was assessed by using the I 2 statistic (16). We did additional analyses in which trials were stratified by study quality, duration of follow-up (shorter or longer than 1 year), hepatitis B e antigen (HBeAg) status, and inclusion of patients with cirrhosis. Role of the Funding Source This research was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the USPSTF. Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions. The AHRQ had no role in study selection, quality assessment, or synthesis. Staff from the AHRQ provided project oversight; reviewed the report to ensure that the analysis met methodological standards; and distributed the draft for peer review, including to representatives of professional societies and federal agencies. The investigators are solely responsible for the content and the decision to submit the manuscript for publication. Results No study compared clinical outcomes or harms in persons screened for HBV infection versus those not screened (the first 2 key questions). Yield of Risk-Based Screening Methods One fair-quality cross-sectional study (n= 6194) done in a French clinic for sexually transmitted infections found that targeted screening of persons born in countries with a prevalence of chronic HBV infection of 2% or greater, men, and unemployed persons identified 98% (48 of 49) of infections while testing approximately two