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Evidence Summary

Other Supporting Document for Hepatitis B Virus Infection: Screening, 2014

Preface

A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation

Release Date: May 27, 2014


By Roger Chou, MD; Tracy Dana, MLS; Christina Bougatsos, MPH; Ian Blazina, MPH; Jessi Khangura, MD; and Bernadette Zakher, MBBS


The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.

This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

This article was first published in Annals of Internal Medicine on May 27, 2014. Select for copyright and source information.

Abstract

Background: In 2004, the U.S. Preventive Services Task Force (USPSTF) recommended against screening for hepatitis B virus (HBV) infection.

Purpose: To update the 2004 USPSTF review on screening for HBV infection in adolescents and adults.

Data Sources: MEDLINE (through January 2014), the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and PsycINFO.

Study Selection: Randomized trials of screening and treatment and observational studies of screening or the association between intermediate and clinical outcomes after antiviral therapy.

Data Extraction: One investigator abstracted data, and a second investigator checked them; 2 investigators independently assessed study quality.

Data Synthesis: No study directly evaluated the effects of screening for HBV infection versus no screening on clinical outcomes. Vaccination against HBV infection was associated with decreased risk in high-risk populations. On the basis of 11 primarily fair-quality trials, antiviral therapy may be more effective than placebo for reducing the risk for clinical outcomes associated with HBV infection. However, differences were not statistically significant. On the basis of 22 primarily fair-quality trials, antiviral therapy was more effective than placebo for various intermediate outcomes, with limited evidence that first-line antiviral agents are superior to lamivudine. Antiviral therapy was associated with a higher risk for withdrawal due to adverse events than placebo, but risk for serious adverse events did not differ.

Limitations: Only English-language articles were included, clinical outcome data for antiviral therapies were limited, and several studies were done in countries where the prevalence and natural history of HBV infection differ from those of the United States.

Conclusion: Antiviral treatment for chronic HBV infection is associated with improved intermediate outcomes, but more research is needed to understand the effects of screening and subsequent interventions on clinical outcomes and to identify optimal screening strategies.

Primary Funding Source: Agency for Healthcare Research and Quality.

Introduction

In 2008, an estimated 704,000 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 100,000 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 4–7. 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 20,000 annually in the mid-1980s to 2,890 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 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 review11 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.

  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 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-α2a) 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-α2a (not approved for HBV infection) that reported clinical outcomes because evidence for interferon-α2b 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.

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 DerSimonian–Laird 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 I2 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

Scope of the Review

We developed a review protocol and analytic framework (Appendix Figure 1) that included the following key questions.

  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 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-α2a) 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-α2a (not approved for HBV infection) that reported clinical outcomes because evidence for interferon-α2b 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.

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 DerSimonian–Laird 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 I2 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.

Discussion

Appendix Table 4 summarizes the evidence reviewed in this update. As in the 2004 review 11, we found no direct evidence on effects of screening for HBV infection versus no screening on clinical outcomes. The USPSTF previously determined that standard serologic markers are accurate for diagnosing HBV infection 13.

Evidence on the usefulness of different screening strategies for identifying persons with HBV infection was limited to a single fair-quality, cross-sectional study. It identified a relatively efficient screening strategy based on country of origin, sex, and employment status but was done in a French clinic for sexually transmitted infections and had limited applicability to primary care settings in the United States 17.

Randomized trials suggest that antiviral therapy may be more effective than placebo for reducing the risk for clinical outcomes associated with HBV infection, such as cirrhosis, hepatocellular carcinoma, and mortality. However, results were based on only a few underpowered trials and differences were not statistically significant. The duration of follow-up and the patient populations (for example, those with or without cirrhosis and HBeAg) varied among trials, and few trials evaluated recommended first-line antiviral agents (entecavir, tenofovir, and pegylated interferon). The pooled estimate for hepatocellular carcinoma nearly reached statistical significance; however, it was heavily influenced by results from 1 Asian trial that primarily enrolled patients with more advanced liver disease, potentially reducing applicability to screen-detected U.S. populations 43.

Our findings are similar to those of a recent systematic review that focused on results from randomized trials 69. Although other reviews found an association between use of antiviral therapy and improved clinical outcomes, results were primarily based on observational studies, including those that did not adjust well for confounders 70–75.

Evidence is stronger for beneficial effects of antiviral therapy versus placebo on intermediate histologic, serologic, and virologic outcomes. Results were generally consistent across individual drugs, although some estimates were imprecise and not statistically significant. Like other recent systematic reviews, we found limited evidence that the currently recommended first-line drugs tenofovir and entecavir are more effective than lamivudine at achieving some intermediate outcomes 69, 76–79.

The degree to which improvements in intermediate outcomes after antiviral therapy are associated with improved clinical outcomes is less clear. Although observational studies generally found an association between an improved intermediate outcome after antiviral therapy and reduced risk for clinical outcomes, results were not statistically significant in some studies; the populations and intermediate and clinical outcomes evaluated varied; and studies had important methodological limitations, including failure to adequately address confounders.

Antiviral therapy was associated with greater risk for withdrawal due to adverse events versus placebo but not with increased risk for serious adverse events. Head-to-head trials found that pegylated interferon-α2a was associated with increased risk for adverse events compared with lamivudine 54, 55, consistent with the high prevalence of adverse events with interferon-based therapies 80. In general, adverse events associated with antiviral therapy, including interferon, were self-limited and resolved after drug discontinuation.

Evidence on effects of other interventions was limited. Trials of health care workers and men who have sex with men found that vaccination was associated with decreased risk for HBV infection on the basis of serologic and biochemical markers but did not evaluate long-term clinical outcomes. Observational studies in countries with a high prevalence of infection indicate that implementation of universal vaccination is associated with declining incidence of HBV infection and reduced rates of hepatocellular carcinoma and other adverse clinical outcomes but were outside the scope of this review 8, 81, 82. As detailed in our full report, we identified no trials on the effectiveness of education or behavior change counseling in HBV-infected patients for reducing transmission or improving health outcomes 12. We did not review evidence on the effectiveness of surveillance for hepatocellular carcinoma in patients with HBV infection, which is currently limited to 2 trials done in Asia with somewhat mixed results 83, 84.

Our review has limitations. We excluded non-English-language articles and did not search for studies published only as abstracts. We could not formally assess publication bias because of the small number of studies. Evidence on effectiveness of current first-line antiviral therapies was limited, particularly for clinical outcomes. We included studies done in countries where the prevalence, characteristics, and natural history of HBV infection differ from those of the United States, potentially limiting applicability to screening in the United States.

Additional research may clarify the benefits and harms of screening for HBV infection. Studies that compare clinical outcomes in persons screened and not screened for HBV infection would require large samples and long follow-up. In lieu of such direct evidence, prospective studies on the accuracy and yield of alternative screening strategies (such as those targeting immigrants from countries with a high prevalence of HBV infection) 85 could help identify optimal screening strategies.

More research is needed on long-term clinical outcomes associated with current first-line antiviral therapies. In particular, entecavir and tenofovir have potent antiviral activity, seem to have low rates of drug resistance, and are better tolerated than pegylated interferon 86. Studies on the association between use of antiviral therapy and risk for transmission would be useful for identifying additional public health benefits from screening 87. Improved standardization of the intermediate and clinical outcomes evaluated would greatly strengthen evidence from observational studies on the association between achieving intermediate outcomes and clinical outcomes, and these studies should be designed to account for important confounders 88.

In conclusion, screening can identify persons with chronic HBV infection, and antiviral treatment is associated with improved intermediate outcomes. However, research is needed to better define the effects of screening and subsequent interventions on clinical outcomes and to identify optimal screening strategies. The declining incidence and prevalence of HBV infection as a result of universal vaccination will probably affect future assessments of screening.

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Copyright and Source Information

Source: This article was first published in Annals of Internal Medicine on May 27, 2014.

Disclaimer: The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by AHRQ or the U.S. Department of Health and Human Services.

Acknowledgment: The authors thank Iris Mabry-Hernandez, MD, MPH, and USPSTF leads Kirsten Bibbins-Domingo, MD, PhD; Mark Ebell, MD, MS; Douglas K. Owens, MD, MS; and Albert L. Siu, MD, MSPH.

Financial Support: By contract HHSA-290-2007-10057-I-EPC3, task order 13, from AHRQ.

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-2837.

Requests for Single Reprints: Roger Chou, MD, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239-3098; e-mail, chour@ohsu.edu.

Current author addresses and author contributions are available at www.annals.org.

Table. Characteristics of Studies of Antiviral Therapy

Study, Year Reference Design Duration Country/Region Sample Size, n Age,
y*
Men, % HBeAg Status
at Baseline
Patients With Cirrhosis
at Baseline, %
Outcomes Reported Quality
Adefovir vs. placebo
Hadziyannis et al, 2003 22 RCT 48 wk Canada, Greece, Israel, France, Italy, Australia, Taiwan, Singapore 185 46 83 Negative 11 Biochemical and virologic response, histologic improvement Fair
Jonas et al, 2008 23 RCT 48 wk Germany, Poland, Spain, United Kingdom, United States 83 14 75 Positive NR Biochemical response, composite outcomes, mortality Fair
Marcellin et al, 2003 24 RCT 48 wk Australia, Canada, France, Germany, Italy, Malaysia, the Philippines, Singapore, Spain, Taiwan, Thailand, United Kingdom, United States 515 35 74 Positive NR Biochemical response, HBeAg loss/seroconversion, histologic improvement Fair
Zeng et al, 2006 25 RCT 12 wk China 480 32 83 Positive NR Biochemical response, HBeAg loss/seroconversion, virologic response, mortality Fair
Interferon-α2b vs. no treatment
Bayraktar et al, 1993 26 Controlled trial 6 mo Turkey 35 36 71 Positive 29 Biochemical response, HBeAg and HBsAg loss/seroconversion Poor
Hadziyannis et al, 1990 27 RCT 14–16 wk of treatment plus 2 y of follow-up Greece 50 49 94 Negative 44 Composite outcomes Poor
Lampertico et al, 1997 28 Open-label RCT 3 y Italy 42 46 86 Negative 17 Composite outcomes, HBsAg loss/seroconversion, histologic improvement, hepatocellular carcinoma Fair
Müller et al, 1990 29 RCT 10 mo Germany 58 NR§ 79 Positive 5 Composite outcomes Fair
Perez et al, 1990 30 RCT 24 wk (control phase) Argentina 35 39 77 Positive 14 Biochemical and virologic response, HBeAg and HBsAg loss/seroconversion Fair
Perrillo et al, 1990 31 RCT 10 mo United States 169 40 85 Positive NR HBsAg loss/seroconversion, composite outcomes, mortality Good
Sarin et al, 1996 32 RCT 16 mo India 41 35 94 Positive 44 HBeAg and HBsAg loss/seroconversion, virologic response, composite outcomes Fair
Waked et al, 1990 33 RCT 16 mo Egypt 40 36 78 Positive 40 HBeAg and HBsAg loss/seroconversion, histologic
improvement, mortality, incident cirrhosis
Fair
Interferon-α2a vs. placebo
Lin et al, 1999 34;
methods: Liaw et al, 1994 35
RCT 18 wk plus mean of 7 y of follow-up Taiwan 101 32 100 Positive 12 Incident cirrhosis, hepatocellular carcinoma, mortality Fair
Mazella et al, 1999 36 RCT 6 mo plus 7 y of follow-up Italy 64 38 78 Positive NA|| Incident cirrhosis, hepatocellular carcinoma, mortality Fair
Lamivudine vs. placebo
Ali, 2003 37 RCT 12 mo Iraq 74 NR NR Negative NR HBsAg loss/seroconversion Poor
Bozkaya et al, 2005 38 Controlled trial 12 mo (control phase) Turkey 55 36 60 Negative NR Biochemical response Poor
Chan et al, 2007 39 RCT 30 mo China 139 39 84 Negative 27 Biochemical and virologic response, HBsAg loss/seroconversion, histologic improvement, hepatocellular carcinoma, mortality Fair
Dienstag et al, 1999 40 RCT 16 mo United States 137 Median, 39 83 Positive 10 Biochemical and virologic response, HBeAg and HBsAg loss/seroconversion, histologic improvement, mortality Fair
Lai et al, 1997 41 RCT 8 wk Hong Kong 42 32 64 Positive NR HBeAg loss/seroconversion Fair
Lai et al, 1998 42 RCT 1 y Hong Kong, Taiwan, Singapore 358 Median, 31 73 Positive 5 Biochemical response, histologic improvement, mortality Fair
Liaw et al, 2004 43 RCT Median, 2.7 y Australia, Hong Kong, New Zealand, Singapore, Taiwan, Thailand 651 Median, 43 85 Positive 33 Disease severity**, hepatocellular carcinoma, mortality Fair
Tassopoulos et al, 1999 44 RCT 24 wk Greece 125 Median, 43 80 Negative 15 HBsAg loss/seroconversion, composite outcomes Fair
Yalçin et al, 2004 45 RCT 1 y Turkey 46 24 44 Positive NR HBeAg and HBsAg loss/seroconversion, virologic response, composite outcomes Fair
Yao et al, 1999 46 RCT 12 wk China 429 32 73 Positive NR Biochemical and virologic response, HBeAg loss/seroconversion Fair
Tenofovir vs. placebo
Murray et al, 2012 47 RCT 72 wk United States, Bulgaria, France, Poland, Romania, Spain, Turkey 106 15 73 Positive NR Biochemical and virologic response, HBeAg and HBsAg loss/seroconversion, composite outcomes Good
Entecavir vs. lamivudine
Chang et al, 2006 48; Gish et al, 2007 49; Chang et al, 2009 50 RCT 96 wk North America, Asia, Australia, South America 709 35 75 Positive 2 Biochemical and virologic response, HBeAg and HBsAg loss/seroconversion, histologic improvement, hepatocellular carcinoma, mortality Good
Lai et al, 2002 51 RCT 24 wk Australia, Belgium, Canada, France, Germany, Hong Kong, Israel, Italy, Malaysia, the Netherlands, the Philippines, Poland, Russia, Singapore, Thailand 87‡‡ 30 75 Positive NR Biochemical and virologic response, HBeAg loss/seroconversion, composite outcomes Fair
Lai et al, 2006 52 RCT 52 wk Europe, Middle East, Asia, Australia, North America, South America 638 44 76 Negative 2 Biochemical and virologic response, histologic improvement, hepatocellular carcinoma, mortality Good
Ren et al, 2007 53 RCT 48 wk China 42†† 32 55 Positive NR Biochemical and virologic response, HBeAg loss/seroconversion, hepatocellular carcinoma, mortality Fair
Pegylated interferon-α2a vs. lamivudine
Lau et al, 2005 54 RCT 72 wk Asia, Australasia, Europe, North America, South America 543†† 32 79 Positive 18 Biochemical and virologic response, HBeAg and HBsAg loss/seroconversion, histologic improvement, composite outcomes, hepatocellular carcinoma, mortality Good
Marcellin et al, 2004 55 RCT 72 wk Asia, Europe 358†† 40 86 Negative 30 Biochemical and virologic response, HBsAg loss/seroconversion, histologic improvement, composite outcomes, hepatocellular carcinoma, mortality Good
Tenofovir vs. adefovir
Marcellin et al, 2008 56 (study 102) RCT 48 wk Europe, North America, Australia, New Zealand 375 44 77 Negative 20 Biochemical and virologic response, HBsAg loss/seroconversion, histologic improvement, composite outcomes, mortality Fair
Marcellin et al, 2008 56 (study 102) RCT 48 wk Europe, North America, Australia, New Zealand 266 34 69 Posiitve 20 Biochemical and virologic response, HBeAg and HBsAg loss/seroconversion, histologic improvement, composite outcomes, mortality Fair

HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; NA = not applicable; NR = not reported; RCT = randomized, controlled trial.
* Mean age unless otherwise indicated.
Definition of histologic improvement varied but most commonly was a reduction of ≥2 points in Histology Activity Index scores. The full report 12 addresses results for biochemical and composite outcomes.
The U.S. sample was 69% Asian.
§ Range, 18 to 65 y.
|| Excluded persons with cirrhosis.
24% had fibrosis.
** Based on Child–Pugh score, separately and in combination with spontaneous bacterial peritonitis with sepsis, renal insufficiency, bleeding gastric or esophageal varices, development of hepatocellular carcinoma, or death related to liver disease.
†† Subset of a larger study group.

Figure 1. Antiviral therapy vs. placebo or no treatment for histologic improvement.

Go to text description below.

M–H = Mantel–Haenszel.

Text Description.

Figure 1 is a forest plot diagram of a meta-analysis of the effect of antiviral treatments on histologic improvement compared to placebo. There are 3 subanalyses according to drug. There are 2 studies comparing adefovir and placebo, with a pooled relative risk of 2.02 and 95% CI of 1.59 to 2.56; heterogeneity was 0%. There are 2 studies comparing interferon alfa 2b and placebo, with a pooled relative risk of 3.65 and a 95% CI of 1.11 to 12.06; heterogeneity was 0%. There are 3 studies comparing lamuvidine and placebo, with a pooled relative risk of 2.32 and 95% CI of 1.70 to 3.17; heterogeneity was 0%. The figure shows that pooling results across drugs from the 7 individual studies results in a relative risk of 2.15 and 95% CI of 1.79 to 2.59; heterogeneity was 0%.

Figure 2. Antiviral therapy vs. placebo or no treatment for HBeAg loss.

Go to text description below.

HBeAg = hepatitis B e antigen; M–H = Mantel–Haenszel.
* Adefovir, 30 mg, vs. placebo.
† 68-wk data.

Text Description.

Figure 2 is a forest plot diagram of a meta-analysis of the effect of antiviral treatments on HBeAg loss compared to placebo. There are 4 subanalyses according to drug. There are 2 studies comparing adefovir and placebo, with a pooled relative risk of 1.83 and 95% confidence interval (CI) of 0.84 to 3.99; heterogeneity was 58%. There are 4 studies comparing interferon alfa 2b and placebo, with a pooled relative risk of 3.62 and a 95% CI of 1.89 to 6.94; heterogeneity was 5%. There are 4 studies comparing lamivudine and placebo, with a pooled relative risk of 1.76 and 95% CI of 1.04 to 3.00; heterogeneity was 0%. There is 1 study comparing tenofovir and placebo, with a relative risk of 1.43 and 95% CI of 0.59 to 3.44. The figure shows that pooling results across drugs from the 11 individual studies results in a relative risk of 2.13 and a 95% CI of 1.59 to 2.85; heterogeneity was 4%.

Figure 3. Antiviral therapy vs. placebo or no treatment for HBV DNA loss.

Go to text description below.

HBV = hepatitis B virus; M–H = Mantel–Haenszel.

Text Description.

Figure 3 is a forest plot diagram of a meta-analysis of the effect of antiviral treatments on HBV DNA loss compared to placebo. There are 4 subanalyses according to drug. There are 2 studies comparing adefovir and placebo, with a pooled relative risk of 28.55 and 95% CI of 3.99 to 204.39; heterogeneity was 0%. There are 2 studies comparing interferon alfa 2b and placebo, with a pooled relative risk of 7.49 and a 95% CI of 1.42 to 39.54; heterogeneity was 0%. There are 4 studies comparing lamuvidine and placebo, with a pooled relative risk of 4.36 and 95% CI of 2.22 to 8.58; heterogeneity was 46%. There is one study comparing tenofovir and placebo, with a relative risk of 96.51 and 95% CI of 6.10 to 1526.38. The figure shows that pooling results across drugs from the 9 individual studies results in a relative risk of 7.22 and 95% CI of 3.20 to 16.31; heterogeneity was 58%.

Figure 4. Antiviral therapy vs. placebo or no treatment for HBsAg loss.

Go to text description below.

HBsAg = hepatitis B surface antigen; M–H = Mantel–Haenszel.

Text Description.

Figure 4 is a forest plot diagram of a meta-analysis of the effect of antiviral treatments on hepatitis B surface antigen (HBsAg) loss compared to placebo. There are 3 subanalyses according to drug. There are 6 studies comparing interferon alfa 2b and placebo, with a pooled relative risk of 2.66 and 95% CI of 1.11 to 6.39; heterogeneity was 0%. There are 5 studies comparing lamivudine and placebo. One study is shown as having no incidence of HBsAg loss in either lamivudine or placebo groups. As a result, evidence from 4 studies was included in the pooled analysis, with a pooled relative risk of 1.72 and a 95% CI of 0.42 to 7.06; heterogeneity was 0%. There is one study comparing tenofovir and placebo, with a relative risk of 3.11 and 95% CI of 0.13 to 74.74. The figure shows that pooling results from the 11 individual studies results in a relative risk of 2.39 and a 95% CI of 1.16 to 4.94; heterogeneity was 0%.

Figure 5. Antiviral therapy vs. placebo or no treatment for hepatocellular carcinoma.

Go to text description below.

M–H = Mantel–Haenszel.

Text Description.

Figure 5 is a forest plot diagram of a meta-analysis of the effect of antiviral treatments on incidence of hepatocellular cancer compared to placebo. There are 3 subanalyses according to drug. There are 2 studies comparing interferon alfa 2a and placebo, with a pooled relative risk of 0.37 and a 95% CI of 0.05 to 2.64; heterogeneity was 47%. There is 1 study comparing interferon alfa 2b and placebo, with a relative risk of 3.00 and a 95% CI of 0.13 to 69.70. There are 2 studies comparing lamivudine and placebo, with a pooled relative risk of 0.57 and a 95% CI of 0.30 to 1.08; heterogeneity was 2%. The figure shows that pooling results across drugs from the 5 individual studies results in a relative risk of 0.57 and a 95% CI of 0.32 to 1.04; heterogeneity was 2%.

Appendix Table 1. Intermediate Outcomes From Head-to-Head Trials*

Outcome Entecavir vs. Lamivudine Pegylated interferon-α2a vs. Lamivudine Tenofovir vs. Adefovir
RR (95% CI) I2, % Trials, n Reference RR (95% CI) I2, % Trials, n Reference RR (95% CI) I2, % Trials, n Reference
HBeAg loss/seroconversion 1.2 (0.9–1.5) 0 3 48, 51, 53 1.6 (1.2–2.1) 1 54 1.2 (0.7–2.1) 1 56
HBsAg loss/seroconversion 1.8 (0.9–3.9) 1 48 16.0 (2.2–121.0) 0 2 54, 55 5.7 (0.3–103.0) 1 56
Virologic improvement 1.6 (1.1–2.5) 94 4 48, 51–53 2.8 (1.9–4.4) 0 2 54, 55 2.9 (0.6–15.0) 97 2 56
Histologic improvement 1.2 (1.1–1.3 0 2 48, 52 1.2 (1.0–1.4) 0 2 54, 55 1.1 (1.0–1.2) 0 2 56

HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; RR = risk ratio.
* Significant RRs are bolded.

Appendix Table 2. Studies of the Association Between Intermediate and Final Health Outcomes

Study, Year (Reference) Country/
Region
Design Intermediate Outcome Evaluated; Patients With Intermediate Outcome, % Treatment; Duration of Follow-up Characteristics of HBV Infection Mean Age,
y
Sex, % Race, % Receiving Antiviral Treatment, n Lost to Follow-up,
n (%)
Quality
Andreone et al, 200459 Italy Cohort (unclear whether prospective or retrospective) No virologic breakthrough (HBV DNA became undetectable during receipt of treatment and remained undetectable); 41 Lamivudine; median, 42 mo HBeAg-positive: None
Mean ALT level: 192 U/L
Mean HBV DNA level: 16 pg/mL
Cirrhosis: 100%
53 Male: 82 NR 22 Unclear Fair
Baltayiannis et al, 200660 Greece Cohort (unclear whether prospective or retrospective) Virologic response (HBV DNA <10,000 copies/mL at 6 mo of treatment); 35 Interferon-α; 6 y HBeAg-positive: None
Median ALT level: 177 U/L
Median HBV DNA level: 1.2 X 106 copies/mL
Cirrhosis: excluded
51 Male: 63 NR NR 63 1 (1.6) Fair
Di Marco et al, 200461 Italy Retrospective cohort No virologic breakthrough (HBV DNA level <1 X 105 copies/mL throughout follow-up after achieving undetectability); 39 Lamivudine; 4 y HBeAg-positive: excluded
ALT level >2 times ULN: 65%
HBV DNA level: NR
Cirrhosis on histologic evaluation: 25%
49 Male: 83 NR 656 NR* Fair
Fattovich et al, 199762 Italy Cohort (unclear whether prospective or retrospective) Biochemical remission (normalization of ALT levels); 28 Interferon-α; mean, 7 y HBeAg-positive: All
Mean ALT level: 5.3 times ULN
HBV DNA level: NR
Cirrhosis: 100%
47 Male: 85 White: 100 40 NR for treated subgroup Poor
Hui et al, 200863 China (Hong Kong) Cohort (unclear whether
prospective or retrospective)
Histologic response (improvement of ≥2 points on HAI score after end of treatment); 40 Interferon-α2a or 2b; median, 9.9 y HBeAg-positive: all
Mean ALT level: 113 U/L
HBV DNA level >1 X 105 copies/mL: 100%
Cirrhosis: 12%
30 Male: 78 NR 89 NR Poor
Lampertico et al, 200364 Italy Cohort (unclear whether prospective or retrospective) Sustained virologic and biochemical response (normalization of serum ALT levels and clearance of HBV DNA); 30 Interferon-α2b; 68 mo HBeAg-positive: none
Mean ALT level: 204 U/L
Detectable HBV DNA level: 61%
Ishak fibrosis score of 4–6: 60%
46 Female: 13 NR 101 4 (4.0) Fair
Lau et al, 199765 United States Cohort (originally enrolled in RCTs) Response (sustained HBV DNA loss and HBeAg clearance within 1 y of starting treatment); 30 Interferon-α; mean, 6.2 y HBeAg-positive: all
Median ALT level: 154 U/L
HBV DNA level: 4843 mq/mL
Cirrhosis: 17%
41 Male: 83 White: 94; Black: 6 103 8 (7.8) Fair
Niederau et al, 199666 Europe Prospective cohort HBeAg loss after therapy; 51 Interferon-α2b; mean, 50 mo HBeAg-positive: all
HBsAg clearance: 9.7%
ALT level: NR
AST level: NR
HBV DNA level: NR
Fibrosis stage: NR
Cirrhosis: NR (Child–Pugh class B or C excluded)
NR Female: NR NR 103 0 (0.0) Fair
Papatheodoridis et al, 200167 Greece Cohort (unclear whether prospective or retrospective) Sustained biochemical response (normalization of ALT levels at the end of interferon therapy and persistently normal ALT levels throughout the posttreatment follow-up period); 27 Interferon-α; mean,6.0 y HBeAg-positive: excluded
Median ALT level: 112 U/L
Median HBV DNA level: 4.4 pg/mL
Cirrhosis: 27%
47 Male: 83 NR 209 9 (4.3) Poor
Papatheodoridis et al, 201168 Greece Retrospective cohort Virologic remission (HBV DNA level <200 IU/mL throughout therapy); 28 Lamivudine;median, 4.7 y HBeAg-positive: excluded
Median ALT level: 98 U/L
HBV DNA level: 400 IU/mL (median, 1 X 103 IU/mL)
Cirrhosis: 26%
54 Male: 72 NR 818 180 (22) Fair

ALT = alanine aminotransferase; AST = aspartate aminotransferase; HAI = Histology Activity Index; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; NR = not reported; RCT = randomized, controlled trial; ULN = upper limit of normal.
* 40 patients had no virologic response and were excluded from the analysis.
Assumed to be alive and without liver-related complications.

Appendix Table 3. Associations Between Intermediate and Clinical Outcomes

Intermediate Outcome Death Hepatocellular Carcinoma Composite Outcome
Studies, n Reference HR (95% CI) Studies, n Reference HR (95% CI) Studies, n Reference HR (95% CI)
Virologic response 1 61 0.34 (0.15–0.80)* 2 59, 68 0.10 (0.01–0.77)*
0.77 (0.35–1.69)*
1 60 0.24 (0.06–0.96)*
HBeAg loss 0 0 1 66 0.06 (0.01–0.61)
Histologic response 0 0 1 63 0.62 (0.06–6.90)
Composite intermediate outcome 1 65 0.59 (0.20–1.67) 0 2 64, 65 0.07 (0.02–0.33)
0.13 (0.03–0.55)*
Normalization of ALT levels 1 62 0.09 (0.01–0.71) 0 1 67 0.48 (0.23–1.0)*

ALT= alanine aminotransferase; HBeAg= hepatitis B e antigen; HR= hazard ratio.
* Study done in HBeAg-negative patients.

Appendix Table 4. Summary of Evidence

Key Question Studies Identified for Update Limitation Consistency Applicability Summary of Findings Quality
What are the benefits of screening for HBV infection vs. no screening in asymptomatic, nonpregnant adolescents and adults on morbidity, mortality, and disease transmission? None No studies NA NA No evidence No evidence
What are the harms of screening for HBV infection? None No studies NA NA No evidence No evidence
How well do different screening strategies identify persons with HBV infection? 1 cross-sectional study Evidence available only from 1 study with methodological limitations NA Study done in high-risk patients at a clinic for sexually transmitted infections 1 study found that screening targeted at persons born in countries with a higher prevalence of chronic HBV infection, men, and unemployed persons identified 98% (48 of 49) of infections.
Number needed to screen to identify 1 case of HBV infection, 82
Poor
In persons without evidence of HBV immunity, how effective is HBV vaccination for improving clinical outcomes? No studies with evidence on long-term clinical outcomes No evidence on long-term clinical outcomes Moderate Studies done in high-risk populations (health care workers or MSM) and/or children Vaccination is associated with decreased risk for HBV acquisition in health care workers (4 trials; RR, 0.51 [95% CI, 0.35 to 0.73]) and MSM (4 trials; RR, 0.21 [CI, 0.11 to 0.39]) on the basis of serologic markers.
Studies did not evaluate the effectiveness of HBV vaccination on long-term clinical outcomes.
Fair
How effective is antiviral treatment at improving intermediate outcomes? 30 RCTs Study duration and patient characteristics varied widely; few good-quality studies High Approximately half of the studies were done outside of the United States/Europe, and approximately one third enrolled HBeAg-negative patients Antiviral treatment was more effective than placebo or no treatment for HBeAg loss/seroconversion (10 trials; RR, 2.1 [CI, 1.6 to 2.9]; I2 = 4%), HBsAg loss/seroconversion (12 trials; RR, 2.4 [CI, 1.2 to 4.9]; I2 = 0%), normalization of ALT levels (12 trials; RR, 2.5 [CI, 2.1 to 3.0]; I2 = 27%), HBV DNA loss (9 trials; RR, 7.2 [CI, 3.2 to 16]; I2 = 58%), and histologic improvement (7 trials; RR, 2.1 [CI, 1.8 to 2.6]; I2 = 0%).
Results were generally consistent across specific antiviral drugs.
Entecavir and pegylated interferon-α2a were each associated with greater likelihood of achieving some intermediate virologic and other outcomes than lamivudine on the basis of a few trials (1–4).
Fair
How effective is antiviral treatment at improving health outcomes? 16 RCTs Many studies were small with few events; only 1 good-quality study Moderate Approximately half of the studies were done outside of the United States/Europe, and approximately one third enrolled HBeAg-negative patients Estimates for incident cirrhosis (3 trials; RR, 0.70 [CI, 0.33 to 1.46]; I2 = 0%), hepatocellular carcinoma (5 trials; RR, 0.57 [CI, 0.32 to 1.04]; I2 = 2%), and mortality (5 trials; RR, 0.55 [CI, 0.18 to 1.71]; I2 = 43%) all favored antiviral therapy over placebo, although differences were not statistically significant.
Clinical events in head-to-head trials of entecavir or pegylated interferon-α2a vs. lamivudine or pegylated interferon vs. nonpegylated interferon were too few to determine effects on clinical outcomes.
Fair
How effective is education or behavior change counseling in reducing transmission and improving health outcomes?* None No evidence NA NA No evidence No evidence
What are the harms associated with antiviral treatment for HBV infection? 29 RCTs Many studies were small with few events High Many studies were done outside of the United States/Europe Treatment and control groups did not differ in serious adverse effects (12 trials; RR, 0.8 [CI, 0.6 to 1.1]; I2 = 0%) or any adverse events (7 trials; RR, 0.96 [CI, 0.90 to 1.00]; I2 = 0%).
Antiviral therapy was associated with more withdrawals due to adverse effects, but estimates were imprecise because of the small number of events (9 trials; RR, 3.97 [CI, 1.40 to 11.00]; I2 = 0%).
Results were generally consistent across specific antiviral drugs.
In 2 head-to-head trials, pegylated interferon-α2a was associated with greater risk for serious adverse events (RR, 2.1 [CI, 1.0 to 4.5]; I2 = 0%) and withdrawal due to adverse events (RR, 7.6 [CI, 1.1 to 52.0]; I2 = 38%) vs. lamivudine.
Fair
Are improvements in intermediate outcomes after antiviral therapy associated with improvements in health outcomes? 10 observational studies Patient characteristics and outcomes evaluated varied greatly; no studies were good-quality; 3 were poor-quality and did not address important confounders Moderate 1 study excluded patients with cirrhosis, 2 included only patients with cirrhosis, and the proportion of patients with cirrhosis ranged from 12% to 60% in the remainder 10 observational studies found an association between various intermediate and clinical outcomes (death, hepatocellular carcinoma, or a composite clinical outcome), but variability in patient populations, intermediate and clinical outcomes evaluated, and methodological limitations make it difficult to draw strong conclusions.
In some studies, results were not statistically significant.
Poor

ALT = alanine aminotransferase; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; MSM = men who have sex with men; NA = not applicable; RCT = randomized, controlled trial; RR = risk ratio.
* The full report 12 does not address this key question.

Appendix Figure 1. Analytic framework.

Go to text description below.

Key Questions
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 for 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?


HBV = hepatitis B virus; HBeAg = hepatitis B e antigen; KQ = key question.
* The full report 12 addresses this KQ.

Text Description.

Appendix Figure 1 is an analytic framework that depicts the pathway that asymptomatic adults at average or high risk for hepatitis B virus (HBV) infection may experience during screening. Adults who undergo screening for HBV infection may have early detection of HBV infection or harms related to screening. The next steps in the pathway for those who have screen-detected HBV are receiving treatment for HBV infection and harms related to treatment. The pathway shows intermediate outcomes of interest after screening and treatment to be virologic improvement, histologic improvement, and hepatitis B e antigen (HBeAg) clearance. Clinical health outcomes of interest include mortality, incidence of cirrhosis or hepatocellular cancer, quality of life, and disease transmission. People undergoing screening for HBV with negative screening results, indicating no HBV infection, may recieve vaccination for HBV. Clinical health outcomes of interest following vaccination include mortality, incidence of cirrhosis or hepatocellular cancer, quality of life, and disease transmission.

Appendix Figure 2. Evidence search and selection.

Go to text description below.

* Cochrane databases include the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews.
† Other sources include reference lists of relevant articles.
‡ Some studies are included for >1 key question.
§ The full report 12 addresses this key question.

Text Description.

Appendix Figure 2 depicts the flow of literature identified for inclusion in the report. The first box shows that 4,628 potentially included studies were identified through searches of MEDLINE, the Cochrane databases, PsycINFO, and other sources. Of those, 3,893 were excluded at the title/abstract level. 619 full-text papers were retrieved, of which 574 were excluded due to wrong population (95 studies), wrong intervention (200 studies), wrong outcome (83 studies), wrong study design for key question (83 studies), wrong publication type (41 studies), wrong comparison (59 studies), or duplicate reporting of data (13 studies). 45 studies, reported in 46 publications, were included in the report. Key Questions 1, 2, 4, and 7 had no studies included. One study was included in Key Question 3, 30 studies (in 31 publications) were included in Key Question 5, 16 studies (in 18 publications) were included in Key Question 6, 29 studies (in 28 publications) were included in Key Question 8, and 10 studies were included in Key Question 9.

Appendix Figure 3. Head-to-head studies of antiviral therapy for HBV DNA loss.

HBV = hepatitis B virus; M–H = Mantel–Haenszel.

Text Description.

Appendix Figure 3 is a forest plot diagram of a meta-analysis of the effect of head-to-head studies of antiviral treatments on HBV DNA loss. There are 3 subanalyses according to drug comparison. There are 4 studies comparing entecavir and lamivudine, with a pooled relative risk of 1.63 and a 95% CI of 1.63 to 2.48. There are 2 studies comparing pegylated interferon alfa 2a and lamivudine, with a pooled relative risk of 2.84 and a 95% CI of 1.85 to 4.36; heterogeneity was 0%. There are 2 studies comparing tenofovir and adefovir, with a pooled relative risk of 2.85 and a 95% CI of 0.56 to 14.56; heterogeneity was 97%. Results for subanalyses were not pooled.

Appendix Figure 4. Antiviral therapy vs. placebo or no treatment for incident cirrhosis.

M–H = Mantel–Haenszel.

Text Description.

Appendix Figure 4 is a forest plot diagram of a meta-analysis of the effect of antiviral treatments on incident cirrhosis compared to placebo. There are 2 subanalyses according to drug. There are 2 studies comparing interferon alfa 2a and placebo, with a pooled relative risk of 0.72 and a 95% CI of 0.33 to 1.57; heterogeneity was 0%. There is 1 study comparing interferon alfa 2b and placebo, with a relative risk of 0.50 and a 95% CI of 0.05 to 5.08. The figure shows that pooling results across drugs from the 3 individual studies results in a relative risk of 0.70 and 95% CI of 0.33 to 1.46; heterogeneity was 0%.

Appendix Figure 5. Antiviral treatment vs. placebo or no treatment for mortality.

Go to text description below.

M–H = Mantel–Haenszel.

Text Description.

Appendix Figure 5 is a forest plot diagram of a meta-analysis of the effect of antiviral treatments on mortality compared to placebo. There are 4 subanalyses according to drug. There are 2 studies comparing adefovir and placebo. There was no incidence of mortality in either study, resulting a a relative risk that is not estimable. There are 2 studies comparing interferon alfa 2a and placebo, with a pooled relative risk of 0.15 and a 95% CI of 0.03 to 0.83; heterogeneity was 0%. There is 1 study comparing interferon alfa 2b and placebo, with a relative risk of 0.60 and a 95% CI of 0.07 to 4.92. There are 3 studies comparing lamivudine and placebo. Two studies had no incidence of mortality in either group, resulting in relative risks that were not estimable. In the third study, the relative risk was 1.48 with a 95% CI of 0.48 to 4.53. The figure shows that pooling results across drugs from the 5 individual studies that had incidence of mortality results in a relative risk of 0.55 and a 95% CI of 0.18 to 1.71; heterogeneity was 43%.

Current as of: May 2014

Internet Citation: Evidence Summary: Hepatitis B Virus Infection: Screening, 2014. U.S. Preventive Services Task Force. May 2014.
https://www.uspreventiveservicestaskforce.org/Page/Document/evidence-summary29/hepatitis-b-virus-infection-screening-2014

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